CA2229036A1 - Substituted phosphinic compounds and their use as pharmaceuticals - Google Patents

Substituted phosphinic compounds and their use as pharmaceuticals Download PDF

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CA2229036A1
CA2229036A1 CA002229036A CA2229036A CA2229036A1 CA 2229036 A1 CA2229036 A1 CA 2229036A1 CA 002229036 A CA002229036 A CA 002229036A CA 2229036 A CA2229036 A CA 2229036A CA 2229036 A1 CA2229036 A1 CA 2229036A1
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compound
formula
group
alkyl
lower alkyl
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Stuart Norman Lile Bennett
Anne Rachel Burton Williams
Wolfgang Frostl
Stuart John Mickel
Nigel Graham Cooke
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Novartis AG
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Priority claimed from GBGB9613047.1A external-priority patent/GB9613047D0/en
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
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Abstract

A compound which is a substituted phosphinic acid of formula (I), or a salt or ester thereof, where R1 is a monovalent aromatic or araliphatic group connected through a carbon atom thereof to the indicated carbon atom, R2 is an unsubstituted or substituted hydrocarbyl group, Rx is hydrogen or an unsubstituted or substituted hydrocarbyl group, Ry is hydrogen, Rya or a NHprotecting group and Rya is an unsubstituted or substituted hydrocarbyl group.

Description

Substituted PhosPhinic Compounds and their Use as Pharmaceuticals This invention relates to chemical compounds which are substituted phosphinic acids or salts or esters thereof, their prepaLration and their use as pharmaceuticals.

In WO 94122843 there are described phosphinic acids of forrnula o ~ N OH

wherc Rl and R~ are both H, Rl and R2 are both methyl or Rl and R2 together with the attached carbon atom are cyclopentyl. These col~lpoullds are said to act as GABAB
antagonists.

It has now been found that compounds having remarkably high GABAB receptor binding affinity can be provided by preparing novel substituted phosphinic acids containing a morpholine ring.

Accordingly, the present invention provides compounds which are substituted phosphinic acids of formula RX>~ ~--P-- R2 RY

or salts or esters thereof, where R1 is a monovalent aromatic or araliphatic group connected through a carbon atom thereof to the in~ir~t~-,cl carbon atom, R2 is an unsubstituted or substituted hydrocarbyl group, Rx is hydrogen or an unsubstituted or substituted hydrocarbyl group, RY is hydrogen, RYa or a NH- protecting group, and RYa is an unsubstituted or substituted hydrocarbyl group.

Rl as an aromatic group may have up to 40 carbon atoms a ld may be an aryl group such as a phenyl, tolyl, xylyl or naphthyl group or a heterocyclic aromatic group such as a thienyl, furyl, indolyl or pyridyl group, which groups may be unsubstituted or substituted by one or more substituents such as halogen, hydroxy, C1 to C4 alkoxy, carboxyl,functionally modified carboxyl inrl~ ng esterified carboxyl, ~mi-l~tP~l carboxyl and cyano, carboxy-C1-C8 alkyl, fllnrtion~lly modified carboxy-Cl-C8 alkyl or nitro.
Preferably, Rl as an aromatic group is an aryl group of 6 to 15 carbon atoms which may be uns--hstitllt~fl or substituted in one or more positions by halogen, carboxyl, functionally m~lifie~ carboxyl, carboxy-Cl-C8 alkyl, functionally modified carboxy-Cl-C8 alkyl or nitro, or Rl as an aromatic group is a 5 to 10-membered heterocyclic aromatic group having one or two nitrogen atoms in the ring system. More preferably, Rl as unsubstituted or substituted aryl is phenyl or phenyl substituted in one or more of the meta and para positions, with respect to the carbon atom thereof linked to the in~lic~t~ll morpholine ring, by halogen, carboxyl, functionally modified carboxyl, or nitro. Examples of suchsubstituted phenyl groups include phenyl mono-or di-substituted by chloro; bromo; iodo;
carboxyl; -CooR3 where R3 is Cl to C8 alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl optionally substituted by halogen, hydroxy or Cl to C4 alkoxy;
carbarnoyl; N-C1-C4 alkyl carbamoyl, such as methyl- or ethyl-carbamoyl, N, N-di(Cl-C4 alkyl) carbamoyl such as dimethyl- or diethyl-carbamoyl; cyano; carboxy-Cl-C4 alkyl such as carboxymethyl; Cl to C8 alkoxy-carbonyl-Cl-C4 alkyl such as methoxy- or ethoxy- carbonylmethyl; carbamoyl-Cl-C4 alkyl such as carbamoylmethyl; N-CI-C4 alkylcarbamoyl-C1-C4 alkyl such as methyl- or ethyl-carba;noylmethyl, N,N-di(Cl-C4 alkyl)carbamoyl-Cl-C4 alkyl such as dimethyl- or diethyl-carbamoylmethyl; cyano-Cl-C4 alkyl such as cyanomethyl; or nitro. More preferably, R1 as a heterocyclic aromatic group is a S to 10-membered heterocyclic group having a nitrogen atom as the only ring hetero atom, e.g. pyridyl or indolyl.

Rl as an araliphatic group may have 7 to 40 carbon atoms and may be phenyl-lower alkyl, for example benzyl or 2-phenylethyl, a, a-diphenyl-lower alkyl such as diphenylmethyl, or a-naphthyl-lower alkyl such as naphthylmethyl, any of which ~roups may be unsubstituted or substituted in one or more positions, which may be ortho, meta or para positions, by a substituent chosen from those hereinbefore specified for Rl as an aromatic group. Preferably, Rl as an araliphatic group is a-phenyl-Cl-C4 alkyl, which is unsubstituted or substituted in one or more positions by halogen, carboxyl, functionally modi~ed carboxyl or nitro.

In especi~lly preferred cc,~ ounds of the invention, Rl 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.

R2 as an unsubstituted or substituted hydrocarbyl group may, in general, have 1 to 40 carbon a~oms. It may be for example an alkyl, cycloalkyl, aL~enyl or alkynyl group or an alkyl, cycloalkyl or alkenyl group substituted by one or more substituents such as halogen, hydroxy, Cl to C~3 alkoxy, thio, Cl to C8 alkylthio, cyano, acylamino, C3 to C8 cycloaL~cyl, C3 to C8 cycloalkyl substituted for example by one or more substit-l~nt~ such as hydroxy, Cl to C8 alkoxy, thio or Cl to C8 alkylthio, C3 to Cg cyclo~lk~nyl,C6 to C15 aryl, C6 to Cls aryl substituted for example by one or more substituents such as hydroxy, Cl to C8 aLkoxy, halogen or trifluoromethyl, het~ a~yl or heteroaryl substituted by one or more substituents such as halogen.

Aliphatic radicals R2 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 aL~cyl.

Cycloaliphatic radicals R2 are, for example, cycloalkyl, hydroxycycloalkyl, oxa, dioxa-, thia- and dithia-cycloalkyl.

Cycloaliphatic-aliphatic radicals R2 are, for example, cycloalkyl-lower alkyl, cyclo-alkenyl-lower aL~cyl, cycloalkyl(hydroxy)-lower alkyl and (lower aLkylthio)cycloalkyl-(hydroxy)-lower alkyl.

Araliphatic radicals R2 are, for example, phenyl-lower alkyl radicals that are unsubstituted or mono-, di- or tri-substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl, preferably a-phenyl-lower alkyl substituted as in~lir~tefl or unsubstituted a,a-diphenyl- or a-naphthyl-lower alkyl.

Heteroarylaliphatic radicals R2 are, for example, thienyl-, furyl- or pyridyl-lower alkyl radicals that are unsubstituted or substituted, especially mono- or di-substituted, by halogen, preferably unsubstituted a-thienyl-, a-furyl- or a-pyridyl-lower alkyl.

Hereinbefore and hereinafter, lower radicals and compounds are to be lln~lerstood, for example, as those containing up to and including 7, preferably up to and in~ Aing 4, carbon atoms.

Lower aLIcyl is, for example, Cl-C7alkyl, preferably Cl-C4alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, but may also be isobutyl, sec-butyl, tert-butyl or a Cs-C7aLIcyl group, such as a pentyl, hexyl or heptyl group.

Lower alkenyl is, for example, C2-C4alkenyl, such as vinyl, allyl or but-2-enyl, but may also be a C5-C7alkenyl group, such as a pentenyl, hexenyl or heptenyl group.

Lower alkynyl is, for exarnple, C2-C7aL~cynyl, preferably C3-CsaL~cynyl, that carries the double bond in a position higher than the a,~-position, for example 2-propynyl (propargyl), but-3-yn- 1 -yl, but-2-yn- 1 -yl or pent-3-yn- 1 -yl.

Oxo-lower alkyl carries the oxo group preferably in a position higher than the a-position and is, for example, oxo-C2-C7alkyl, especially oxo-C3-C6alkyl, such as 2-oxopropyl, 2-or 3-oxobutyl or 3-oxopentyl.

Phenyl-lower aL~yl is, for example, benzyl, l-phenylethyl, 2-phenylprop-2-yl or, in the second place, 2-phenylethyl, 2-phenylprop-1-yl or 3-phenylprop-1-yl.

Thienyl-, furyl- or pyridyl-lower alkyl is, for exarnple, thienyl-, furyl- or pyridyl-methyl, 1-thienyl-, l-furyl- or 1-pyridyl-ethyl, 2-thienyl-, 2-furyl- or 2-pyridyl-prop-2-yl, or, in the second place, 2-thienyl-, 2-furyl- or 2-pyridyl-ethyl, 2-thienyl-, 2-furyl- or 2-pyridyl-prop-1-yl or 3-thienyl-, 3-furyl- or 3-pyridyl-prop-1-yl.

Hydroxy-lower alkyl carries the hydroxy group preferably in the a- or ~-position and is, for example, corresponding hydroxy-C2-C7alkyl, such as 1-hydroxyethyl, 1- or 2-hydroxy-propyl, 2-hydroxyprop-2-yl, l- or 2-hydroxybutyl, l-hydroxyisobutyl or 2-hydroxy-3-methylbutyl.

Dihydroxy-lower alkyl carries the hydroxy groups especially in the a,~-position and is, for example, a"B-dihydroxy-C3-C7alkyl, such as 1,2-dihydroxyprop-2-yl.

Hydroxy-lower alkenyl carries the hydroxy groups preferably in the a-position and the double bond preferably in a position higher than the a,~-position and is, for example, c~ yonding a-hydroxy-C3-Csalkenyl, for example l-hydroxybut-2-enyl.

Mono-, di- or poly-halo-lower alkenyl is, for exarnple, mono- di- or t~i-fluoro-C2-Cs-alkenyl, such as l-fllloro~ut-2-enyl.

Mono-, di- or polyhalo(hydroxy)-lower alkyl carries the hydroxy group preferably in the a-position and the halogen atoms preferably in a position higher than the a-position and is, for example, corresponding mono- di- or tri-fluoro-cx-hydroxy-C2-C7alkyl, such as 4,4,4-~ifluoro- 1-hydroxybutyl.

Mono-, di- or poly-halo-lower alkyl is, for example, mono- di- or tri-fluoro-c2-c5aL~yl~
such as 3,3,3-trifluoLupiupyl, 4,4,4-trifluorobutyl, 1- or 2-fluorobutyl or l,l-difluorobutyl.

Lower alkoxy is, for exarnple, C1-C7alkoxy, preferably Cl-C4aLt~oxy, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy, but may also be isobutoxy, sec-butoxy, tert-butoxy or a Cs-C7alkoxy group, such as a pentyloxy, hexyloxy or heptyloxy group.
Acylamino-lower aLkyl is, for exarnple Cl-C4 alkylcarbonylamino-CI-C4 alkyl such as acetylarninopropyl or C6-C10 arylcarbonylamino-CI-C4 aL~cyl such as benzoylaminomethyl.

Cyano-lower aL~cyl is, for exarnple cyano-CI-C4 alkyl, such as cyanomethyl or 2-cyanoethyl.

Mono-, di- or poLy-halo(hydroxy)-lower aLkenyl ca~ies the hydroxy group preferably in the ~ positlon and the halogen atoms preferably in a position higher than the a-position and is, for example, corresponding mono-, di- or tri-fluoro-oc-hydroxy-C2-CsaLkerlyl, such as 2-fluoro-1-hydroxybu~en-2-yl.

Lower aLkoxy-lower aLkyl is, for example, Cl-C4aLkoxy-C~-C4alkyl, such as methoxy- or ethoxy-methyl, 2-methoxyelhyl, 2-ethoxyethyl, 3-methoxy- or 3-ethoxy-propyl or 1- or 2-methoxybutyl.

Di-lower alkoxy-lower alkyl is, for example, di-CI-~-alkoxy-CI-C4alkyl, for example dimethoxymethyl, dipropoxymethyl, 1,1- or 2,2-diethoxyethyl. diisopropoxymethyl,dibutoxymethyl or 3,3-dimethoxypropyl.

Lower alkoxy~hydroxy)-lower alkyl is, for exarnple, Cl-c4aLlcoxy-c2-cr(hydroxy)aLk such as 2-hydroxy-3-methoxyprop-2-yl.

Lower alkoxy(halo)-lower alkyl is, for example, Cl-C4alkoxy-C2-Cs-(halo)aLlcyl, such as 2-fluoro-3-methoxybutyl.

Lower alkylthio-lower alkyl is, for example, Cl-C4alkylthio-CI-C4alkyl, such as methyl-thio- or ethylthio-methyl, 2-methylthioethyl, 2-ethylthioethyl, 3-methylthio- or3-ethylthio-propyl or 1- or 2-methylthiobutyl.

Di-lower alkylthio-lower alkyl is, for example, di-CI-C4alkylthio-Cl-C4alkyl, for example dimethylthiomethyl, dipropylthiomethyl, 1,1- or 2,2-diethylthioethyl, diisopropylthio-methyl, dibutylthiomethyl or 3,3-dimethylthiopropyl.

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

Cycloalkyl is, for example, C3-C8cycloalkyl, especially C3-C6cycloalkyl, such as cyclo-propyl, cyclobutyl, cyclopentyl or cyclohexyl.

Hydroxycycloalkyl is, for example, a-hydroxy-C3-C6cycloaL~yl, such as 1-hydroxycyclo-propyl, 1-llyd~o~ycyclobutyl or 1-hydroxycyclohexyl.

Oxa- or thia-cycloalkyl is, for example, oxa- or thia-C3-C8cycloalkyl, especially oxa- or thia-C3-C6cycloalkyl, such as 2-oxacyclopropyl (oxiranyl), 2- or 3-oxacyclobutyl (oxetan-yl), 2- or 3-thiacyclobutyl (thietanyl), 2- or 3-oxacyclopentyl (tetrahy~lluful~nyl), 2- or 3-thiacyclopentyl (thiolanyl) or 2-oxacyclohexyl (tetrahydropyra~nyl).

Dioxacycloalkyl is, for example, 1,3-dioxa-C3-C8cycloaL~cyl, such as 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl.

Dithiacycloalkyl is, for example, 1,3-dithia-C3-C8cycloalkyl, such as 1,3-dithiolan-2-yl or 1,3-dithian-2-yl.

Cycloalkyl-lower alkyl is, for example, C3-C8-cycloalkyl-Cl-C4alkyl, especially C3-C6-cycloalkyl-Cl-C4alkyl, such as a-(C3-C6cycloalkyl)-Cl-C4alkyl, for example cyclopropyl-methyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

Cycloalkenyl-lower alkyl is, for example, C3-C8cycloalkenyl-Cl-C4alkyl, especially C3-C6cycloalkenyl-Cl-C4a'lkyl1 such as a-(C3-C6cyclo~lk~1lyl)-cl-c4alkyL for example cyclopent-1-enylmethyl, cyclopent-2-enylmethyl, cyclopent-3-enylmethyl, cyclohex-1-enyl rmethyl, cyclohex-2-enylmethyl or cyclohex-3-enylmethyl.

..
CycloaLkyl(hydroxy)-lower alkyl is, for example, C3-C6cycloalkyl-C~-C4(hydroxy)alkyl, such as ~c-(C3-C6cycloalkyl)-a-hydroxy-CI-C4a'lkyl, for example cyclopropyl(hydroxy) methyl, cyclobutyl(hydroxy)methyl, or cyclohexyl(hydroxy)methyl.

(Lower alkylthiocycloalkyl)(hydroxy)-lower alkyl is, for example, 1-(Cl-C4alkylthio-C3-C6cycloalkyll-l-hydroxy-CI-C4alkyl, such as (2-methylthiocycloprop-1-yl)hydroxy-methyl.

