KR19990044452A - Substituted phosphinic acid compounds and their use as medicaments - Google Patents

Abstract

A compound which is a substituted phosphinic acid of formula (I), or a salt or ester thereof.

<Formula I>

Wherein R ¹ is a monovalent aromatic or araliphatic group bonded to the carbon atom via its carbon atom, R ² is an unsubstituted or substituted hydrocarbyl group, and R ^x is hydrogen or unsubstituted or Substituted hydrocarbyl group, R ^y is hydrogen, R ^y _a or NH-protecting group, R ^y _a is unsubstituted or substituted hydrocarbyl group.

Description

Substituted phosphinic acid compounds and their use as medicaments

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

International Publication No. 94/22843 describes phosphinic acids of the formula:

<Formula>

Wherein R ¹ and R ² are both H, R ¹ and R ² are both methyl, or R ¹ and R ² are cyclopentyl together with the carbon atom to which they are attached. These compounds are known to act as GABA _B antagonists.

We have now found that compounds having significantly high binding affinity for the GABA _B receptor can be provided by making novel substituted phosphinic acids comprising morpholine rings.

Accordingly, the present invention provides compounds which are substituted phosphinic acids, or salts or esters thereof, of the formula:

Wherein R ¹ is a monovalent aromatic or araliphatic group bonded to the carbon atom via its carbon atom, R ² is an unsubstituted or substituted hydrocarbyl group, and R ^x is hydrogen or unsubstituted or Substituted hydrocarbyl group, R ^y is hydrogen, R ^y _a or NH-protecting group, R ^y _a is unsubstituted or substituted hydrocarbyl group.

R ¹ as an aromatic group contains 40 carbon atoms or less, and may be an aryl group such as phenyl, tolyl, xylyl or naphthyl group, or a heterocyclic aromatic group such as thienyl, furyl, indolyl or pyridyl group, These groups are unsubstituted or functionally modified carboxyl, carboxy-C ₁ -including halogen, hydroxy, C ₁ to C ₄ alkoxy, carboxyl, esterified carboxyl, amidated carboxyl and cyano. Or one or more substituents such as C ₈ alkyl, functionally modified carboxy-C ₁ -C ₈ alkyl or nitro.

Preferably, R as an aromatic group^OneIs unsubstituted or halogen, carboxyl, functionally modified carboxyl, carboxy-C_One-C₈Alkyl, Functionally Modified Carboxy-C_One-C₈An aryl group having 6 to 15 carbon atoms which may be substituted at one or more positions by alkyl or nitro, or as an aromatic group^OneIs a 5-10 membered heterocyclic aromatic group containing one or two nitrogen atoms in the ring system. More preferably, R as unsubstituted or substituted aryl^OneIs phenyl or phenyl substituted with halogen, carboxyl, functionally modified carboxyl or nitro in one or more of the meta and para positions relative to its carbon atom bonded to the morpholine ring. Examples of such substituted phenyl groups include chloro; Bromo; Iodo; Carboxyl; -COOR³(Wherein³Is halogen, hydroxy or C_OneTo C₄C, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl optionally substituted by alkoxy_OneTo C₈Alkyl); Carbamoyl; N-C such as methyl- or ethyl-carbamoyl_One-C₄N, N-di (C, such as alkyl carbamoyl, dimethyl- or diethyl-carbamoyl)_One-C₄Alkyl) carbamoyl; Cyano; Carboxy-C, such as carboxymethyl_One-C₄Alkyl; C such as methoxy- or ethoxy-carbonylmethyl_OneTo C₈Alkoxy-carbonyl-C_One-C₄Alkyl; Carbamoyl-C such as carbamoylmethyl_One-C₄Alkyl; N-C such as methyl- or ethyl-carbamoylmethyl_One-C₄Alkylcarbamoyl-C_One-C₄Alkyl; N, N-di (C, such as dimethyl- or diethyl-carbamoylmethyl_One-C₄ Alkyl) carbamoyl-C_One-C₄Alkyl; Cyano-C such as cyanomethyl_One-C₄Alkyl; Or phenyl di- or di-substituted. More preferably, R as a heterocyclic aromatic group^OneIs a 5-10 membered heterocyclic group having a nitrogen atom as the only ring hetero atom, for example pyridyl or indolyl.

R ¹ as an araliphatic group may have 7 to 40 carbon atoms, and α, α-diphenyl-lower alkyl or naphthylmethyl such as phenyl lower alkyl such as benzyl or 2-phenylethyl, diphenylmethyl, etc. Α-naphthyl-lower alkyl, and the like, any of these groups may be unsubstituted or substituted with substituents selected from those described above for R ¹ as aromatic groups at one or more positions which may be ortho, meta or para positions have. Preferably, R ¹ as an araliphatic group is α-phenyl-C ₁ -C ₄ alkyl which is unsubstituted or substituted at one or more positions with halogen, carboxyl, functionally modified carboxyl or nitro.

In particularly preferred compounds of the invention, R ¹ is 3-iodophenyl, 3,4-dichlorophenyl, 3-carboxyphenyl, 3-cyanophenyl, 3- (methoxycarbonyl) phenyl, 3-nitrophenyl , Benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl.

As an unsubstituted or substituted hydrocarbonyl group, R ² may generally have from 1 to 40 carbon atoms. For example, alkyl, cycloalkyl, alkenyl or alkynyl groups or hydroxy, C ₁ to C ₈ alkoxy, thio, C ₁ to C ₈ alkylthio, cyano, acylamino, C ₃ to C ₈ cycloalkyl, Or C ₃ to C ₈ cycloalkyl substituted with one or more substituents such as hydroxy, C ₁ to C ₈ alkoxy, thio or C ₁ to C ₈ alkylthio, or C ₃ to C ₈ cycloalkenyl, C ₆ to C ₁₅ aryl, or C ₆ to C ₁₅ aryl substituted with one or more substituents such as, for example, hydroxy, C ₁ to C ₈ alkoxy, halogen or trifluoromethyl, or substituted with one or more substituents such as heteroaryl or halogen And cycloalkyl or alkenyl groups substituted with one or more substituents such as alkyl or halogen, heteroaryl, and the like.

Aliphatic radicals R ² are, for example, lower alkyl, lower alkenyl, lower alkynyl, oxo-lower alkyl, hydroxy- or dihydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di- or poly -Halo-lower alkyl, mono, di- or poly-halo-lower alkenyl, mono-, di- or poly-halo- (hydroxy) -lower alkyl, mono-, di- or poly-halo (hydroxy) Lower alkenyl, lower alkoxy-lower alkyl, di-lower alkoxy-lower alkyl, lower alkoxy (hydroxy) -lower alkyl, lower alkoxy (halo) -lower alkyl, lower alkylthio-lower alkyl and di-lower alkylthio Lower alkyl.

Cycloaliphatic radicals R ² are, for example, cycloalkyl, hydroxycycloalkyl, oxa-, dioxa-, thia- and dithia-cycloalkyl.

Cycloaliphatic-aliphatic radicals R ² are, for example, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl, cycloalkyl (hydroxy) -lower alkyl and (lower alkylthio) cycloalkyl (hydroxy) -lower alkyl .

The araliphatic radical R ² is, for example, mono-, di- or tri-substituted phenyl-lower alkyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and / or trifluoromethyl. It is a radical, Preferably it is the (alpha) -phenyl-lower alkyl substituted by the said substituent, or unsubstituted (alpha), (alpha)-diphenyl- or (alpha)-naphthyl- lower alkyl.

Heteroarylaliphatic radicals R ² are, for example, unsubstituted or halogen-substituted, in particular mono-, di-substituted thienyl-, furyl- or pyridyl-lower alkyl radicals, preferably unsubstituted α- Thienyl, α-furyl- or α-pyridyl-lower alkyl.

Lower radicals and compounds above and below are understood to be, for example, those having 7 or less carbon atoms, preferably 4 or less carbon atoms.

Lower alkyl is for example C ₁ -C ₇ alkyl, preferably C ₁ to C ₄ such as methyl, ethyl, propyl, isopropyl or butyl but also isobutyl, sec-butyl, t-butyl, or pentyl Or a C ₅ -C ₇ alkyl group such as a hexyl or heptyl group.

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

Lower alkynyl is, for example, C ₂ -C ₇ alkynyl, preferably C ₃ -C ₅ alkynyl, such as 2-propynyl (propargyl), butt, having a double bond at the α, β-position or more -3-yn-1-yl, but-2-yn-1-yl or pent-3-yn-1-yl.

The oxo-lower alkyl preferably has an oxo group at positions above the α-position, for example oxo-C ₂ -C ₇ alkyl, in particular oxo such as 2-oxopropyl, 2- or 3-oxobutyl or 3-oxopentyl -C ₃ -C ₆ alkyl.

Phenyl-lower alkyl is for example benzyl, 1-phenylethyl, 2-phenylprop-2-yl or then 2-phenylethyl, 2-phenylprop-1-yl or 3-phenylprop- 1-day.

Thienyl-, furyl- or pyridyl-lower alkyl is for example thienyl-, furyl- or pyridyl-methyl, 1-thienyl-, 1-furyl- or 1-pyridyl-ethyl, 2-thier Nyl, 2-pyridyl-prop-2-yl, or second 2-thienyl-, 2-furyl- or 2-pyridyl-ethyl, 2-thienyl-, 2-furyl- or 2-furyl- Or 2-pyridyl-prop-1-yl or 3-thienyl-, 3-furyl- or 3-pyridyl-prop-1-yl.

The hydroxy lower alkyl preferably has a hydroxy group in the α- or β-position, for example 1-hydroxyethyl, 1- or 2-hydroxypropyl, 2-hydroxyprop-2-yl, 1- Or the corresponding hydroxy-C ₂ -C ₇ alkyl such as 2-hydroxybutyl, 1-hydroxyisobutyl or 2-hydroxy-3-methylbutyl.

Dihydroxy-lower alkyl especially has a hydroxy group at the α, β-position, for example α, β-dihydroxy-C ₃ -C ₇ alkyl such as 1,2-dihydroxyprop-2-yl Can be mentioned.

The hydroxy-lower alkenyl preferably has a hydroxy group at the α-position, preferably a double bond at a position higher than the α, β-position, for example the corresponding α-hydroxy-C ₃ -C ₅ egg. Kenyl such as 1-hydroxybut-2-enyl.

Mono-, di- or poly-halo-lower alkenyl is, for example, mono-di- or tri-fluoro-C ₂ -C ₅ -alkenyl, such as 1-fluorobut-2-enyl.

Mono-, di- or poly-halo (hydroxy) -lower alkyl preferably has a hydroxyl group at the α-position and a halogen atom at a position higher than the α-position, for example 4,4,4-tri Corresponding mono-di- or tri-fluoro-α-hydroxy-C ₂ -C ₇ alkyl, such as fluoro-1-hydroxybutyl.

Mono-, di- or poly-halo-lower alkyl is for example 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 1- or 2-fluorobutyl or 1, Mono-, di- or tri-fluoro-C ₂ -C ₅ alkyl such as 1-difluorobutyl.

Lower alkoxy is, for example, C ₁ -C ₇ alkoxy, preferably C ₁ -C ₄ such as methoxy, ethoxy, propoxy, isopropoxy or butoxy, but also isobutoxy, sec-butoxy, or a C ₅ -C ₇ alkoxy group such as a pentyloxy, hexyloxy or heptyloxy group.

Acylamino-lower alkyl, e.g., acetylamino, etc. of the profile C ₁ -C ₄ alkylcarbonylamino -C ₁ -C ₄ alkyl or benzoyl of the C ₆ -C ₁₀ aryl, such as amino-methyl-carbonyl-amino -C ₁ - C ₄ alkyl.

Cyano lower alkyl is, for example, cyano-C ₁ -C ₄ alkyl such as cyanomethyl or 2-cyanoethyl.

Mono-, di- or poly-halo (hydroxy) -lower alkenyl preferably has a hydroxy group at the α-position, preferably a halogen atom at a position higher than the α-position, for example 2-fluoro And mono-, di- or tri-fluoro-α-hydroxy-C ₂ -C ₅ alkenyl such as -1-hydroxybuten-2-yl.

Lower alkoxy-lower alkyl is, for example, methoxy- or ethoxy-methyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxy- or 3-ethoxypropyl or 1- or 2-methoxy C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl such as butyl.

Di-lower alkoxy-lower alkyl is for example di-C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl such as dimethoxymethyl, dipropoxymethyl, 1,1- or 2,2-diethoxyethyl , Diisopropoxymethyl, dibutoxymethyl or 3,3-dimethoxypropyl.

Lower alkoxy (hydroxy) -lower alkyl is, for example, C ₁ -C ₄ alkoxy-C ₂ -C _7- (hydroxy) alkyl, such as 2-hydroxy-3-methoxyprop-2-yl. .

Lower alkoxy (halo) -lower alkyl is, for example, C ₁ -C ₄ alkoxy-C ₂ -C _5- (halo) alkyl, such as 2-fluoro-3-methoxybutyl.

Lower alkylthio-lower alkyl is, for example, methylthio- or ethylthio-methyl, 2-methylthioethyl, 2-ethylthioethyl, 3-methylthio- or 3-ethylthio-propyl or 1- or 2- methylthio C ₁ -C ₄ alkyl, such as butylthio is -C ₁ -C ₄ alkyl.

Di-lower alkylthio-lower alkyl is, for example, di-C ₁ -C ₄ alkylthio-C ₁ -C ₄ alkyl such as dimethylthiomethyl, dipropylthiomethyl, 1,1- or 2,2-di Ethylthioethyl, diisopropylthiomethyl, dibutylthiomethyl or 3,3-dimethylthiopropyl.

Halogen is halogen having an atomic number of 53 or less, ie fluorine, chlorine, bromine or iodo.

Cycloalkyl is, for example, C ₃ -C ₈ cycloalkyl, especially C ₃ -C ₆ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Hydroxycycloalkyl is, for example, α-hydroxy-C ₃ -C ₆ cycloalkyl, such as 1-hydroxycyclopropyl, 1-hydroxycyclobutyl or 1-hydroxycyclohexyl.

Oxa- or thia-cycloalkyl is for example oxa- or thia-C ₃ -C ₈ cycloalkyl, in particular 2-oxacyclopropyl (oxyranyl), 2- or 3-oxacyclobutyl (oxetanyl), 2- or 3-thiacyclobutyl (thiethanyl), 2- or 3-oxacyclopentyl (tetrahydrofuranyl), 2- or 3-thiacyclopentyl (thiolanyl) or 2-oxacyclohexyl (tetrahydro Pyranyl), or oxa- or thia-C ₃ -C ₆ cycloalkyl.

Dioxacycloalkyl is, for example, 1,3-dioxa-C ₃ -C ₈ cycloalkyl, such as 1,3-dioxalan-2-yl or 1,3-dioxan-2-yl.

