USE OF PHOSPHONIC ACID ESTERS FOR THE TREATMENT OF FUNCTIONAL DISORDERS OF THE BRAIN AND DEPRESSION

UTILISATION D'ESTERS D'ACIDE PHOSPHONIQUE POUR LE TRAITEMENT DE TROUBLES FONCTIONNELS DU CERVEAU ET DE LA DEPRESSION

English Abstract

The present invention relates to the use of phosphonic acid esters for the
treatment and prevention of functional disorders of the brain and depression.

French Abstract

L'invention concerne l'utilisation d'esters d'acide phosphonique pour le traitement et pour la prévention de troubles fonctionnels du cerveau et de la dépression.

Claims

- 26 -
Claims
1. Compound of the general formula
<IMG>
in which
R represents straight-chain or branched alkyl which has up
to 6 carbon atoms and is optionally substituted by
one or more halogen atoms,
R1 represents hydrogen or straight-chain or branched
alkyl with up to 6 carbon atoms,
R2 represents hydrogen or
represents straight-chain or branched alkyl,
alkylcarbonyl, alkoxycarbonyl or alkylsulphonyl with
in each case up to 6 carbon atoms in the alkyl
group, or
represents alkyl- or dialkylaminocarbonyl with in
each case up to 4 carbon atoms in the alkyl groups,
R3 represents straight-chain or branched alkyl with up
to 6 carbon atoms, and can be identical or different,
and
X represents oxygen or sulphur,
but does not denote oxygen where R represents
tri-chloromethyl, R1 represents hydrogen and
R2 represents hydrogen or propylcarbonyl,

- 27 -
and their salts and isomers,
for therapeutic use.
2. Compounds according to Claim 1, wherein
R represents straight-chain or branched alkyl with up
to 4 carbon atoms or trifluoromethyl,
trichloromethyl, difluoromethyl, 1,1-dichloroethyl,
dichloromethyl, fluoromethyl, chloromethyl,
dichlorofluoromethyl, difluorochloromethyl or
represents the radical of the formula -CCl2CH2Cl,
(1,1,2-trichloroethyl),
R1 represents hydrogen or straight-chain or branched
alkyl with up to 4 carbon atoms,
R2 represents hydrogen or
represents straight-chain or branched alkyl,
alkylcarbonyl, alkoxycarbonyl or alkylsulphonyl with
up to 4 carbon atoms in the alkyl group, or
represents alkyl or dialkylaminocarbonyl with in
each case up to 3 carbon atoms in the alkyl groups,
R3 represents straight-chain or branched alkyl with up
to 3 carbon atoms, and can be identical or different,
and
X represents oxygen or sulphur,
but does not denote oxygen where R represents
trichloromethyl, R1 represents hydrogen and R2
represents hydrogen or propylcarbonyl,
and their salts and isomers,
for therapeutic use.

- 28 -
3. Compounds according to Claim 1, wherein
R represents methyl, tert. -butyl, 1,1-dichloroethyl,
chloromethyl, dichloromethyl, trichloromethyl,
trifluoromethyl, dichlorofluormethyl,
difluorochloromethyl or
the radical -CCl2CH2Cl, (1,1,2-trichloroethyl),
R1 represents hydrogen or methyl,
R2 represents hydrogen, methyl, ethyl, methylcarbonyl,
ethylcarbonyl, propylcarbonyl, tert.-butylcarbonyl,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
tert.-butoxycarbonyl, methylsulphonyl,
e t h y l s u l p h o n y l, p r o p y l s u l p h o n y l,
methylaminocarbonyl, dimethylaminocarbonyl or
propylaminocarbonyl,
R3 represents methyl, ethyl or propyl,
and
X represents oxygen or sulphur,
but does not denote oxygen where R represents
trichloromethyl and R1 represents hydrogen or
propylcarbonyl,
and their salts and isomers,
for therapeutic use.
4. Compounds according to any of claims 1 to 3, wherein
R represents methyl, trifluoromethyl or tert.-butyl,
R1 represents hydrogen or methyl,

- 29 -
R2 represents hydrogen,
R3 represents methyl
and
x represents oxygen,
and their salts and isomers,
for therapeutic use.
5. Medicaments containing at least one phosphonic acid
ester according to claim 1 to 4 as well as suitable
formulation auxiliaries.
6. Medicaments according to claim 5 for the treatment
and prevention of functional disorders of the brain and
depression.
7. Use of compounds according to claim 1 to 4 for the
preparation of medicaments.
8. Use of compounds according to claim 1 to 4 for the
preparation of medicaments for the treatment and
prevention of functional disorders of the brain and
depression.
9. Compounds of the general formula (I),
selected from the following:
dimethyl (1-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate
dimethyl (1-methanesulphonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (1-ethanesulphonyloxy-2,2,2-trichloroethane)-
phosphonate,

- 30 -
dimethyl (1-methoxycarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (1-acetyloxy-2,2,2-trifluoroethane)-phosphonate,
dimethyl (1-methoxycarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (1-propylcarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (1-methanesulphonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (1-dimethylaminocarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl-(1-propylaminocarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (1-acetyloxy-2,2,2-trichloroethane)-thiophosphonate
dimethyl (1-methoxycarbonyloxy-2,2,2-trichloroethane)-thio-
phosphonate,
dimethyl (1-dimethylaminocarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate
dimethyl (1-hydroxy-2,2,2-trifluoroethane)-thiophosphonate,
dimethyl (1-propylaminocarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (1-methanesulphonyloxy-2,2,2-trichloroethane)-thio-
phosphonate
dimethyl (1-propylcarbonyloxy-2,2,2-trichloroethane)-thio-
phosphonate,
dimethyl (1-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl-(1-ethoxycarbonyloxy-2,2,2-trichloroethane)-thio-
phosphonate,
dimethyl (R)-(1-acetyloxy-2,2,2-trichloroethane)-phosphonate,
dimethyl (S)-(1-acetyloxy-2,2,2-trichloroethane)-phosphonate,
dimethyl (R)-(1-hydroxy-2,2,2-trichloroethane)thiophosphonate,
dimethyl (S)-(1-hydroxy-2,2,2-trichloroethane)thiophosphonate,
dimethyl (R)-(1-hydroxy-2,2,2-trifluoroethane)thiophosphonate,
dimethyl (S)-(1-hydroxy-2,2,2-trifluoroethane)thiophosphonate,
dimethyl (R)-(1-ethylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate

- 31 -
dimethyl (S)-(1-ethylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (2,2-dichloro-1-hydroxypropane)-phosphonate,
dimethyl (1-hydroxy-2,2,3-trichloropropane)-phosphonate,
dimethyl (1-hydroxy-2,2,2-trimethylethane)-phosphonate,
dimethyl (R)-(1-hydroxy-2,2,2-trimethylethane)-phosphonate,
dimethyl (S)-(1-hydroxy-2,2,2-trimethylethane)-phosphonate,
dimethyl (R)-(1-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (S)-(1-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (R)-(1-methanesulphonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (S)-(1-methanesulphonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (R)-(1-ethanesulphonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (S)-(1-ethanesulphonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (R)-(1-methoxycarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (S)-(1-methoxycarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (R)-(1-acetyloxy-2,2,2-trifluoroethane)-phosphonate,
dimethyl (S)-(1-acetyloxy-2,2,2-trifluoroethane)-phosphonate,
dimethyl (R)-(1-methoxycarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (S)-(1-methoxycarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (R)-(1-propylcarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (S)-(1-propylcarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (R)-(1-methanesulphonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (S)-(1-methanesulphonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (R)-(1-dimethylaminocarbonyloxy-2,2,2-trifluoro-
ethane)-phosphonate,

- 32 -
dimethyl (S)-(1-dimethylaminocarbonyloxy-2,2,2-trifluoro-
ethane)-phosphonate,
dimethyl (R)-(1-propylaminocarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (S)-(1-propylaminocarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (R)-(1-acetyloxy-2,2,2-trichloroethane)-thio-
phosphonate,
dimethyl (S)-(1-acetyloxy-2,2,2-trichloroethane)-thio-
phosphonate,
dimethyl (R)-(1-methoxycarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (S)-(1-methoxycarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (R)-(1-dimethylaminocarbonyloxy-2,2,2-trichloro-
ethane)-thiophosphonate,
dimethyl (S)-(1-dimethylaminocarbonyloxy-2,2,2-trichloro-
ethane)-thiophosphonate,
dimethyl (R)-(1-hydroxy-2,2,2-trifluoroethane)-thio-
phosphonate,
dimethyl (S)-(1-hydroxy-2,2,2-trifluoroethane)-thio-
phosphonate,
dimethyl (R)-(1-propylaminocarbonyloxy-2,2,2-trichloro-
ethane)-thiophosphonate,
dimethyl (S)-(1-propylaminocarbonyloxy-2,2,2-trichloro-
ethane)-thiophosphonate,
dimethyl (R)-(1-methanesulphonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (S)-(1-methanesulphonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (R)-(1-propylcarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (S)-(1-propylcarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (R)-(1-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (S)-(1-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (R)-(1-ethoxycarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (S)-(1-ethoxycarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate.

- 33 -
10. Compounds of the general formula (I),
selected from the following:
dimethyl (1-acetyloxy-2,2,2-trichloroethane)-phosphonate,
dimethyl 1-hydroxyethanephosphonate,
dimethyl (R)-(1-hydroxyethane)-phosphonate,
dimethyl (S)-(1-hydroxyethane)-phosphonate,
dimethyl (1-hydroxy-2,2,2-trifluoroethane)phosphonate,
dimethyl (1-hydroxy-2,2,2-trichloroethane)thiophosphonate,
dimethyl (1-ethylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (1-hydroxy-1-methylethane)-phosphonate.
for therapeutic use.
11. Process for the preparation of phosphonic acid esters
according to claims 1, 2, 3, 4, 9 or 10,
characterised in that
1-hydroxy-phosphonic acid esters of the formula (II)
<IMG>
are reacted in a known manner with halogen compounds of
the formula (III)
Hal-R2 (III)
optionally in the presence of acid-binding agents or
optionally in the form of their alkali metal, alkaline earth
metal or ammonium salts and optionally in the presence of
solvents, or,where R2 represents alkylcarbonyl, alternatively

- 34 -
with carboxylic anhydrides of the formula (IV)
R2-O-R2 (IV)
optionally in the presence of catalytic amounts of a mineral
acid.
12. Process according to claim 11, characterised in that
basic nitrogen compounds are used as the acid-binding
agents.

Description

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~se of phospho~ic acid esters for the treatment of functional
disorders of the brain and depression
The invention relates to the use of phosphonic acid esters
for the treatment and prevention of functional disorders of the
brain and depression, and to new compounds and their production.
DE-1 ~78 370 discloses phosphonic acid esters used for the
control of insects.
It is also known that the anthelmintic metrifo~ate is
suitzble for the treatmer.t OI Al7heimerls disease (US
4,9~0,658). The assumed mode of ~ction Is thct
metri~onate is converted slowly into the organo-
phosphoric acid ester dichlorvos and thereby induces
a long-lasting inhibition of cholinesterase. In the
further pursuit of tnis theory ~utonate wzs proposed as a
suitzble precursor for metrifonate/dichlor~os (~
Holmstedt and ~. ~ordgren, in Cholinergic Basis ~or
Alzheimer Therapy (R.E. Becker and ~. Giacobini, eds),
3ir~hcuser, 3Oston, 155-161, 1591).
~t has now surprisingly been found that phosphonic ~cid
estersof the general formula
R X
R'- C - !(OR~)2 a)
oR2
in ~hich
represents straisht-ch2in or branched alkyl which has u~
to 6 carbon Gtoms and is optionally substi.ute~ by
one or more halogen atoms,