In plcfG~lGd compounds of the invention, R2 is lower alkyl, lower alkenyl, lower alkynyl, oxo-lower alkyl, hydroxy- or dihydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di- or poly-halo-lower a~kyl, mono-, di- or poly-halo-lower alkenyl, mono-, di- or poly-halo-(hydroxy)-lower alkyl, mono-, di- or poly-halo(hydroxy)-lower alkenyl, lower aLlkoxy-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-7 dioxa-, thia- and dithia-cycloalkyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl, cycloalkyl-(hydr~xy)-lower alkyl, (lower alkylthio)cycloalkyl(hydroxy)-lower alkyl, or mono- or di-phenyl-lower aLkyl that is unsubstituted or mono-, di- or tri-substituted by lower alkyl, lower alkoxy, halogen, hydroxy and/or by trifluoromethyl, naphthyl-lower alkyl or unsub-stituted or halo-substituted thienyl-, furyl- or pyridyl-lower alkyl.

In more preferrel1 compounds of formula I, R2 is C1-C7alkyl, such as methyl, ethyl, propyl, isopropyl, butyl isobutyl or pentyl, a,a-di-C1-C4alkoxy-Cl-C4alkyl, especially a,a-di-Cl-C4aLcoxy-methyl or ethyl, such as dimethoxy- or diethoxy-methyl or 1, l-dieehoxyethyl, cyano-C1-C4 alkyl such as cyanomethyl or 2-cyanoethyl, acylamino-Cl-C5 aL~yl such as acetyl:lminoethyl, acetylaminopropyl, acetylaminopentyl or benzoylaminomethyl, C3-C6cycloalkyl-C1-C4alkyl, such as cyclopropyl- or cyclo-hexyl-methyl, C.,-C6cyclo~1kt-nyl-C1-C4aLcyl, such as cyclohex-3-enylmethyl, or is phenyl-C1-C4alkyl, such as benzyl, that is unsubstituted or mono-, di- or tri-substituted by C1-C4alkyl, such as methyl, C1-C4alkoxy, such as methoxy, hydroxy and/or by halogen, such as fluorine, chlorine or iodine.

In more preferred compounds of the invention, R2 is C1-C5 alkyl such as methyl, ethyl or butyl, a,o~-di-(CI-C4 alkoxy)methyl such as diethoxymethyl, a,a-di-(Cl-C4 aL~coxy)ethyl such as 1, 1-diethoxyethyl, C3-C6 cycloalkyl-Cl-C4 aLkyl such as cyclopropylmethyl or cyclohexylmethyl, benzyl or 4-methoxybenzyl. In especially preferred compounds, R2 is cyclohexylmethyl or 4-methoxybenzyl.

Rx as an unsubstituted or substituted hydrocarbyl group may have up to 40 carbon atoms and may be a Cl to C10 alkyl, C2 to C10 alkenyl, C3 to C8 cycloaL~cyl, C4 to C13cycloalkylalkyl, C6 to C1O aryl or C7 to C13 aralkyl group, any of which groups may be substituted by one or more subsliLuc--ls chosen from those hereinbefore specified for Rl.
Preferably R~ is hydrogen, lower alkyl, C3 to C6 cycloalkyl, C6 to C8 aryl or C7 to Cg aralkyl, especially hydrogen or isopropyl.

RY as an unsubstituted or substituted hydrocarbyl group RYa may have up to 40 carbon atoms and may be, for exarnple, a Cl to C10 alkyl, C3to C8 cycloaLkyl or C7to C~3 araL~cyl group, any of which groups may be unsubstituted or substituted by hydroxy or Cl to C4 aL~oxy. RY as a NH-protecting group may be, for example, an acyl group such as acetyl, trifluoroacetyl, benzoyl or p-nitrobenzoyl or an aL~oxycarbonyl or aralkoxycarbonyl group such as tert-butoxycarbonyl or benzyloxyc~l,onyl. Preferably RY is hydrogen, lower alkyl, C7 to Cg aralkyl, acetyl, benzoyl, tert-butoxycarbonyl or benzyloxycarbonyl, especially hydrogen, methyl, ethyl, benzyl, acetyl, benzoyl, tert-butoxycarbonyl or benzyloxycarbonyl.

Specific especially ~l~re..~,d compounds of the invention are those of formula I in which Rl is phenyl, 3-iodophenyl, 3, 4-dichlorophenyl, 3-cyanophenyl, 3-(methoxycarbonyl)phenyl, 3-carboxyphenyl, 3-nitrophenyl, benzyl, 4-iodobenzyl,4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl, R2 is cyclohexyimethyl or4-methoxybenzyl, Rx is hydrogen or isopropyl and RY is hydrogen, methyl or benzyloxycarbonyl, and salts and esters thereof.

The compounds of formula I may be in the form of internal salts and can 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, their pharmaceutically acceptable salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example meth~neslllfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylslllf~ tes (cyclamates).

Salts of compounds of formula I with bases are, for example, their salts with ph~Tn~reut-ically acceptable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb, for example aL~ali metal salts, especially sodium or potassium salts. ~lk~linf~.
earth metal salts, especially c~lri-lm or m~En~sil~m salts, and also ammonium salts with ammonia or organic amines or quaternary ammonium bases, such as unsubstituted orC-hydroxylated aliiphatic ~minÇs7 especially mono-, di- or tri-lower alkyl~minPs, for example methyl-, ethyl- or diethyl-amine, mono-, di- or tri-(hydroxy-lower alkyl)~min~s, such as ethanol-, diethanol- or trieth~nQl-amine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower alkyl~minPs or N-(polyhydroxy-lower aL~cyl)-lower aL~cyl~m;nes, such as 2-(dimethylamino)ethainol or D-gluc~mine7 or quaternary aliphatic ammonium hydroxides, for example tetrabutyl-ammonium hydroxide.

As well as forming salts with bases, the hydroxy group ~tt~rhefl to phosphorus in formula I may also be esterified. Thus, the invention infl~ s compounds of formula I in the form of their esters with an alcohol, which may be a Cl to C10 aLkanol in which the a~kyl radical is unsubstituted or substituted, for example by halogen, cyano or Cl to C4 alkoxy, such as methanol, ethanol, isopropanol, isobutanol, 2-ethylhexanol, 2-chloroethanol, 2-cyanoethanol, 2;-ethoxyethanol or 2-n-butoxyethanol, a C3 to C8 cycloaliphatic alcohol such as cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol,methylcyclohexanol or cyclooctanol, or a C7 to Cl3 araliphatic alcohol such as benzyl alcohol.

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

I~crc~l~d isomers of compounds of formula I are those in which Rl and the group ~tt~ch~-l to the 2- position of the in-1ir~te-1 morpholine ring are trans with respect to each other,i.e.
those of formula O

R~ R2 J I ~A) ~ - N OH
Rl RY

or of fonnula RX ~ ~ P R2 ~ N J OH (E-) where R1, R2, Rx and RY are as hereinbefore defined.

Other preferred isomers of formula I are those in which Rl and the group ~t~rhell to the 2-position of the indicated morpholine ring are cis with respect to each other, i.e. those of formula ~ ...""'~11 ~ N ) P R2 (IC) Rl RY OH
or of formula RX j~ ~--P R2 Rl Nl ¦ (ID) RY OH
where Rl, R2, Rx and RY are as hereinbefore clefinecl Examples of specific compounds of formula I are 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)hydroxyphosphinoyl-methyl]morpholin-3-yl } benzoic acid, 3-[(3R*,6R*)-6-(butylhydroxyphosphinoylmethyl)-W O 97/0~335 PCT/G1396/02113 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*,SR*)-5-[(3-methoxycarbonyl)phenyl]-morpholin-2-ylmethyl } phosphinic acid, cyclohexylmeth yl-[(2R*,SR*)-5-phenylmorpholin-2-ylmethyl]-phosphinic acid, diethoxymethyl [(2R*,5R*)-5-(3-nitrophenyl)-morpholin-2-ylnnethyl]phosphinic acid, butyl-[(2R*,SRY )-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, cyclohexylmeth yl-[(2R*,5R*)-5-(3,4-dichlorophenyl)-morpholin-2-ylnnethyl]phosphinic acid, butyl-[(2R*,5R*)-5-(3,4-dichlorophenyl)morpholin-2-ylmethyl]-phosphinic acid, benzyl-L(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-methoxyphenyl-methylphosphinic acid, 4- { (3R~',6R*)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl]-morpholin-3-ylrneehyl } benzoic acid, 4- { (3R*,6R*)-6-[(4-methoxyphenylmethyl)hydroxyphospinoyl-methyl]morpholin-3-ylmethyl } benzoic acid, ' 4-[(3R*,6R*)-6- (benzylhydroxyphosphinoylmethyl)-morpholin-3-ylrnethyl]benzoic acid, 4-[(3R*,6R*)-6- (bul:ylhydroxyphosphinoylmethyl)morpholin-3-ylmethyl]benzoic acid, 4- { (3R*,6R*)-6-[(diethoxymethyl)hydroxyphosphinoylmethyl]-morpholin-3-ylmethyl } benzoic acid, cyclohexylmethyl- [(2R* ,SR*)-5-(4-iodobenzyl)morpholin-2-ylmethyl]phosphinic acid, [(2R*,SR*)-5-(4-iodobenzyl3morpholin-2-ylmethyl] -4-methoxyphenylmethylphosphinic acid, cyclohexylmethyl- { (2R*,5R*)-5-[4-ethoxycarbonyl)-phenylmethyl]mo;pholin-2-ylmethyl] phosphinic acid, 4-[(3R*,6R*)-6-(butylhydroxyphosphinoylmethyl)-N-methyl-morpholin-3-ylmethyl]benzoic acid, 4- { (3R*,6R*)-6-[(cyclohexylmethyl)hyd;oxyphosphinoylmethyl]-N-benzyloxycarbonylmorpholin-3-ylmethyl } benzoic acid, 3- { (3R*,6R*)-[(5-acetylaminopentyl)hydroxyphosphinoyl-methyl]-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-(benzylhyd;oxyphosphinoylmethyl) -3-methylmorpholin-3-yl]benzoic acid, 3- { (3R*,6R*)-6-[(4-methoxyphenylmethyl)hydroxyphosphinoyl-methyl]-3-methylmorpholin-3-yl } benzoic acid, 3- { (3R*,6R*)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl]-3-methylmorpholin-3-yl } benzoic acid, S-acetylaminopentyl-[(2R*,SR*)-5-(6-oxo- 1 ,6-dihydropyridin-3-yl)-morpholin-2-ylmethyl]phosphinic acid, cyclohexylmethyl-[(2R*,5R*)-5-(6-oxo- 1 ,6-dihydropy;idin-3-yl)-morpholin-2-ylmethyl]-phosphinic acid, butyl-~(2R*,5R*)-5-(6-oxo- 1 ,6-dihydropyridin-3-yl)moipholin-2-ylmethyl]phosphinic acid, benzyl-[(2R*,5R*)-5-(6-oxo- 1 ,6-dihydropyridin-3-yl)mo~pholin-2-ylmethyl]phosphinic acid, 4-methoxyphenylmethyl-[(2R*,SR*)-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, W O 97/0933S PCT/G]B96/02113 cyclohexylmethyl-[(2R*,SR*)-5-(2-oxo- 1 ,2-dihydropyridin-4-yl)-morpholin-2-ylmethyl]phosphinic acid, S-acetylaminopentyl-[(2R*,5R*)-5-(2-oxo-1,2-dihydropy;idin-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*,SR*)-5-(2-oxo- 1 ,2-dihydropyridin-4-yl)-morpholin-2-ylmethyl]phosphinic acid, benzyl-[(2R*,5R~*)-5-(2-oxo- 1,2-dihydropy;idin-~yl)morpholin-2-ylmethyl]phosphinic acid, 4-methoxyphenylmethyl-[(2R*,5R*)-5-(2-oxo- 1 ,2-dihyd;opyridin-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-(benzylhyd;oxyphosphinoylmethyl)morpholin-3-ylmethyl]benzoic acid, 3- { (3R*,6R*)-6 -[(cyclohexylmethyl)hydroxyphosphinoylmethyl]-morpholin-3-ylmethyl } benzoic acid, 3- { (3R*,6R*)-6 -[(4-methoxyphenylmethyl)hydroxyphosphinoyl-methyl]morpholin-3-ylmethyl } benzoic acid, ~ 3- { (3R*,6R*)-6 -[(diethoxymethyl)hydroxyphosphinoylmethyl]-mo~pholin-3-yln:lethyl } benzoic acid, 3- { (3R*,6R*)-6 -[(S-acetylaminopentyl)hydroxyphosphinoylmethyl]-morpholin-3-yln;lethyl } benzoic acid, 3-[(3R*,6R*)-6- (butylhydroxyphosphinoylmethyl)morpholin-3-ylmethyl]benz:oic acid, 3-[(3R*,6R*)-6-(benzylhydroxyphosphinoylmethyl)morpholin-3-ylmethyl]benzoic acid, benzyl- ( (2R*,5R*)-5-[4-([ 1 ,3,4]o7c~ 7r 1 -2-yl)phenyl]morpholin-2-ylmethyl}phosphinic acid, butyl- { (2R*,5R*)-5-[4-(5-trifluoromethyl-[ 1 ,2,4]ox~ 7--1-3-yl)-phenyl] morpholin-2-ylmethyl } phosphinic acid, 1-(4- { (3R*,6R*)-6-[(4-methoxybenzyl)hydroxyphosphinoylmethyl]-morpholin-3-yl}phenyl)-lH-rl,2,4]triazole-3-carboxylic acid, { (2R*,SR*)-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]o~ 7nl-5-yl)phenyl]morpholin-2-ylmethyl } cyclohexylmethylphosphinic acid, diethoxymethyl- { (2R*,5R*)-5-[3-(lH-tetrazol-5-yl)phenyl]morpholin-2-ylmethyl}phosphinic acid, 3- { (3R*,6S*)-6-[(5-acetylaminopentyl)hydroxyphosphinoyl-methyl]morpholin-3-yl}benzoic acid, 3- { (3R* ,6S *) -6- [(cyclohexylmethyl)hydroxyphosphinoylmethyl] -morpholin-3-yl } benzoic acid, 3-~(3R*,6S*)-6-[(4-methoxyphenylmethyl)hydroxyphosphinoyl-methyl]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*,SS*)-S-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*,SS*)-5-(3-cyanophenyl)morpholin-2-ylmethyl]phenyl-methylphosphinic acid, S-acetylaminopentyl-[(2R*, 5S*)-5-(3,4-dichlorophenyl)-morpholin-2-ylmethyl]phosphinic acid, :