Dithiacycloalkyl is, for example, 1,3-dithia-C ₃ -C ₈ cycloalkyl, such as 1,3-dithiolan-2-yl or 1,3-dithia-2-yl.

Cycloalkyl-lower alkyl is, for example, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₄ alkyl, in particular α- (C ₃ -C ₆ cycloalkyl) -C ₁ -C ₄ alkyl, such as C ₃ - C ₈ -cycloalkyl-C ₁ -C ₄ alkyl such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

Cycloalkenyl-lower alkyl is for example C ₃ -C ₈ -cycloalkenyl-C ₁ -C ₄ alkyl, in particular α- (C ₃ -C ₆ cycloalkenyl) -C ₁ -C ₄ alkyl and the like. C ₃ -C ₆ cycloalkenyl-C ₁ -C ₄ alkyl such as cyclopent-1-enylmethyl, cyclopent-2-enylmethyl, cyclopent-3-enylmethyl, cyclohex-1-enylmethyl, cyclo Hex-2-enylmethyl or cyclohex-3-enylmethyl.

Cycloalkyl (hydroxy) -lower alkyl is for example α- (C ₃ -C ₆ cycloalkyl) -α-hydroxy-C ₁ -C ₄ alkyl, such as cyclopropyl (hydroxy) methyl, cyclobutyl ( C ₃ -C ₆ cycloalkyl-C ₁ -C ₄ (hydroxy) alkyl, such as hydroxy) methyl or cyclohexyl (hydroxy) methyl.

(Lower alkylthiocycloalkyl) (hydroxy) -lower alkyl is, for example, 1- (C ₁ -C ₄ alkylthio-C, such as (2-methylthiocycloprop-1-yl) hydroxy-methyl, etc. ₃ -C ₆ cycloalkyl) -1-hydroxy-C ₁ -C ₄ alkyl.

In a preferred compound of the invention, R ² is lower alkyl, lower alkenyl, lower alkynyl, oxo-lower alkyl, hydroxy- or dihydroxy-lower alkyl, hydroxy-lower alkenyl, mono, -di- Or poly-halo-lower alkyl, mono-, di- or poly-halo-lower alkenyl, mono-, di- or poly-halo (hydroxy) -lower alkyl, mono-, di- or poly-halo (hydr Hydroxy) -lower alkenyl, lower alkoxy-lower alkyl, di-lower alkoxy-lower alkyl, lower alkoxy (hydroxy) -lower alkyl, lower alkoxy (halo) -lower alkyl, lower alkylthio-lower alkyl, di-lower Alkylthio-lower alkyl, cyano-lower alkyl, acylamino-lower alkyl, cycloalkyl, hydroxycycloalkyl, oxa-, dioxa-, thia- and dithia-cycloalkyl, cycloalkyl-lower alkyl, cycloal Kenyl-lower alkyl, cycloalkyl (hydroxy) -lower alkyl, (lower alkylthio) cycloalkyl (hydroxy)- Mono-, di- or tri-substituted mono-, di- or tri-substituted with lower alkyl, or unsubstituted or lower alkyl, lower alkoxy, halogen, hydroxy and / or trifluoromethyl, naphthyl-lower alkyl -Lower alkyl, or unsubstituted or halo-substituted thienyl-, furyl- or pyridyl-lower alkyl.

In more preferred compounds of Formula I, R ² is C, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl, α, α-di-C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, etc. Α, α-di-C ₁ -C ₄ alkoxy-methyl or ethyl, cyanomethyl or 2-cyano, such as _1- C ₇ alkyl, in particular dimethoxy- or diethoxy-methyl or 1,1-diethoxyethyl cyano and methyl furnace -C ₁ -C ₄ alkyl, acetylamino-ethyl, acetylamino-propyl, butyl acetyl or benzoyl acetaminophen acylamino such as aminomethyl -C ₁ -C _{5 ..} alkyl, cyclopropyl- or cyclohexyl-methyl such as C ₃ -C ₆ cycloalkyl, -C ₁ -C ₄ alkyl, cyclo hex-3-enyl, or C ₃ -C ₆ cycloalkenyl -C ₁ -C ₄ alkyl such as methyl, or unsubstituted or methyl or the like Benzyl, such as mono-, di- or trisubstituted by C ₁ -C ₄ alkoxy such as C ₁ -C ₄ alkyl, methoxy, hydroxy and / or halogen such as fluorine, chlorine or iodo Phenyl-C ₁ -C ₄ alkyl.

In a more preferred compound of the present invention, R ² is C ₁ -C ₅ alkyl such as methyl, ethyl or butyl, α, α-di- (C ₁ -C ₄ alkoxy) methyl, such as diethoxymethyl, 1,1 C ₃ -C ₆ cycloalkyl-C ₁ -C ₄ alkyl, benzyl or 4-, such as α, α-di- (C ₁ -C ₄ alkoxy) ethyl, cyclopropylmethyl or cyclohexylmethyl, such as -diethoxyethyl Methoxybenzyl. In particularly preferred compounds, R ² is cyclohexylmethyl or 4-methoxybenzyl.

As an unsubstituted or substituted hydrocarbyl group, R ^x may have up to 40 carbon atoms, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₃ to C ₈ cycloalkyl, C ₄ to C ₁₃ cycloalkylalkyl, C ₆ to C ₁₀ aryl or C ₇ to C ₁₃ aralkyl groups, any of which may be substituted with one or more substituents selected from those described above for R ¹ . Preferably, R ^x is hydrogen, lower alkyl, C ₃ to C ₆ cycloalkyl, C ₆ to C ₈ aryl or C ₇ to C ₉ aralkyl, in particular hydrogen or isopropyl.

As an unsubstituted or substituted hydrocarbyl group R ^y _a , R ^y may have up to 40 carbon atoms, for example C ₁ to C ₁₀ alkyl, C ₃ to C ₈ cycloalkyl or C ₇ to C ₁₃ aralkyl groups And any of these groups may be unsubstituted or substituted by hydroxy or C ₁ to C ₄ alkoxy. As the NH-protecting group, R ^y is, for example, an acyl group such as acetyl, trifluoroacetyl, benzoyl or p-nitrobenzoyl or an alkoxycarbonyl or aralkyloxycarbonyl group such as t-butoxycarbonyl or benzyloxycarbonyl Can be. Preferably, R ^y is hydrogen, lower alkyl, C ₇ to C ₉ aralkyl, acetyl, benzoyl, t-butoxycarbonyl or benzyloxycarbonyl, in particular hydrogen, methyl, ethyl, benzyl, acetyl, benzoyl, t -Butoxycarbonyl or benzyloxycarbonyl.

Particularly preferred particular compounds of the invention are those wherein R ¹ is phenyl, 3-iodophenyl, 3,4-dichlorophenyl, 3-cyanophenyl, 3- (methoxycarbonyl) phenyl, 3-carboxyphenyl, 3-nitro Phenyl, benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl, R ² is cyclohexylmethyl or 4-methoxybenzyl, and R ^x is hydrogen or iso Propyl and a compound of formula (I), salts and esters thereof, wherein R ^y is hydrogen, methyl or benzyloxycarbonyl.

The compounds of formula (I) may be in the form of intramolecular salts and may form both acid addition salts and salts with bases by conventional salt forming reactions.

Acid addition salts of compounds of formula (I) are, for example, pharmaceutically acceptable salts with suitable inorganic acids such as hydrogen halide, sulfuric acid or phosphoric acid, such as hydrochloride, hydrobromide, sulfate, hydrogen sulphate or phosphate, or suitable aliphatic or aromatic Salts with sulfonic acids or N-substituted sulfamic acids, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate or N-cyclohexylsulfamate (cyclamate).

Salts with bases of compounds of formula (I) are salts with pharmaceutically acceptable bases, such as, for example, non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb, such as alkali metal salts, in particular sodium or potassium Salts, alkaline earth metal salts, in particular calcium or magnesium salts, also unsubstituted or C-hydroxylated aliphatic amines, in particular mono-, di- or tri-lower alkylamines such as methyl-, ethyl-, or diethyl- Mono-, di-, tri- (hydroxy-lower alkyl) amines such as amine, ethanol-, diethanol- or triethanol-amine, tris (hydroxymethyl) methylamine or 2-hydroxy-t-butylamine, Or N- (hydroxy-lower alkyl) -N, N-di-lower alkylamine, such as 2- (dimethylamino) ethanol or D-glucamine, or (N- (polyhydroxy-lower alkyl) -lower alkyl Amines or quaternary aliphatic ammonium hydroxy such as tetrabutyl-ammonium hydroxy Ammonium salt with ammonia or organic amine or quaternary ammonium base.

In addition to salt formation with bases, hydroxy groups bound to phosphorus of formula (I) can also be esterified. Accordingly, the present invention includes compounds of formula (I) in ester form with alcohols, which are C ₁ to C ₁₀ alkanes which are unsubstituted or substituted with, for example, halogen, cyano or C ₁ to C ₄ alkoxy alkyl radicals. ol, such as methanol, ethanol, isopropanol, isobutanol, 2-ethylhexanol, 2-chloro-ethanol, 2-cyano-ethanol, such as ethanol or 2-ethoxy-2-n- butoxy-ethanol in C ₁ to C Cycloaliphatic alcohols such as C ₃ to C ₈ such as ₄ alkoxy, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol, methylcyclohexanol or methylcyclooctane, or C ₇ such as benzyl alcohol To C ₁₀ araliphatic alcohols.

If asymmetric carbon atoms are present, the compounds according to the invention may be in the form of isomeric mixtures, in particular in the form of racemates, or in the form of pure isomers, in particular enantiomers.

Preferred isomers of the compounds of formula (I) are those in which the groups bonded at the 2-position of R ¹ and the aforementioned morpholine rings are trans relative to one another, ie compounds of formula (IA) or of formula (IB).

In the formula, R ¹ , R ² , R ^x and R ^y are as defined above.

Other preferred isomers of the compounds of formula (I) are those in which R ¹ and the group bonded to the 2-position of the morpholine ring described above are cis relative to one another, ie compounds of formula (IC) or of formula (ID).

In the formula, R ¹ , R ² , R ^x and R ^y are as defined above.

Examples of certain compounds of formula I include

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

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

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

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

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

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

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

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

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

Cyclohexylmethyl-[(2R ^* , 5R ^* )-5- (4-iodobenzyl) morpholine-2-methyl] 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-methyl-morpholin-3-ylmethyl] benzoic acid,

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

3-{(3R ^* , 6R ^* )-[(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,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Benzyl-{(2R ^* , 5R ^* )-5- [4-([1,3,4] oxadiazol-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} force Finsan,

1- (4-{(3R ^* , 6R ^* )-6-[(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] -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,

[(2R ^* , 5S ^* )-5- (3-cyanophenyl) morpholin-2-ylmethyl] phenyl-methylphosphinic acid,

5-acetylaminopentyl-[(2R ^* , 5S ^* )-5-[(3,4-dichlorophenyl) morpholin-2-ylmethyl] phosphinic acid,

Cyclohexylmethyl-[(2R ^* , 5S ^* )-5- (3,4-dichlorophenyl) -morpholin-2-ylmethyl] phosphinic acid,

Butyl-[(2R ^* , 5S ^* )-5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] phosphinic acid,

Benzyl-[(2R ^* , 5S ^* )-5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] phosphinic acid,

[(2R ^* , 5S ^* ) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] pyridin-2-ylmethylphosphinic acid,

[(2R ^* , 5S ^* ) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] pyridin-2-ylmethyl] diethoxymethylphosphinic acid,

[(2R ^* , 5S ^* )-5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] -4-methoxy-phenylmethylphosphinic acid,

[(2R ^* , 5S ^* )-5-benzylmorpholin-2-ylmethyl] -4-methoxyphenyl-methylphosphinic acid,

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

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

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

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

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

Cyclohexylmethyl-[(2R ^* , 5S ^* )-5- (4-iodobenzyl) morpholin-2-ylmethyl] phosphinic acid,

[(2R ^* , 5S ^* )-5- (4-iodobenzyl) morpholin-2-ylmethyl] -4-methoxyphenylmethylphosphinic acid,

Cyclohexylmethyl-{(2R ^* , 5S ^* )-5-[(4-ethoxycarbonyl) phenylmethyl] morpholin-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 ^* )-6-[(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,

3-{[(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) -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,

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

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

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

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

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

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

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

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

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

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

3-[(3R ^* , 6S ^* )-6- (benzylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl} benzoic acid,

Benzyl-{(2R ^* , 5S ^* )-5- [4-([1,3,4] oxadiazol-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} force Finsan,

1- (4-{(3R ^* , 6S ^* ) -6-[(4-methoxybenzyl) hydroxyphosphonoylmethyl] morpholin-3-yl} phenyl) -1H- [1,2,4] tria Sol-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,

Diethoxymethyl-{(2R ^* , 5S ^* )-5- [3- (1H-tetrazol-5-yl) phenyl] morpholin-2-ylmethyl} phosphinic acid.

We have found that the compounds of formula (I) and their pharmaceutically acceptable salts have useful pharmacological properties. This compound shows effective binding to GABA _B and has been found to be an antagonist of GABA (γ-aminobutyric acid) at its receptor. For the mechanism, antagonism at the GABA _B receptor can increase the rapid release of rapid excitatory amino acid delivery, namely glutamate and aspartate, thereby improving information processing in the brain. It has been found that late post-synaptic inhibition potentials in the hippocampus, caused by the GABA _B mechanism, are blocked by antagonists, allowing for a faster order of neurostimulation delivery.

We have also found that chronic treatment with antidepressants and repeated electric shocks increases the number of GABA _B receptors in the rat cerebral cortex. According to the receptor theory, chronic treatment with GABA _B antagonists should have the same effect. Thus, for this and other reasons, GABA _B antagonists can act as antidepressants.

GABA _B antagonists according to the invention interact with GABA _B receptors at IC ₅₀ values of 10 ⁻⁷ to 10 ⁻¹⁰ M (mol / liter) on the rat cortex. In contrast to GABA _B agonists such as baclofen, this compound does not allow noradrenaline stimulation of adenylate cyclase on the compartments of the rat brain cortex, but acts as an antagonist of baclofen action. Antagonists not only antagonize baclofen, but also act independently as antagonists of endogenous GABA.

In view of their good GABA _B antagonistic properties, the compounds of the present invention are suitable for the treatment and prevention of diseases characterized by the stimulation of GABA _B receptors. Thus, they are recognized, for example, in the treatment of central nervous system diseases such as anxiety, depression, brain failure, epilepsy of the "minor seizure" class, ie lack of consciousness in epilepsy in children and adults, and dysplasia such as Lennox-Gastant syndrome. It is a non-tropic, antidepressant and anxiety remover for the treatment of diseases that require improved behavior and is suitable for use as an antidote to baclofen.