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W097/39756 PCT~S97/06469
represents hydrogen or straight-chain or brznched
al~yl with up to 6 carbon atoms,
~2 represents hydrogen or
represents straight-chain or branched alkyl,
alkylcarbonyl, alkoxycarbonyl or alkylsulphonyl with
in each case up to 6 car~on ztoms in the alkyl
group, or
represents alkyl- or dialkylaminocarbcnyl ~ith in
each case up to 4 carbon atoms in the alkyl groups,
~3 represents straight-ch~in or branch.ed alkyl with up
to 6 carbon atoms
and
X represents oxygen or sulphur,
but does not denote oxygen where R represents
trichloromethyl, Rl represents hydrogen and R2
represents hydrogen or propylcarbonyl,
and the C21ts and isomers thereof,
can be used for the treatment and prevention of functional
disorders of the brain and depression, even without any
con~r~rsion into a cholinesterase inhibitor taking place.
The compounds of the formula (I) are s~itzble for the
treatment and prevention of cognitive znd affective
diseases, znd in particulcr lor the treatment of senile
and presenile dementia, dementia of the Alzheimerls type,
AIDS-rel2ted dementia, cognitive deficits in Parkincon's
and Huntington's disease or functional disorders of the brain
as a result of infarction, multi-infarct dementia (MID),
primary degenerative dementia ( PDP ) and other forms of dementia

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WO 9?/39756
and for the treatment of depression.
They are also suitable for the treatmen~ of functional
disorders of the brain in the elderly, organic brain syndrome
(OBS) and age-associated me~ory impairment (AAMI).
~he compounds o~ the general ~Ormt~l ~ (I) are extremely
suitabl~ for t~e treatment and pre~ention of senile and
presenilQ dementia and dementia o~ t~e ~1 ~h~; m~ ~ S type .
The compounds of the formula (I)
in ~hich
R represents strcight-chGin or branched alkyl with up
to 4 carbon ztoms or trifluoromethyl,
trichlorome.hyl, dill~oromethyl, 1,1-dichloroethyl,
dichloromethyl, rluoromethyl, chloromethyl,
dichlorofluoro~.ethyl, difluorochlorome-hyl or
sepresents the radical o~ the formula -CCl2C~2Cl,(1,1,2-
t~ichloroethyl),
R~ represents ny~rosen or str2ight-chain or branched
alkyl with p to 4 carbon atoms,
R2 represents nydrogen or
represents straight-chain or branched alkyl,
~alkylcarbonyl, alkoxycarbonyl or alkylsulphonyl with
up to 4 carbon atoms in the alkyl group, or
represents alkyl or dialky}aminocarbonyl with in
each case up to 3 carbon atoms in the alkyl groups,
R3 represents straight-chain or branched alkyl w th up
to 3 c~rbon atoms
and
X represent~ oxysen or sulphur,

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WO 97/39756 PCT/US97/06469
but does not denote oxygen where R represents
trichloromethyl, R1 represents hydrogen and R2
represents hydrogen or propylcarbonyl,
and their salts 2nd isomers are particularly suitable for
the treatment and pre~7enticn of cogniti~.-e and affective
disorders .
Compounds of the general formula (I)
in which
represents methyl, tert . -butyl, 1, l-dichloroethyl,
chlorcmethyl, dichloromethyl, trichloromethyl,
trifluoromethyl, dichlorofluormethyl,
difluorochloromethyl or
t~e radical -CCl2C~2Cl, ( 1 ,1, 2- tri chl oroethyl )
represen~s hydrosen or methyl,
~,2 represents ~ydrosen, methyl, ethyl, methylczrbonyl,
ethylcaribon3rl, propylcarbonyl, t-butylcar~cnyi,
methoxyccrbonyl, ethcxyc2rbonyl, propoxycarbonyl,
tert . -butoxycarbo~yl, me~hylsulphonyl,
ethy 1 sulphonyl, propyl sulphonyl,
methylaminocarbonyl, dimethylaminocarbonyl or
propyla3ninocarbonyl,
R3 represents methyl, etnyl or propyl,
and
X represents oxygen or sulp~,ur,
but does not denote oxygen where R represents
trichloromethyl and R~ represents hydrogen or
propylcarbonyl,

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W097/39756 PCT~S97/06469
and their salts and isomers are particularly preferred.
- The compounds according to the invention ca~ e~ist in
stereoiso~eric forms Yhich are either in the form of image
and mirror image (enantiomers) or are not in the form of
image and mirror image (diastereomers). The inYentio~
relates both to the enantiomers and the diastereomers and to
respecti~e m~xture~ thereo~. Both the racemic forms and the
diastereomers can be separated by the kno~n methods into the
stereoisomerically homogeneous components.
The invention also relates to the following compounds:
dimethyl (1-tert-.-b~.~tylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate
dimethyl (l-methanesulphonyloxy-2,2,2-trichloroeth2ne)-
phosphonate,
dimethyl (1-ethanesulphonyloxy-2,2,2-trichloroethzne)-
phosphonate,
dimethyl (l-methoxycarbonyloxy-2,2,2-trichloroeth2ne)-
phosphonate,
dimethyl (l-acetyloxy-2,2,2-trifluoroethane)-phosphonate,
dimethyl (1-methoxycarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (l-propylcarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (l-methanesulphonyloxy-2,2,2-tri~luoroethane3-
phosphonate,
dimethyl (l-dimethylaminocarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,dimethyl-(1-propylaminocarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (1-acetyloxy-2,2,2-trichloroethane)-thiophosphonate
dimethyl (l-methoxycarbonyloxy-2,2,2-trichloroethane)-thio-
phosphonate,
dimethyl (1-dimethylaminocarbonyloxy-2,2,2-trichloro2thane)-
thiophosphonate
dimethyl (l-hydro~y-2,2,2-trifluoroethane)-thiophosphonate,