W O 97/0933~ PCT/GB96/02113 cyclohexylmethyl-[(2R*,SS*)-5-(3,4-dichlorophenyl)-morpholin-2-ylmethyl]phosphinic acid, butyl-[(7R*,SS * )-5-(3,4-dichlorophenyl)-morpholin-2-ylmethyl]phosphinic acid, benzyl-[(2R*,5S *)-5-(3,4-dichlorophenyl)-morpholin-2-ylmethyl]phosphinic acid, [(2R*, SS*)-5-(3,4-dichlorophenyl)morpholin-2-ylmethyl]pyridin-2-ylmethylphosphinic acid, [(2R*,5S *)-5-(3 ,4-dichlorophenyl)morpholin-2-ylmethyl]-diethoxymethylphosphinic acid, [(2R*,5S *)-5-(3 ,4-dichlorophenyl)morpholin-2-ylmethyl] -4-methoxy-phen.ylmethylphosphinic acid, [(2R*,SS *)-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)hydroxyphospinoyl-methyl]morpholin-3-ylmethyl } benzoic acid, 4-[(3R*,6S *)-6-(benzylhydroxyphosphinoylmethyl)morpholin-3-ylmethyl]benz:oic acid, 4-[(3R*,6S*)-6-(butylhydroxyphosphinoylmethyl)morpholin-3-ylrnethyl]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*,SS*)-5-(4-iodobenzyl)morpholin-2-ylmethyl]-4-methoxyphenylmethylphosphinic acid, cyclohexylmethyl- 1 ~2R*,5S*)-5-[4-ethoxycarbonyl)phenyl-methyl]morpho].in-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)hydroxyphosphinoyl-methyl] -3-meth ylmorpholin-3-yl } benzoic acid, 3-{(3R*,6S*)-6-[(diethoxymethyl)hydroxyphosphinoylmethyl]-3-methylmorpholin-3-yl } benzoic acid, 3-[(3R*,6S*)-6-(butylhydroxyphosphinoylmethyl)-3-methyl-morpholin-3-yl]benzoic acid, 3-[(3R*,6S *)-6-(benzylhydroxyphosphinoylmethyl)-3-methyl-morpholin-3-yl]benzoic acid, 3- ~ (3R*,6S *)-6-[(4-methoxyphenylmethyl)hydroxyphosphinoyl-methyl]-3-methylmorpholin-3-yl } benzoic acid, 3- { (3R*,6S*)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl]-3-methylmorpholin-3-yl ~ benzoic acid, 5-acetylaminopentyl-[(2R*,SS*)-5-(6-oxo- 1 ,6-dihydropyridin-3-yl)-morpholin-2-ylmethyl]phosphinic acid, cyclohexylmethyl-[(2R*,SS *)-5-(6-oxo- 1 ,6-dihydropy;idin-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-dihydropy;idin-3-yl)mo;pholin-2-ylmethyl]phosphinic acid, 4-methoxyphenylmethyl-[(2R*,5S*)-5-(6-oxo- 1 ,6-dihydropy;idin-3-yl)morpholin-2-ylmethyl]phosphinic acid, diethoxymethyl-[(2R*,SS *)-5-(6-oxo- 1 ,6-dihydropyridin-3-yl)-morpholin-2-ylmethyl]phosphinic acid, cyclohexylmethyl-[(2R*,SS*)-5-(2-oxo- 1,2-dihydropyridin-4-yl)-morpholin-2-ylmethyl]phosphinic acid, 5-acetylaminopentyl-[(2R*,SS *)-5-(2-oxo- 1 ,2-dihydropy;idin-4-yl)-morpholin-2-ylmethyl]phosphinic acid, butyl-[(2R*,SS *)-5-(2-oxo- 1 ,2-dihydropyridin~-yl)morpholin-2-ylmethyl]phosphinic acid, diethoxymethyl-[(2R*,SS*)-5-(2-oxo- 1,2-dihyd;opy;idin-4-yl)-mo;pholin-2-ylmethyl]phosphinic acid, benzyl-[(2R*,SS *)-5-(2-oxo- 1 ,2-dihydropy;idin-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]-W O 97/0~335 PCT/G1396/02113 morpholin-3-ylrnethyl } benzoic acid, 2- { (3R*,6S *)-6- [(diethoxymethyl)hydroxyphosphinoylmethyl] -morpholin-3-ylrnethyl } benzoic acid, 2- { (3R It,6S*)-6--t(5-acetylaminopentyl)hydroxyphosphinoylmethyl]-morpholin-3-ylrnet,hyl } 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]-morphc,lin-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*,SS*)-5-[4-([1,3,4]oxadiazol-2-yl)phenyl]morpholin-2-ylmethyl}phosphinic acid, butyl- { (2R*,5S ~)-5-[4-(5-trifluoromethyl-[ 1 ,2,4]o~ 7nl -3-yl)-phenyl}morpholin-2-ylmethyl } phosphinic acid, 1-(4- { (3R*,6S*)-6-t(4-methoxybenzyl)hydroxyphosphinoylmethyl]-morpholin-3-yl ~ phenyl)- lH-[ 1 ,2,4]triazole-3-carboxylic acid, { (2R*,5S*)-5-[4-(3-amino-[1,2,4]oxadiazol-5-yl)phenyl]morpholin-- 2-ylmethyl } cyclohexylmethylphosphinic acid, { (2R*,5S*)-5-[3-(3-arnino-[1 ,2,4]oxadiazol-5-yl)phenyl]morpholin-~ 2-ylmethyl } cyclohexylmethylphosphinic acid, diethoxymethyl-{(2R*,SS*)-5-[3-(lH-tetrazol-5-yl)phenyl]morpholin-2-ylmethyl } phosphinic acid.

It has been found that the compounds of formula I and their pharm~re~ltic~lly acceptable salts have valuable pharmacological p,o~ ies. They exhibit an effective binding to the GABAB receptor and have been found to be antagonists of GABA (~-aminobutyric acid) at that receptor. With regard to the mççh~nicm, antagonism at GABAg ,~cepl~ . can increase the release of rapid stimulant amino acid tr~ncmittprs~ that is to say, ~lnt~m~te and aspartate, and thus improve information processing in the brain. This is in keeping with the finding that the late post-synaptic inhibition potential in the hippocampus, which is attributed to a GABAB mech~nicm, is broken down by the ~nt~gonictC and thus permits a faster nerve impulse tr~ncmicsiQn sequence.

It has also been found that chronic tre~tm~nt with anti-depressants and repeated electric shocks increase the number of GABAB receptors in the cerebral cortex of rats. In accord-ance with receptor theories, chronic treatment with GABAB antagonists should have the sarne effect. For this and other reasons, GABAB antagonists can accordingly act as anti-depresc~ntc The GABAB antagonists according to the invention interact at the GABAB ~~,ce~lul with IC50 values from 10-7 to 10-1~M (mole/litre) on cerebral cortex membranes of rats. In contrast to GABAB agonists, such as baclofen, they do not potentiate the stimulation by noradrenalin of adenylate cyclase on sections of the cerebral cortex of rats but act as antagonists of the baclofen action. The antagonists not only exhibit ~nt~gonicm tow~ds baclofen but also have an independent action as antagonists of endogenous GABA.

In view of their excellent GABAB antagonistic lJ~u~e- Lies, the compounds of the invention are suitable for use in the treatment or prevention of conditions characterised by stimulation of GABAB receptors. Thus they are suitable for use as nootropics, antidepressants and anxiolytics, for example in the treatment of central nervous system disorders such as anxiety, depression, cerebral insufficiency, epilepsy of the "petit mal"
type, i.e. absence epilepsy in children and adolescçntc, atypical absences such as the Lennox-Gastant syndrome, in the treatment of conditions requiring enh~nrernent of cognitive l clro,l--ance and as an antidote to baclofen.

Compounds of formula I where RY is hydrogen may be prepared by reacting a compound of formula OH

R
R4 / \MH2 where R4 is R1 as hereinbefore defined except that R4 may not be substituted by carboxyl, and Rx is as hereinbefore defined except that it may not be substituted by carboxyl with a compound of folmula X /\ ll R2 m where R2 is as hereinbefore f1efin~-1 X is halogen, e.g. chlorine or bromine, and Rs is Cl to C8 alkyl, e.g. n-hexyl, n-octyl, preferably Clto C4 alkyl such as methyl, ethyl, isopropyl or isobutyl, especially ethyl, in the presence of a base, to give a compound of forrnula RX~ ~ l l R2 ~ IV

where ~4 and R~ are as defined in formula II, followed, where required, by one or more substitution reactions to change the nature of a substituent in R4 and/or Rx andlor by hydrolysis of an ester substituent in R4 and/or RX to carboxyl and/or by conversion of the ~ ester group -oR5 to -OH.

- By alJ~ iate selection of the base and reaction conditions, the reaction of compounds of formulae II and rII, which proceeds by monoalkylation of the amino group followed by cycli~tion, may be effected in a one-step procedure. Preferably, to avoid complit~tions resul~ing from dialkylation of the amino group, the reaction is carried out in two stages. In the first stage, a weak base, for example a hindered amine such as 1, 8-diazabicyclo~5.4.0]undec-7-ene (DBU) is added slowly to a mixture of the W O 97/0933~ PCT/GB96/02113 compounds of formulae II and III in a solvent, preferably a hydrocarbon such as benzene, toluene or xylene, at a tel.lp~,lature of 70 to 110~C, to give a novel intermeAi~tP product of formula R

where R2, R4, R5 and Rx are as hereinbefore defined. This interme~ t~ is then treated with a base under harsher conditions than those employed in its formation, for example with a similar base at a higher temperature or, preferably, with a stronger base such as an a~cali metal hydride at a temperature from 10 to 50~C. The treatment of the intermediate with base may be carried out in a solvent, preferably a hydrocarbon such as toluene, benzene or xylene.

Interrne~ te compounds of formula V may also themselves be used as pharmaceuticals, for example in the treatment or prevention of a condition characterised by stimulation of a GABAB receptor, particularly in de-esterified form, i.e. where Rs as aL~yl has been replaced by hydrogen and any carboxylic ester group in R4 and/or Rx has been converted into a carboxyl group. Accordingly, the invention includes novel compounds of formula OH

RX ~ ¦ VA

Rl N ~ P R2 H

OH
where Rl, R2 and Rx are as hereinbefore defined, or salts or esters thereof.

Compounds of formula I or IV in which Rx and/or Rl or R4 respectively con~ins a cyano substituent on an aryl or heteroaryl ring may be prepared by reacting an aL~cali metal cyanide with a compound of formula I or IV where Rx and/or Rl or R4 respectivelycontains a halogen substituent on an aryl or heteroaryl ring, which compound may be pre~ed by diazotisation, followed by reaction with an aL~ali metal halide, of a co~ oul~d of formula I or IV where Rx and/or Rl or R4 respectively contains an amino group on an aryl or heteroaryl ring, which compound may be prepared by re~ ction of a compound of formula I or IV in which Rx and/or R1 or R4 respectively contains a ni~o group on an aryl W O 97/0~335 PCT/G1396/02113 or he~eroaryl ring. All of these reactions can be effected using known procedures.

Compounds of f~rmula I or IV in which Rx and/or R1 or R4 respectively cQnt:~inc an esteriifled carboxyl substituent can also be prepared from other compounds of formula I or IV respectively. For example, they may be prepared by reacting a compound of forrnula I
or IV in which Rx and/or Rl or R4 respectively contains a halogen substituent on an aryl or hete~u~yl ring vvith carbon monoxide and an alcohol in the presence of a p~ m complex as cata]lyst, using known procedures.

Compounds of formula I in which Rx and/or Rl cont~inc a carboxyl substituent may be d by hydrolysis of a compound of forrnula I or IV in which Rx and/or Rl or R4 respectively contains an esterified carboxyl substituent using conventional hydrolysis procedures.

Where, in a compound of formula IV or V, R4 cont~inc an esterified carboxyl group, this may be hydrolysed to a free carboxyl group using conventinn~l methods. Where R4 in the compound of fo:rmula IV contains a nitro group on an aryl or hetclua-yl ring, this group may be converted in turn to amino by reduction, to halo by diazotisation of arniino followed by reaction with an alkali metal halide, to cyano by reaction of halo ~ith an alkali metal cyanide and thence to carboxyl by hydrolysis of cyano, these reactions conveniently be ing carried out using known procedures.

The conversion of the ester group -ORs in a compound of formula IV or V into -OH can be effected by tre~tment with a suitable basic or acidic agent, such as an alkali metal hydroxide, for example sodium hydroxide or lithium hydroxide, an alkali metal halide, especia]ly an aLkali metal bromide or iodide, such as lithium bromide or sodium iodide, thiourea, an alkali metal thiophenolate, such as sodium thiophenQl~t~. or a protonic acid or a Lewis acid, such as a mineral acid, for example hydrochloric acid, or a tri-lower alkyl-halosilane, for example trimethylchlorosilane. rhe replacement reaction can be effected in the absence or presence of a solvent and, if necessary, with heating or with cooling in a closed vessel and/or under an inert gas atmosphere.

The conversion of -oR5 in a compound of formula IV or V into -OH can also be carried out by treatmenlt with an acid under hydrolytic conditions, especially with a mineral acid, such as a hydrohalic acid, for example hydrochloric acid, which is used in dilute or concentrated aqueous form, or by treatment with an organic silyl halide, such astrimethylsilyl iodide or bromide, and, if necessary, by subsequent hydrolysis. The reaction is preferably calTied out at elevated temperature, for example by m~inr~ining the reaction W O 97/09335 PCT/GB9~/02113 mixture at reflux te~llpc.dtul~, and, where appropriate, using an organic diluent in a closed vessel and/or under an inert gas atmosphere.

Compounds of formula II are in some in~t~nres commçrcially available, e.g. (R) - and (S) - phenyl glycinols. Compounds of formula II may be prepared by re~ ction of an ~minoc~rboxylic acid of formula R4C(RX)(NH2)CooH, where R4 and R~ are as hereinbefore defined in formula II, by reaction with borane dimethyl sulphide in the presence of a boron trifluoride complex such as boron trifluoride diethyl etherate. This reaction may be carried out using known procedures. Novel colll~oullds of formula II, where (i) R4 is iodobenzyl, particularly 4-iodobenzyl, and R~ is hydrogen and (ii) R4 is phenyl and Rx is isopropyl, may be prepared by this method.

The compounds of formula II where R4 is substituted by nitro may be ~Icp~,d from an aminocarboxylic acid of formula R4C(RX)(NH2)CooH where R4 is otherwise unsubstituted by nitration to introduce a nitro group into R4, converting the amino group in the product into a protected amino group, for example by reaction with di-tert-butyl dicarbonate to form a tert-butylcarbamate group, esterifying the carboxyl group in the proL~ Gd product for example by conversion into a methyl ester, then reducing the ester group to -CH20H by treatment with an ~ u~liate reducing agent such as an alkali metal borohydride and finally removing the amino-protecting group by tre~tment with acid to re-form a free amino group. These reactions may be carried out using known procedures or minor mo lific~tions thereof. The known compound of forrnula II where R4 is nitrophenyl may be prepared by such a reaction sequence.

Compounds of formula II may also be prepared by a Strecker synthesis in which analdehyde or ketone of fo;mula R4C(=o)RX, where R4 and Rx are as hereinbefore ~lefin~l is reacted with a compound of formula R6NH2, where R6 is hydrogen or an alkyl group of 1 to 8 carbon atoms optionally substituted by a C6 to C10 aryl group which is unsubstituted or substituted, for example by hydroxy or Cl to C4 alkoxy, and an alkali metal cyanide to give a compound of formula CN

VI

where R4, R6 and Rx are as hereinbefore clefin~-l, reacting the compound of formula VI

W O 97/0~33~ PCT/GB96/02113 with an alcohol of forrnula R70H, where R7 is an alkyl group of 1 to 10 carbon atoms, e.g.
n-hexyl, 2-ethylhexyl, n-octyl or decyl, preferably Clto C4 alkyl such as methyl, ethyl, isopropyl or n-butyl, especially methyl or ethyl, in the presence of an acid to form a compound of folmula CooR7 R4 ¦ - NHR6 V~

where R4, R6, R 7 and Rx are as hereinbefore de~med, removing R6, when this is other than hydrogen, from ~he compound of formula VII using, for exarnple, known procedures to give a compound of formula CoOR7 V~

I X
where R4, R7 and Rx are as hereinbefore fl~fin~-l, for exarnple, where R6 is an optionally substituted benzyl group, by catalytic hydrogen~tion in the presence of an organic acid, e.g. acetic acid, l:o give a compound of formula VIII in the form of a salt the;eof with the organic acid, reacting the compound of formula VIII with an amino-protecting agent such as tert-butyl dicarbonate to convert the amino group into a protected amino group, reducing the ester group -CooR7 in the ~l~.t~lt;d compound to-CH2OH by reaction with an ap~ liate re~ cing agent such as an aLkali metal borohydride, and finally removing the protecting group to form a free amino group. This sequence of reactions may be carried out using known procedures, or minor moriific~tion~ thereof. Where R4 issubstituted by a carboxylic ester group, the protected amino group formed should be a group such as a eert-butyl carbamate group which will permit the ester group -CooR7 to be reduced to -CH20H while leaving the ester group in R4 and then be removable by a re~rtion, for exarnple in a non-aqueous medium, which leaves the ester group in R4.

In a mo-lifir~tion of the Strecker synthesis hereinbefore described, the compound of formula VI may be subjected to acid hydrolysis, for example using convention:~l procedures, to convert the in(lic~te~l cyano group to carboxyl and the resulting aminocarboxylic acid may be reduced to a compound of formula II by reaction withborane dimethyl sulphide in the presence of a boron trifluoride complex such as boron trifluoride diethyl etherate, for in~t~nre using known procedures.

Compounds of formula II, VI, VII or VIII in which R4 is 3-methoxycarbonylphenyl, which may be prepared from an aldehyde or ketone of forrnula R4C(=o)RX by the reactionsequence as hereinbefore described, are believed to be novel per se. Compounds of formula II or VIII where R4 is 3,4-dichlorophenyl and R~ is Cl-C1o alkyl are also believed to be novel.

Compounds of formula II in which R4 is a monovalent aromatic group as hereinbefore defined and Rx is an unsubstituted or substituted hydrocarbyl group are believed to be novel, with the exception of compounds of formula II in which R4 is phenyl and Rx is methyl, chloromethyl, ethyl, -(CH2)3 S CH3, allyl or methylol, compounds of forrnula II in which Rx is aminomethyl and R4 is phenyl, p-hydroxyphenyl or p-methoxyphenyl, compounds of formula II in which Rx is methylol and R4 is 4-decylphenyl or 5-[(7-chloro-4-quinolinyl)amino]-2-hydroxyphenyl, a compound of forrnula II in which R4 is 4-methoxyphenyl and Rx is ethyl,and a compound of forrnula II in which R4 is 2,4-dichlorophenyl and Rx is N-triazolylmethyl.

Compounds of formula II in which R4 is a monovalent araliphatic group as hereinbefore defined and Rx is an unsubstituted or substituted hydrocarbyl group as hereinbefore defined other than methylol are believed to be novel, with the exception of compounds of formula II where Rx is methyl and R4 is benzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 2-phenylethyl, 1,3-benzodioxol-5-methyl, 3-phenyl-1-aminopropyl, a-bydroxybenzyl, a-hydroxy-a-methylbenzyl, or a-hydroxy-a-methyl-4-ni~-)be,-~yl, and with the exception of compounds of formula II where R4 is benzyl and Rx is allyl or -CH2CH2SCH3.

