Note: Descriptions are shown in the official language in which they were submitted.
CA 02309388 2000-OS-15 -
r
BOEHRINGER INGELHEIM PHARMA KG Case 5/1226-Ro
D-5521.6 Ingelheim/Rhein Foreign filing text
New urethanes derived from azacycloalkanes, the thin and
dithio analogues thereof, the salts thereof, pharmaceutical
. compositions containing these compounds and their use as well
as processes for preparing them
The present invention relates to new urethanes derived from
azacycloalkanes, the thin and dithio analogues thereof, the
salts thereof with physiologically acceptable organic and
inorganic acids, processes for preparing these compounds and
pharmaceutical compositions containing them.
The compounds according to the invention are inhibitors of
cholesterol biosynthesis, particularly inhibitors of the
enzyme'2,3-epoxysqualene-lanosterol-cyclase, a key enzyme in
cholesterol biosynthesis. The compounds according to the
invention are suitable for the treatment and prophylaxis of
hyperlipidaemias, hypercholesterolaemias and atherosclerosis.
Other possible applications are in the treatment of
hyperproliferative skin and vascular diseases, tumours,
gallstone problems and mycoses.
Compounds which affect cholesterol biosynthesis are important
for the treatment of a number of diseases. These include in
particular hypercholesterolaemias and hyperlipidaemias which
are risk factors for the occurrence of atherosclerotic
vascular changes and their sequelae such as coronary heart
disease, cerebral ischaemia, Claudicatio intermittens and
gangrene.
The significance of elevated serum-cholesterol levels as a
main risk factor for the occurrence of atherosclerotic
vascular changes is generally known. Extensive clinical
studies have led to the finding that the risk of developing
CA 02309388 2000-OS-15
,_ - 2 -
coronary heart diseases can be reduced by lowering serum
cholesterol (Current Opinion in Lipidology 2(4), 234 [1991);
Exp. Opin. Ther. Patents 7(5), 441-455 [1997)). Since the
majority of the cholesterol is synthesised in the body itself
and only a small proportion is taken in with the food,
inhibiting biosynthesis is a particularly attractive method of
lowering raised cholesterol levels.
In addition, other possible applications for cholesterol
biosynthesis inhibitors are the treatment of
hyperproliferative skin and vascular diseases and tumours, the
treatment and prophylaxis of gallstone problems and their use
in treating mycoses. The latter case involves intervening in
the ergosterol biosynthesis in fungal organisms which proceeds
substantially analogously to cholesterol biosynthesis in
mammalian cells.
The cholesterol or ergosterol biosynthesis takes place,
starting from acetic acid, via a large number of reaction
steps. This multi-stage process offers a number of possible
interventions, of which the following are examples:
For inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme
y A (HMG-CoA) -synthase, [3-lactones and (3-lactams with a
potential antihypercholesterolaemic activity are mentioned
(cf. J. Antibiotics 40, 1356 (1987), US-A-4,751,237,
EP-A-0 462 667, US-A-4,983,597).
Examples of inhibitors of the enzyme HMG-CoA-reductase are
3,5-dihydroxycarboxylic acids of the mevinolin type and their
8-lactones, of which lovastatin, simvastatin, pravastatin,
fluvastatin, atorvastatin and cerivastatin are used in the
treatment of hypercholesterolaemias. Other possible
applications for these compounds are fungal infections (US-A-
4,375,475, EP-A-0 113 881, US-A-5,106,992), skin diseases
(EP-A-0 369 263) and gallstone problems and tumour diseases
(US-A-5,106,992; Lancet 339, 1154-1156 [1992)).
CA 02309388 2000-OS-15
- _ 3 _
The inhibition of the proliferation of smooth muscle cells by
lovastatin is described in Cardiovasc. Drugs. Ther. 5, Suppl.
3, 354 [1991]. Tocotrienol, an unsaturated analogue of vitamin
E, and its analogues make up another class of substances which
act on HMG-CoA-reductase (Exp. Opin. Ther. Patents 7 (5), 446
(1997]) .
Inhibitors of the enzyme squalene-synthetase are e.g.
isoprenoid-(phosphinylmethyl)-phosphonates, the suitability of
which for treating hypercholesterolaemias, gallstone problems
and tumour diseases is described in EP-A-0 409 181 and in
J. Med. Chemistry 34, 1912 [1991], and also a-
phosphonosulfinate compounds (EP-A-0 698 609), the compounds
J-104,118 and J-104,123 (Tetrahedron 52, 13881-13894, [1996])
and cyclobutane derivatives (WO 96/33159). A survey of
squalene-synthethase inhibitors can be found in Exp. Opin.
Ther. Patents 7 (5), 446-448 [1997].