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-- 6
dimethyl (l-propyl2minocarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (l-methanesulphonyloxy-2,2,2-trichloroethane)-thio-
phosphonate
dimethyl (1-propylcarbonyloxy-2,2,2-trichloroethane)-thio-
phosphonate,
dimethyi. (l-tert.-butylcarbonyloxy-2,2,2-trichloroethane)_
thiophosphonate,
dimethyl-(l-ethoxycarbonyloxy-2~2~2-trichloroethane)-thi
phosphonate,
dimethyl (R)-(l-acetyloxy-2,2,2-trichloroethane)-phosphonate,
dimethyl tS)-(l-acetylo~y-2,2,2-trichloroethane)-phosphonate,
dimethyl (R)-(l-hydroxy-2,2,2-trichloroethane)thiophosphonate,
dimethyl (S)-(l-hydroxy-2,2,2-trichloroethane)thiophosphonate,
dimethyl (R)~ hydroxy-2,2,2-trifluoroethane)thiophosphonate,
dimethyl (S)-(l-hydroxy-2,2,2-trifluoroethane)thiophosphonate,
dimethyl (R)-(l-ethylcarbonyloxy-2~2~2-trichloroethane)
phosphonate
dimethyl (S)-(l-ethylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (2,2-dichloro-1-hydroxypropane)-phosphonate,
dimethyl (l-hydroxy-2,2,3-trichloropropane)-phosphonate,
dimethyl (l-hydro~y-2,2,2-trimethylethane)-phosphonate,
dimethyl (R)-(l-hydroxy-2,2,2-trimethylethane~-phosphonate,
dimethyl (S)-(l-hydroxy-2,2,2-trimethylethane)-phosphonate,
dimethyl (R)-(l-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (S)-(l-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (R)-(l-methanesulphonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (S)-(l-methanesulphonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (R)-(l-ethanesulphonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (s)-tl-ethanesulphonyloxy-2~2~2-trichloroethane)
phosphonate,

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-- 7 --
dimethyl (R)-(l-methoxycarbonyloxy-2,2,2-trichloroethane)-
phosphonate,
dimethyl (S)-(l-methoxycarbonylo~y-2,2,2-trichloroethane)-
phosphonate,
dimethyl (R)~ acetyloxy-2,2,2-trifluoroethane)-phosphonate,
dimethyl (S)-(l-acetyloxy-2,2,2-trifluoroethane)-phosphonate,
dimethyl (R)-(l-methoxycarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (S)-(l-methoxycarbonyloxy-2~2~2-trifluoroethane)
phosphonate,
dimethyl (R)-(l-propylcarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (S)-(l-propylcarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (R)-(l-methanesulphonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (S)-(l-methanesulphonyloxy-2~2~2-trifluoroethane)
phosphonate,
dimethyl (R)-(l-dimethylaminocarbonyloxy-2,2,2-trifluoro-
ethane)-phosphonate,
dimethyl (S)-(l-dimethylaminocarbonyloxy-2,2,2-trifluoro-
ethane)-phosphonate,
dimethyl (R)-(l-propylaminocarbonyloxy-2,2,2-trifluoroethane)-
phosphonate,
dimethyl (S)-(l-propylaminocarbonyloxy-2~2~2-trifluoroethane)
phosphonate,
dimethyl (R)-(l-acetyloxy-2,2,2-trichloroethane)-thio-
phosphonate,
dimethyl (S)-(l-acetyloxy-2,2,2-trichloroethane)-thio-
phosphonate,
dimethyl (R)-(l-methoxycarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (S)-(l-methoxycarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (R)-(1-dimethylaminocarbonyloxy-2,2,2-trichloro-
ethane)-thiophosphonate,
dimethyl (S)-(l-dimethylaminocarbonyloxy-2,2,2-trichloro-
ethane)-thiophosphonate,

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dimethyl (R)-(l-hydroxy-2,2,2-trifluoroethane)-thio-
phosphonate,
dimethyl (S)-(l-hydroxy-2,2,2-trifluoroethane)-thio-
phosphonate,
dimethyl (R)-(l-propylaminocarbonyloxy-2~2~2-trichlor
ethane)-thiophosphonate,
dimethyl (S)-(l-propylaminocarbonyloxy-2~2~2-trichloro-
ethan ~ thiophosphonate,
dimethyl (R)-(l-methanesulphonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (S)-(l-methanesulphonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (R)-(l-propylcarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (S)-(l-propylcarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (R)-(l-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (S)-(l-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (R)-(l-ethoxycarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate,
dimethyl (S~-(l-ethoxycarbonyloxy-2,2,2-trichloroethane)-
thiophosphonate.
The present invention also relates to the use of the follo~ing
compounds which are already k~o~n:
Literature
dimethyl (l-acetyloxy-2,2,2-trichloroethane)-phosphonate,
dimethyl l-hydroxyethanephosphonate, 2
dimethyl (R)-(l-hydroxyethane)-phosphonate, 3
dimethyl (S)-(l-hydroxyethane)-phosphonate, 3
dimethyl (l-hydroxy-2,2,2-trichloroethane)thiophosphonate, 4
dimethyl (l-ethylcarbonyloxy-2,2,2-trichloroethane)- 1
phosphonate,
dimethyl (l-hydroxy-l-methylethane)-phosphonate. 2
dimethyl (1-hydroxy-2,2~-2-trifluoroethane)-phosphonate 5