Compounds of formula II in which R4 is iodobenzyl, particularly 4-iodobenzyl, and Rx is hydrogen or an unsubstituted or substituted hydrocarbyl group, as hereinbefore defined are also believed to be novel.

Compounds of formula III which, with the exception of the compound where R2 is methyl and Rs is ethyl, are believed to be novel, particularly those where R2 is cycloalkylalkyl such as cyclohexylmethyl, may be prepared by reacting a compound of formula W O 97/0933S PCT/G]B96/02113 oR5 with a compound of formula where R~2, Rs and X are as hereinbefore defimed, in the presence of a silylating ;agent such as a bis(trialkylsilyl) derivative of an arnide, which agent undergoes reaction with the compound of formula IX to form a P(III) silyl compound which then reacts with the compound of formula X. The reaction may be carried out at a ~e~pe-dture frorn O to 50~C; it is preferably carried out in a solvent, for exarnple a hydrocarbon such as toluene or a halohydrocarbon such as dichloromethane.

Esters of forrnula ~ may be p.~ d by reacting a protected phosphinate ester of forrnula Il Q P H Xl where R5iS as hereinbefore defined and Q is a P-H-protecting group, with a compound of forrnula where R2 is as hereinbefore defined and Z is a leaving moiety, to give a compound of formula ~ Il Q p R XI~
I

ORS
and then replacing the protecting group Q in the compound of formula XIII by hydrogen.

The leaving moiety Z may be, for example, a halogen atom or an organic sulphon~te group. Preferably Z is chlorine, bromine, iodine, or a meth~nPs~llphonate~
trifluorometh~nesulphonate or p-toluenesulphonate group. The reaction between the compounds of formulae XI and XII and the depl~)te-;Lion reaction on the co~ ou.,d of formula XIII may be carried out using known procedures, for example as described in EP
0569333.

Protected phosphinate esters of formula XI may be prepared by known methofl~, for example as described in US 4 933 478. Compounds of formula XII are either comm~rcially available or may be prepared by known procedures.

Compounds of formula X are rlih~loalk~-nes which are either commercially available or may be ~-c~ared using known methods.

Compounds of formula I where RY is RYa may be Illcl ~1d by reacting a compound of formula I where RY is hydrogen with a co~lpoulld of formula RYaZ, where RYa and Z are as hereinbefore defined, or by reductive alkylation using an aldehyde of formula RYb CHO, where RYb is hydrogen or RYa as hereinbefore ~l~fin~l, and a reducing agent which reduces imines to amines, for example sodium cyanoborohydride. Such reactions may be carried out using conventional procedures.

Compounds of formula I where RY is a NH-protecting group may be plcpa cd by reacting a compound of formula I where RY is hydrogen with a reagent known to introduce the desired protecting group. For exarnple, where the protecting group is an acyl group, the compound of forrnula I where RY is hydrogen may be reacted with an acyl halide or carboxylic acid anhydride such as acetyl chloride, acetic anhydride or benzoyl chlnri~
for inst~nce using known procedures. Where the protecting group is an alkoxycarbonyl or aralkoxycarbonyl group, the compound of formula I where RY is hydrogen may be reacted with an alkoxycarbonyl or aralkoxycarbonyl halide or an alkyl or aralkyl dicarbonate such as benzyl chloroforrnate or di-tert-butyl dicarbonate, for example using known procedures.

In general, compounds of formula I where RY is RYa or a NH-~ tccLi.-g group may also be e~ d by the method hereinbefore described for the preparation of compounds of formula I where RY is hydrogen, in which method the compound of formula II is replaced by a compound of formula W O 97/09335 PCT/GE~96/02113 OH

RX

\ ~A

where R4 and RX are as hereinbefore defined in formula II and RY is RYa or a NH-protecting group, the reaction of the compound of formula IIA with the cornpound of formula III in the presence of a base giving directly a compound of formula O ~ 1I R2 N I rVA
oR5 where R4 and Rx are as defined in formula II, R2 and R5 are as hereinbefore defined and RY is RYa as hereinbefore defined or a NH-protecting group. This reaction may be carried out in a solvent, usually a hydrocarbon such as benzene, toluene or xylene, and is generally carried. out under harsher conditions than those used for the reaction of compounds of formulae II and III, for exarnple using sodium hydride as the base and at a temperature of 10~C to 70~C. This reaction may be followed, where required, by one or more substitl-tiol- reactions to change the nature of a substituent in R4 and/or R' and/or by hydrolysis of an ester substituent in R4 and/or Rx to carboxyl and/or by conversion of the ester group -ORs to -OH.

Compounds of forrnula I may also be ~ a,ed by reacting a compound of formula ~' R2 N~ ¦
R4 ¦ ORS
RY

to convert the in~ic~tefl primary hydroxyl group into a leaving moiety Z as hereinbefore defin~od, thereby effecting cyclisation to give a compound of formula ~~--R2 4~N xv R I oR5 RY

where R2, R4, Rs, Rx and RY are as hereinbefore defined followed, where required, by replacement of RY as an NH-protecting group by hydrogen andlor by one or more subs~ -SiQn re~c tion~ to change the nature of a substituent in R4 and/or Rx and/or by hydrolysis of an ester substituent in R4 and/or Rx to carboxyl and/or by conversion of the ester group -oR5 to -OH.

The conversion of the prima;y hydroxyl group in the compound of formula XIV into Z
may be carried out using known procedu.~s. For exarnple, where Z is an iodine atom, the conversion may be effected by reacting the compound of formula XIV with triphenylphosphine, im~ 7ole and iodine in a solvent such as acetonitrile or tetrahydrofuran at 0~C to 50~C, and where Z is a trifluoromethanesulphonate group, the conversion may be effected by reacting the compound of formula XIV with trifluoromethanesulphonic anhydride in pyridine at -100~C to 50~C.

The replacement of RY as an NH-protecting group by hydrogen may be carried out using known procedures for removal of the NH-protecting g,roup. For example, where RY is an acyl group such as acetyl or benzoyl, replacement by hydrogen may be effected byreaction with aqueous hydrochloric acid, while where RY is trifluoroacetyl, replacement by hydrogen may be effected by reaction with aqueous po~,.c~itlm carbonate.

The other optional subsequent reactions of compounds of formula XV may be carried out as hereinbefore described for corresponding reactions of compounds of formula IV.

Compounds of formula XIV, which are themselves believed to be novel, may be l,lcpal~d by reacting a compound of formula II with a compound of formula W O 97/0933~ PCT/GB96/02113 HO
\~ ' R2 XVI
oR5 z where R2, R5 and Z are as hereinbefore rlefint~.r1, in the presence of a hindered base, to give a compound of formula RX~ R2 XVII
R4 lRS

where R2, R4, Rs and Rx are as hereinbefore nP,fin~-~l, and replacing the in-lir~t~cl hydrogen att~<~h~l to nitrogen by a NH-protecting group RY as hereinbefore defined, for example using known procedures such as those hereinbefore described. The reaction between the compounds of formula II and XVI may be carried out, for example, at a temperature of 20 to 10û~C, preferably in an organic solvent such as an alcohol, especially ethanol. The hindered base may be, for example, a diazabicyclo compound such as 1,5-diazabicyclo t4.3.0]non-5-ene or 1,8-diazabicyclo t5.4.0]undec-7-ene or preferably, a tertiary amine such as dicyclohexyl(ethyl)amine or, especially, diisopropylethylamine.

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

Compounds of fc,rmula XIV or XVII may them~çlves be used as pharmaceuticals, forexample in the treatment or prevention of a co~ tiQn characterised by stimulation of a GABAB receptor, particularly in de-esterified form, i.e. where Rs as aL~cyl has been replaced by hydrogen and any carboxylic ester group in R4 and/or Rx has been converted into a carboxyl g3roup, for example using known procedures. Accordingly, the invention inclllcles novel compounds of formula ~1 xvm ~Y
where Rl, R2, Rx and RY are as hereinbefore f~efin~ , or salts or esters thereof.

Compounds of the invention obtained as salts can be converted into the free compounds in a manner known ~ se, for example by tre~tment with a base, such as an alkali metal hydroxide, a metal carbonate or metal hydrogen carbonate, or ammonia, or another of the salt-forming bases mentioned hereinbefore, or with an acid, such as a mineral acid, for example with hydrochloric acid, or another of the salt-forming acids mentiQn~
hereinbefore.

Salts of the invention can be converted into different salts of the invention in a manner known per se; for example, acid addition salts can be converted by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of another acid in a suitable solvent in which an inorganic salt being forrned is insoluble and is thus excluded from the reaction equilibrium, and base salts can be converted by freeing the free acid and converting into a salt again.

The compounds of formula I, inl~hl-ling their salts, may also be obtained in the form of hydrates or may include the solvent used for cryst~ tiQn Owing to the close rel~tion~hip between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter the free compounds and their salts are also optionally to be understood as being the corresponding salts and free compounds, respec-tively, where a~ op~iate and where the context so allows.

For compounds of forrnula I, and interme~ tto,s in the preparation thereof, diastereoisomeric mixtures and mixtures of r~cem~t~os can be separated in known manner into the pure diastereoisomers and racemates, respectively, on the basis of the physico-chernic~l differences between their constituents, for example by chromatography and/or fractional crystallisation.

Resulting racemates can also be resolved into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, with the aid of micro-CA 02229036 l998-02-06 W O 97/0~335 PCT/GB96/02113 or~nicm~ or, by reaction of the resulting diastereoi~Qm~ric ,.,i~Lu~ or r~rPm~e with an optically active auxiliary compound, for example according to the acidic, basic or fimrtiQn~lly morlifi~ble groups cont~inrfl in compounds of formula I, with an optically ~ active acid, base or an optically active alcohol, into ,.,i~Lules of diastereoisomeric salts or functional derivatives, such as esters, separation of the same into the diastereoisomers from which the desired enantiomer can be freed in c~ tnm~ry manner. Suitable bases, acids and alcohols for the purpose are, for example, optically active ~lk~loicl bases, such as strychnine, cinchonine or brucine, or D- or L-(l-phenyl)ethylamine, 3-pipecr~line, ephedrine, amphet~minP and similar bases that can be obtained by synthesis, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluoyltartaric acid, D- or L-malic acid, D- or L-m~ndelic acid, or D- or L-camphor-sulfonic acid, or optically active alcohols, such as borneol or D- or L-(1-phenyI)eth~nol Compounds of formula I, VA or XVIII may be isotopically labelled, particularly with llC, l4C, 2H, 3H or ~25I, for use in ~ gnostics.

The compounds of formula I, VA or XVIII may be used, for exarnple, in the form of ph~l~n~re,utical compositions that comprise a therapeutically effective amount of the active ingredient, where a~ u~,iate together with pharm~reu~ic~lly acceptable carriers that are suitable for enteral, for example oral, or parenteral ~lmini~tration, which carriers may be solid or liquid and organic or inorganic. For example, tablets or gelatin capsules are used that contain the active ingredient together with diluents, for example lactose, dex-trose, saccharose, m~nnitol, sorbitol, cellulose and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as m~gnesillm or c~lcinm stearate, and/or polyethylene glycol. Tablets may also contain binders, for example m~gnesillm ~lllmininm silicate, star~hes, such as corn, wheat, rice or arrowroot starch, gelatin, tr~g~r~nth, methyl-cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, for example sodium alginate, and/or effervescent mixtures, or absorbents, colourings, flavourings an sweeteners. The compounds of formula I can also be used in the form of parenterally ~ aflmini~trable compositions or in the form of infusion solutions. Such solutions are prefer-ably isotonic aqueous solutions or suspensions which, for example in the case of- lyophilised cornpositions that comprise the active ingredient on its own or together with a carlier, for example m~nnitol, can be prepared before use. The pharmaceutical compositions rnay be sterilised and/or may comprise excipients, for example preserv-atives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic ~rtS'.U~, and/or buffers. The present pharmzlreutiral compositions which, if desired, may comprise other pharmacologically active substances, may be prepared in a manner known ~er se, for example by conventional mixing, gr~n~ ting, confectioning, dissolving or lyophilising processes, and may co~ lise a~lu~illlately from 0.1 % to 100 %, especially from approxim~t~ly 1 % to ap~,u~ ately S0 %, and, in the case of lyophilic~tes, up to a~lù~d",ately 100 %, active ingredient.

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

The dose may depend on various factors, such as the mode of ~flminictration, specieC, age and/or individual condition. The doses to be ~-lminictered daily may, in the case of oral ~-lminictration~ be from approximately 1 to ap~io~ -ately 50 mg/kg, especially from 5 to approximately 25 mg/kg, and, in the case of warm-blooded ~nim~lc having a body weight of approximately 70 kg, preferably from a~p,u~d~-~ately 70 mg to a~,u,~i".ately 3500 mg, especially from approximately 350 to a~ul"u~il"ately 1750 mg, expediently divided into from 2 to 6, for example 3 or 4, single doses.

The invention accordingly includes a method of treating or preventing a conflition in warm-blooded m~mm~lc, particularly humans, characterised by stimulation of a GABAB
~cce~tor which comprises ~-lminictering to the warm-blooded m~mm~l a compound offormula I, VA or XVIII, or a pharm~centic~lly acceptable salt or ester thereof.

The invention is illustrated by the following Examples.

Compound D used in the Examples is prepared as follows. In subsequent formulae, Boc denotes tert-butoxycarbonyl.

Phenyl glycine (42g) is dissolved in concentrated sulphuric acid (210ml) and the solution is cooled to 0~C. Fuming nitric acid (15.5ml) is added dropwise to the cooled solution over 30 minutes and the mixture is stirred for a further 30 minutes at 0~C, then 18 hours at room temperature. The solution obtained is poured over l litre of ice and carefully adjusted to pH7 by adding approximately 875ml of lOM aqueous sodium hydroxide whilst keeping the temperature of the solution below 20~C. The resulting mixture is stirred for 3 hours at room temperature and the precipitate obtained is filtered off. The precipitate is washed three times with water and recrystalized from l litre of water to afford 3-nitrophenylglycine, mpt 165-6~C.

3-Nitrophenyl glycine (Sg) is added to a mixture of methanol (200ml) and triethylamine (20ml) and the mixture is stirred vigorously for lO minutes at room tem~,aLulc.

wo 97/09335 PCT/GB96/02113 Di-tert-butyl dicarbonate (11.13g) is added and the reaction mixture is heated under reflux for 2 hours. The solution obtained is cooled to room te,l,~ dture and then conc~n~ t~ to dryness under reduced pressure to afford a dark orange residue. The residue is purified by flash chromatography [silica gel, CH2Cl2 (95%), CH30H (2.5%), CH3COOH (2.5%)] toafford Compound A as an orange foam.

COOH

NHBoc ~ mr~ A

13Cnmr (lOOMH.z; CDC13): ~ (ppm)27.9 (q), 5B.2(d), 82.6(s), 122.4(d), 123.0(d), 129.5(d), 133.0(d), 140.4(s), 148.2(s~, 156.8(s), 172.1(s).

A solutic-n of Compound A (14.54g) and p-tolllent-sl-lrhonic acid (1.87g) in meth~nol (200ml) is stirred at room temperature for 24 hours. Ethyl acetate and saturated aqueous NaHCO3 are added, the organic phase is separated, dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure. The product obtained is purified by flash chromatography [silica gel, hexane:ethyl acetate (2:1)] to yield Compound B as a yellow solid, mpt = 86~C, mrlmfi B

NHBoc Analysis: calculated for Cl4Hl8N2O6; C, 54.19; H, 5.85; N, 9.03%.
Found, C, 54.32; H, 6.00; N, 8.93%.

A solution of sodium borohydride (2.33g) in absolute ethanol (30ml) is added dropwise to a stirred solution of Compound B (9.57g) in absolute ethanol (120ml) at room tem~.d~ure~
The reaction mixture is stirred for 18 hours at room temperature, after which excess sodium borohydride is destroyed by adding glacial acetic acid. The solvents are removed under reduced pressure and the residue is triturated with ethyl acetate (3 x 50ml). The combined ethyl acetate phases are evaporated to dryness and the residue is then co-evaporated with toluene (3 x 50ml). The res-llt~nt residue is purified by flash chromatography [silica gel, ethyl acetate: hexane (1:1)] to afford Compound C, m.p. 100~C, OH

C-, 'C

Analysis: calculated for C13H,8N2Os; C, 55.31; H, 6.43; N, 9.92%. Found, C, 55.25; H, 6.63; N, 9.76%.

Trifluo;oacetic acid (60ml) is added to a flask cont~ining Compound C (5g) cooled to 0~C.
The resulting solution is stirred for 20 minutes at 0~C, then allowed to warm to room temperature and stirred for a further 3 hours. The solvent is ;emoved under reduced ~ ,S~.ulc and the residue is purified by ion e~rh~nge chromatography (Dowex 50WX2-200 (H+ form) resin, elutant 3% aqueous ammonium hydroxide solution) to affordCompound D as a pale brown foam.