R ^y is as required, and then the obtained the compound of reacting a compound of a compound of the compound of formula is hydrogen Ⅰ formula Ⅱ formula Ⅲ in the presence of a base formula Ⅳ,, R ⁴ and (or) of R ^x By carrying out one or more substitution reactions that change the properties of the substituents and / or hydrolysis of the ester substituents of R ⁴ and / or R ^{x to} the carboxyl and / or conversion of the ester group -OR ⁵ to -OH. Can be prepared.

Wherein, R ⁴ is and R ¹ and are as defined above, except that there may be substituted with carboxyl, R and ^x are the same as defined above, except that there may be substituted with carboxyl,

The reaction of the compounds of the formulas (II) and (III) can be carried out in a one step reaction by appropriately selecting the base and reaction conditions, monoalkylating the amino group and then cyclization. Preferably, the reaction can be carried out in two steps to avoid the complexity resulting from the dealkylation of the amino groups. In a first step, a weak base, such as a hindered amine such as 1,8-diazabicyclo [5.4.0] undes-7-ene (DBU), is solvent at 70 to 110 ° C., preferably benzene, toluene or Slow addition to compounds of formulas (II) and (III) in hydrocarbons such as xylene yields novel intermediate products of formula (V).

Wherein R ² , R ⁴ , R ⁵ and R ^x are as defined above. Subsequently, the intermediate is treated with a base, for example at a higher temperature, under the conditions more stringent than those used for its formation, with a stronger base, such as an alkali metal hydride, at a temperature of from 10 to 50 ° C. do. Treatment of the intermediate with a base can be carried out in a solvent, preferably a hydrocarbon solvent such as toluene, benzene or xylene.

Intermediate compounds of formula (V), in particular in the de-esterified form, ie in which R ⁵ is substituted with hydrogen as alkyl and any carboxyl ester groups of R ⁴ and / or R ^x are converted to carboxyl groups, As an example, it can be used for the treatment or prevention of diseases characterized by stimulation of the GABA _B receptor. Accordingly, the present invention includes novel compounds of formula (VA), or salts or esters thereof.

In the formula, R ¹ R ² R ^x is as defined above.

R ^x and (or) R ¹ or R ^4, each aryl or heteroaryl formula Ⅰ or compounds Ⅳ containing a cyano substituent on the ring is R ^x and (or) R ¹ or R ^4, each aryl or heteroaryl Reducing the compound of formula (I) or (IV) containing a nitro group on the ring to obtain a compound of formula (I) or (IV) wherein each of R ^x and / or R ¹ or R ⁴ comprises an amino group on an aryl or heteroaryl ring, Diazotizing the compound and reacting with an alkali metal cyanide to obtain a compound of formula I or IV wherein each of R ^x and / or R ¹ or R ⁴ comprises a halogen substituent on an aryl or heteroaryl ring, It can be prepared by reacting with an alkali metal cyanide. All of these reactions can be carried out using known reactions.

Compounds of formula (I) or (IV), wherein R ^x and / or R ¹ or R ⁴ each comprise an esterified carboxyl substituent, may also be prepared from other compounds of formula (I) or (IV), respectively. For example, they can be prepared by using known methods in the presence of palladium complexes as catalysts to form compounds of formula (I) or (IV) wherein each of R ^x and / or R ¹ or R ⁴ comprises a halogen substituent on an aryl or heteroaryl ring. It can be prepared by reacting with carbon monoxide and alcohol.

Compounds of formula (I) wherein R ^x and / or R ¹ comprise carboxyl substituents, comprise a carboxyl substituent in which each of R ^x and / or R ¹ or R ⁴ is esterified using conventional hydrolysis reactions It can be prepared by hydrolyzing the compound of Formula I or IV.

If R ⁴ in the compound of formula (IV) or (V) comprises an esterified carboxyl group, it can be hydrolyzed to the free carboxyl group using conventional methods. When R ⁴ of the compound of formula IV comprises a nitro group on an aryl or heteroaryl ring, this group is also converted to an amino group by reduction, followed by diazotization of amino followed by reaction with an alkali metal halide to halo and The halo is reacted with alkali metals to convert to cyano, and the cyano is hydrolyzed to carboxyl, which is usually carried out using known methods.

Conversion of the ester group -OR ⁵ of the compound of formula IV or V to -OH is an alkali metal hydroxide, a suitable base or acidic agent, for example an alkali metal halide such as sodium hydroxide or lithium hydroxide, in particular lithium bromide or iodide Alkali metal thiophenolates such as alkali metal bromide or iodide such as sodium, thiourea, sodium thiophenolate, or inorganic acids or tri-lower alkyl-halosilanes such as protonic acid or Lewis acid such as hydrochloric acid, For example by treatment of trimethylchlorosilane. The substitution reaction may be carried out in the absence or presence of a solvent, if necessary, under heating or cooling in an airtight container and / or under an inert gas atmosphere.

The conversion of -OR ⁵ to -OH of the compound of formula IV or V is carried out under hydrolysis conditions, in particular hydrochloric acid treatment in the form of an inorganic acid such as hydrochloric acid, for example diluted or concentrated aqueous solution, or trimethylsilyl iodo By treatment of organosilyl halides such as cargoes or bromide and, if necessary, by continuous hydrolysis. The reaction can preferably be carried out by maintaining the elevated temperature, for example the reaction mixture at reflux, and, if appropriate, using organic diluents in a closed vessel and / or under an inert gas.

Compounds of formula (II) are, in certain cases, commercially available, for example (R)-and (S) -phenyl glycine. Compounds of formula (II) are selected from aminocarboxylic acids of formula R ⁴ C (R ^x ) (NH ₂ ) COOH, wherein R ⁴ and R ^x are as defined in formula (II) above, boron trifluoride diethyl etherate It can be prepared by reduction by reaction with borane dimethyl sulfide in the presence of boron trifluoride complex compounds. This reaction can be carried out using known methods. (Iii) novel compounds of formula II wherein R ⁴ is iodobenzyl, in particular 4-iodobenzyl, and R ^x is hydrogen, and (ii) novel compounds of formula II wherein R ⁴ is phenyl and R ^x is isopropyl It can be produced by this method.

R ⁴ is a compound of Formula Ⅱ substituted with nitro is R ⁴ is not substituted with the formula ^{R 4 C ((R x)} (NH 2) by screen-nitro to amino acid of COOH and introducing a nitro group on R ^4, for example, For example, by reacting with a di-t-butyl dicarbonate forming a t-butylcarbamate group, the carboxyl groups of the protected product are converted into esters such as methyl esters, followed by treatment with a suitable reducing agent such as alkali metal hydride borides. Can be prepared by reducing the ester group to -CH ₂ OH, and finally removing the amino protecting group by acid treatment to form the free amino group again These reactions are carried out using known methods or slight modifications thereof. Known compounds of the formula (II) wherein R ⁴ is nitrophenyl can be prepared by this reaction sequence.

Compounds of formula (II) also contain aldehydes or ketones of formula R ⁴ C (= 0) R ^x , wherein R ⁴ and R ^x are as defined above, wherein R ⁶ NH ₂ , wherein R ⁶ is hydrogen or Reacted with an alkali metal cyanide and a compound of unsubstituted or optionally substituted alkyl group having 1 to 8 carbon atoms, for example optionally substituted with hydroxy or a C ₆ to C ₁₀ aryl group substituted with C ₁ to C ₄ alkoxy Obtain a compound of formula VI, wherein the compound of formula VI and formula R ⁷ OH (wherein R ⁷ is an alkyl group having 10 carbon atoms, for example n-hexyl, 2-ethylhexyl, n-octyl or decyl, preferably, other than methyl, ethyl, isopropyl or n- butyl and the like of C ₁ to C ₄ alkyl, especially methyl or ethyl, Im) and the compound is reacted under acid present to give a compound of formula ⅶ, R ⁶ is hydrogen of For example, using the known method of formula (VII) Removal from the compound yields a compound of formula (VII), where R ⁶ is optionally substituted benzyl to obtain formula (VII) in salt form with organic acid by catalytic catalytic hydrogenation in the presence of an organic acid, for example acetic acid, Reaction of the compound with an amino protecting agent such as t-butyl dicarbonate converts the amino group to a protected amino group, and reaction with a suitable reducing agent such as alkali metal borohydride to react the ester group -COOR ⁷ of the protected compound with -CH ₂ OH It can be prepared by Strecker synthesis, which is then reduced to and finally removes the protecting groups to form free amino groups.

In the formula, R ² , R ⁴ , R ⁶ , R ⁷ and R ^x are as defined above. The reaction of this sequence of reactions can be carried out using known methods, or slight modifications thereof. When R ⁴ is substituted with a carboxylic ester group, the protected amino group formed is reduced to -CH ₂ OH leaving the ester group of -COOR ⁷ with R ⁴ leaving the ester group, followed by R ⁴ in, for example, a non-aqueous medium. It should be a t-butyl carbamate group, etc. which can be removed by the reaction which leaves an ester group in.

In the modification of the above-mentioned stretcher synthesis, the compound of formula VI can be acid hydrolyzed using, for example, conventional methods to convert the cyano group described above into a carboxyl group, and the resulting amino carboxylic acid is a known method. It can be reduced to the compound of formula (II) by reaction with borane dimethyl sulfide in the presence of boron trifluoride complex compounds such as boron trifluoride diethyl etherate.

Compounds of formula (II), (VI), (VIII) or (VIII) wherein R ⁴ is 3-methoxycarbonylphenyl, which may be prepared from aldehydes or ketones of formula R ⁴ C (═O) R ^x by the above reaction sequence, It is considered new. Also considered novel are compounds of formula II or V wherein R ⁴ is 3,4-dichlorophenyl and R ⁷ is C ₁ -C ₁₀ alkyl.

A compound of Formula II wherein R ⁴ is phenyl, R ^x is methyl, chloromethyl, ethyl,-(CH ₂ ) ₃ SCH ₃ , allyl or methylol, R ^x is aminomethyl, R ⁴ is phenyl, p-hydroxy Is a phenyl or p-methoxyphenyl; R ^x is methylol, R ⁴ is 4-decylphenyl or 5-[(7-chloro-4-quinolinyl) amino] -2-hydroxyphenyl Is a compound of Formula II wherein R ⁴ is 4-methoxyphenyl, R ^x is ethyl, and R ⁴ is 2,4-dichlorophenyl, and R ^x is N-triazolylmethyl Except for the compounds, compounds of formula (II) wherein R ⁴ is a monovalent aromatic group as defined above and R ^x is an unsubstituted or substituted hydrocarbyl group are considered novel.

R ^x is methyl, R ⁴ is benzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 2-phenylethyl, 1,3-benzodioxol-5-methyl, 3- A compound of formula II wherein phenyl-1-aminopropyl, α-hydroxybenzyl, α-hydroxy-α-methylbenzyl, or α-hydroxy-α-methyl-4-nitrobenzyl, R ⁴ is benzyl, R ^{With the} exception of compounds of formula II, wherein ^x is allyl or -CH ₂ CH ₂ SCH ₃ , R ⁴ is a monovalent aliphatic group as described above and R ^x is unsubstituted or substituted hydrocarbyl as defined above other than methylol Compounds of formula II that are bicyclic are considered novel.

As defined above, compounds of formula II are considered novel wherein R ⁴ is iodobenzyl, in particular 4-iodobenzyl, and R ^x is hydrogen or an unsubstituted or substituted hydrocarbyl group.

Except for compounds wherein R ² is methyl and R ⁵ is ethyl, compounds of formula III that are considered novel, in particular compounds of formula III wherein R ² is cycloalkylalkyl, such as cyclohexylmethyl, Reacting in the presence of a silylating agent such as a bis (trialkylsilyl) derivative of an amide with a compound of formula (VII), the silylating agent reacts with a compound of formula (VII) to form a P (III) silyl compound, followed by reaction with a compound of formula (VII) Can be produced.

In the formula, R ² , R ⁵ and X are as defined above. The reaction can be carried out at a temperature of 0 to 50 ° C., preferably in a solvent such as hydrocarbons such as toluene or halohydrocarbons such as dichloromethane.

Esters of formula (VII) can be prepared by reacting a protected phosphinate ester of formula (VII) with a compound of formula (III) to yield a compound of formula (III), and then substituting hydrogen for protecting group Q of compound of formula (III) .

R ² Z

Wherein R ² and R ⁵ are as defined above, Q is a PH protecting group and Z is a leaving group. The leaving group Z may be, for example, a halogen atom or an organic sulfonate group. Preferably, Z may be a chlorine, bromine, iodo, or methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate group. Chemical formula The reaction between the compounds of and? And the deprotection reaction for the compound of the formula (XIII) can be carried out using a known method, for example, the method described in European Patent No. 0569333.

Protected phosphinate esters of the formula? Can be prepared using known methods, for example, as described in US Pat. No. 4, 933,478. Compounds of formula? Are commercially available or can be prepared by known methods.

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

By the compounds and the reaction of R ^y is R ^y _a compound of formula Ⅰ is R ^y has the formula R ^y _a Z of a compound of formula Ⅰ hydrogen (in the formula, R ^y _a, and Z are as defined above), or formula An aldehyde of R ^y _b CHO, wherein R ^y _b is hydrogen or R ^y _{a as} defined above, and a reducing group alkylation using a reducing agent for reducing imine to an amine, such as sodium cyanoborohydride. Can be. This reaction can be carried out using conventional methods.

Compounds of formula I wherein R ^y is an NH-protecting group can be prepared by reacting a compound of formula I wherein R ^y is hydrogen with a reagent known to introduce the desired protecting group. For example, when the protecting group is an acyl group, compounds of formula I wherein R ^y is hydrogen may be prepared by known reactions with acyl halides or carboxylic acid anhydrides such as acetyl chloride, acetic anhydride or benzoyl chloride. When the protecting group is an alkoxycarbonyl or aralkyloxycarbonyl group, the compound of formula I wherein R ^y is hydrogen may be alkoxycarbonyl or aralkyloxycarbonyl halide or benzyl chloroformate or di-t-butyl dicarbonate. The alkyl or aralkyl dicarbonates can be reacted using known methods, for example.

In general, the compounds of formula (I) wherein R ^y is R ^y _a or NH-protecting groups are also described in the above-described method for the preparation of compounds of formula (I) wherein R ^y is hydrogen, replacing the compound of formula (II) with the compound of formula (IIA) Thus, a compound of formula (IIA) may be prepared by a method of reacting a compound of formula (IIA) with a compound of formula (III) in the presence of a base which directly provides the compound of formula (IVA)

Wherein R ² , R ⁴ , R ⁵ and R ^x are as defined in formula (II), and R ^y is R ^y _a or NH-protecting group.