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W097/39756 PCT~S97/06469
g
The new and known compounds of the formula (I) used according to
the invention are prepared by reacting
l-hydroxy-phosphonic acid esters of the formula (II)
R X
R~- C (oR3)2 ~I)
OH
in a known manner with halogen compounds of the formula
(III)
Hal-R2 (III)
optionally in the presence of acid-'Dinding zgents or
optionally in the form of their alkali metal, alkaline earth
metal or ammonium salts and optionally in the pres2nce of
sol~ents, or,where R2 re~resents alkylcarbonyl, alternatively
with carboxylic anhydrides of the formula (IV)
R2_o_~2 (I~)
optionally in the presence of catalytic amounts of a mineral
acid,
and in the case of the enantiomerically pure hydroxyl
compounds the racemates are separated by col umn chromatography
by the method desc~ibed in W0 93/24130 or by other known methods
and i~ the case of the acylated compounds the hydroxyl
compounds which are already enantiomerically pure are used.
The starting compounds of the formulae (II), (III) and (IV)
are known or can be prepared by known methods.

CA 022~2~67 1998-10-22
W097/39756 PCT~S97/06469
-- 10 --
The process for the preparation of the compounds of the
formula (I) by reaction with the halogen compounds of the
formula (III) is preferably carried out using diluents.
Suitable diluents are virtually all inert organic sol~ents.
These preferably include aliphatic and aromatic, optionally
halogenated hydrocarbons such as pentane, hexane, heptane,
cyclohexane, petroleum ether, bènzine, ligroin, benzene,
toluene, xylene, methylene chloride, ethylene chloride,
chloroform, carbon tetrachloride, chlorobenzene and
o-dichlorobenzene, ethers such as diethyl and dibutyl ether,
glycol dimethyl ether and diglycol dimethyl ether,
tetrahydrofuran and dioxan, ketones such as acetone,- methyl
ethyl, methyl isopropyl and methyl isobutyl ketone, esters
such as methyl and ethyl acetate, nitriles,such as for example
acetonitrile and pro?ionitrile, amides such as for example
dimethyl formamide, dimethyl acetamide and N-methylpyrrolidone
as well as dimethyl sulphoxide, tetramethylene sulphone and
hexamethylphosphoric triamide.
Those acid-binding agents which can usually be employed for
such reactions can be used as acid acce~tors. Alkali metal and
alkaline earth metal hydrides such as lithium, sodium,
potassium and calcium hydride, alkali metal and alkaline earth
metal hydroxides, such as lithium, sodium, potassium and
calcium hydroxide, alkali metal and alkaline earth metal
carbonates and hydro~en carbonates, such as sodium and
potassium car~onate or sodium and potassium hydro~en carbonate
as well as calcium carbonate, alkali metal acetates, such as
sodium and potassium acetate, alkali metal alcoholates, such
as sodium and potassium tert.-butylate, and furthermore basic
nitrogen compounds such as trimethylamine, triethylamine,
tripropylamine, tributylamine, ethyldiisopropylamine~
ethyldicyclohexylamine, N,N-dimethylbenzylamine, N,N-dimethyl-
aniline, pyridine, 2-methyl-, 3-methyl-, 4-methyl-,
2,4-dimethyl-, 2,6-dimethyl-, 2,6-dimethyl-, 2-ethyl, 4-ethyl-

CA 022~2~67 1998-10-22
W097/39756 PCT~S97/06469
and 5-ethyl-2-methylpyridine, 1,5-diazabicyclo-
~4,3,Q7-non-5-ene (DBN), 1,8-diazabicyclo-~,4,07undec-7-ene
(DB~) and 1,4-diazabicyclo-~2,2,27-octane (DA~C0) are
preferably usable.
The reaction temperatures can be varied over a relati~ely
large range. In general temperatures of between 0~C and
100~C, and preferably temperatures of between 10~C and 80~C
are used.
The process is generally carried out under normal pressure.
It is ho~ever also possible to use increased or reduced
pressure.
When carryiny out the process the starting materials re~uired
in each case are generally use~ in approximately equimolar
quantities. It is however also possible to use one of the two
components employed in each case in a relatively large excess.
The reaction is generally carried out in a suitable diluent
in the presence of an acid acceptor and the reaction mixture
is stirred for several hours at the temperature required in
each case. The working up process is carried out in each case
by the usual methods (cf. the preparation examples).
The process for the preparation of the compounds (I) by
reaction with the carboxylic anhydrides of the formula (IV)
can als-o be carried out without diluents. All the usual
mineral acids can be used as the catalys~. Preferred acids
are sulphuric acid, hydrochloric acid or phosphoric acid. They
are used in a quantity of 0.001 to 10 mol '~.
The compounds are-usually obtained in the form of oils which
in some cases cannot be distilled without decomposition, but
which can be freed from the residual volatile constituents by
so-called "incipient" distillation, i-e- by heating the
compounds at moderat21y increased tem2eraturec for relatively

CA 022~2~67 1998-10-22
WO 9?139756 PCT/US97/06469
-- 12 --
long periods under reduced pressure, as a result of which they
are purified. The compounds are characterised by means of
their refractive index. The crystalline compounds are
characterised by their melting point.
The activity of the phosphonic acid esters for the treatment
and prevention of cognitive disorders is demonstrated by
means of an animal experiment based on spatial memory. In
this test, which was ori~inally described by l~orris (~.G.M.
Morris, J. ~7eurosci. Methods 11:47-60, 1984), rats have to
learn how to~localise a platform which they cannot see but
which is the only way out of a pool filled with water. For
this purpose the animals (young, adult, male, approximately
3-month-old rats) undergo 4 training cycles per day
over a period of 3 days. The latent period before the rats
discover the platform and the distance covered are determined.
During the course of the training not only the latent period
but also the distance swum becomes shorter as a result of the
rats' adoption of a strategy for spatially localising the
destination. The cosnition-improving activity of the test
substances is manifested by a shortening of the time
required for the learning process, i.e. the learning curve
becomes steeper. Test subst2nces are administered once daily
(60 mins. before the first training cycle). Control animals are
administered a corresponding amount of the vehicle.
At the-end of the training phase, i.e. after the end of the
12th training cycle the platform is removed from the water and
an additional swi~ing test is carried out in order to examine
whether the test animals look for the platform within a
defined small area surrounaing the training position of the
platform (retenti-;n test).
The activity of some compounds in relation to learning and
remembrance processes were examined in the "Active Avoidance
Testll. In this aversion-motivated test rats have to learn to