OH

Nh2 ~nm7~ D

Analysis: c~lcnl~te~l for C8HloN203; C, 52.74; H, 5.53; N, 15.38%.
Found, C, 53.12; H, 5.75; N, 15.07%.

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

Compound G used in the Exa~mples is ~le~al~,d as follows:

Sodium cyanide (4.9g, 0.1M) and ammonium chloride (5.88g, 0.11M)are stirred in water (20ml) at room temperature. A solution of 3,4-dichlorobenzaldehyde (17.5g, 0.1M) in meth~nol (30ml) is added dropwise over one minute. Aqueous ammonia soluhon (lOml, W O 9'7/0~335 PCT/GB96/02113 specific gravity 0.88) is added and the reaction is sti;red for 3 hours at room t~ alu~G.
Etnyl acetate is added and the organic phase s~dLGd, dried over m~gn~Sillm s;ulphate, filteTed and evaplorated. The residue is dissolved in ethyl acetate and repeatedly çY~ceA
with 2N hydrochloric acid. The combined aqueous layers are adjusted to pH9 usingaqueous ammonia solution and re-extracted repeatedly with ethyl acetate. The combined organic layers a~ dried over m~gn~Sillm s~lph~tP, filtered and evaporated under reduced .SUlc: to afford an orange Oil which is purified by flash chromatography on silica using h~y~.ne:ethyl acetate (1:1) as eluant to afford Compound G. m.p. 64-65~C

CN

~ (~nm~~ l C
J~ NH2 Cl Cl Found: C, 47.81; H, 2.99; N, 13.92%.
C8H6Cl2N2 requires C, 47.79; H, 3.01; N, 13.93%.

Compound J used in the Examples is ~l~pa,ed as follows:

Using subst,.nh~lly the same procedure as described for the preparation of compound G, a mixture of 3-bromo-ben7~ ehyde (18.5g, O.lM), sodium cyanide (4.9g, O. lM), ~mmon;nm chloride (5.9g, 0.1 lM) and aqueous ammonia solution ( lOml, specific gravity 0.88) in methanoVwater (30ml/20ml) is reacted for 24 hours at room temperature to afford Compound H as a redlbrown waxy solid.

CN

NH2 r~m~..~H

Br 3C nmr (100 MHz; CDc13):~ (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 (10.5g, 49.8mM) in 6M hydrochloric acid (200ml) is heated under r,flux for 68 hours. The supernatent is ~lec~nt~(l off, cooled to room temperature and adjusted to pH7 using aqueous ammonia soluhon The ~ te~l product is collected by filtration, washed with water and dried. Trituration with ethyl acetate followed by drying affords Compound J as a brown solid. m.p. 201-204~C (dec).

NH2 Cnm~.._~J

Br ~3C nmr (lOOMHz; CD30D): ~ (ppm) 56.9 (d), 124.0 (S), 128.1 (d), 132.2 (2 x d), 134.0 (d), 136.0 (S), 170.1 (S).

Example 1 CN

~~nmr~lm~l 1 H ~

COCC~3 3-methoxycarbonylben7~1dlohyde (1.6g, lO.OmM) in methanol (lOml) is added to a solution of ~methoxybenzylamine hydrochloride (1.7g, lO.OmM) and sodium cyanide (0.490g, lO.OmM) in water (lOml) and the mixture is stirred for 3 hours at room temperature. Water (20ml) is added and the mixture extracted with dichloromethane. The organic phase is washed with brine, dried (MgS04) and evaporated to dryness to afford an oil which is purified by silica gel chromatography using 20% ethyl acetate in hexane as eluant to afford Compound 1.

Analysis: calculated for C18 Hl8 N2 ~3; C, 69.66; H, 5.85; N, 9.03%.
Found, C, 69.40; H, 5.94; N, 8.73%.

13C nmr (lOOMHz; CDC13):~(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).
-W O 97/09335 PCT/G]B96/02113 Example 2 H ~ Cn~ 2 A solution of Compound 1 (7g, 22.56mM) in methanol (75ml) is cooled to 0~C and saturated with hydrogen chloride gas. Once saturated, the reaction ~ Lul~;iS stored at -20~C for 4 days and then concentrated under reduced ~ S~ to a quarter of its original volume. Ethyl acetate and saturated aqueous sodium bicarbonate solution are added and the organic phase is separated, washed with water and brine, d~ied over mAgnes~ n sulphate, filtered and evaporated to give an oil. Purific~*on by flash chromatography on silica using hexane: ethyl acetate (1:1) as eluant affords Compound 2 as an oil.
31C nmr (100MHz; CD C13):~5 (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 Cn~..~A3 A mixture of Compound 2 (8.0g, 23.3mM) and p~ m black (2.0g) in glacial acetic acid (SOml) and meth~nol (SOml) is hydrogen~t~d for 4 hours at room ~ ture. After cht-~'cing completion of the reaction by thin layer chromatography (tlc), the mixture is filtered and the filtrate evaporated under reduced p-es ,ure. The residue is co-evapol~ted three times with toluene (3 x 20ml) and then purified by flash chromatography on silica using ethyl acetate as eluant to afford Compound 3 as a pale yellow oil.

Analysis: e~le~ tel1 for Cl3HI7NO6; C, 55.12; H, 6.05; N, 4.94%.

Found; C, 55.46; H, 5.99; N, 5.05%
13C nmr (lOOMHz; cDcl3):~(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 OH

NH2 rnmro~A4 Step 1 A solnti~ n of di-tert-butyl-dicarbonate (4.5g, 20.83mM) in methanol (lOml) is added to a vigorously stirred solution of Compound 3 (3.1g, lO.9mM) and triethylamine (lOrnl, 71.75mM) in methanol (40ml). The mixture is then heated at 60~C for 30 minute-~, cooled to room ~ .dture and evaporated under reduced pressure. The residue is purified by flash chromatography on silica using hexane: ethyl acetate (4:1) as eluant to afford Compound E m.p. 88-90~C.

e3~NHBoc Cnmro~E

Analysis: calculated for C16H21NO6; C, 59.43; H, 6.55; N, 4.33%.
Found, C, 59.54; H, 6.72; N, 4.32%.

Step 2 Sodium borohydride (800mg, 21.2mM) is added in eight equal portions, at 30 minute intervals, to a stirred solution of Compound E (3.2g, 9.9mM) in methanol (50ml). On completion of the reaction (tlc), the rem~ining sodium borohydride is destroyed with glacial acetic acid and the reaction mixture evaporated under reduced pressure to afford an oily solid. This ~esidue is co-evaporated with toluene (2 x 20ml) and tritll~te~ with e~hyl acetate. Evaporation of the ethyl acetate extracts under reduced ~)le;~:iUlc affords a colourless oil which is purified by flash chromatography on silica using h~Y~ne ethyl acetate (1:1) as eluant to afford Compound F, m.p. 102-104~C.

~3--NHBoc rnm~n~F

Analysis: c~ t~.l for C15H2lNO5; C, 61.01; H, 7.17; N, 4.74%.
Found; C, 61.11; H, 7.23; N, 4.70%.

Step 3 Trifluoroacetic acid (3.0ml, 39.17mM) is added to a stured solution of Co-nl,.au-ld F (2.2g, 7.45mM) in dry dichloromethane (25ml) under argon at room te---~c-~ture. The ~ is stirred for 5 hours at room temperature. On completion of the reaction (tlc), the mixture is evaporated under reduced ~l-,S~ul~ without heating and the residue is co-evaporated with chloroform (2 x 20ml). After drying under high vacuum, the residue is purified by ion exch~nge chromatography on Amberlyst A21 resin using water as eluant to afford Compound 4 as a colourless oil.

Found: C, 58.98; H, 6.73; N, 6.53%.
Cl0 Hl3 NO3 . lH20 requires C, 58.8; H, 6.91; N, 6.86%.

13C nrnr (100 MHz; CD30D): ~ (ppm) 52.6(q), 58.1(d), 67.4(t), 129.1(d), 129.8(2 x d), 131.6(s), 132.9(d)V 142.4(s), 168.2(s).

Example S

~ NH2 Cl Cl Cnmr~ S
A solution of Compound G (1.4g, 5.98mM) in meth~nol (20ml) is cooled to 0~C and s~hl~te~l with hydrogen chloride gas. Once saturated, the reaction mixture is stored at -20~C for 2 days. The solvent is removed under reduced pressure and the residue co-evaporated with methanol (3 x 20ml). The residue is suspended in ethyl acetate and the organic phase is washed successively with saturated aqueous sodium bicarbonate solution, water and brine. The organic layers are dried over m~nesillm sulphate, filtered and evaporated under reduced pressure to afford an oil which is purified by flash chromatography on silica using hexane: ethyl acetate (1:1) as eluant to afford Compound 5.

Found: C, 46.12; H, 3.85; N, 6.09%. CgHgCI2NO requires C, 46.18; H, 3.88; N, 5.98%.

13C nmr (100MHz; CD C13):~ (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).

ExamDle 6 ~NHBoc Cl C~ , '6 Cl Compound 5 (6.0g, 25.63mM), di-tert-butyl dicarbonate (11.19g, 51.26mM) and triethylamine (20ml, 143.50mM) are reacted in meth~nol (200m1) using s~lbst~nti~lly the same procedure as ~les~he~l for the prep~tion of Compound E in Example 4. The crude product is purified by chromatography on silica using 2()% ethyl acetate in hexane as eluant to afford Compound 6 as a yellow solid. m.p. 90-92~C.

Found: C, SO.55; H, 5.16; N, 4.08%. Cl4Hl7C12NO4 requires C, 50.32; H, 5.13; N, 4.19%.

Exa~mple 7 _,,OH

~NHBoc Cl / T
Cl Cnm7l~lm~7 To a solution of Compound 6 (6.78g, 20.28mM) in absolute ethanol (lOOml) is dropwise added a solution of sodium borohydride (1.15g, 30.43mM) in absolute ethanol (30ml). The reaction is stirred for 6 hours at room temperature and then left to stand for 48 hours at room temperature. The solvent is removed under reduced ~,-es~ur~ and the residue is purified by flash chromatography on silica using hexane: ethyl acetate (1:1) as eluant to afford Compound 7 as a white solid. m.p. 113-114~C.

Found: C, 51.21; H, 5.69; N, 4.43%. Cl3HI7C12NO3 requires C, 51.00; H, 5.60; N, 4.57%.

Example 8 _" OH

J ~ NH2 Cl Cl Cn~ m~s Compound 7 (4.7, 15.35mM) is reacted with trifluo~acetic acid (75ml) using subst~ntis~.lly the same procedure as described for the preparation of Compound D from Compound C.
The crude product is purified by ion ~yrh~n ~ chromatography on Dowex SOWX 2-200~H~ form) resin using methanol: water: aqueous ammonia solution (50%: 47%: 3%) as eluant to afford Compound 8 as a cream coloured solid. m.p. 65-67~C.

Found: C, 46.61; H, 4.37; N, 6.59%. C8HgCl2NO requires C, 46.63; H, 4.40; N, 6.80%.

Example 9 Br ~1--0 OC2H5 (~. ~ 9 Bis(trimethylsilyl)~et:lmi-le (28.5 lml) is added d~.~pwise to a sohltion of 18.22g of ethyl cyclohexylmethylphosphinate, p.~ d as described in EP 0569333, in lOOml of dryCH2Cl2 under argon. The solution is stirred at room tem~cl~Lu~c for 1 hour, then trimethyl phosphate (13.42ml) is added, followed by 1,3-dibromopropene (mixture of cis/trans isomers) (9.57ml). After stirring the solution at room temperature for 18 hours, it is poured into saturated aqueous NaHCO3 solution (lOOml) and stirred for lQ mimltes The product is extracted with CH2C12 (3 x 50 ml) and the combined organic extracts are washed with brine, then dried with MgSO4 and filtered. The filtrate is evaporated under reduced l,.cs~.u.e, then excess trimethyl phosphate is removed by evaporation at 80~C at 0.45mm Hg. The residue is purified by flash chromatography (silica gel, ethyl acetate) to yield Compound 9 as a mixture of cis and trans isomers.

31p nmr (162MHz, CDC13): ~ (ppm) 51.1 and 52.2.

Example 10 ~OH

~HN !P ~

~C2H5 Cnmro~ln~ 10 A mixture of (R)-2-amino-2-phenylethanol (0.88g, 6.47mM) and Compound 9 (1.Og, 3.23mM) in toluene (lOml) is heated underreflux. 1, 8-Diazabicyclo[5.4.0]undec-7-ene (0.48ml, 3.23mM) is added in ten aliquots at 30 minute intervals. The reaction is heated under reflux for a further hour and allowed to stand overnight at room ~ )e.dtul~. The C; is filtered and the filtrate evaporated under reduced ~ ul., to afford a yellow oil which is purified by flash chromatography on silica using 5% methanol in dichlort)m~th~ne as eluant to afford Cu...~ound 10 as a 1: 1 mixture of diasL.,~,olllers at phosphorus.

31P nmr (162Hz; CDCl3): ~ (ppm) 43.49 and 43.55.

Example 1 1 OH
O

0--'H ~P ~ ~1 ~. . Il (S)-2-arnino-2-phenyl ethanol (2.66g,19.4mM), Compound 9 (3.0g, 9.7mM) and 1,8-diazabicyclorS.4.0]undec-7-ene (1.40g, 9.7mM) are reacted in toluene (30ml) using the procedure described for the preparation of Compound 10. The crude product is purified by flash chromatography on silica using 5% methanol in dichloromethane as eluant to afford Compound 11 as a 1: 1 mixture of diastereomers at phosphorus.

31p nmr (162MHz; CDC13): ~(ppm) 43.37 and 43.43.
Example 12 OH
/ O
~J~N ~P ~

COOCH3 ~ mr~ n~ 12 A mixture of Compound 4 (1.3g, 6.66mM) and Compound 9 (2.06g, 6.66mM) in tohlene~rI~ (25ml, 1: 1 mixture) is heated to 80~C under argon. A solution of 1,8-diazabicyclo [5.4.0]undec-7-ene (1.52g, 9.95mM) in toluene/l~ (lSml, 1:1 mixture) is added over 5 hours. The mixture is cooled to room temperature and allowed to stand for 18 hours. The mixture is filtered and the filtrate evaporated under reduced ~S~ , to afford a yellow oil which is purified by flash chromatography on silica using 5% meth~n in dichlorometh~ne as eluant to give Compound 12 as a 1:1 mixture of dia~Lw~ol.lers at phosphorus.

31p (162MHz; CDCl3): ~ (ppm) 43.53 and 43.58.
ExamPle 13 ~ OH

Cl Cl cn nr~n~ 13 Using substantially the same procedure as described for the ~l~aldlion of Compound 12, a mixture of Compound 8 (2.76g, 13.39mM) and Compound 9 (4.14g, 13.39mM) in toluene/THF (SOmU4ml) is reacted with a solution of 1,8-diazabicyclo[5.4.0~undec-7-ene (2.03g, 13.39mM) in THF (6ml) at 110~C to afford Compound 13 as a 1:1 mixture ofdiastereomers at phosphorus.

31P nmr (162MHz; CDC13): ~ (ppm) 43.73 and 43.82.

Example 14 OH

NO2 rnm~~ 14 Using substantially the same procedure as described for the preparation of Compound 12, a mixture of Compound D ~3.19g, 17.50mM) and Compound 9 (5.41g, 17.~0mM) in toluenel I~ (5QmU4ml) is reacted with a solution of 1 ,8-diazabicyclo[5.4.0]undec-7-ene CA 02229036 l998-02-06 W O 97/09335 PCT/G]B96/02113 -4~-(2.66g, 17.5mM) in THF (6ml) at 110~C to afford Compound 14 as a 1~ U;~-t of diastereomers at phosphorus.

31P nmr (162MHz; CDCl3): ~ (ppm) 43.60 and 43.66.

Exarnple lS

nA 15 A suspension of sodium hydride (0.079g, 3.31mM) in dry toluene (lOml) is stirred at 0~C.
A solution of Compound 10 (l.lg, 3.01mM) in dry toluene (20ml) is added dropwise.
The reaction mixture is allowed to warm to room temperature and stirred for 20 hours.
Sa~u~dLed aqueous arnmonium chloride solution (Sml) is added, then the reaction llli~lu~G
is partitioned between ethyl acetate and water. The aqueous layer is extracted with ethyl acetate and the combined organic phases are dried over ma~neSillm sulphate, filtered and evaporated. The residue is purified by flash chromatography on silica using 5% merh~n in dichloromethane as eluant to afford Compound lS as a mixture of dia.LGl~,o-llers at phosphorus.

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

31p nmr (162MHz; CDC13): ~ (ppm) 54.0~ and 54.63.

ExamPle 16 o N~
C~ n-i 16 Using subst~nti~lly the same procedure as described for the preparation of Compound lS, Compound 11 (1 20g, 3.28mM) and sodium hydride (0.086g, 3.61mM) are reacted in toluene (40ml) to afford Compound 16 as a mixture of diastereomers at phosphorus.