This reaction can be carried out in a solvent, typically hydrocarbons such as benzene, toluene or xylene, and generally under more stringent conditions than those used for the reaction of compounds of formulas (II) and (III), for example using sodium hydride as the base. It is carried out at 10 to 70 ℃. After the reaction, if necessary, R ⁴ and (or) at least one substitution reaction, and (or) R ⁴ and (or) R ^x of the hydrolyzed to the ester substituents carboxylic changing the nature of the substituents of R ^x and ( Or) conversion of the ester group -OR ⁵ to -OH can be carried out.

The compound of formula (I) is reacted with a compound of formula (XIV) to convert the first hydroxy to the leaving group (Z) as defined above, cyclization to yield a compound of formula (XV), and if necessary, is an NH-protecting group. substituted to a R ^y hydrogen and (or) R ⁴ and (or) one or more substitution reactions to change the nature of the substituents of R ^x and (or) R ⁴ and (or) R ^x of the back to the ester substituents carboxylic It can be produced by performing hydrolysis and / or converting the ester group -OR ⁵ to -OH.

In the formula, R ² , R ⁴ and R ^y are as defined above.

The conversion of the primary hydroxyl group to Z of the compound of formula XIV can be carried out using known methods. For example, when Z is an iodo atom, the conversion can be carried out by reacting the compound of formula XIV with triphenylphosphine, imidazole and iodo in a solvent such as acetonitrile or tetrahydrofuran at 0 ° C. to 50 ° C. In the case where Z is a trifluoro methanesulfonate group, the conversion may be carried out by reacting the trifluoromethanesulfonic anhydride at -100 ° C to 50 ° C with a compound of the formula XIV and pyridine.

Substitution of the NH-protecting group R ^y with hydrogen can be carried out using known methods for removing NH-protecting groups. For example, when R ^y is an acyl group such as acetyl or benzoyl, the substitution with hydrogen may be performed by reaction with aqueous hydrochloric acid, and if R ^y is trifluoroacetyl, the substitution with hydrogen may be aqueous carbonic acid. It can be carried out by reaction with potassium.

Any other subsequent reaction of the compound of Formula IV can be carried out as described above for the corresponding reaction of the compound of Formula IV.

The compound of formula (VII) is considered to be novel in itself, and the compound of formula (II) is reacted with a compound of formula (VI) in the presence of a hindered base to obtain a compound of formula (VII), and its hydrogen bound to nitrogen, for example, as defined above. It can be prepared by substituting the NH-protecting group R ^y as defined above using a known method as described above.

In the formula, R ² , R ⁴ , R ⁵ , Z and R ^x are as defined above. The reaction between the compounds of the formulas (II) and (VI) can be carried out, for example, at a temperature of 20 to 100 ° C., preferably in an organic solvent such as alcohol, in particular ethanol. The hindered base is, for example, a diazabicyclo compound such as 1,5-diazabicyclo [4.3.0] non-5-ene or 1,8-diazabicyclo [5.4.0] undes-7-ene or It may preferably be a tertiary amine such as dicyclohexyl (ethyl) amine or in particular diisopropylethylamine.

Compounds of formula (VI) are described in J. Chem. Med. Chem, 1995, 38, 3313].

Compounds of formula (VI) or (X), in particular in the de-esterified form, ie in which R ^{5 which} is alkyl is substituted by known methods and any carboxylic ester groups of R ⁴ and / or R ^x are converted to carboxyl groups Can be used as a medicament for the treatment or prophylaxis of diseases characterized by, for example, stimulation of the GABA _B receptor. Accordingly, the present invention includes novel compounds of formula (VII), or salts or esters thereof.

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

The compounds of the present invention obtained as salts are treated with methods known per se, for example alkali metal hydroxides, metal carbonates, or hydrogen carbonates, or ammonia, or other salt-forming bases described above, or for example Can be converted to the free compound by treatment with hydrochloric acid or with another salt-forming acid described above.

Salts of the present invention can be converted to different salts of the present invention by methods known as their own. For example, acid addition salts can be converted by treatment with a suitable metal salt, such as sodium, barium or silver salts of other acids, in a suitable solvent excluded from the reaction equilibrium since the inorganic salts formed are poorly soluble, and the base salts are free acids. It can be converted by removing and again converting to salt.

In addition to salts thereof, the compounds of formula (I) may also be obtained in the form of hydrates or may include the solvent used for crystallization.

Because of the close relationship between the free form and the novel compounds in its salt form, the above and the following free compounds and their salts are also optionally suitable and, if not semantically problematic, will be arbitrarily understood as the corresponding salts and free compounds, respectively.

In the case of compounds of formula (I), the mixtures of intermediates, diastereomeric mixtures and racemates in their preparation are based on known physicochemical properties of these constituents, for example by known methods such as chromatography and / or fractionation. The crystals can be separated into pure diastereomers and racemates, respectively.

The resulting racemates are also known methods, for example recrystallization from optically active solvents using microorganisms, or reaction of the resulting diastereomeric mixtures or racemates with optically active auxiliary compounds, for example Reaction with an acidic, basic or functionally modifiable group contained in the compound of formula (I) with an optically active acid, base or optically active alcohol yields a mixture of diastereomeric salts or functional derivatives such as esters, and the desired enantiomers are conventional It can be resolved into optical symmetries by separating it into diastereomers which can be separated by the phosphorus method. Bases, acids and alcohols suitable for this purpose can be obtained, for example, by strikin, cinchon or brucin, or D- or L- (1-phenyl) ethylamine, 3-pipecoline, ephedrine, amphetamine and synthesis Optically active alkaloid bases such as similar bases, 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 optically active carboxylic acids or sulfonic acids such as D- or L-camphorsulfonic acid, or optically active alcohols such as borneo or D- or L- (1-phenyl) ethanol.

Ⅰ formula, the compound of ⅤA ⅩⅧ or may be labeled with a radioactive isotope, especially ^{11 C,, 14 C, 2} H, 3 H or ¹²⁵ I to be used for diagnostic purposes.

The compounds of formula (I), (VA) or (VIII) can be used, for example, in a therapeutically effective amount of the active ingredient, as appropriate, pharmaceutically acceptable, which may be solid or liquid and organic or inorganic suitable for enteral, for example oral, parenteral administration. It can be used in the form of a pharmaceutical composition comprising with a carrier. For example, the active ingredient may be a diluent such as lactose, dextrose, saccharose, mannitol, sorbitol, cellulose and / or lubricants such as silica, talc, stearic acid, or salts of magnesium stearate or calcium stearate and the like; (Or) tablets or gelatin capsules comprising with polyethylene glycol are used. Tablets may also require binders such as magnesium aluminum silicate, corn, wheat, rice or chopped starch, such as starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and Disintegrating agents such as starch, agar, alginic acid or salts thereof, such as sodium alginate, and / or saturating or absorbing agents, colorants, seasonings and sweeteners. The compounds of formula I can also be used in the form of parenterally administrable compositions or in the form of infusions. Such solutions are preferably isotonic aqueous solutions or suspensions which can be prepared before use, for example in the case of lyophilized compositions comprising the active ingredient itself or together with a carrier such as mannitol. The pharmaceutical composition may be sterile and / or may contain excipients such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, osmotic pressure regulating salts and / or buffers. The present pharmaceutical composition may, if necessary, comprise other pharmacologically active substances and may be prepared by methods known per se, such as conventional mixing, granulation, glycosylation, dissolution or lyophilization, and 0.1% to 100%. , Especially about 1% to about 50%, in the case of lyophilized liquor, up to 100% may comprise the active ingredient.

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

Dosage may vary depending on various factors, including the method of administration, species, age, and / or individual health condition. The dosage to be administered daily may be about 1 to about 50 mg / kg, in particular 5 to about 25 mg / kg, for oral administration, preferably about 70 mg to about 70 kg of warm-blooded animals 3500 mg, especially about 350 to about 1750 mg, and can conveniently be divided into two to six times, for example three to four single doses.

Accordingly, the invention is directed to warm blooded animals, in particular human diseases, characterized by the stimulation of the GABA _B receptor, comprising administering to a warm blooded animal a compound of Formula I, VA or VIII, or a pharmaceutically acceptable salt or ester thereof Treatment or prevention methods.

The invention is illustrated by the following examples.

Compound D used in the examples was prepared as follows. In the continuous formula, Boc represents t-butoxycarbonyl.

Phenyl glycine (42 g) was dissolved in concentrated sulfuric acid (210 ml) and the solution was cooled to 0 ° C. Fuming nitric acid (15.5 ml) was added dropwise to the cooled solution for 30 minutes, and the mixture was further stirred at 0 ° C. for 30 minutes and then at room temperature for 18 hours. The resulting solution was poured into 1 liter of ice and ca. 875 ml of 10 M aqueous sodium hydroxide was added to carefully adjust pH to 7 while keeping the temperature of the solution below 20 ° C. The resulting mixture was stirred at rt for 3 h and the precipitate obtained was filtered off. The precipitate was washed three times with water and recrystallized from 1 liter of water to give 3-nitrophenylglycine at melting point of 165-6 ° C.

3-nitrophenylglycine (5 g) was added to a mixture of methanol (200 ml) and triethylamine (20 ml) and the mixture was vigorously stirred at room temperature for 10 minutes.

Di-t-butyl bicarbonate (11.13 g) was added and the reaction mixture was heated at reflux for 2 hours. The resulting solution was cooled to room temperature, then concentrated under reduced pressure and dried to give a black orange residue. The residue was purified by flash chromatography [silica gel, CH ₂ Cl ₂ (95%), CH ₃ OH (2.5%), CH ₃ COOH (2.5%)] to afford the compound of formula A as an orange foam.

¹³ Cnmr (100 MHz; CDCl ₃ ): δ (ppm) 27.9 (q), 58.2 (d), 82.6 (s), 122.4 (d), 123.0 (d), 129.5 (d), 133.0 (d), 140.4 ( s), 148.2 (s), 156.8 (s), 172.1 (s).

Compound A (14.54 g) and p-toluenesulfonic acid (1.87 g) in methanol (200 ml) were stirred at room temperature for 24 hours. Ethyl acetate and saturated aqueous NaHCO ₃ were added, the organic phase was separated, dried over MgSO ₄ , filtered and the filtrate was evaporated under reduced pressure. The obtained product was purified by flash chromatography [silica gel, hexane: ethyl acetate (2: 1)] to yield the compound of formula B as a yellow solid at melting point 86 占 폚.

C ₁₄ H ₁₈ N ₂ O ₆ analysis

Theoretical: C, 54.19; H, 5.85; N, 9.03%.

Found, C, 54.32; H, 6.00; N, 8.93%.

Sodium borohydride solution in anhydrous ethanol (30 ml) was added dropwise to a stirred solution of compound B (9.57 g) in anhydrous ethanol (120 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 hours, after which glacial acetic acid was added to decompose excess sodium borohydride. The solvent was removed under reduced pressure and the residue was digested with ethyl acetate (3 x 50 ml). The combined ethyl acetate phases were evaporated to dryness and the residue was then evaporated with toluene (3 × 50 ml). The resulting residue was purified by flash chromatography [silica gel, ethyl acetate: hexanes (1: 1)] to afford a compound of formula C having a melting point of 100 ° C.

C ₁₃ H ₁₈ N ₂ O ₅ analysis

Theoretical: C, 55.31; H, 6. 43; N, 9.92%.

Found: C, 55.25; H, 6.63; N, 9.76%.

Trifluoroacetic acid (60 ml) was added to the flask containing Compound C (5 g) cooled to 0 ° C. The resulting solution was stirred at 0 ° C. for 20 minutes, then warmed up to room temperature and stirred for another 3 hours. The solvent was removed under reduced pressure, and the residue was purified by ion exchange chromatography (Dowex 50WX 2-200 (H ⁺ form) resin, eluent 3% aqueous solution of ammonium hydroxide) to give a compound of formula D which is a pale brown foam.

C ₈ H ₁₀ N ₂ O ₃ Analysis

Theoretical: C, 52.74; H, 5.53; N, 15.83%.

Found: C, 53.12; H, 5.75; N, 15.07%.

¹³ C nmr (100 MHz; MeOH): δ (ppm) 58.0 (d), 68.2 (t), 122.8 (d), 123.1 (d), 130.4 (d), 134.5 (d), 146.3 (s), 149.6 ( s).

The compound of formula G used in the examples was prepared as follows.

Sodium cyanide (4.9 g, 0.1M) and ammonium chloride (5.88 g, 0.11M) were stirred in water at room temperature. A solution of 3,4-dichlorobenzenealdehyde (17.5 g, 0.1M) in methanol (30 ml) was added dropwise over 1 minute. Aqueous ammonia solution (10 ml, specific gravity 0.88) was added and stirred at room temperature for 3 hours. Ethyl acetate was added and the organic phase was separated, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in ethyl acetate and extracted repeatedly with 2N hydrochloric acid. The combined aqueous layers were adjusted to pH 9 using aqueous ammonia solution and repeatedly extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure to give an orange oil, which was purified by flash chromatography on silica using hexanes: ethyl acetate (1: 1) as eluent to have a melting point of 64-65 ° C. The compound of formula G was obtained.

C ₈ H ₆ Cl ₂ N ₂ analysis

Found, C, 47.81; H, 2.99; N, 13.92%

Theoretical: C, 47.79; H, 3.01; N, 13.93%.

The compound of formula J used in the examples was prepared as follows.

3-bromo-benzaldehyde (18.5 g, 0.1M), sodium cyanide (4.9 g, 0.1M) in methanol / water (30 ml / 20 ml) using substantially the same method as the preparation of the compound of formula G, A mixture of ammonium chloride (5.4 g, 0.11 M) and aqueous ammonia solution (10 ml, specific gravity 0.88) was reacted at room temperature for 24 hours to obtain a compound of formula H as a red / brown waxy solid.

¹³ C nmr (100 MHz; CDCl ₃ ): δ (ppm) 46.6 (d), 120.4 (s), 122.9 (s), 125.2 (d), 129.7 (d), 130.5 (d), 132.1 (d), 138.3 (s).

A mixture of compound H (10.5 g, 49.8 mM) in 6M hydrochloric acid (200 ml) was heated at reflux for 68 hours. The supernatant was drained off, cooled to room temperature and adjusted to pH 7 with aqueous ammonia solution. The precipitated product was collected by filtration, washed with water and dried. After decomposition with ethyl acetate, it was dried to give the compound of formula J as a brown solid at melting point 201-204 ° C. (decomposition).

¹³ C nmr (100 MHz; CD ₃ OD): δ (ppm) 56.9 (d), 124.0 (S), 128.1 (d), 133.2 (2 xd), 134.0 (d), 136.0 (S), 170.1 (S) .