CA 022~2~67 1998-10-22
W097/39756 PCT~S97/06469
_ 13 -
move to the other side of a shuttle box consisting of two
compartments (Coulbourn Instruments) as soon as a conditioned
stimulus is actuated. The conditioned stimulus consists of the
simultaneous sounding of an acoustic signal and the flashing
of a small light. If the rat does not leave the compartment
of the shuttle box within 6 seconds after the onset of the
stimulus it is given a slight electric shoc~ (0.5 mA) via the
base grid of the shuttle box. The acquisition of the active
avoidance behaviour is recorded over 20 conditioning
tests on each of two successive days. The individual
tests are separated from each other by variable breaks of 20
to 60 seconds. The increase in the correct avoidance
reactions during the course of the training is used as a
criterion for the learning activity of the animals.
In order to record the effects of substances on memory
performance adult male rats are treated with test substances
30 minutes before the first test; the control animals are
administered a corresponding amount of the vehicle.
The test results show that the abovementioned compounds have a
positive effect on the learning behaviour of the animals and
the retention of what has been learned. The special advantage
of the abovementioned compounds is that they do not induce
any inhibition of cholinesterase activity in the brain within
their active dosage range. This results in improved tolerance
compared with procholinergic reference substances; such as for
example tetrahydroaminoacridine, physostigmine or metrifonate.
The abovementioned phosphonic-acid esters can therefore be
used both for the therapeutic and the preventive treatment of
cognitive disorders in general, and in particular dementias
of the Alzheimerls type.
The activity of the phosphonic acid esters for the treatment
and prevention of affective disorders is demonstrated with the
aid of the ~Rat Forced Swimming Test". This behavioural model
was described for the first time by Porsolt et al. (R.D.

CA 022~2~67 1998-10-22
W097/39756 PCT~S97/06469
- 14 -
Porsolt, M. Le Pichon, M. Jalfre, ~ature 266:730-732, 1977)
and is today a widely acce~ted in vivo screening model for
detecting new antidepressants. It is based on the finding
that rats remain in a motionless state in a desperate
situation ("behavioural despair"). In a preliminary test
young, adult (3-4-month-old) rats are placed individually in
glass cylinders (40 cm in height and 20 cm in diameter) which
are filled with water up to a level of 15 cm, for 20 minutes.
24 hours after this preliminary test the animals are again
placed in the cylinders and the duration of their immobility
is determined over a period of 5 minutes. The abovementioned
phosphonic acid esters are administered in the interval
bet~een the two swimming tests. The control animals are
administered the vehicle.
Similarly to the clinically active antidepressants described
in the literature the abovementioned phosphonic acid esters
shorten the duration of immobility and result in behavioural
activation. By reason of these results the abovementioned
compounds are also suitable for the treatment of affective
disorders, and in particulzr depression.
As with the cognition-imprcvin~ activity this antidepressive
component can also not be explained by the inhibition of
cholinesterase.
R X
Biological data on: R - C (OR )2
oR2

CA 02252567 1998-10-22
WO 9?t39756 _ 1 5 - PCT/US97/06469
R' R Rl R3 X EDs
RatFor~d MomsM~(M~
Sw~Tcst A~iveAvoid~cc
(AA)
-H -CC~3 -H -CH3 O Ir~t~r~ne~ 2~ mgXg AA125-2Smy~g
-H -CC13 -COC;H,-n -CH, o ~t~f~nc~) 17mg~g ~ 1-3mg~g
-H -CCl -SO,-CH, -CHl O 43mg~o M~3mo~g
-H -CCll -COCH~ -CH3 O 0.03mg~;g ~0,0i-0.1m~g
-H -CH~ -H -CH, O 0.8m_~o ~3mC~o
-H -CCI3 -H -CH~ S 0.9mg~g AAI-3mg~g
-H -CCI3 -SO,-CH, -CH~ S 2.1moJ~g AA ;-10mJ~g
-H -CCI -COC~ -CH, 5 0.~ g A~ 5m~
The activity of dimethyl(1-hydroxy-2,2,2-trimethylethane)-
phosphonate and its enantiomers can be tested by the following
experi~ent:
6-8-~eek old ICR mice (Yeighing approx. 22-28 g) from
Harlan-Sprague-Da~ley, Inc. (Indianapolis Indiana, USA) Yere
used for this test. 8 animals at a time ~ere placed together
in a cagei they had free access to feed and Yater.
The Morris Maze consisted of a circular, gal~anised steel tank
Yhich Yas painted vhite (and vas open at the top) and had a
diameter of 76 cm; at the base of the tank a plastic holding
device~for the attachment of the e~it platform Yas arranged in
each of 4 identically sized circular segments. Prior to the
behavioural test the tank vas filled ~ith Yater to such a
level that the 25 cm high platform Yas 1 cm belo~ the surface
of the Yater; the Yater had been preheated to 22~C and
rendered opaque by adding O.9 kg of dried milk povder.
Numerous firmly fi~ed optical "cues" Yere present in the test
chamber. The data Yere obtained using a "Multiple Zone
Distance Traveled" programme from the Video-A Analytical
System (Columbus Instruments International Corp., Columbus
Ohio, ~SA).