-Found: C, 63.39; H, 8.75; N, 3.70%. C2oH32NO3P . 0.75 H20 l~,~uil~,s C, 63.39; H, 8.91;
N, 3.70%.

31p (162MHz; CD C13):~ (ppm) 54.08 and 54.65.

Example 17 H ~

~nm~ln~17 A solution of Compound 12 (50mg, 0.12mM) in dry toluene (O.Sml) is stirred at room Le.l-p~,ldture. A suspension of sodium hydride (6.2mg, 0.26mM) in toluene (0.5ml) is added in one portion and the reaction mixture is stirred for 3 hours at room tempeldtulG.
The reaction is then quenched with glacial acetic acid and the product is extracted with ethyl acetate. The combined organic phases are washed with water and brine, then dried over m~gne~ m sulphate, filtered and evaporated. The residue is purified by flash chromatography on silica using 5% meth~nol in dichloromethane as eluant to afford trans-2,5-disubstituted morpholine racemic Compound 17 as a mixture of diastereomers at phosphorus.

31p nmr (162MHz; CDC13): ~ (ppm) 54.06 and 54.64.

W O 97/09335 PCT~GB96/02113 EXa'inPle 18 O

,,~,J~ N ~o ~u Cl Cl Cnm~''~18 Using subst~nti~lly the same procedure as described for the ple~a.dLion of Compound 15, Compound 13 (2.24g, 5.15mM) and sodium hydride (0.136g, 5.67mM) are ;eacted in toluene ~80ml) to afford trans-2,5-disubstituted morpholine T~ mi~ Compound 18 as a mixture of diastereomers at phosphorus.

Analysis: Found, C, 54.21; H, 7.08; N, 3.11%. C20H30Cl2 NO3P . 0.5H2O requin_s C, 54.18;
H, 7.05; N, 3.16%.

31p nmr (162MHz; CDCl3): ~ (ppm) 53.80 and 54.40.

Example 19 N ~

N02 ~ A 19 Using subst~nti~lly the same procedure as descTibed for the preparation of Compound 15, Compound 14 (5 38g, 13.1mM) and sodium hydride ~0.346g, 14.41mM) are reacted in toluene (150ml) to afford trans-2,5-disubstituted morpholine racemic Compound 19 as a mixture of dia~le;l~,GIl~ers at phosphorus.

CA 02229036 l998-02-06 31p nmr (162MHz, CDCl3): ~ (ppm) 53.73 and 54.33.
Example 20 N~t~

('nmro~71A 20 To a stirred solution of Compound 15 (650mg, 1.78mM) in dichlorometh~ne (25ml) under argon is added dropwise bromotrimethylsilane (0.939ml, 7.12mM). The reaction mixture is stirred for 24 hours at room temperature. The reaction is then quenched by the ~Mitir~n of a mixture of meth~nol: water (95:5). T~le solvent is removed under reduced ~l~,'7~Ult to afford an oily residue which is purified by ion exchange chromatography on DowexSOVVX 2-200 resin (H~ form) using methanol: water: aqueous ammonia solution (50%:
47%: 3%) as eluant. The resulting product is dried under high vacuum (< O.O5mm Hg) to affo;d Compound 20 as a white solid. m.p. > 250~C. [a]D = +10.8~ (C=l, CH30H).

Found: C, 63.72; H, 8.44; N, 4.02%. Cl8H28NO3P requires C, 64.08; H, 8.36; N, 4.15%.

31p nmr (162MHz, D2O): ~ (ppm) 55.22.

Example 21 N~ t'H--[~
C~ . '21 Using the same procedure as described for the preparation of Compound 20, Compound 16 (670mg, 1.83mM) and bromotrimethylsilane (l.lg, 7.3mM) are reacted in dichloromtoth~n~o (20ml) to afford Compound 21. m.p. > 250~C. [a]D = -10.5~ (C = 1, CH3~H)-Found: C, 63.62; H, 8.50; N, 4.05%. C18H2gNO3P requires C, 64.08; H, 8.36; N, 4.15%.
31p nrnr ~162MHz; D2O/DCl): ~ (ppm) 55.36.
Example 22 Cl ~ ~ OH
Cl Cnmro~ 22 Using the same procedure as described for the preparation of Compound 20, Compound 18 (0.979g, 2.25mM) and bromotrime~hylsilane (0.89ml, 6.76mM) are reacted in dichloromethane (40ml) to afford trans-2,5-disubstituted morpholine racemic Compound 22. m.p. > 200~C (dec).

Found: C, 52.45; H, 6.53; N, 3.29%. Cl8H26C12NO3P . 0.25H20 requires C, 52.63; H, 6.50; N, 3.41%.

31P nmr (202.5MHz; d4-acetic acid): ~ (ppm) 45.45.

Sodium salt, 31P nmr (162MHz; D2O/DCl): ~ (ppm) 41.89.

Example 23 ~/~ N ~ 0;~

N02 ~nm~lln~l 23 Using the same procedure as described for the preparation of Compound 20, Compound 19 (0.50g, 1.20mM) and bromotrimethylsilane (0.48ml, 3.65mM) are reacted in dichloromethane (25ml) to afford trans-2,5-disubstituted morpholine the racemic Compound23. m.p. 128-130~C.

Found: C, 54.23; H, 7.25; N, 6.93%. Cl8H27N2OsP . H2O requires C, 53.99; H, 7.30; N, 7.00%.

31p nmr (162MHz; CD30D): ~ (ppm) 37.64.

Example 24 ~)~ N U~

~-nmrllntl 24 ~H2 A mixture of Compound 19 (2.98g, 7.26mM) and 10% p~ m on activated charcoal (0.5g) in absolute ethanol (150ml) is hydrogenated for 18 hours. The mixture is filtered and the filtrate is evaporated. The residue is purified by flash chromatography on silica using 10% methanol in dichloromethane as eluant to afford trans-2,5-disubstituted morpholine racemic Compound 24 as a mixture of diastereomers at phosphorus. m.p.115-118~C.

~ Found: C, 62.52; H, 8.88; N, 7.18%. C2oH33N203P . 0.25 H20 requires C, 62.40; H, 8.77;
N, 7.31%.

31p (162MHz; CDCl3): ~ (ppm) 54.16 and 54.72.

Exa~mple 25 ~ N ~0~ ~

C-~m7l~o-lnf1 25 I

Crushed ice (l5g) is added to a stirred solntion of Compound 24 (2.43g, 6.38mM) in con~en~rated hydrochloric acid (50ml) and the resulting mixture is cooled to OIDC. A
solution of sodium nitrite (0.48g, 7.02mM) in water (25ml) is added dropwise and the r~s--lting mixture is stirred for 10 minu~t~.s at 0~C. The resulting solution is then added dropwise to a solution of potassium iodide (11.13g, 67.01mM) in water (200ml). The reaction mixture is stirred for a further 2~ hours at room Le~ ,.dture and then allowed to stand overnight at room temperature. Ethyl acetate is added and the two phases sep~ n-.cl The aqueous phase is neutralized by addition of solid sodium bicarbona~e and extracted witn ethyl acetate. These ethyl acetate extracts are combined with the original organic phase and the combined organic phases are washed with aqueous 10% sodium hydroxide solution followed by aqueous 5% sodium bisulphite solution then water. The organic phase is dried over m~gnesillm sulphate, filtered and evaporated under reduced ~res~.ulc~
The residue is purified by flash chromatography on silica using 10% meth~nQl in ethyl acetate as eluar t to afford trans-2,5-disubstituted morpholine racemic Compound 25 as a mixture of diasLt~Go."ers at phosphorus. Mass spec. (CI/NH3): (m+l)+ m/z = 492.

31p nmr (162MEIz; CDC13): ~ (ppm) 54.21 and 54.77.

Example 26 N gH

~m~ol-71~26 Using snbst~nti~lly the same procedure as described for the ~l~,p~Lion of Compound 20, Co~ .ound 25 (0.lg, 0.20mM) and bromo~imethylsilane (0.427ml, 3.20mM) are reacted in dichloromethane (lOml) for 78 hours at room temperature. The crude product is purified by ion exch~n~e chromatography on Dowex 50WX 2-200 resin (H+ forrn) using meth~n-)l water: aqueous ammonia solution (50%: 47%: 3%) as eluant and the product is dried under high vacuum (~ 0.05 mm Hg) to afford trans-2,5-~ ubstitllte~ morpholine racemic Compound 26. m.p. > 230~C (dec).

Found: C, 44.48; H, 5.70; N, 2.95%. Cl8H27INO3P . 1.2H20 requires C, 44.59; H, 6.11; N, 2.89%.

31p nmr (162MHz; CD30D/DCI): ~ (ppm) 53.08.

Example 27 N~oc~

mr~l~n~l 27 CN
Sodium cyanide impregnated alumina (SmM NaCN per gram of ~ min~) is plG~a.~d by the p~cedure of S. L. Regen, S. Quici and S. J. Liaw described in the Journal Organic Chemistry,1979, 44(12), 2029. To a mixture of tris (dibenzylideneacetone) ~ip~ rlillm W O 97/0933~ PCT/G B96/02113 (O) [0.17g, 0.18lmM], sodium cyanide impregnated ~ min~ (4.7g) and tri(2-furyl)phosphine (0.34g, 1.45mM) under argon is added a solution of Compound 25 (0.89g, 1.8mM) in dry degassed toluene (SOml). The reaction is heated at 80~C for 12 hours. The reaction is monitored by tlc and if required further tris(dibenzyli~lenes~cetc?nf~) rlir~ m (O) ~0.17g, 0.18mM] and tri(2-furyl)phosphine (0.34g, 1.45mM) are added and the reaction heated for 8 hours at 80~C. On completion of the reaction, the ~ LulciS
filtered and the solids washed with ether. The combined filtrate is evaporated under reduced l11GS~I11C: and the residue is purified by flash chromatography on silica using 10%
methanol in ethyl acetate as eluant to afford trans-2,5-disubstituted morpho~ine racemic Compound 27 as a mixture of diastereomers at phosphorus.

Mass spec. (CVNH3): (M+l)+ m/z = 391.

31p nmr (162MHz; CDCl3): ~ (ppm) 53.95 and 54.57.

Example 28 N ~ OH

CN ~n~r~n~28 Using substantially the same procedure as described for the preparation of Compound 20, Compolmd 27 (0.16g, 0.41mM) and bromotrimethylsilane (0.81ml, 6.14mM) are reacted in dichlorometh~ne to afford trans-2,5-disubstituted morpholine racemic Compound 28.

Mass spec. (CI, NH3): M+ m/z = 362.

31p nmr (162~;z; D20tDCl): ~ (ppm) 55.31.

Example 29 N ~ OH

C~m~ 29 COOH
A mixture of Compound 27 (0.09g, 0.23mM), 6M hydrochloric acid solution (lOml) and ethanol (lrnl) is heated under reflux for 72 hours. On completion of the reaction (31p nmr), the solvent is removed under reduced ~l~,S~ulc. The residue is purified by ion exchange chromatography on Dowex 50WX 2-200 resin (H+ form) using methanol: water: aqueous ~mmoni~ solution (50%: 47%: 3%) as eluant and the product is dried under high vacuum (<0.05mm Hg) to afford trans-2,5-disubstituted morpholine racemic Compound 29. m.p.
> 260~C.

31p nmr (162MHz; D2O): ~ (ppm) 40.67.

Example 30 A mixture of Compound 17 (0.50g, 1.18mM), 6M hydrochloric acid solution (25ml) and glacial acetic acid (5ml) is heated at 100~C for 16 hours. On completion of the reaction (31p nmr), the solvent is removed under reduced pressure. The residue is purified by ion exch~nge chromatography on Dowex 50WX 2-200 resin (H+ form) using methanol: water:
aqueous ammonia solution (50%: 47%: 3%) as eluant and the product is dried under high vacuum (S0.05mm Hg) to afford trans-2,5-disubstituted morpholine racemic Compound 29.

Found: C, 58.68; H, 7.35; N, 3.71%. ClgH28N OsP . 0.5H2O requires C, 58.45; H, 7.49; N, 3.59%.

31p nmr (162MHz; D20): ~ (ppm) 40.71.

W O 97/09335 PCT/G~96/02113 Exam~le 31 .

,~/~ N OH--O
H

('nm~l~nri 30 A solution of Compound 29 (317mg, 0.83mM) in methzanol (20ml) is saturated with gaseous hydrogen chloride and the reaction ~ Lul~ stirred for 16 hours at room temp~ ldLu~G. The solvent is removed under reduced plGS~ulc and the residue is purified by ion exchange chromatography on Dowex 50WX 2-200 resin (H+ form) using methanol:
water: aqueous ammonia solution (50%: 47%: 3%) as eluant. The product is d~ied under high vacuum (S0.05 mm Hg) to afford trans-2,5-disubstituted morpholine racemic Compound 30.

Found: C, 60.26; H. 7.57; N, 3.45%. C20H30N OsP . 0.25 H2O requires C, 60.01; H, 7.68;
N, 3.~0%.

31P nmr (162MH:z; CD30D): ~ (ppm) 37.21.

Example 32 OH
O

o;;

cnn.~n.l 31 Using substzln*z~lly the same procedure as described for the preparation of Compound 20, Compound 10 (90mg, 0.246mM) and bromotrimethylsilane (200~1,1.57mM) are reacted in dichloromçth~ne (2ml) to afford Compound 31.
[a]D -38.5~ (C = 0.6, CH30H) 31p nmr (162MHz; CD30D): ~ (ppm) 29.00.
Example 33 OH
r O
IH~
OIm~ 32 Using substantially the same procedure as described for the preparation of Cu~ oul~d 20, Compound 11 (9Omg, 0.246mM) and bromotrimethylsilane (200,u1,1.57mM) are reacted in dichloromethane to afford Compound 32.

[a]D +41.3~ (C = 0.6, CH30H) 31P nmr (162MHz; CD30D): ~ (ppm) 28.84.

Example 34 ~OH
~N ~P--O
COOH (~nm~l ~n~ 33 To a stirred solution of Compound 12 (lOOmg, 0.24mM) in dichloromethane (2ml) under argon is added bromotrimethylsilane (300~L1, 2.4mM) and the reaction is stirred for 24 hours at room te.npeldture. The solvent is removed under reduced ~l-,SSulc and the residue is co-evaporated with a 1:1 mixture of meth~nnl: water. The resulting residue is then dissolved in a mixture of 6M hydrochloric acid (5ml) and methanol (0.3ml) and the mixture is heated under reflux for 4 hours. The solvent is removed under reduced pl~,S , and the residue is co-e~dpoldted three times with water. The resulting residue ,;s purified by ion exch~nge chromatography on Dowex SOWX 2-200 resin using methanol: water:
aqueous ammonia sohltion (50%: 47%: 3%) as eluant to afford Compound 33.

31P nmr (162MHz; CD30D): ~ (ppm) 29.28.

Example 35 N ~~P~O

Cl Cl ('n~-~nri 34 Using subst~nti~lly the same procedure as described for the ~repdlduon of Compound 20, Compolmd 13 (O.Sg, 1.15mM) and bromotrimethylsilane (0.91ml, 6.9mM) are reacted in dichloromethane (lSml) to afford Compound 34.

31p nmr (162MHz; CD30D): ~ (ppm) 29.06.

Exam~,~le 36 OH

N02 Cnm~"n" 35 Using subst~nri~lly the same procedure as described for the preparation of Compound 20, Compound 14 (9Omg, 0.219mM) and bromotrimethylsilane (200~11, 1.57mM) are reacted in dichloromethane (2ml) to afford Compound 35.

31p nmr (162MHz; CD30D): ~ (ppm) 29.57.

ExamPle 37 ~ OH

('nm~-m-l 36 Boron trifluoTi~le ethyl etherate ( 1.25ml, lOmM) is added dropwise to a su~pen~ion of 2-amino-3-(4-iodophenyl)propionic acid (2.9g, lOmM) in THF (lOml) over 20 minut~os The mixture is heated under reflux for 2 hours, then borane dimethyl sulphide complex (l.lml, 1 lmMol) is added dropwise over 1 hour whilst m~int:~ining the mixture at reflux.
The mixture is heated under reflux for a further S hours and then stirred for lS hours at room temperature.

A 1:1 mixture of water and THF (20ml) is added followed by SN sodium hydroxide solution (7.5ml). The reaction mixture is heated under reflux for 7 hours, cooled to room temperature and filtered. The filter cake is washed with THF (2 x lOml) and the filtrate is evaporated to 25% of its original volume and then extracted with dichloromethane. The combin~o-1 organic layers are dried over magnesium sulphate, filtered and evaporated under reduced ~lGS:il.llG to afford a pale yellow solid which is recrystallised from hexane: ethyl acetate (1:2) to afford Compound 36, m.p. 105-107~C.

Found: C, 38.69; H, 4.40; N, 4.92~Yo. C9H,2INO requires C, 39.01; H, 4.37; N, 5.06%.