<Example 1>

3-methoxycarbonylbenzaldehyde (1.6 g, 10.0 mM) in methanol (10 ml) was added to an aqueous solution of 4-methoxybenzylamine hydrochloride (1.7 g, 10.0 mM) and sodium cyanide (0.490 g, 10.0 mM). The mixture was stirred at rt for 3 h. Water (20 ml) was added and the mixture was extracted with dichloromethane. The organic phase was washed with brine, dried (MgSO ₄ ) and evaporated to dryness to afford an oil, which was purified by silica gel chromatography using 20% ethyl acetate in hexane as eluent to afford the compound of formula (I).

C ₁₈ H ₁₈ N ₂ O ₃ analysis

Theoretical: C, 69.66; H, 5.85; N, 9.03%.

Found: C, 69.40; H, 5.94; N, 8.73%.

¹³ C nmr (100 MHz; CDCl ₃ ): δ (ppm) 50.6 (t), 52.2 (q), 52.8 (d), 55.2 (q), 114.0 (d), 118.3 (s), 128.3 (d), 129.0 (d), 129.6 (d), 129.8 (s), 130.1 (d), 130.9 (s), 131.6 (d), 135.3 (s), 159.1 (s), 166.2 (s).

<Example 2>

A solution of compound 1 (7 g, 22.56 mM) in methanol (75 ml) was cooled to 0 ° C. and saturated with hydrogen chloride gas. If saturated, the reaction mixture was stored at -20 ° C for 4 days, then concentrated under reduced pressure to 1/4 of the initial volume. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added, the organic phase was removed, washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give an oil. Purification by flash chromatography on silica using hexanes: ethyl acetate (1: 1) as eluent gave the compound of formula 2 as an oil.

³¹ C nmr (100 MHz; CDCl ₃ ): δ (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), 129.2 (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>

A mixture of compound 2 (8.0 g, 23.3 mM) and palladium black (2.0 g) in glacial acetic acid (50 ml) and methanol (50 ml) was hydrogenated at room temperature for 4 hours. After confirming the reaction was terminated by thin layer chromatography (tlc), the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was evaporated together with toluene (3 × 200 ml) three times and then purified by flash chromatography on silica using ethyl acetate as eluent to afford the compound of formula 3 as pale yellow oil.

C ₁₃ H ₁₇ NO ₆ analysis

Theoretical: C, 55.12; H, 6.05; N, 4.94%.

Found: C, 55.46; H, 5.99; N, 5.05%

¹³ C nmr (100 MHz; CDCl ₃ ): δ (ppm) 20.8 (q), 52.1 (q), 52.5 (q), 57.9 (d), 127.9 (d), 128.9 (d), 129.3 (d), 130.7 (s), 131.4 (d), 139.9 (s), 166.6 (s), 173.5 (s), 175.9 (s).

<Example 4>

<Step 1>

A solution of di-t-butyl-bicarbonate (4.5 g, 20.83 mM) in methanol (10 ml) was added to a mixture of compound 3 (3.1 g, 10.9 mM) and triethylamine (10 ml, 71.75 mM) in methanol (40 ml). To the solution. The mixture was then heated at 60 ° C. for 30 minutes, then cooled to room temperature and evaporated under reduced pressure. Purification of the residue by flash chromatography on silica using hexanes: ethyl acetate (4: 1) as eluent gave a compound of formula E having a melting point of 88-90 ° C.

C ₁₆ H ₂₁ NO ₆ analysis

Theoretical: C, 59.43; H, 6.55; N, 4.33%.

Found: C, 59.54; H, 6. 72; N, 4.32%

<Step 2>

Sodium borohydride (800 mg, 21.2 mM) was added in eight portions to a stirred solution of compound E (3.2 g, 9.9 mM) in methanol (50 ml) at 30 minute intervals. At the end of reaction (tlc), residual sodium borohydride was removed with glacial acetic acid and the reaction mixture was evaporated under reduced pressure to give an oily solid. This residue was evaporated with toluene (2 × 20 ml) and decomposed with ethyl acetate. Ethyl acetate was evaporated under reduced pressure to form a colorless oil, which was purified by flash chromatography on silica using hexanes: ethyl acetate (1: 1) as eluent to afford the compound of formula F having a melting point of 102-104 ° C.

C ₁₅ H ₂₁ NO ₅ analysis

Theoretical: C, 61.01; H, 7. 17; N, 4.74%.

Found; C, 61.11; H, 7. 23; N, 4.70%

<Step 3>

Trifluoroacetic acid (3.0 ml, 39.17 mM) was added to a solution of stirred Compound F (2.2 g, 7.45 mM) in anhydrous dichloromethane (25 ml) at room temperature, under argon. The mixture was stirred at rt for 5 h. At the end of reaction (tlc), the mixture was evaporated under reduced pressure without applying heat, and the residue was evaporated with chloroform (2 x 20 ml). After evaporation under high vacuum, the residue was purified by ion exchange chromatography on Amberlyst (A21) resin using water as eluent to afford the compound of formula 4 as colorless oil.

_{C 10 H 13 NO 3 · ½H} 2 O Analysis

Found: C, 58.98; H, 6.73; N, 6.53%

Theoretical: C, 58.8; H, 6.91; N, 6.86%.

¹³ C nmr (100 MHz; CD ₃ OD ₃ ): δ (ppm) 52.6 (q), 58.1 (d), 67.4 (t), 129.1 (d), 129.8 (2 xd), 131.6 (s), 132.9 ( d), 142.4 (s), 168.2 (s).

Example 5

A solution of compound G (1.4 g, 5.98 mM) in methanol (20 ml) was cooled to 0 ° C. and saturated with hydrogen chloride gas. If saturated, the reaction mixture was stored at -20 ° C for 2 days. The solvent was removed under reduced pressure and the residue was evaporated with methanol (3 x 20 ml). The residue was suspended in ethyl acetate and the organic phase was washed successively with saturated aqueous sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give an oil, which was purified by flash chromatography on silica using hexanes: ethyl acetate (1: 1) as eluent to afford the compound of formula 5 It was.

C ₉ H ₉ Cl ₂ NO Analysis

Found: C, 46.12; H, 3. 85; N, 6.09%.

Theoretical: C, 46.18; H, 3.88; N, 5.98%.

¹³ C nmr (100 MHz; CDCl ₃ ): δ (ppm) 52.5 (q), 57.5 (d), 126.2 (d), 128.9 (d), 130.8 (d), 131.9 (s), 132.6 (s), 140.2 (s), 173.4 (s).

<Example 6>

Compound 5 (6.0 g, 25.63 mM), di-t-butyl bicarbonate (11.19 g, 51.26 mM) and triethylamine (20 ml, 143.50 mM) were subjected to substantially the same method as the preparation of Compound E of Example 4. Reaction was carried out in methanol (200 ml). The crude product was purified by chromatography on silica using 20% ethyl acetate in hexane as eluent to afford the compound of formula 6 as a yellow solid at melting point 90-92 ° C.

C ₁₄ H ₁₇ Cl ₂ NO ₄ Analysis

Found: C, 50.55; H, 5. 16; N, 4.08%.

Theory C, 50.32; H, 5.13; N, 4.19%.

<Example 7>

A solution of compound 6 (6.78 g, 20.28 mM) in anhydrous ethanol (100 ml) was added dropwise to a solution of sodium borohydride (1.15 g, 30.43 mM) in anhydrous ethanol (30 ml). The reaction was stirred at rt for 6 h and then left at rt for 48 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica using hexanes: ethyl acetate (1: 1) as eluent to afford the compound of formula 7 as a white solid at melting point 113-114 ° C. .

C ₁₃ H ₁₇ Cl ₂ NO ₃ Analysis

Found: C, 51.21; H, 5.69; N, 4.43%

Theory C, 51.00; H, 5.60 N, 4.57%.

<Example 8>

Compound 7 (4.7, 15.35 mM) was reacted with trifluoroacetic acid (75 ml) using substantially the same method as the preparation of Compound D from Compound C. The crude product was purified by ion exchange chromatography on a Dowex 50WX 2-200 (H ⁺ form) resin using an aqueous methanol: water: ammonia solution (50%: 47%: 3%) as eluent to a melting point of 65-67 ° C. A compound of formula 8 was obtained as a cream solid.

C ₈ H ₉ Cl ₂ NO analysis

Found: C, 46.61; H, 4. 37; N, 6.59%.

Theory C, 46.63; H, 4.40 N, 6.80%.

Example 9

Bis (trimethylsilyl) acetamide (28.5 ml) was added dropwise to a solution of 18.22 g of ethyl cyclohexylmethylphosphinate in 100 ml of anhydrous CH ₂ Cl ₂ , prepared under argon as described in EP 0569333. The solution was stirred at rt for 1 h, then trimethyl phosphinate (13.42 ml) was added followed by 1,3-dibromopropene (a mixture of cis / trans isomers). The solution was stirred at rt for 18 h, then poured into saturated aqueous NaHCO ₃ (100 ml) and stirred for 10 min. The product was extracted with CH ₂ Cl ₂ (3 × 50 ml) and the combined organic extracts were washed with brine, then dried over MgSO ₄ and filtered. The filtrate was evaporated under reduced pressure and then evaporated at 80 ° C., 0.45 mm Hg to remove excess phosphate. Purification of the residue by flash chromatography (silica gel, ethyl acetate) afforded the compound of formula 9 as a mixture of cis and trans.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 51.1 and 52.2.

<Example 10>

A mixture of (R) -2-amino-2-phenylethanol (0.88 g, 6.47 mM) and compound 9 (1.0 g, 3.23 mM) in toluene (10 ml) was heated under reflux. 1,8-diazabicyclo [5.4.0] undes-7-ene (0.48 ml, 3.23 mM) was added in 10 equal portions over a 30 minute period. The reaction was heated at reflux for another hour and left at room temperature overnight. The mixture was filtered and the filtrate was evaporated under reduced pressure to give a yellow oil which was purified by flash chromatography using 5% methanol in dichloromethane as eluent to give a 1: 1 mixture of diastereomers in phosphorus. The compound was obtained.

³¹ P nmr (162 Hz; CDCl ₃ ): δ (ppm) 43.49 and 43.55.

<Example 11>

(S) -2-amino-2-phenyl ethanol (2.66 g, 19.4 mM), compound 9 (3.0 g, 9.7 mM) and 1,8-diazabicyclo [5.4.0] undes-7-ene (1.40 g, 9.7 mM) was reacted in toluene (30 ml) using the method for preparing compound 10. The crude product was purified by flash chromatography on silica using 5% methanol in dichloromethane as eluent to afford the compound of formula 11 as a 1: 1 mixture of diastereomers in phosphorus.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 43.37 and 43.43.

<Example 12>

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

³¹ P (162 MHz; CDCl ₃ ): δ (ppm) 43.53 and 43.58.

Example 13

Using a substantially the same method as the preparation of Compound 12, a mixture of Compound 8 (2.76 g, 13.39 mM) and Compound 9 (4.14 g, 13.39 mM) in toluene / THF (50 ml / 4 ml) was mixed with THF (6 ml). Reacted with a solution of 1,8-diazabicyclo [5.4.0] undes-7-ene (2.03 g, 13.39 mM) at 110 ° C. as a 1: 1 mixture of diastereomers at the phosphorus position The compound of was obtained.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 43.73 and 43.82.

<Example 14>

Using a substantially the same method as the preparation of Compound 12, a mixture of Compound D (3.19 g, 17.50 mM) and Compound 9 (5.41 g, 17.50 mM) in toluene / THF (50 ml / 4 ml) was diluted with THF (6 ml). Reacted with a solution of 1,8-diazabicyclo [5.4.0] undes-7-ene (2.66 g, 17.5 mM) at 110 ° C. as a 1: 1 mixture of diastereomers at the phosphorus position The compound of was obtained.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 43.60 and 43.66.

<Example 15>

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

Mass spectrum (FAB): (m + 1) ⁺ m / z = 366.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 54.05 and 54.63

<Example 16>

Using substantially the same method as the preparation of compound 15, a mixture of diastereomers at the phosphorus position by reacting compound 11 (1.20 g, 3.28 mM) and sodium hydride (0.086 g, 3.61 mM) in toluene (40 ml) As a compound of formula (16).

C ₂₀ H ₃₂ NO ₃ P0.75H ₂ O Analysis

Found: C, 63.39; H, 8.75; N, 3.70%.

Theory C, 63.39; H, 8.91 N, 3.70%.

³¹ P (162 MHz; CDCl ₃ ): δ (ppm) 54.08 and 54.65.

<Example 17>

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

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 54.06 and 54.64.

Example 18

Using substantially the same method as the preparation of compound 15, compound 13 (2.24 g, 5.15 mM) and sodium hydride (0.136 g, 5.67 mM) were reacted in toluene (80 ml) of the diastereomer at the phosphorus position. Trans-2,5-disubstituted racemic compound 18 was obtained as a mixture.

C ₂₀ H ₃₀ Cl ₂ NO ₃ P. 0.5H ₂ O Analysis

Found: C, 54.21; H, 7.08; N, 3.11%.

Theoretical: C, 54.18; H, 7.05 N, 3.16%.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 53.80 and 54.40.

Example 19

Using substantially the same method as the preparation of compound 15, compound 14 (5.38 g, 13.1 mM) and sodium hydride (0.346 g, 14.41 mM) were reacted in toluene (150 ml) of the diastereomer at the phosphorus position. As a mixture, trans-2,5-disubstituted morpholine racemic compound 19 was obtained.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 53.73 and 54.33.

Example 20

A stirred solution of compound 15 (650 mg, 1.78 mM) in dichloromethane (25 ml) was added dropwise to bromotrimethylsilane (0.939 ml, 7.12 mM). The reaction mixture was stirred at rt for 24 h. The reaction was then quenched by adding a mixture of methanol: water (95: 5). Removal of solvent under reduced pressure gave an oil residue, ion exchange chromatography on Dowex 50WX 2-200 resin (H ⁺ form) using methanol: water: ammonia aqueous solution (50%: 47%: 3%) as eluent. Purification by chromatography. The product was dried under high vacuum (<0.05 mmHg) to afford the compound of formula 20 as a white solid at melting point> 250 ° C. [a] _D = + 10.8 ° (C = 1, CH ₃ OH).

C ₁₈ H ₂₈ NO ₃ P Analysis

Found: C, 63.72; H, 8. 44; N, 4.02%.

Theoretical: C, 64.08; H, 8.36 N, 4.15%.

³¹ P nmr (162 MHz; D ₂ O): δ (ppm) 55.22.

Example 21

Using substantially the same method as the preparation of compound 20, compound 16 (670 mg, 1.83 mM) and bromotrimethylsilane (1.1 g, 7.3 mM) were reacted in dichloromethane (20 ml) to a formula of melting point> 250 ° C. 21 compound was obtained. [a] _D = -10.5 ° (C = 1, CH ₃ OH).

C ₁₈ H ₂₈ NO ₃ P Analysis

Found: C, 63.62; H, 8.50; N, 4.05%.