CA 022~2~67 1998-10-22
W097/39756 PCT~S97/06469
- 16 -
After one ~eek's acclimatisation in animal housing the mice
had the opportunity to svim freely in the abovementioned steel
tan~ (no platform present) for 9O seconds. One to three days
later the ac~uisition training began ~hich consisted of 4
cycles on each of three successive days (a total of l2
cycles). No test substances ~ere ad~inistered. The
allocation of the mice to the target quadra~ts, in each of
~hich the platforms were arranged Yas based o~ random
selection. The mice ~ere placed in the ~ater facing the wall
of the tank at one of 4 points uniformly distributed around
the circumference of the Morris ~aze; the starting position
varied per mouse from one cycle to the next in such a manner
that each mouse started from each of the four starting points
once a day. In each of the training cycles the mice had a
period of 120 seconds to reach the target platform. If they did
not do so ~ithin this period they Yere placed on the target
platform by hand. There ~as an interval of 30 seconds, in Yhich
the mouse remained on the target platform, bet~een each cycle.
On the fourth day the behaviour of the animals Yas examined
for 30 seconds in a trial cycle in ~hich no platform was
present; the period of time ~hich the mice spent in each of
the four quadrants was determined. The mice had been
administered the substance to be tested or the vehicle 30
minutes or one hour before the test cycle; the-selection of mice
for the vehicle and test substance groups ~as carried out at
random. Dimethyl(1-hydroxy-2,2,2-trimethylethane)-phosphonate showed an ED50
of 0.1-~ mg/kg after oral administration.
The present invention also relates to pharmaceutical agents
containing the abovementioned compounds in an effective
quantity as well as their ~roduction and use for the treatment
and prevention of the abovementioned diseases
The new active compounds c,n be converted into the usual
formulations such as tablets, coated tablets, ?ills, ~ranules,
aerosols, syrups, emulsions, susp~nsions and solutions by known
methods using inert, non-toxic pharmaceutically suitable

CA 022~2~67 1998-10-22
W097t397S6 PCT~S97/06469
- 17 -
excipients or solvents- The therapeutically active compound
should be used in each case in a concentration of
approximately 0.5 to 90% by weight of the total mixture, i.e.
in quantities which are sufficient to obtain the indicated
dosage range.
The formulations are for example prepared by extendin~ the
active compounds with solvents and/or excipients, o~tionally
using emulsifiers and/or dispPrsants, it being possible
optionally to use organic solvents as auxiliary solvents
where wa~er is for example used as a diluent.
Administration is carried out in the usual manner, preferably
orally or parenterally, and in particular perlingually or
intravenously. Administration can also be carried out
transdermally, such as for example by mPans of plasters.
In the case of parenteral administration solutions of the
active compound can be employed using suitable liquid
excipient materials.
In the case of intravenous administration it has in general
proven advantageous to administer quantities of approximately
0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg
of body weight for the obtainment of effective results and in
the case of oral administration the dosage is approximately
0.01 to 20 mg/kg, preferably 0-1 to 10 mg/kg of body weight.
It may nevertheless possibly be necessary to deviate from the
abovementioned quantities depending on the body weight
involved and the type of administration employed, on the
individual response to the medicament, and the typ~ of
formulation used and the time or interval at which it is
administered. Thus it can in some cases be sufficient to use
less than the abovementioned minimum quantity, whereas in
other cases the abovementioned upper li.~it must be exceeded.
Where larger ~uantities are used it can be recommendable to
distribute them over 5everal individual doses p2r day.

CA 02252567 lsss-l0-22
WO 97/39756 PCT/US97/06469
- 18 -
Abbre~i at i ons used:
P~v
(C~3)3c ~,
Ms = C~3 S--
G
Es = CH3CH2
Moc
CH30-~--
AC
CH3 _--
But~ r~l = ¦
CH3CH2CH2 ;~--
CON~IPr
CH3CH2C1-l2NH-C--
o
Propionyl = ll
CH3CH2--C--
o
Eoc = ll
CH~CH~ 0-C

CA 022~2~67 1998-10-22
W097/39756 PCT~S97/06469
- 19 -
~reparation examples
~Y~ e 1
Il
C13C - I H P(OCH3)2
o so2CH3
6.3 g (0.055 mol) of methanesulphonic acid chloride are added
dropwise with cooling at 5~C to a mixture of 12.87 g ~0.05
mol) of dimethyl (1-hydroxy-2,2,2-trichloroethane)-phosph-
onate, 6 g (0.06 mol) of triethylamine and 100 ml of
methylene chloride and the mixture is then subsequently
stirred for 18 hours at rocm temperature.The reaction mixture is
extracted twice, each time with 30 ml of water. The
organic phase is separated off, dried over sodium sulphate
and freed from the solvent in vacuo. 14.5 g t86 % of
theory) of dimethyl ll-meth2nesulphonyloxy-2,2,2-tri-
chloroethane)-phosphonate remain in the form of colourless
crystals with a melting point of 74 to 75~C.
FY~mrle 2
R
C13C - CH P(OCH3)2
I
O-CO-C~Hg-t.
A mixture of 13 g of (0.05 mol) of dimethyl (l-hydroxy-
2,2,2-trichloroethane)-phosphonate, 60 ml of toluene, 9.5
g (0.05 mol) of pivalic anhydride and 0.05 g of conc.
sulphuric acid is stirred for 15 hours at 40~C. Then 50
ml of a saturated sodium bicarbonate solution are added
and stirring is continued until the evolution of CO2
ceases. The organic phase is separated off, dried over