59 _ Example 38 ~ oc~
I OH
~ ' . '37 Using substantially the same procedure as described for the preparation of Comlpound 12, a mixt~-e of Compound 36 (2.40g, 8.66mM) and Compound 9 (2.7g, 8.66mM) in toluene (20ml) is reactecl with a sohltion of 1,8-diazabicyclo~5.4.0]undec-7-ene (1.30g, 8.66mM) in TH~ (lOml) at 75~C to afford Compound 37 as a 1:1 mixtuIe of diastereomers atphosphorus.

31p nmr (202MHz; CDCL3) ~(ppm) 43.69 and 43.72.

Example 39 ~~~ P~

38 l~ans]
C~.,Y.~n.i 39 [c~s]
A suspension of sodium hydride (O.105g, 4.4mM) in dry toluene (5ml) is added portionwise over 30 seconds to a stirred solution of Compound 37 (2.0g, 4.0m~) in dry toluene (25ml). The mixture is stirred for 30 minUt~s at 0~C and then for 3 hours at room lenlp~.~ture. Glacial acetic acid (lml) is added, then the reaction mixture is diluted with ethyl acetate (75ml). The organic phase is washed with saturated sodium bicarbonate solution, water and tnen brine. The combined organic phases are dried over m~ne~ m sulphate, filtered and evaporated. The residue is purified by flash chromatography on silica using 20% methanol in ethyl acetate as eluant to afford trans-2, S-disubstituted morpholine racemic Compound 38 and cis-2, 5- disubstituted morpholine racemic CA 02229036 l998-02-06 Compound 39 each as a mixture of diasL~.~o",ers at phosphorus.

Compound 38: 31p nmr (162MHz; CDCl3) ~ (ppm) 53.93 and 54.60 Compound 39: 31p nmr (162MHz; CDCl3) ~ (ppm) 54.25 and 54.82 ppm.

Example 40 \\~ ~N O N~

('nmr~l~nfJ 40 To a stirred solution of Compound 38 (180 mg, 0.356 mM) in dichloromethane (5ml)under argon is added dropwise brc.motrimethylsilane (0.20ml, 1.52mM). The reaction mixture is stirred for 20 hours at room temperature. The solvent is removed under reduced pl~ C and the residue coevaporated with 1: 1 water:methanol (2 x 0.5ml). The residue is purified by ion exchange chromatography on Dowex SOWX 2-200 resin (H+ form) using meth~noh 2% sodium hydroxide solution (1:1) to elute the product. The resulting product is further purified by gel filtration on a Bio-Gel P2 column using water as eluant to afford trans-2, 5-disubstituted morpholine racemic Compound 40, m.p. >250~C (dec).

Found: C, 41.42; H, 5.40; N, 2.42%. ClgH28I NO3 P.Na. 3H2O requires C, 41.20; H, 6.10;
N, 2.53%.
31p nmr (161MHz; D2O): ~ ~ppm) 41.~1.

CA 02229036 l998-02-06 Example 41 o CH3CH2~

N OcH2cH

C.~ 4 1 A mixture of Compound 38 (0.180g, 0.36mM) and bis triphenylphosphine p~ m (II) chloride (0.200g, 0.28mM) in absolute ethanol (2ml) and triethylamine (lml) is rleg~
by sparging with argon for 5min. The mixture is heated under reflux and vigorously stirred under an atmosphere of carbon monoxide for 3 hours. The mixture is cooled to room temperature and the solvent is removed under reduced pressure to afford an oily solid which is triturated with ethyl acetate. The combined ethyl acetate washings are evaporated under reduced ~ u~c and the residue is purified by flash chromatography on silica using 10% methanol in chloroform as eluant to afford trans-2, S-disubstituted morpholine racemic Compound 41 as a mixture of diastereomers at phosphorus.

31p nmr (161 M Hz; CDC13): ~ (ppm) 53.93 and 54.60.

Example 42 N-+ O2C N ~ ¦

c. . 42 A mixture of Compound 41 (0.095g, 0.21mM) and 6M hydrochloric acid solution (4ml) is heated under reflux ~or 20 hours. On completion of the reaction (31p nmr) the solvent is removed under reduced ~ s~ure and the residue is purified by ion exchange CA 02229036 l998-02-06 chromatography on Dowex 50WX 2-200 resin (H+ form) using meth~nol- 2% sodium hydroxide solution (1: 1) to elute the product. The resulting product is further purified by gel filtration on a BIO-GEL P2 column using water as eluant to afford trans-2, 5-disubstituted morpholine racemic Compound 42, m.p. >250~C (dec).

Found: C, 50.53; H, 7.40; N, 2.96%. C20H2gNOsP. Na. 2H20 ~ u-l~s C, 50.52; H, 6.79;
N, 2.95%.

31p nmr (202MHz, D20): ~ (ppm) 42.38.

Example 43 ~ 1~

C02~Na ~n~ro~ln~43 A buffered stock solution of formaldehyde is ~lGpal~,d by dissolving sodium acetate (1.8g, 21.4mM), acetic acid (1.3ml, 22.7mM) and40% aqueous formaldehyde sohlticn (7.0ml;
lOlmM) in water (Sml). An aliquot (lOml) of the above stock solution is added to a mixture of Compound 29 (O.lOg, 0.262mM) in methanol (2ml) and the mixture is stirred for 10 mimlt~s at room temperature. Sodium cyanoborohydride (0.165g, 2.62mM) is added portionwise over 2 minutes. The ~ cLule iS stirred for 24 hours at room lc~ ,.dture. The solvent is removed under reduced p~es~u~c; and the residue purified by ion e~ch~nge chromatography on Dowex 50WX 2-200 resin (H+ form) using meth~nol 2% sodium hydroxide solution (1:1) to elute the product. The resulting product is further purified by gel filtration on a BIO-GEL P2 column using water as eluant to afford the trans-2, 5- disubstituted morpholine racemic Compound 43, m.p. >250~C (dec).

Found: C, 52.60; H, 6.82; N, 3.10%. C20H28NOsP. 2Na. H20 requires C, 52.52; H, 6.61;
N, 3.06%.

31p nmr (202 MHz; D20) ~ (ppm) 41.93.

Example 44 N ~ j/~
o~a+

C02~a+ ~3 I'nmr~
Compound 29 (0.25g, 0.66mM) is dissolved in a 1: 1 mixture of dioxan: water ~4mlj and the pH of the resulting solution is adjusted to pH 9 by the addition of 0. lM sodium hydroxide solution. The mixture is vigorously stirred and benzyl chloroformate (0.188ml, 1.32mM) is added dropwise over lS minnttos The pH of the Illi~lUlC iS adjusted to pH9 by further addition of 0. lM sodium hydroxide solution and the mixture is stirred for 20 hours at room temperature. The Illi~Lulcisconcentrated under reduced p,es~.u,~ to one half of its ~rigin~l volume and ?~ci-lified with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and the combined organic phases are washed with water then brine, dried over m~gnç~illm sulphate, fi1tered and evaporated. The residue is purified by flash chromatography on silica using acetic acid: meth~nol: chlolv~l-n (2% :10%: 88%) as eluant. The product is further purified by ion exchange chromatography on Dowex 50 WX 2-2!00 resin (H~- form) using THF: water (3:1) as eluant. The reslllting product is dissolved in 1% sodium hydroxide solution (2.5ml) and purified by gel filtration on a BIO-GEL P2 column using water as eluant to afford trans-2, 5-disubstituted morpholine ~ racemic Compound 44, m.p. > 250~C (dec).

Found: C, 52.27; H, 6.00; N, 2.24%. C27 H32 N O7 P. 2 Na. 3H2O requires C, 52.85; H, 6.24; N, 2.28%.

31p nmr (161 MHz; D2O) ~ (ppm) 41.75.

Example 45 OH

~ nm7r-171~45 Boron t;iflu~-ri~le ethyl etherate (75.0ml, 0.61M) is added dropwise to a suspension of compound J (70.2g, 0.3 lM) in THF (350ml) over 20 minutes. The mixture is heatedunder reflux for 2 hours, then borane dimethyl sulphide complex (57.9ml, 0.61M) is added dropwise over 1.5 hours whilst m~int~ining the mixture at reflux. The mixture is heated under reflux for a further 3 hours and then stood for 18 hours at room tem~.,,dLulc.

A 1: 1 mixture of water and THF (350ml) is added followed by SM sodium hydroxidesolution (350ml). The reaction mixture is heated under rcflux for 5 hours then cooled to room L~ dture. The two layers are separated and the aqueous layer extracted withethyl acetate. The combined organic phases are washed with brine, d;ied over m~nesinm sulphate, filtered and evaporated under reduced plCSSUlC to afford a brown oil.

This residue is triturated with diethyl ether/hexane then recrystallised fro;n ethyl acetate to afford compound 45, m.p. 74-76~C.

Found C, 44.40; H, 4.67; N, 6.35%.
C8HlOBr NO requires C, 44.46; H, 4.67; N, 6.48%.

Example 46 .

OH

On..~ ri 4 A mixture of compound 45 (15.0g, 69.4mM) and bis(triphenylphosphine) p~ rn (II) chloride (4.0g, 5.70mM) in methanol (lOOml) and triethylamine (25ml) is degassed by sparging with argon for 5 minuteS The mixture is saturated with carbon monoxide and then pressurised ~o 30 psi in a IJlCS~UlC vessel. The mixture is slowly heated to 100~C
whilst m~int~ining the ~l~,..'.Ult; below 50psi for 5 hours. The mixture is cooled to room .ature, filtered and evaporated. The residue is triturated with ethyl acetate and the filtrate evaporated. The residue is purified by flash chromatography on silica using a gradient from 10% to 20% methanol in chloroform as eluant to afford compound 4.

13C mnr (lOOMHz; CD30D): ~(ppm) 52.6 (q), 58.3 (d), 68.1 (t), 129.0 (d), 129.5 (d), 129.7 (d), 131.5 (s), 132.9 (d), 143.6 (s), 168.4 (s).

Example 47 OH O

¦ H ¦

f'~m~-~n-1 46 (2R/S)-2-amino-2- (lH-indol-3-yl)ethanol is prepared by the procedure of A.H. Katz et.al described in the Journal ~lic inz~l Chemistry, 1988, 31, 1244.

Using subst~nti~lly the same procedure as described for the preparation of Compound 12, a uli~Lulc of (2R,/S)-2-amino-2-(lH-indol-3-yl) ethanol (0.39g, 2.21mM) and Compound 9 (0.68g, 2.20mM) in toluene/l~ (lOmU15ml) is reacted with a sollltion of1,8-diazabicyclo ~5.4.0~undec-7-ene (0.33g, 2.17mM) in toluene (Sml) at 75~C to afford Compound 46 as a 1 ~ cLul~, of diasL~.~ul--ers at phosphorus.

31p nmr (162 MHz; CDCl3): â(ppm) 43.25 and 43.43.

Example 48 0\ N ~ OCII~C lll A sncp~oncion of sodium hydride (0.014g, 0.59mM) in dry toluene (lOml) is stirred at 0~C.
A solution of Compound 46 (0.200g, 0.49mM) in dry toluene (7ml) is added dropwise.
The reaction mixture is allowed to warm slowly to room temperature and stirred for 4 hours. Glacial acetic acid is added to quench the reaction, then the mixture is filtered and evaporated. The residue is purified by flash chromatography on silica using 20%
methanol in ethyl acetate as eluant to afford trans-2,5-disubstituted morpholine racemic Compound 47 as a mixture of diastereomers at phosphorus.

Mass spec. (CI/NH3): (M+1)+ m/z = 405.

31 p nmr (162 MHz; CDC13): ~ (ppm) 54.44 and 55.32.

Example 49 H o N.~

Cn~.ln.1 4g Using subst~nh~lly the same procedure as ~1~scrihe~l for the preparation of Compound 40, Compound47 (O.llSg,0.28mM) andbromotrimethylsilane (0.15ml, 1.13mM) arereacted in dichloromethane (5ml) for 3 days at room ~ eldture to afford trans-2,5-disub~ ut~d morpholine race:mic Compound 48.

13C nrrLr (lOOMHz; D20) ~ (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).

31p nmr (202 MHz; D20) ~ (ppm) 42.6.

Example 50 CH3 ~

Cnm~n~49 Using subs~n*~lly the same procedure as described in Example 37, DL-2-amino-3-methyl-2-penylbutyric acid (10.Og, 51.8mM), boron trifluoride ethyletherate (6.4ml, S 1.8mM) and borane dimethyl sulphide complex (4.9ml, S l.~mM) are reacted in dry THF (SOml) to afford Compound 49.

W O 97/0933~ PCT/G B96/02113 Mass spec. (CI, NH3): (m+l)+ m/z = 180.

13C nmr (lOOMHz; CDCl3) 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 S 1 CH ~ N

Cnn~ nA 50 Using substantially the same procedure as described in Example 12, a mixture of Compound 49 (1.07g, 6.0mM) and Compound 9 (1.86g, 6.0mM) in toluene (20ml) is reacted with a solution of 1, 8 - diazabicyclo [5.4.0]undec-7-ene (l.lg, 7.2mM) in toluene (Sml) at 75~C to afford Compound 50 as a 1: 1 mixture of diastereomers at phosphorus.

r~ass spec. (CI, NH3): (m + 1)+ m/z = 408.
31p (202.~ MHz; CDC13) ~ (ppm) 44.22 and 44.25.

Example 52 (2R~, 5R*) Cnmrl~nA 51 (2R~. SS~ Imr~llnr1 52 Using subst~nti~lly the same procedure as described in Example 39, Compound 50 (200mg, 0.49mM) and sodium hydride (12mg, 0.49mM) and sodium hydride (12mg, 0.49mM) are reated in dry toluene (3ml). The crude product is purified by flash chromatography on silica using 10% methanol in ethyl acetate as eluant to afford (2R*, 5R*) morpholine racemic Compound 51 and (2R*, 5S*) morpholine racemic Compound 52 each as a mixlure of diastereomers at phosphorus.
Compound 51: 3 I P nmr (162MHz; CDCl3) ~ (ppm) 54.3 and 55Ø
Compound 52: 31p nmr (162MHz; CDCl3) ~ (ppm) 54.2 and 55.5.
Example 53 CH~ ~N ~o ~O

~~ nrr~ n~1 53 Using subst~nri~lly the same procedure as described in Example 40, Compound 51 (40mg, O.lmM) and bromotrimethylsilane (0.066ml, 0.5mM) are reacted in d~ry dichloromethane (1 ml) to afford (2R*, 3R*) morpholine racemic Compound 53.
31p nmr (202.5MHz; D20) ~ (ppm) 42.5.

Example 54 CH3 ~ N
1 O~Na+

Cnm~ n~S4 Using subst~nti~lly the same procedure as described in Exarnple 40, Compound 52 (180mg, 0.2mM)I and bromotrimethylsilane (0.132ml, l.OmM) are reacted in dry dichloromethane (2 ml) to affo;d (2R*, 5S*) morpholine racemic Compound 54.
31P nmr (202.5M:Hz; D20) ~ (ppm) 42.2.

Example 55 o CH3 OcH2cH3 ~ ~ OCH2CH3 t'nmrolm-i 55 A 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (50ml, 25mM) is added dropwise to a cooled (-70~C) solution of ethyl l,l-diethoxyethylphosphinate (5.25g, 25mM) in dry THF (30ml). The mixture is stirred for 0 5 hours at -70~C. The rçslliting solution is added dropwise over ten min~t~s to a cooled solution of 4-methoxybenzyl chloride (3.9g, 25mM) in THF (30ml). The resulting mixture is stirred for 1 hour at -70~C
and then allowed to warm to room lc-..peldture. Reaction is stirred for 18 hours at room temperature. Glacial acetic acid is added and the reaction is evaporated. The residue is partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase is separated and washed with water then brine, dried over magnt~sillm sulphate, filtered and evaporated. The residue is purified by flash chromatography on silica using ethyl acetate: hexane (2:1) as eluant to afford Compound 55.

31P nmr (162MHz; CDC13) ~ (ppm) 44.6.

Example 56 ~- H
~1 .

Comrol~nA56 Chlorotrimethylsilane (3.8ml, 30.3mM) is added to a solution of Compound 55 (l.Og, 3.03mM) in a 9:1 mixture of chl~oful.,l: ethanol (lOml) and the mixture is stirred for 18 hours at room le,--~G~ture. The mixture is evaporated under reduced pressure and the residue is co-evaporated with chloroform. After drying under high vacuum, the residue is CA 02229036 l998-02-06 purified by flash chromatography on silica using ethyl acetate as eluant to afford Compound 56 as a colourless oil.

Mass spec. (CI, N H3): (m + N H4)+ m/z = 232.
31p mnr (162MH[z; CDCl3): ~ (ppm) 37.3.

Example 57 ~ i'~~--6~'Br Cnm~nAS7 Using substantially the same procedure as described in Example 9, Compound 56 (O.Sg, 2.33mM), bis(trimethylsilyl)acetamide tO.69ml, 2.80mM), trimethyl phosphate (0.33ml, 2.80mM) and 1,3-dibromo~lvpene (mixture of cis/trans isomers) (0.23ml, 2.33mM) are reacted in dry dichloromethane (lOml) to afford Compound 57 as a mixture of cis and trans isomers.