Theoretical: C, 64.08; H, 8. 36; N, 4.15%.

³¹ P nmr (162 MHz; D ₂ O / DCl): δ (ppm) 55.36.

<Example 22>

Using substantially the same method as the preparation of compound 20, compound 18 (0.979 g, 2.25 mM) and bromotrimethylsilane (0.89 ml, 6.76 mM) were reacted in dichloromethane (40 ml) to trans-2,5- Disubstituted morpholine racemic compound 22 was obtained. Melting point> 200 ° C. (decomposition).

C ₁₈ H ₂₆ Cl ₂ NO ₃ P. 0.25H ₂ O Analysis

Found: C, 52.45; H, 6.53; N, 3.29%.

Theoretical: C, 52.63; H, 6. 50; N, 3.41%.

³¹ P nmr (202.5 MHz; d ₄ -acetic acid): δ (ppm) 45.45.

Sodium salt, ³¹ P nmr (162 MHz; D ₂ O / DCl): δ (ppm) 41.89.

<Example 23>

Using substantially the same method as the preparation of compound 20, compound 19 (0.50 g, 1.20 mM) and bromotrimethylsilane (0.48 ml, 3.65 mM) were reacted in dichloromethane (25 ml) to trans-2,5- Disubstituted morpholine racemic compound 23 was obtained. Melting point 128-130 ° C.

C ₁₈ H ₂₇ N ₂ O ₅ P. H ₂ O analysis

Found: C, 54.23; H, 7. 25; N, 6.93%.

Theoretical: C, 53.99; H, 7. 30; N, 7.00%.

³¹ P nmr (162 MHz; CD ₃ OD): δ (ppm) 37.64.

<Example 24>

A mixture of compound 19 (2.98 g, 7.26 mM) and 10% palladium on activated carbon in anhydrous ethanol (150 ml) was hydrogenated for 18 hours. The mixture was filtered and the filtrate was evaporated. Purification of the residue by flash chromatography on silica using 10% methanol in dichloromethane as eluent gave trans-2,5-disubstituted morpholine racemic compound 24 as a mixture of diastereomers at the phosphorus position. . Melting point 115-118 ° C.

C ₂₀ H ₃₃ N ₂ O ₃ P. 0.25H ₂ O

Found: C, 62.52; H, 8.88; N, 7.18%.

Theoretical: C, 62.40; H, 8. 77; N, 7.31%.

³¹ P (162 MHz; CDCl ₃ ): δ (ppm) 54.16 and 54.72.

<Example 25>

Crushed ice (15 g) was added to a stirred solution of compound 24 (2.43 g, 6.38 mM) in concentrated hydrochloric acid (50 ml) and the resulting mixture was cooled to 0 ° C. A solution of sodium nitrite (0.48 g, 7.02 mM) in water (25 ml) was added dropwise and the resulting mixture was stirred at 0 ° C. for 10 minutes. The resulting solution was then added dropwise to a solution of potassium iodide (11.13 g, 67.01 mM) in water (200 ml). The reaction mixture was stirred for another 2½ hours at room temperature and then left at room temperature overnight. Ethyl acetate was added and the two phases were separated. The aqueous phase was neutralized by the addition of solid sodium bicarbonate and extracted with ethyl acetate. This ethyl acetate extract was combined with the original organic phase, which was washed with 10% aqueous sodium hydroxide solution followed by 5% sodium sulfite solution followed by water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica using 10% methanol in ethyl acetate as eluent to afford trans-2,5-disubstituted morpholine racemic compound 25 as a mixture of diastereomers at the phosphorus position. . Mass spectrum (CI / NH ₃ ): (m + 1) ⁺ m / z = 492.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 54.21 and 54.77.

Example 26

Using substantially the same method as the preparation of compound 20, compound 25 (0.1 g, 0.20 mM) and bromotrimethylsilane (0.427 ml, 3.20 mM) were reacted in dichloromethane (10 ml) for 78 hours at room temperature. The crude product was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (H ⁺ form) using methanol: water: ammonia aqueous solution (50%: 47%: 3%) as eluent and the product was subjected to high vacuum ( Drying under <0.05 mm Hg) gave trans-2,5-disubstituted morpholine racemic compound 26. Melting point> 230 ° C. (decomposition).

C ₁₈ H ₂₇ INO ₃ P1.2H ₂ O analysis

Found: C, 44.48; H, 5. 70; N, 2.95%.

Theoretical: C, 44.59; H, 6. 11; N, 2.89%.

³¹ P nmr (162 MHz; CD ₃ OD / DC1): δ (ppm) 53.08.

Example 27

Alumina impregnated with sodium cyanide (5 mM NaCN per gram of alumina) was prepared by the methods of S. L. Regen, S. Quici and S. J. Liaw, Journal Organic Chemistry, 1979, 44 (12), 2029. A mixture of tri (dibenzylideneacetone) dipalladium (O) [0.17 g, 0.18 mM], alumina (4.7 g) impregnated with sodium cyanide and tris (2-furyl) phosphine (0.34 g, 1.45 mM) was obtained by argon. To a solution of compound 25 (0.89 g, 1.8 mM) in toluene (50 ml) degassed under. The reaction was heated at 80 ° C for 12 h. The reaction was monitored by tlc and, if necessary, further tris (dibenzylideneacetone) dipalladium (O) [0.17 g, 0.18 mM) and tri (2-furyl) phosphine (0.34 g, 1.45 mM) were added, The reaction was heated at 80 ° C for 8 h. At the end of the reaction, the mixture was filtered and the solids washed with ether. The combined filtrates were evaporated under reduced pressure and the residues were purified by flash chromatography on silica using 10% methanol in ethyl acetate as eluent to trans-2,5-disubstituted mor as a mixture of diastereomers at the phosphorus position. Pauline racemic compound 27 was obtained.

Mass spectrum (CI / NH ₃ ): (M + 1) ⁺ m / z = 391.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 53.95 and 54.57.

<Example 28>

Using substantially the same method as the preparation of compound 20, compound 27 (0.16 g, 0.41 mM) and bromotrimethylsilane (0.81 ml, 6.14 mM) were reacted in dichloromethane to trans-2,5-disubstituted racemic Compound 28 was obtained.

Mass spectrum (CI, NH ₃ ): M ⁺ m / z = 362.

³¹ P nmr (162 MHz; D ₂ O / DCl): δ (ppm) 55.31.

<Example 29>

A mixture of compound 27 (0.09 g, 0.23 mM), 6M hydrochloric acid solution (10 ml) and ethanol (1 ml) was heated at reflux for 72 hours. When the reaction ( ³¹ P nmr) was terminated, the solvent was removed under reduced pressure. The residue was purified by ion exchange chromatography on a Dowex 50WX 2-200 resin (H ⁺ form) using an aqueous methanol: water: ammonia solution (50%: 47%: 3%) as eluent and the product was subjected to high vacuum ( Drying under ≦ 0.05 mm Hg) afforded trans-2,5-disubstituted morpholine racemic compound 29. Melting point> 260 ° C.

³¹ P nmr (162 MHz; D ₂ O): δ (ppm) 40.67.

<Example 30>

A mixture of compound 17 (0.50 g, 1.18 mM), 6M hydrochloric acid solution (25 ml) and glacial acetic acid (5 ml) was heated at 100 ° C. for 16 hours. When the reaction ( ³¹ P nmr) was terminated, the solvent was removed under reduced pressure. The residue was purified by ion exchange chromatography on a Dowex 50WX 2-200 resin (H ⁺ form) using an aqueous methanol: water: ammonia solution (50%: 47%: 3%) as eluent and the product was subjected to high vacuum (≦ Drying under 0.05 mm Hg) afforded trans-2,5-disubstituted morpholine racemic compound 29.

C ₁₉ H ₂₈ NO ₅ P0.5 H ₂ O Analysis

Found: C, 58.68; H, 7. 35; N, 3.71%.

Theoretical: C, 58.45; H, 7. 49; N, 3.59%.

³¹ P nmr (162 MHz; D ₂ O): δ (ppm) 40.71.

<Example 31>

A solution of compound 29 (317 mg, 0.83 mM) in methanol (20 ml) was saturated with gaseous hydrogen chloride and the reaction mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure and the residue was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (H ⁺ form) using methanol: water: ammonia aqueous solution (50%: 47%: 3%) as eluent. It was. The product was dried under high vacuum (≦ 0.05 mm Hg) to give trans-2,5-disubstituted morpholine racemic compound 30.

C ₂₀ H ₃₀ NO ₅ P0.25H ₂ O Analysis

Found: C, 60.26; H, 7.57; N, 3.45%

Theoretical: C, 60.01; H, 7.68; N, 3.50%.

³¹ P nmr (162 MHz; CD ₃ OD): δ (ppm) 37.21.

<Example 32>

Using substantially the same method as the preparation of compound 20, compound 10 (90 mg, 0.246 mM) and bromotrimethylsilane (200 μl, 1.57 mM) were reacted in dichloromethane (2 ml) to obtain a compound of formula 31 It was.

[α] _D -38.5 ° (C = 0.6, CH ₃ OH)

³¹ P nmr (162 MHz; CD ₃ OD): δ (ppm) 29.00.

<Example 33>

Using substantially the same method as the preparation of compound 20, compound 11 (90 mg, 0.246 mM) and bromotrimethylsilane (200 μl, 1.57 mM) were reacted in dichloromethane to give a compound of formula 32.

[α] _D + 41.3 ° (C = 0.6, CH ₃ OH)

³¹ P nmr (162 MHz; CD ₃ OD): δ (ppm) 28.84.

<Example 34>

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

³¹ P nmr (162 MHz; CD ₃ OD): δ (ppm) 29.28.

<Example 35>

Using substantially the same method as the preparation of compound 20, compound 13 (0.5 g, 1.15 mM) and bromotrimethylsilane (0.91 ml, 6.9 mM) were reacted in dichloromethane (15 ml) to obtain a compound of formula 34 It was.

³¹ P nmr (162 MHz; CD ₃ OD): δ (ppm) 29.06.

<Example 36>

Using substantially the same method as the preparation of compound 20, compound 14 (90 mg, 0.219 mM) and bromotrimethylsilane (200 μl, 1.57 mM) were reacted in dichloromethane (2 ml) to obtain a compound of formula 35 It was.

³¹ P nmr (162 MHz; CD ₃ OD): δ (ppm) 29.57.

<Example 37>

Boron trifluoride ethyl atate (1.25 ml, 10 mM) was added dropwise to a suspension of 2-amino-3- (4-iodophenyl) propionic acid (2.9 g, 10 mM) in THF (10 ml) over 20 minutes. . The mixture was heated at reflux for 2 hours, then the borane dimethyl sulfide complex (1.1 ml, 11 mMol) was added dropwise over 1 hour to maintain the mixture at reflux. The mixture was further heated at reflux for 5 hours and then stirred at room temperature for 15 hours.

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

C ₉ H ₁₂ INO Analysis

Found: C, 38.69; H, 4.40; N, 4.92%.

Theoretical: C, 39.01; H, 4. 37; N, 5.06%.

<Example 38>

Using a method substantially the same as the preparation of compound 12, a mixture of compound 36 (2.40 g, 8.66 mM) and compound 9 (2.7 g, 8.66 mM) in toluene (20 ml) was added to 1,8 in THF (10 ml). Reaction with a solution of -diazabicyclo [5.4.0] undes-7-ene (1.30 g, 8.66 mM) at 75 ° C. yielded a compound of formula 37 as a 1: 1 mixture of diastereomers in phosphorus.

³¹ P nmr (202 MHz; CDCl ₃ ): δ (ppm) 43.69 and 43.72.

<Example 39>

[Trans]

[Cis]

A suspension of sodium hydride (0.105 g, 4.4 mM) in anhydrous toluene (5 ml) was added in portions over 30 minutes to a stirred solution of compound 37 (2.0 g, 4.0 mM) in anhydrous toluene (25 ml). The mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 3 hours. Glacial acetic acid (1 ml) was added and the reaction mixture was then diluted with ethyl acetate (75 ml). The organic phase was washed with saturated sodium bicarbonate solution, water and then brine. The combined organic phases were dried over magnesium sulfate, filtered and evaporated. Purify the residue by flash chromatography on silica using 20% methanol in ethyl acetate as eluent to trans-2,5-disubstituted morpholine racemic compound 38 and cis-2, as diastereomeric mixtures in phosphorus Each of 5-disubstituted morpholine racemic compound 39 was obtained.

Compound 38: ³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 53.93 and 54.60.

Compound 39: ³¹ P nmr (202 MHz; CDCl ₃ ): δ (ppm) 54.25 and 54.82.

<Example 40>

A stirred solution of compound 38 (180 mg, 0.356 mM) in dichloromethane (5 ml) was added to bromotrimethylsilane (0.20 ml, 1.52 mM) under argon. The reaction mixture was stirred at rt for 20 h. The solvent was removed under reduced pressure and the residue was evaporated with a 1: 1 mixture of water: methanol (2 x 0.5 ml). The product was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (H ⁺ form) using methanol: 2% sodium hydroxide solution (1: 1) to elute the product. The product was further purified by gel filtration on a Bio-Gel P2 column using water as eluent to afford trans-2,5-disubstituted morpholine racemic compound 40. Melting point> 250 ° C. (decomposition).

C ₁₉ H ₂₈ INO ₃ P.Na. 3H ₂ O analysis

Found: C, 41.42; H, 5.40; N, 2.42%.

Theoretical: C, 41.20; H, 6. 10; N, 2.53%.

³¹ P nmr (161 MHz; D ₂ O): δ (ppm) 41.81.

<Example 41>

A mixture of compound 38 (0.180 g, 0.36 mM) and bis triphenylphosphine palladium (II) chloride (0.200 g, 0.28 mM) in anhydrous ethanol (2 ml) and triethylamine (1 ml) with argon for 5 minutes The gas was removed by sparging. The mixture was heated to reflux and stirred vigorously for 3 hours under a carbon monoxide atmosphere. The mixture was cooled to room temperature and the solvent was removed under reduced pressure to give an oily solid which was decomposed with ethyl acetate. The combined washes of ethyl acetate were evaporated under reduced pressure and the residue was purified by flash chromatography on silica using 10% methanol in chloroform as eluent to trans-2 as a mixture of diastereomers in phosphorus. , 5-disubstituted morpholine racemic compound 41 was obtained.

³¹ P nmr (161 MHz; CDCl ₃ ): δ (ppm) 53.93 and 54.60.

<Example 42>

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

C ₂₀ H ₂₈ INO ₅ P.Na. 2H ₂ O analysis

Found: C, 50.53; H, 7. 40; N, 2.96%.

Theoretical: C, 50.52; H, 6.79; N, 2.95%.

³¹ P nmr (202 MHz; D ₂ O): δ (ppm) 42.38.