Known inhibitors of the enzyme squalene-epoxidase are
allylamines such as naftidine and terbinafine, which have been
used in therapy to fight fungal diseases, and also the
allylamine NB-598 with an antihypercholesterolaemic activity
(J. Biol. Chemistry 265, 18075-18078 (1990]) and fluorosqualene
derivatives with a hypocholesterolaemic activity (US-A-
5,011,859). Moreover, piperidines and azadecalines with a
potential hypocholesterolaemic and/or antifungal activity are
described, the mechanism of activity of which has not been
fully explained and which are squalene epoxidase and/or 2,3-
epoxisqualene-lanosterol-cyclase inhibitors (EP-A-0 420 116,
EP-A-0 468 434, US-A-5,084,461 and EP-A-0 468 457). Other
examples are described in Exp. Opin. Ther. Patents 7 (5), 448-
449 [1997].
Examples of inhibitors of the enzyme 2,3-epoxisqualene-
lanoster~ol-cyclase are diphenyl derivatives (EP-A-0 464 465),
aminoalkoxybenzene derivatives (EP-A-0 410 359, J. Lipid. Res.
CA 02309388 2000-OS-15
_ 4 _
38, 373-390, [1997]) and piperidine derivatives (J. Org. Chem.
57, 2794-2903 [1992] which have an antifungal activity.
Moreover this enzyme is inhibited in mammalian cells by
decalines, azadecalines and indane derivatives (WO 89/08450;
J. Biol. Chemistry 254, 11258-11263 [1981]; Biochem.
Pharmacology 37, 1955-1964 [1988] and J 64 003 144), and also
by 2-aza-2,3-dihydro-squalene and 2,3-epiminosqualene
(Biochem. Pharmacology 34, 2765-2777 [1985]), by squalenoid-
epoxide-vinylether (J. Chem. Soc. Perkin Trans. I, 461 [1988])
and 29-methylidene-2,3-oxidosqualene (J. Amer. Chem. Soc. 113,
9673-9674 [1991]). Other examples are. pyridine and pyrimidine
derivatives (WO 97/06802), heterobicyclic alkylamines (WO
96/11201), imidazole derivatives (EP-A-0 757 988) and
isoquinoline derivatives (J. Med. Chemistry 39, 2302-2312,
[1996]). Other compounds described are ureas (DE-A-4 438 021),
oximes (DE-A-4 412 692), a number of amides (DE-A-4 407 134,
DE-A-4 407 135, DE-A-4 407 136, DE-A-4 407 138,
DE-A-4 407 139, DE-A-4 412 691, DE-A-4 437 999,
DE-A-4 438 000, DE-A-4 438 020, DE-A-4 438 082,
DE-A-4 438 029, DE-A-4 438 054, DE-A-4 438 055,
DE-A-4 438 082, DE-A-4 438 083, EP-A-0 599 203,
EP-A-0 596 326) and esters (WO 95/29148). Other examples are
described in Exp. Opin. Ther. Patents 7(5), 448-449 [1997].
Finally, inhibitors of the enzyme lanosterol-14a-demethylase
also include steroid derivatives with a potential
antihyperlipidaemic activity which simultaneously influence
the enzyme HMG-CoA-reductase (US-A-5,041,431; J.Biol.
Chemistry 266, 20070-20078 [1991]; US-A-5,034,548). This enzyme
is also inhibited by the antimycotics of the azole type which
constitute N-substituted imidazolea and triazoles. This class
includes, for example, the commercially available antimycotics
ketoconazole and fluconazole.
The compounds of the following general formula I are new. It
has been~found that, surprisingly, they are highly effective
CA 02309388 2000-OS-15
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inhibitors of the enzyme 2,3-epoxisqualene-lanosterol-cyclase
(International Classification: EC 5.4.99.7)
The enzyme 2,3-epoxisqualene-lanosterol-cyclase catalyses a
key step of cholesterol or ergosterol biosynthesis, namely the
conversion of 2,3-epoxisqualene into lanosterol, the first
compound with a steroid structure in the biosynthesis cascade.
Inhibitors of this enzyme lead one to expect the advantage of
higher selectivity, compared with inhibitors of earlier stages
of biosynthesis, such as for example HMG-CoA-synthase and HMG-
CoA-reductase, since inhibiting these early stages of
biosynthesis leads to a reduction in biosynthetically formed
mevalonic acid and consequently may have a negative effect on
the biosynthesis of the mevalonic acid-dependent substances
dolichol, ubiquinone and isopentenyl-t-RNA (cf. J. Biol.
Chemistry 265, 18075-18078 [1990].