31p nmr (162MHz; ~L)C13) ~ (ppm) 47.2 and 48.1.

Example 58 OH O

N ~ ~y6~ ~

rn~..nA58 Using subst~nti~llly the same procedure as described in Example 12, a mixture ofCompound 4 (O.193g, 0.99mM) and Compound 57 (0.330g, 0.99mM) in toluene/l~IF
(lOml, 4:1 mixhlre) is reacted with a solution of 1,8-diazabicyclo [5.4.0]undec-7-ene (0.181g7 1.19mM) in toluene (2ml) at 80~C to afford Compound 58 as a 1:1 mixture of diastereomers at phosphorus.

Mass spec. (CI, NH3): (m+1)+ m/z = 448.

31p nmr (162MHz; CDCl3) ~ (ppm) 39.40 and 39.49.

Example S9 OCnt~l~ 3 ~nm~lm-l 59 Using substantially the same procedure as described in Example 39, Compound 58 (200mg, 0.45mM) and sodium hydride (10.8mg, 0.45mM) are reacted in toluene (2ml) to afford trans-2,5-disubstituted morpholine racemic Compound 59 as a mixture of diastereomers at phosphorus.

31p nmr (162MHz; CDC13) ~ (ppm) S0.0 and 50.8.

ExamPle 60 ~ OCH3 CO~2Na+
c~ 60 Bromotrimethylsilane (0.074ml, O.SSmM) is added to a solution of Compound 59 (50mg, 0.1 lmM) in dichloromethane (1 ml) and the reaction is stirred for 24 hours at room Jcldture. The solvent is removed under reduced pressure and the residue is co-evaporated with a 1: 1 mixture of methanol: water. The resulting residue is dissolved in 6M hydrochloric acid (2ml) and the mixture is heated under reflux for 4 hours. The solvent is removed under reduced pressure and the residue is co-evaporated three times with water. The resulting residue is purified by ion exchange chromatography on Dowex 50 WX 2-200 resin (H+ form) using meth~n~ 2% sodium hydroxide solution (1:1) to elute the product:. The resulting product is further purified by gel filtration on a. BIO-GEL
P2 column using water as eluant to afford the trans-2,5-disubstituted morpholine racemic Compound 60.
31p nmr (2Q2.5MHz; D20) ~ (ppm) 37 4

Claims (37)

Claims
1. A compound which is a substituted phosphinic acid of formula or a salt or ester thereof, where R1 is a monovalent aromatic or araliphatic group connected through a carbon atom thereof to the indicated carbon atom, R2 is an unsubstituted or substitutedhydrocarbyl group, Rx is hydrogen or an unsubstituted or substituted hydrocarbylgroup, Ry is hydrogen, Rya or a NH-protecting group and Rya is an unsubstituted or substituted hydrocarbyl group.
2. A compound according to claim 1, in which R1 is an aryl group of 6 to 15 carbon atoms which is unsubstituted or substituted in one or more positions by halogen,hydroxy, C1 to C4 alkoxy, carboxyl, functionally modified carboxyl, carboxy - C1-C8 alkyl, functionally modified carboxy - C1-C8 - alkyl or nitro, or R1 is a 5 to 10-membered heterocyclic aromatic group having one or two nitrogen atoms in the ring system.
3. A compound according to claim 1, in which R1 is phenyl or phenyl substituted in one or more of the meta and para positions, with respect to the carbon atom thereof linked to the indicated morpholine ring, by halogen, carboxyl, functionally modified carboxyl or nitro, or R1 is a 5 to 10-membered heterocyclic aromatic group having a nitrogen atom as the only ring hetero atom.
4. A compound according to claim 1, in which R1 is a phenyl-lower alkyl, .alpha., .alpha.-diphenyl - lower alkyl or .alpha.-naphthyl-lower alkyl group, said group being unsubstituted or substituted in one or more positions by halogen, hydroxy, C1 to C4 alkoxy, calboxyl, functionally modified carboxyl, carboxy - C1-C8 alkyl, functionally modified carboxy - C1-C8 alkyl or nitro.
5. A compound according to claim 1, in which R1 is .alpha.-phenyl - C1-C4 alkyl which is unsubstituted or substituted in one or more positions by halogen, carboxyl, functionally modified carboxyl or nitro.
6. A compound according to claim 1, in which R1 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. A compound according to any of the preceding claims, in which R2 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(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, cycloalkyl-(hydroxy)-lower alkyl, (lower alkylthio)cycloalkyl(hydroxy)-lower alkyl, or mono-or di-phenyl-lower alkyl that is unsubstituted or mono-, di- or tri-substituted by lower alkyl, lower alkoxy, halogen, hydroxy and/or by trifluoromethyl, naphthyl-lower alkyl or unsubstituted or halo-substituted thienyl-, furyl- or pyridyl-lower alkyl.
8. A compound according to claim 7, in which R2 is C1-C7alkyl, .alpha.,.alpha.-di-C1-C4alkoxy-C1-C4alkyl, cyano-C1-C4 alkyl, acylamino-C1-C5 alkyl, C3-C6cycloalkyl-C1-C4-alkyl, C3-C6cycloalkenyl-C1-C4alkyl or is phenyl-C1-C4alkyl that is unsubstituted or mono-, di- or tri-substituted by C1-C4alkyl, C1-C4alkoxy, hydroxy and/or by halogen.
9. A compound according to claim 7, in which R2 is C1-C5 alkyl, .alpha.,.alpha.-di-(C1-C4 alkoxy)methyl, .alpha.,.alpha.-di-(C1-C4 alkoxy)ethyl, C3-C6 cycloalkyl-C1-C4 alkyl, benzyl or 4-methoxybenzyl.
10. A compound according to claim 7, in which R2 is cyclohexylmethyl or 4-methoxybenzyl.
11. A compound according to any of the preceding claims, in which Rx as unsubstituted or substituted hydrocarbyl is a C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C8 cycloalkyl, C4 to C13 cycloalkylalkyl, C6 to C10 aryl or C7 to C13 aralkyl group, said group being unsubstituted or substituted by halogen, hydroxy, C1 to C4 alkoxy, carboxyl, functionally modified carboxyl, carboxy - C1-C8 alkyl, functionally modified carboxy - C1 - C8 alkyl or nitro.
12. A compound according to any of the preceding claims, in which Rx is hydrogen, lower alkyl, C3 to C6 cycloalkyl, C6 to C8 aryl or C7 to C9 aralkyl.
13. A compound according to claim 12, in which Rx is hydrogen or isopropyl.
14. A compound according to any of the preceding claims, in which RY is RYa and is a C1 to C10 alkyl, C3 to C8 cycloalkyl or C7 to C13 aralkyl group, said group being unsubstituted or substituted by hydroxy or C1 to C4 alkoxy.
15. A compound according to any of claims 1 to 13, in which RY is a NH-protecting group and is an acyl, alkoxycarbonyl or aralkoxycarbonyl group.
16. A compound according to any of claims 1 to 13, in which RY is hydrogen, lower alkyl, C7 to C9 aralkyl, tert-butoxycarbonyl or benzyloxycarbonyl.
17. A compound according to claim 1, in which R1 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, R2 is cyclohexylmethyl or4-methoxybenzyl, Rx is hydrogen or isopropyl and Ry is hydrogen, methyl or benzyloxycarbonyl.
18. A compound according to any of the preceding claims, which is of formula or or or where R1 is as defined in any of claims 1 to 6, R2 is as defined in any of claims 1 and 7 to 10, Rx is as defined in any of claims 1 and 11 to 13 and Ry is as defined in any of claims 1 and 14 to 16.
19. A compound of formula where R1 is as defined in any of claims 1 to 6, R2 is as defined in any of claims 1 and 7 to 10 and Rx is as defined in any of claims 1 and 11 to 13, or a salt or ester thereof.
20. A compound of formula where R2 is as defined in any of the claims 1 and 7 to 10, X is halogen and R5 is C1 to C8 alkyl, provided that R2 is not methyl when R5 is ethyl.
21. A compound of formula or or or where R4 is 3-metnoxycarbonylphenyl, R6 is hydrogen or an alkyl group of 1 to 8 carbon atoms which is unsubstituted or substituted by an unsubstituted or substituted C6 to C10 aryl group, R7 is an alkyl group of 1 to 10 carbon atoms and Rx is hydrogen or unsubstituted or substituted hydrocarbyl, or a compound of formula II or VIIIwhere R4 is 3,4-dichlorophenyl and R7 is an alkyl group of 1 to 10 carbon atoms, or a compound of formula II in which R4 is a monovalent aromatic group connected through a carbon atom thereof to the indicated carbon atom and Rx is an unsubstituted or substituted hydrocarbyl group with the provisos that when R4 isphenyl Rx is not methyl, ethyl, -(CH2)3SCH3, allyl or methylol, that when Rx is aminomethyl R4 is not phenyl, p-hydroxyphenyl or p-methoxyphenyl and that when R4 is 2,4-dichlorophenyl, Rx is not N-triazolylmethyl, or a compound of formula II
in which R4 is iodobenzyl and Rx is hydrogen or an unsubstituted or substituted hydrocarbyl group, or a compound of formula II in which R4 is a monovalent araliphatic group R1 as defined in any of claims 1 and 4 to 6 and Rx is an unsubstituted or substituted hydrocarbyl group as defined in any of claims 1 and 11 to 13 other than methylol, with the provisos that when Rx is methyl, R4 is not benzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 2-phenylethyl, 1,3-benzodioxol-5-methyl, 3-phenyl-1-aminopropyl, .alpha.-hydroxybenzyl, .alpha.-hydroxy-.alpha.-methylbenzyl or .alpha.-hydroxy-.alpha.-methyl-4-nitrobenzyl, and that when R4 is benzyl, Rx is not allyl or -CH2CH2SCH3.
22. A compound of formula where R1 is as defined in any of claims 1 to 6, R2 is as defined in any of claims 1 and 7 to 10, Rx is as defined in any of claims 1 and 11 to 13 and Ry is as defined in any of claims 1 and 14 to 16, or a salt or ester thereof.
23. A method of preparing a compound according to claim 1 where Ry is hydrogen which comprises reacting a compound of formula where R4 is R1 as defined in any of claims 1 to 6, with the proviso that R4 is not substituted by carboxyl, and Rx is as defined in any of claims 1 and 11 to 13 with the proviso that it is not substituted by carboxyl, with a compound of formula where R2 is as defined in any of claims 1 and 7, to 10, X is halogen and R5 is C1 to C8 alkyl, in the presence of a base to give a compound of formula where R4 and Rx are as defined in formula II, followed, where required, by one or more substitution reactions to change the nature of a substituent in R4 and/or Rx and/or by hydrolysis of an ester substituent in R4 and/or Rx to carboxyl and/or by conversion of the ester group -OR5 to -OH.
24. A method according to claim 23, in which the reaction of the compounds of folmulae II and III is carried out by adding a weak base to a mixture of the compounds of formulae II and III in a solvent to give an intermediate of formula where R2, R4, R5 and Rx are as defined in claim 23, and then treating the intermediate with base under harsher conditions than those employed in its formation.
25. A method according to claim 23 or 24, in which R4 in the compound of formula IV
contains a nitro group on an aryl or heteroaryl ring and this group is converted in turn to amino by reduction, to halo by diazotisation of amino followed by reaction with an alkali metal cyanide and thence to carboxyl by hydrolysis of cyano.
26. A method of preparing a compound according to claim 20 which comprises reacting a compound of formula with a compound of formula where R2, R5 and X are as defined in claim 20, in the presence of a silylating agent which undergoes reaction with the compound of formula IX to form a P(III) silyl compound which then reacts with the compound of formula X.
27. A method of preparing a compound of formula II according to claim 21, which comprises reacting an aldehyde or ketone of formula R4C(=O)Rx with an amine of formula R6NH2 and an alkali metal cyanide to give a compound of formula and either(a) reacting the compound of Formula VI with an alcohol of Formula R7OH in the presence of an acid to form a compound of formula removing R6, when R6 is other than hydrogen, from the compound of formula VII togive a compound of formula reacting the compound of formula VIII with an amino-protecting agent to convert the amino group into a protected amino group, reducing the ester group -COOR7 inthe protected compound to -CH2OH and removing the protecting group to form a free amino group, where R4, R6, R7 and Rx are as defined in claim 21; or (b) subjecting the compound of formula VI to acid hydrolysis to convert the indicated cyano group to carboxyl and reducing the resulting aminocarboxylic acid by reaction with borane dimethyl sulphide in the presence of a boron trifluoride complex.
28. A method of preparing a compound of formula II according to claim 21, which comprises reducing an aminocarboxylic acid of formula R4C(Rx)(NH2)COOH, where R4 and Rx are as defined in claim 21,by reaction with borane dimethyl sulphide in the presence of a boron trifluoride complex.
29. A method of preparing a compound according to claim 1 in which Ry is Rya which comprises reacting a compound of formula I as defined in claim 1 where Ry is hydrogen with either (a) a compound of formula RyaZ where Rya is as defined in claim 1 and Z is a leaving moiety or (b) an aldehyde of formula Ryb CHO, where Ryb is hydrogen or Rya as defined in claim 1, and a reducing agent which reducesimines to amines.
30. A method of preparing a compound according to claim 1 in which Ry is a NH-protecting group which comprises reacting a compound according to claim 1 in which Ry is a NH-protecting group which comprises reacting a compound according to claim 1 in which Ry is hydrogen with an acyl halide, a carboxylic acid anhydride, an alkoxycarbonyl or aralkoxycarbonyl halide or an alkyl or aralkyl dicarbonate.
31. A method of preparing a compound according to claim 1 in which Ry is Ry, or a NH-protecting group, which comprises reacting a compound of formula with a compound of formula III as defined in claim 23 in the presence of a base to give a compound of formula where R4, Rx, R2 and R5 are as defined in claim 23 and Ry is Rya or a NH-protecting group as defined in any of claims 1 and 14 to 16 followed, where required, by one or more substitution reactions to change the nature of a substituent in R4 and/or Rx and/or by hydrolysis of an ester substituent in R4 and/or Rx to carboxyl and/or by conversion of the ester group -OR5 to -OH.
32. A method of preparing a compound according to claim 1 which comprises reacting a compound of formula to convert the indicated primary hydroxyl group into a leaving moiety, thereby effecting cyclisation to give a compound of formula where R2, R4, Rx and Ry are as defined in claim 1 and R5 is as defined in claim 23, followed, where required, by replacement of Ry as a NH-protecting group by hydrogen and/or by one or more substitution reactions to change the nature of a substituent in R4 and/or Rx and/or by hydrolysis of an ester substituent in R4 and/or Rx to carboxyl and/or by conversion of the ester group -OR5 to -OH.
33. A method of preparing a compound of formula XIV as defined in claim 32 whichcomprises reacting a compound of formula II as defined in claim 23 with a compound of formula where R2 and R5 are as defined in claim 32, and Z is a leaving moiety, in the presence of a hindered base, to give a compound of formula where R2, R4, R5 and Rx are as defined in claim 32, and replacing the indicated hydrogen attached to nitrogen by a NH-protecting group.
34. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of claims 1 to 19 or 22, optionally together with a pharmaceutically acceptable carrier.
35. A compound according to any of claims 1 to 19 or 22 for use in a therapeutic method of treating a warm-blooded animal.
36. Use of a compound according to any of claims 1 to 19 or 22 in the preparation of a medicament for the treatment or prevention of a condition characterised by stimulation of a GABAB receptor.
37. A method of treating or preventing a condition in a warm-blooded mammal characterised by stimulation of a GABAB receptor which comprises administering to the mammal a compound according to any of claims 1 to 19 or 22.
CA002229036A 1995-09-07 1996-08-30 Substituted phosphinic compounds and their use as pharmaceuticals Abandoned CA2229036A1 (en)

Applications Claiming Priority (4)

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GB9518186.3 1995-09-07
GBGB9518186.3A GB9518186D0 (en) 1995-09-07 1995-09-07 Chemical Compounds
GBGB9613047.1A GB9613047D0 (en) 1996-06-21 1996-06-21 Chemical compounds
GB9613047.1 1996-06-21

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CA (1) CA2229036A1 (en)
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CA3174516A1 (en) 2014-03-06 2015-09-11 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
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PL324987A1 (en) 1998-07-06
AR004682A1 (en) 1999-03-10
NO980994D0 (en) 1998-03-06
JPH11512111A (en) 1999-10-19
IL123191A0 (en) 1998-09-24
MX9801839A (en) 1998-08-30
AU6831996A (en) 1997-03-27
CN1196057A (en) 1998-10-14
CZ66498A3 (en) 1998-07-15
TR199800414T1 (en) 1998-05-21
SK30198A3 (en) 1998-08-05
HUP9802260A3 (en) 1999-10-28

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