<Example 43>

A buffered stock solution of formaldehyde was prepared by dissolving sodium acetate (1.8 g, 21.4 mM), acetic acid (1.3 ml, 22.7 mM) and 40% aqueous solution of formaldehyde (7.0 ml, 101 mM) in water (5 ml). A aliquot of this stock solution (10 ml) was added to a mixture of compound 29 (0.10 g, 0.262 mM) in methanol (2 ml) and the mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (0.165 g, 2.62 mM) was added in portions over 2 minutes. The mixture was stirred at rt for 24 h. The solvent was removed under reduced pressure and the residue was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (H ⁺ form) using methanol: 2% sodium hydroxide solution (1: 1) to elute the product. The product was subjected to gel filtration on a BIO-GEL P2 column using water as eluent to further purify the residue to give 43 of a trans-2,5-disubstituted morpholine racemic compound having a melting point> 250 ° C (decomposition). .

C ₂₀ H ₂₈ NO ₅ P. ₂ Na. 2H ₂ O analysis

Found: C, 52.60; H, 6. 82; N, 3.10%.

Theoretical: C, 52.52; H, 6. 61; N, 3.06%.

³¹ P nmr (202 MHz; D ₂ O): δ (ppm) 41.93.

<Example 44>

Compound 29 (0.25 g, 0.66 mM) was dissolved in a 1: 1 mixture of dioxane: water (4 ml) and the pH of the resulting solution was adjusted to pH9 by addition of 0.1M sodium hydroxide solution. The mixture was stirred vigorously and benzyl chloroformate (0.188 ml, 1.32 mM) was added dropwise over 15 minutes. The pH of the mixture was adjusted to pH9 by further addition of 0.1 M sodium hydroxide solution and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated under reduced pressure to half the original volume and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate and the combined organic phases were washed with water followed by brine, dried over magnesium sulfate, filtered and evaporated. Purification by flash chromatography on silica using acetic acid: methanol: chloroform (2%: 10%: 88%) as eluent. The product was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (H ⁺ ) using THF: water (3: 1) as eluent. The product was dissolved in 1% sodium hydroxide solution (2.5 ml) and further purified by gel filtration on a BIO-GEL P2 column using water as eluent to trans-2,5-disubstituted at melting point> 250 ° C. (decomposition). 44 was obtained for the morpholine racemic compound.

C ₂₇ H ₃₂ NO ₇ P. ₂ Na. 3H ₂ O analysis

Found: C, 52.27; H, 6.00; N, 2.24%.

Theoretical: C, 52.85; H, 6. 24; N, 2.28%.

³¹ P nmr (161 MHz; D ₂ O): δ (ppm) 41.75.

<Example 45>

Boron trifluoride ethyl etherate (75.0 ml, 0.61 M) was added dropwise over 20 minutes to a suspension of compound J (70.2 g, 0.31 M) in THF (350 ml). The mixture was heated at reflux for 2 hours, then the borane dimethyl sulfide complex (57.9 ml, 0.61 M) was added dropwise over 1.5 hours to maintain the mixture at reflux. The mixture was heated at reflux for 3 more hours and then left at room temperature for 18 hours.

A 1: 1 mixture of water and THF (350 ml) was added followed by 5M sodium hydroxide solution (350 ml). The reaction mixture was heated at 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 dried under reduced pressure to give a brown oil.

The residue was digested with diethyl ether / hexanes and then recrystallized with ethyl acetate to give a compound of formula 45 at melting point 74-76 ° C.

C ₈ H ₁₀ BrNO Assay

Found: C, 44.40; H, 4.67; N, 6.35%.

Theoretical: C, 44.46; H, 4.67; N, 6.48%.

Example 46

<Formula 4>

Argon sprayed over 5 minutes compound 45 (15.0 g, 69.4 mM) and bis (triphenylphosphine) palladium (II) chloride (4.0 g, 5.70 mM) in methanol (100 ml) and triethylamine (25 ml) Gas of the mixture) was removed. The mixture was saturated with carbon monoxide and then the pressure in the pressure vessel was maintained at 30 psi. The mixture was slowly heated to 100 ° C. while maintaining the pressure below 50 psi for 5 hours. The mixture was cooled to room temperature, filtered and evaporated. The residue was digested with ethyl acetate and the filtrate was evaporated. The residue was purified by flash chromatography using a gradient of 10% to 20% methanol in chloroform as eluent to afford the compound of formula 4.

¹³ C nmr (100 MHz; CD ₃ OD): δ (ppm) 52.6 (q), 58.3 (q), 68.1 (t), 129.0 (d), 129.5 (d), 129.7 (d), 131.5 (s) 132.9 (d), 143.6 (s), 168.4 (s).

<Example 47>

(2R / S) -2-amino-2- (1H-indol-3-yl) ethanol was prepared by the method of AH Karz et al., See Journal Medicinal Chemistry, 1988, 31 , 1244.

Using (2R / S) -2-amino-2- (1H-indol-3-yl) ethanol (0.39 g, 2.21 in toluene / THF (10 ml / 15 ml) using substantially the same method as for preparing compound 12 mM) and a mixture of compound 9 (0.68 g, 2.20 mM) were added at 75 ° C. with a solution of 1,8-diazabicyclo [5.4.0] undes-7-ene (0.33 g, 2.17 mM) in toluene (5 ml). Reaction at gave a compound of formula 46 as a 1: 1 mixture of diastereomers in phosphorus.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 43.25 and 43.43.

<Example 48>

A suspension of sodium hydride (0.014 g, 0.59 mM) in anhydrous toluene (10 ml) was stirred at 0 ° C. A solution of compound 46 (0.200 g, 0.49 mM) in anhydrous toluene (7 ml) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 4 hours. After adding glacial acetic acid to quench the reaction, the mixture was then filtered and evaporated. The residue was purified by flash chromatography on silica using 20% methanol in ethyl acetate as eluent to afford trans-2,5-disubstituted morpholine racemic compound 47.

Mass spectrum (CI / NH ₃ ): (M + l) ⁺ m / z = 405.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 54.44 and 55.32.

<Example 49>

Using substantially the same method as the preparation of compound 40, compound 47 (0.115 g, 0.28 mM) and bromotrimethylsilane (0.15 ml, 1.13 mM) were reacted in dichloromethane (5 ml) for 3 days at room temperature for trans -2,5-disubstituted racemic compound 48 was obtained.

¹³ C nmr (100 MHz; D ₂ O): δ (ppm) 28.6 (t), 28.7 (t), 35.1 (d), 37.6 (t), 37.7 (t), 37.9 (t), 38.3 (t) , 41.6 (t), 53.8 (d), 54.2 (t), 74.7 (t), 75.6 (d), 114.8 (d), 115.6 (s), 121.3 (d), 122.3 (d), 125.0 (d) 125.4 (d), 128.3 (s), 138.8 (s).

³¹ P nmr (202 MHz; D ₂ O): δ (ppm) 42.6.

<Example 50>

DL-2-amino-3-methyl-2-phenylbutyric acid (10.0 g, 51.8 mM), boron trifluoride ethyl etherate (6.4 ml, 51.8 mM) and borane, using substantially the same method as the preparation of compound 37 Dimethyl sulfide complex (4.9 ml, 51.8 mM) was reacted in anhydrous THF (50 ml) to give a compound of formula 49.

Mass spectrum (CI, NH ₃ ): (m + 1) ⁺ m / z = 180.

¹³ C nmr (100 MHz; CDCl ₃ ): 16.8 (q), 17.4 (q), 34.8 (d), 61.7 (s), 69.2 (t), 126.2 (d), 126.4 (d), 127.8 (d) , 144.2 (s).

<Example 51>

Using substantially the same method as the preparation of Example 12, compound 49 (1.07 g, 6.0 mM) and compound 9 (1.86 g, 6.0 mM) in toluene (20 ml) were added in 1,8- in toluene (5 ml). Reaction with a solution of diazabicyclo [5.4.0] undes-7-ene (1.1 g, 7.2 mM) at 75 ° C. yielded compound 50 as a 1: 1 mixture of diastereomers in phosphorus.

Mass spectrum (CI, NH ₃ ): (m + 1) ⁺ m / z = 408.

³¹ P (202.5 MHz; CDCl ₃ ): δ (ppm) 44.22 and 44.25.

<Example 52>

(2R ^* , 5R ^* )

(2R ^* , 5S ^* )

Using substantially the same method as in Example 39, compound 50 (200 mg, 0.49 mM), sodium hydride (12 mg, 0.49 mM) and sodium hydroxide (12 mg, 0.49 mM) were reacted in anhydrous toluene (3 ml) I was. The crude product was purified by flash chromatography on silica using 10% methanol in ethyl acetate as eluent to afford (2R ^* , 5R ^* ) morpholine racemic compounds 51 and (2R ^* , 5S as diastereomeric mixtures in phosphorus. ^* ) Each obtained morpholine racemic compound 52.

Compound 51: ³¹ P (162 MHz; CDCl ₃ ): δ (ppm) 54.3 and 55.0.

Compound 52: ³¹ P (162 MHz; CDCl ₃ ): δ (ppm) 54.2 and 55.5.

<Example 53>

Using substantially the same method as in Example 40, compound 51 (40 mg, 0.1 mM) and bromotrimethylsilane (0.066 ml, 0.5 mM) were reacted in anhydrous dichloromethane (1 ml) (2R ^* , 3R ^* Morpholine racemic compound 53 was obtained.

³¹ P nmr (202.5 MHz; D ₂ O): δ (ppm) 42.5.

<Example 54>

Using substantially the same method as in Example 40, compound 52 (180 mg, 0.2 mM) and bromotrimethylsilane (0.132 ml, 1.0 mM) were reacted in anhydrous dichloromethane (2 ml) (2R ^* , 5S ^* Morpholine racemic compound 54 was obtained.

³¹ P nmr (202.5 MHz; D ₂ O): δ (ppm) 42.2.

<Example 55>

0.5M solution of potassium bis (trimethylsilyl) amide in toluene (50 ml, 25 mM) was cooled with ethyl 1,1-diethoxyethylphosphinate (5.25 g, 25 mM) in THF (30 ml) (-70 Drop wise). The mixture was stirred at -70 ° C for 0.5 h. The resulting solution was added dropwise over 10 minutes to a cold solution of 4-methoxybenzyl chloride (3.9 g, 25 mM) in THF (30 ml). The resulting mixture was stirred at -70 ° C for 1 hour and then heated to room temperature. The reaction was stirred at rt for 18 h. Glacial acetic acid was added and the reaction was evaporated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated, washed with water, then brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica using ethyl acetate: hexane (2: 1) as eluent to afford the compound of formula 55.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 44.6.

<Example 56>

Chlorotrimethylsilane (3.8 ml, 30.3 mM) was added to a solution of compound 55 (1.0 g, 3.03 mM) in a 9: 1 mixture (10 ml) of chloroform: ethanol and the mixture was stirred at rt for 18 h. The mixture was evaporated under reduced pressure and the residue was evaporated with chloroform. After drying under high vacuum, the residue was purified by flash chromatography on silica using ethyl acetate as eluent to afford the compound of formula 56 as a colorless oil.

Mass spectrum (CI, NH ₃ ): (m + NH ₄ ) ⁺ m / z = 232.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 37.3.

<Example 57>

Compound 56 (0.5 g, 2.33 mM), bis (trimethylsilyl) acetamide (0.69 ml, 2.80 mM), trimethyl phosphate (0.33 ml, 2.80 mM) and 1,3 using substantially the same method as in Example 9 -Dibromopropene (mixture of cis / trans isomers) (0.23 ml, 2.33 mM) was reacted in anhydrous dichloromethane (10 ml) to afford the compound of formula 57 as a mixture of cis and trans isomers.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 47.2 and 48.1.

<Example 58>

Using substantially the same method as Example 12, Compound 4 (0.193 g, 0.99 mM) and Compound 57 (0.330 g, 0.99 mM) in toluene / THF (10 ml, 4: 1 mixture) were added to toluene (2 ml). Was reacted at 80 ° C. with a solution of 1,8-diazabicyclo [5.4.0] undes-7-ene (0.181 g, 1.19 mM) in to give a compound of formula 58 as a mixture of diastereomers in phosphorus .

Mass spectrum (CI, NH ₃ ): (m + 1) ⁺ m / z = 448.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 39.40 and 39.49.

<Example 59>

Using substantially the same method as Example 39, compound 58 (200 mg, 0.45 mM) and sodium hydride (10.8 mg, 0.45 mM) were reacted in anhydrous toluene (2 ml) as a mixture of diastereomers in phosphorus. Trans-2,5-disubstituted morpholine racemic compound 59 was obtained.

³¹ P nmr (162 MHz; CDCl ₃ ): δ (ppm) 50.0 and 50.8.

<Example 60>

Bromotrimethylsilane (0.074 ml, 0.55 mM) was added to a solution of compound 59 (50 mg, 0.11 mM) in dichloromethane (1 ml) and the reaction was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was evaporated with a 1: 1 mixture of methanol: water. The resulting residue was dissolved in 6M hydrochloric acid (2 ml) and the mixture was heated at reflux for 4 hours. The solvent was removed under reduced pressure and the residue was evaporated together with water three times. The resulting residue was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (H ⁺ form) using methanol: 2% sodium hydroxide solution (1: 1) to elute the resulting residue. The product was further purified by gel filtration on a BIO-GEL P2 column using water as eluent to yield trans-2,5-disubstituted morpholine racemic compound 60.

³¹ P nmr (202.5 MHz; D ₂ O): δ (ppm) 37.4.