CA 022~2~67 1998-10-22
w097139756 PCT~S97/06469
- 20 -
sodium sulphate and concentrated in vacuo. The residue is
chromatographed over silica gel (eluent: petroleum
ether/acetone 7:3). 6.85 g (40 ~ of theory) of dimethyl
(l-tert.-butylcarbonyloxy-2,2,2-trichloroethane)-
phosphonate are obtained in the form of a colourless oil
with a refractive index n2~ = 1.4655.
FY~mrle 3
C13C - I H P(OCH3)2
O-SO2Ctl3
2.3 g (0.02 mol) of methanesulphonic acid chloride are
added dropwise with cooling at 5~C to a mixture of 5.5 g
(0.02 mol) of dimethyl (1-hydroxy-2,2,2-trichloroethane)-
thiophosphonate, 2.5 g (0.025 mol) of triethyl2mine and 30
ml of diethyl ether and the mixture is then subsequently
stirred for 3 hours at room temperature. The reaction
mixture is extracted twice, each time with 20 ml of water.
The organic phase is separated off, dried over sodium
sulphate and freed from the solvent in vacuo. 6.5 g (92
% of theory) of dimethyl (1-methznesulphonyloxy-2,2,2-tri-
chloroethane)-thiophosphonate remain in the form of
colourless crystals with a melting point of 47.5 to
50.5~C.
The following compounds can be prepared analogously to
one of examples 1 to 3:

CA 02252567 l998-l0-22
WO 97/39756 PCT/US97/06469
- Exa~ple 4
C~3C--ICH P(OCH3)2
O-COOCH3
Exam~le 5
Cl3C--ICH P(~CH3)2
o-so2-C2HS
Exam~?le 6
C13c--ICH P(OCHs)2 n20 = 1.5101
O-CO-CH3

CA 02252567 l998-l0-22
W097/39756 PCT~S97/06469
- 22 -
Fy~mrle 7
11
CIC-H - P(OCH3)2 n20 = 1 . 4958
O-CO-n-propy
F~mrle 8
OH
(CH3)3Cl~P' 'CH3
O~CH3
1 mol o~ triethylamine is added to 1 05 mols of pi~alic
aldehyde and 1 mol of dimethyl phosp~ite ~hile cooling
with ice. The mixture i-~ stirred o~ernight at 25~C and
then concentrated. The residue is kept at 40~C overnight
under high vacuum. D
n20 1,4485
Examples 9 and 10
CH3
0~0
Cl;Cl~P' 'CH3 ena~tiomer
O~CH3
1 ml of conc. sulphuric acid was adde~ to 1 mol of
enantiomerically pure dimethyl (1-hydroxy-2,2,2-
trichloroethane)-phosphonate in 1 l of acetic anhydride
and the mixture was heated ~or 2 hours at 90~C. The
product is removed directly from the reaction mixture by
distillation under an oil pump vacuum (b.p. 95-100~C /
O.15 mbars). The enantiomeric purity ~as d~termined by
chiral GC (Lipodex 15).
The compounds listed in Tabl~ 1 were prepared analogously
to the abovementioned.preparation instructions:

CA 02252567 1998-10-22
PCT/US97/06469
WO 97/39756
- 23 -
Table l:
R 7 P - O CH3
oR2 O-CH3
No. R R2 X
1 I CCI, Piv O R
12 CCI, PiY O S
13 CCI, Ms O R
14 CCI, Ms O S
1~ CCIs Es O R
16 CCI, Es O S
17 CCI, Moc O R
1 8 CCI, J~loc O S
19 CFs Ac O R
CF, Ac O S
21 CF, Ac O RJS
22 CF, Moc O R
23 CF, Moc O S
24 CF, l~oc O RIS
2~ CF, But~ ryl O R
26 CF, But~y1 O S
27 CF, But~ ly1 O R/S
28 CF, J~Is O R
29 CF, J~Is O S
CF, Ms O R/S
;I CF, COJ'71~ O ~S
;' CF~ CON~ O R
33 CF, CO~ O S
34 CF, CO~'ElPr O RIS
3~ CF, COJ~IPr O R
36 CF, COl~'HPr O S
37 CCI, Ac S R

CA 02252567 l998-l0-22
PCT/US97/06469
WO 97/39756
- 24 -
No. R R2 X r '~Tr~tion
38 CCI, Ac S S
39 CCI, l~Ioc S RIS
CCI, ~Ioc S R
4 1 CCI, r~soc S S
42 CCI, CO.'~ e, S RJS
43 CCI, CO.~ Ie, S R
4 4 CCI, CO.~'J\Se, S S
CF, H S R/S
46 CF, H S R
47 CF, H S S
48 CCI, CO.~'HPr S R/S
49 CCI, COl~IPr S R.
~0 CCI, CO.~':HPr S S
51 CCI, l~Is S R
~2 CCI, J~Is S S
53 CCI, But~ r~ l S R
~4 CCI, Bu~ r~l S S
~5 CCI, Pi. S RJS
56 CCI, Piv S R
57 CCI, Pi~ S S
~8 CCI, Eoc S RIS
~9 CCI, Eoc S R
CCI, Eoc S S
61 CCI, H S R
62 CCI, H S S
63 CF, H O R
64 CF, H O S
CCI, Propi onyl O R
66 CCI~ Propionyl o S
67 C.JC~ ~i ~
6~ CH,CICCI, H O
69 (CH,),C H O R
(CH,),C H O S
(R/S)= P~acemate

CA 022~2~67 l998-l0-22
W097t39756 PCTtUS97/06469
Lite~ature
1 Dakl. Bolg. Akad. Nauk. 1979, 32, 1357 - 1360
2 Sbornik Statei Obshchei Khim., AXad. Nauk. S.S.S.R.
1953, 1, 393 - 397
3 Tetrahedron: Assymetry 1993, 4, 109 - 120
4 DE 2 512 375
J. Chem. Soc. Perkin Trans. 1, 1994, 1180