Claims (37)

A compound which is a substituted phosphinic acid of formula (I), or a salt or ester thereof. <Formula I> Wherein R ¹ is a monovalent aromatic or araliphatic group bonded to the carbon atom via its carbon atom, R ² is an unsubstituted or substituted hydrocarbyl group, and R ^x is hydrogen or unsubstituted or A substituted hydrocarbyl group, R ^y is hydrogen, R ^y _a (R ^y _a is an unsubstituted or substituted hydrocarbyl group) or NH-protecting group. The compound of claim 1, wherein R ¹ is unsubstituted or halogen, hydroxy, C ₁ to C ₄ alkoxy, carboxyl, functionally modified carboxyl, carboxy-C ₁ -C ₈ alkyl, functionally modified carboxy An aryl group having 6 to 15 carbon atoms which may be substituted at one or more positions with -C ₁ -C ₈ alkyl or nitro, or a 5-10 membered heterocy, wherein R ¹ has one or two nitrogen atoms in the ring system A compound which is a click aromatic group. The compound of claim 1, wherein R ¹ is phenyl or phenyl substituted with halogen, carboxyl, functionally modified carboxyl or nitro in one or more meta and para positions relative to its carbon atom bonded to the morpholine ring, or Or R ¹ is a 5-10 membered heterocyclic aromatic group having nitrogen as the only ring hetero atom. The compound of claim 1, which is unsubstituted or halogen, hydroxy, C ₁ to C ₄ alkoxy, carboxyl, functionally modified carboxyl, carboxy-C ₁ -C ₈ alkyl, functionally modified carboxy-C _1- R ¹ is a phenyl lower alkyl, α, α-diphenyl-lower alkyl or α-naphthyl-lower alkyl group, substituted at one or more positions with C ₈ alkyl or nitro. The compound of claim 1, wherein R ¹ is α-phenyl-C ₁ -C ₄ alkyl which is unsubstituted or substituted at one or more positions with halogen, carboxyl, functionally modified carboxyl or nitro. The compound of claim 1, wherein R ¹ is phenyl, 3-iodophenyl, 3,4-dichlorophenyl, 3-carboxyphenyl, 3-cyanophenyl, 3- (methoxycarbonyl) phenyl, 3-nitrophenyl, Benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl. 7. The compound of claim 1, wherein R ² is lower alkyl, lower alkenyl, lower alkynyl, oxo-lower alkyl, hydroxy- or dihydroxy-lower alkyl, hydroxy-low alkenyl , Mono-, di- or poly-halo-lower alkyl, mono, di- or poly-halo-lower alkenyl, mono-, di- or poly-halo- (hydroxy) -lower alkyl, mono-, di- Or poly-halo (hydroxy) -lower alkenyl, lower alkoxy-lower alkyl, di-lower alkoxy-lower alkyl, lower alkoxy (hydroxy) -lower alkyl, lower alkoxy (halo) -lower alkyl, lower alkylthio- Lower alkyl, di-lower alkylthio-lower alkyl, cyano-lower alkyl, acylamino-lower alkyl, cycloalkyl, hydroxycycloalkyl, oxa-, dioxa-, thia- and dithia-cycloalkyl, cycloalkyl -Lower alkyl, cycloalkenyl-lower alkyl, or cycloalkyl (hydroxy) -lower alkyl, (lower alkylthio) cycloalkyl ( Hydroxy) -lower alkyl, or mono-, di- or tri-substituted, mono-, or di-phenyl- unsubstituted or lower alkyl, lower alkoxy, hydroxy, halogen and / or trifluoromethyl Lower alkyl or naphthyl lower alkyl, or thienyl-, furyl- or pyridyl-lower alkyl unsubstituted or substituted with halo. 8. The compound of claim 7 wherein R ² is C ₁ -C ₇ alkyl, α, α-di-C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, cyano-C ₁ -C ₄ alkyl, acylamino-C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl-C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkenyl-C ₁ -C ₄ alkyl, or unsubstituted or C ₁ -C ₄ alkyl, And phenyl-C ₁ -C ₄ alkyl mono-, di-, or trisubstituted with C ₁ -C ₄ alkoxy, hydroxy and / or halogen. 8. The compound of claim 7 wherein R ² is C ₁ -C ₅ alkyl, α, α-di- (C ₁ -C ₄ alkoxy) -methyl, α, α-di- (C ₁ -C ₄ alkoxy) ethyl, C ₃ -C ₆ cycloalkyl-C ₁ -C ₄ alkyl, benzyl or 4-methoxybenzyl. 8. Compounds according to claim 7, wherein R ² is cyclohexylmethyl or 4-methoxybenzyl. The unsubstituted or substituted hydrocarbyl according to claim 1, wherein R ^x is unsubstituted or halogen, hydroxy, C ₁ to C ₄ alkoxy, carboxyl, functionally modified. C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₃ to C ₈ substituted with carboxyl, carboxy-C ₁ -C ₈ alkyl, functionally modified carboxy-C ₁ -C ₈ alkyl or nitro A cycloalkyl, a C ₄ to C ₁₃ cycloalkylalkyl, a C ₆ to C ₁₀ aryl or a C ₇ to C ₁₃ aralkyl group. The compound of any one of claims 1-11, wherein R ^x is hydrogen, lower alkyl, C ₃ to C ₆ cycloalkyl, C ₆ to C ₈ aryl or C ₇ to C ₉ aralkyl. The compound of claim 12, wherein R ^x is hydrogen or isopropyl. 14. C ₁ to C ₁₀ alkyl according to any one of claims 1 to 13, wherein R ^y is R ^y _a and unsubstituted or substituted with hydroxy or C ₁ to C ₄ alkoxy, C ₃ to C ₈ A cycloalkyl or a C ₇ to C ₁₃ aralkyl group. The compound according to any one of claims 1 to 13, wherein R ^y is an NH-protecting group and is an acyl, alkoxycarbonyl or aralkyloxycarbonyl group. The compound of any one of claims 1-13, wherein R ^y is hydrogen, lower alkyl, C ₇ to C ₉ aralkyl, t-butoxycarbonyl or benzyloxycarbonyl. The compound of claim 1, wherein R ¹ is phenyl, 3-iodophenyl, 3,4-dichlorophenyl, 3-cyanophenyl, 3- (methoxycarbonyl) phenyl, 3-carboxyphenyl, 3-nitrophenyl, Benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl, R ² is cyclohexylmethyl or 4-methoxy Benzyl, R ^x is hydrogen or isopropyl, and R ^y is hydrogen, methyl or benzyloxycarbonyl. 18. The compound of any one of claims 1 to 17, wherein the compound of formula (IA), (IB), (IB) or (ID) <Formula IA> <Formula IB> <Formula IC> <Formula ID> Wherein R ¹ is as defined in any one of claims 1 to 6, R ² is as defined in any one of claims 1 and 7 to 10, and R ^x is the first And as defined in any one of claims 11 to 13, and R ^y is as defined in any one of claims 1 and 14 to 16. A compound of formula (VA), or a salt or ester thereof. <Formula VA> Wherein R ¹ is as defined in any one of claims 1 to 6, R ² is as defined in any one of claims 1 and 7 to 10, and R ^x is the first And as defined in any one of claims 11 to 13. A compound of formula III <Formula III> Wherein R ² is as defined in any one of claims 1 and 7 to 10, X is halogen and R ⁵ is C ₁ to C ₈ alkyl, provided that R ⁵ is ethyl , R ² is not methyl. R ⁴ is 3-methoxycarbonylphenyl, R ⁶ is hydrogen or an unsubstituted or substituted alkyl group having 1 to 8 carbon atoms or unsubstituted or substituted C ₆ to C ₁₀ aryl group, and R ⁷ is Is an alkyl group having 1 to 10 carbon atoms and R ^x is hydrogen or unsubstituted or substituted hydrocarbyl, or a compound of formula II, VI, V or V, or R ⁴ is 3,4-dichlorophenyl Or a compound of formula (II) or (VII) wherein R ⁷ is an alkyl group having 1 to 10 carbon atoms, or R ⁴ is a monovalent aromatic group bonded to the carbon atom via its carbon atom, and R ^x is unsubstituted or substituted Hydrocarbyl group provided that R ⁴ is ^not methyl, ethyl,-(CH ₂ ) ₃ SCH ₃ , allyl or methylol when R ⁴ is phenyl, and R ⁴ is phenyl, p-hydr when R ^x is aminomethyl When R ⁴ is 2,4-dichlorophenyl and not oxyphenyl or p-methoxyphenyl Where R ^x is not N-triazolylmethyl, or a compound of Formula II wherein R ⁴ is iodobenzyl and R ^x is hydrogen or an unsubstituted or substituted hydrocarbyl group, or R ⁴ Is a monovalent araliphatic group, R ¹ is as defined in any one of claims 1 and 4 to 6, and R ^x is in any one of claims 1 and 11 to 13. Substituted or unsubstituted hydrocarbyl groups other than methylol as defined, provided that when R ^x is methyl, R ⁴ is benzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 2 -Phenylethyl, 1,3-benzodioxol-5-methyl, 3-phenyl-1-aminopropyl, α-hydroxybenzyl, α-hydroxy-α-methylbenzyl or α-hydroxy-α-methyl- And not 4-nitrobenzyl and R ⁴ is benzyl, wherein R ^x is not allyl or —CH ₂ CH ₂ SCH ₃ . <Formula II> <Formula VI> <Formula Ⅶ> <Formula Ⅷ> A compound of formula (VII), or a salt or ester thereof. <Formula ⅩⅧ> Wherein R ¹ is as defined in any one of claims 1 to 6, R ² is as defined in any one of claims 1 and 7 to 10, and R ^x is the first And as defined in any one of claims 11 to 13, and R ^y is as defined in any one of claims 1 and 11 to 16. To then give the following compounds by reacting the compound with the presence of a base of formula Ⅲ a compound of formula Ⅱ formula Ⅳ, if desired, R ⁴ and (or) one or more substitution reactions to change the nature of the substituents of R ^x and (Or) hydrolysis of an ester substituent of R ⁴ and / or R ^x to carboxyl and / or a conversion reaction of ester group -OR ⁵ to -OH, wherein R ⁴ is hydrogen. Process for the preparation of the compound according to the invention. <Formula II> <Formula III> <Formula IV> Wherein R ⁴ is R ¹ as defined in any one of claims 1 to 6 except that it is not substituted with carboxyl, and R ^x is first except that it is not substituted with carboxyl Claims 1 to 11 to 13, R ² is as defined in any one of claims 1 and 7 to 10, and R ⁵ is C ₁ to C ₈ alkyl. to be. 24. The process according to claim 23, wherein the reaction of the compounds of the formulas (II) and (III) is carried out by the addition of a weak base to a mixture of the compounds of the formulas (II) and (III) in a solvent to obtain the intermediates of the following formula (V) A method of treating an intermediate with a base under more stringent conditions. <Formula Ⅴ> In the formula, R ² , R ⁴ , R ⁵ and R ^x are as defined in claim 23. The compound of claim 23 or 24, wherein R ⁴ of the compound of formula IV comprises a nitro group on an aryl or heteroaryl ring, which group is also converted to amino by reduction, and amino to diazotization followed by alkali A method of reacting with a metal cyanide to convert to halo and then to carboxyl by hydrolysis of cyano. A compound of formula (VII) is reacted with a compound of formula (VII) in the presence of a silylating agent so that the silylating agent reacts with formula (VII) to form a P (III) silyl compound, which is then reacted with a compound of formula (VII) 20. A process for the preparation of a compound according to claim 20. <Formula I> <Formula Ⅹ> In the formula, R ² , R ⁵ and X are as defined in claim 20. Reacting an aldehyde or ketone of the formula R ⁴ C (= 0) R ^x with an amine of the formula R ⁶ NH ₂ and an alkali metal cyanide yields a compound of formula VI, wherein (a) the compound of formula R ⁷ OH in to form an alcohol and reacting the compound of formula ⅶ the presence of an acid present, R ⁶ is the following by removing the R ⁶ if they are other than hydrogen from a compound of formula ⅶ obtain a compound of formula ⅷ, and a compound of formula ⅷ Reacting with an amino protecting agent to convert the amino group to a protected amino group, reducing the ester group -COOR ⁷ of the protected compound to -CH ₂ OH, removing the protecting group to form a free amino group, or (b) Aminocars produced by acid hydrolysis of the compound to convert its cyano group to carboxyl and reaction with borane dimethyl sulfide in the presence of boron trifluoride complex A process for the preparation of a compound of formula Ⅱ according to claim 21 comprising reducing the acids. <Formula VI> <Formula Ⅶ> <Formula Ⅷ> In the formula, R ⁴ , R ⁶ , R ⁷ and R ^x are as defined in claim 21. Reaction with borane dimethyl sulfide in the presence of a boron trifluoride complex to form an aminocarboxyl of formula R ⁴ C (R ^x ) (NH ₂ ) COOH, wherein R ⁴ and R ^x are as defined in claim 21; A process for the preparation of a compound of formula (II) according to claim 21 comprising reducing an acid. Is a compound of formula (I) as defined in claim 1 wherein R ^y is hydrogen: (a) a compound of formula R ^y _a Z wherein R ^y _a is as defined in claim 1 wherein Z is a leaving group; or b) reacting any of the aldehydes of the formula R ^y _b CHO (R ^y _b is hydrogen or R ^y _a as defined in claim ₁ and Z is a leaving group) and a reducing agent for reducing the imine to an amine. The method for producing a compound according to claim 1, wherein R ^y is R ^y _a . R ^y is an acyl halide, which comprises a compound according to claim 1, wherein a hydrogen, carboxylic acid anhydride, alkoxycarbonyl or aralkoxy Brassica Viterbo carbonyl halide or an alkyl or aralkyl bicarbonate and reaction, R ^y is NH- A method for producing a compound according to claim 1, which is a protecting group. The compound of formula (IIA) is reacted with a compound of formula (III) as defined in claim 23 in the presence of a base to give a compound of formula (IVA), and if necessary, a carboxyl of an ester substituent of R ⁴ and / or R ^x . A method for producing a compound according to claim 1, wherein R ^y is R ^y _a , which comprises performing hydrolysis to and / or a conversion reaction of the ester group -OR ⁵ to -OH. <Formula IIA> <Formula IVA> Wherein R ⁴ , R ^x , R ² and R ⁵ are as defined in claim 23 and R ^y is a R ^y _a or NH-protecting group as defined in claims 1 and 14 to 16. Cyclization was carried out by reacting the general formula (IV) to convert its primary hydroxyl group into a leaving group to obtain a compound of the general formula (XV), and if necessary, substituting hydrogen for the NH-protecting group R ^y and / or R ⁴ and (or) one or more substitution reactions to change the nature of the substituents of R ^x and (or) R ⁴ and (or) the hydrolysis and (or) an ester group of a carboxylic acid ester of the substituent of the R ^x -OR ⁵ A process for producing a compound according to claim 1 which comprises performing a conversion reaction to -OH. <Formula XIV> <Formula XV> In the formula, R ² , R ⁴ , R ^x and R ^y are as defined in claim 1, and R ⁵ is as defined in claim 23. A compound of formula (II) as defined in claim 23, comprising reacting a compound of formula (VI) with a hindered base under a hindered base to give a compound of formula (VII), wherein the hydrogen bonded to nitrogen is substituted with an NH-protecting group. Process for the preparation of compounds of formula (XIV) as defined in the section. <Formula XIV> <Formula ⅩⅦ> Wherein Z is a leaving group and R ² , R ⁴ , R ⁵ and R ^x are as defined in claim 32. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 19 or 22, optionally together with a pharmaceutically acceptable carrier. 23. A compound according to any one of claims 1 to 19 or 22 for use in a method of treating warm blooded animals. Use of a compound according to any one of claims 1 to 19 or 22 in the manufacture of a medicament for the treatment or prevention of diseases characterized by the stimulation of the GABA _B receptor. A method of treating or preventing a disease in a warm blooded mammal, characterized by stimulation of the GABA _B receptor, comprising administering to a mammal the compound according to any one of claims 1 to 19 or 22.