When stages of biosynthesis after the conversion of 2,3-
epoxysqualene into lanosterol are inhibited, there is a risk
of the accumulation of intermediate products with a steroid
structure in the body and the triggering of toxic effects
caused by them. This has been described, for example, in the
case of triparanol, a desmosterol-reductase inhibitor. This
substance had to be taken off the market on account of the
formation of cataracts, ichthyosis and alopecia (mentioned in
J. Biol. Chemistry 265, 18075-18078 [1990]).
As already stated hereinbefore, inhibitors of 2,3-
epoxisqualene-lanosterol-cyclase have already been described
in the literature. However, absolutely no urethanes or their
thio or dithio analogues are known as inhibitors of
2,3-epoxisqualene-lanosterol-cyclase.
The invention relates to the preparation of antihyperchole-
sterolaemic substances which are suitable for the treatment
and prophylaxis of atherosclerosis and are distinguished from
known active substances by their superior
CA 02309388 2000-OS-15
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antihypercholesterolaemic activity with greater selectivity
and hence greater safety. Since the compounds according to the
invention are also able to inhibit ergosterol biosynthesis in
fungal oganisms by virtue of their great efficacy as
inhibitors of the enzyme 2,3-epoxisqualene-lanosterol-cyclase,
they are also suitable for treating mycoses.
The present invention relates to the new urethanes derived
from azacycloalkanes and the thio and dithio analogues thereof
of general formula
R~
Rs
(I) .
R E N-
R ~C ~ (CH2)m/ X
~N/ ~ 4 Rs Rs
R
R2
wherein
m denotes the numbers 0 or 1,
n denotes the numbers 1 or 2,
w A denotes a single bond, a straight-chained or branched C1_e-
alkylene group, a Ca_e-alkenylene or Cz_e-alkynylene group,
whilst an unsaturated group is not directly bound to the group
Y.
X denotes an oxygen or sulphur atom,
Y denotes an oxygen or sulphur atom,
R1 denotes a straight-chained or branched C1_6-alkyl group, a
Cl_,-alkenyl group or a Cl_,-alkynyl group, whilst the multiple
bond is isolated from the nitrogen-carbon bond,
CA 02309388 2000-OS-15
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R2 denotes a straight-chained or branched C1_6-alkyl group, a
Cl_,-alkenyl group or a C,_,-alkynyl group, whilst the multiple
bond is isolated from the nitrogen-carbon bond, or
Rl and R~ together with the nitrogen atom denotes a 5- to 7-
membered, saturated heterocyclic ring wherein a methylene
group isolated from the nitrogen atom may be replaced by an
oxygen or sulphur atom or by an -NH- or -N(alkyl)- group,
R3 to R6, which may be identical or different, denote hydrogen
atoms or alkyl groups,
R' denotes a C3_.,-cycloalkyl group, a phenyl or naphthyl group
optionally substituted by one or two halogen atoms or by an
alkyl, alkoxy, trifluoromethyl or cyano group or, if A does
not denote a single bond, R' also denotes a hydrogen atom,
E denotes an oxygen or sulphur atom, a methylene, carbonyl or
sulphinyl group and
RB denotes a hydrogen atom or
E denotes the group -C (R'R1°) -, wherein
R9 denotes a hydrogen atom and
R1° together with the adjacent group Re denotes a carbon-
carbon band,
whilst, unless otherwise stated, alkyl groups contained in the
groups mentipned above may contain 1 to 3 carbon atoms and a
halogen atom mentioned above may be a fluorine, chlorine or
bromine atom,
the enantiomers, diastereomers, the mixtures thereof and the
salts thereof,, particularly the physiologically acceptable
acid addition salts thereof.
CA 02309388 2000-OS-15
a
- 8 -
The preferred compounds are the compounds of general formula
I, wherein
m denotes the number 1,
n denotes the number 1, -
A denotes a single bond, a straight-chained or branched C1_,-
alkylene group or a Ca_~-alkenylene group, wherein an
unsaturated group is not directly bound to the group Y,
X denotes an ox~rgen or sulphur atom,
Y denotes an oxygen or sulphur atom,
R1 denotes a straight-chained or branched C1_6-alkyl group, an
allyl or propargyl group; whilst the multiple bond is isolated
from the nitrogen-carbon bond,
Ra denotes a straight-chained or branched C1_6-alkyl group, an
allyl or propargyl group, whilst the multiple bond is isolated
from the nitrogen-carbon bond,
Rl and Ra together with the nitrogen atom denote a 5- to 7-
membered, saturated heterocyclic ring wherein a methylene
t
group isolated from the nitrogen atom may be replaced by an
oxygen or sulphur atom,
R' to R6, which may be identical or different, denote hydrogen
atoms or methyl groups,
R' denotes a C,_~-cycloalkyl group, a phenyl or naphthyl group
optionally substituted by one or two halogen atoms or by an
alkyl, alkoxy, trifluoromethyl or cyano group,
E denotes a sulphur atom, a methylene, carbonyl or sulphinyl
group aad
CA 02309388 2000-OS-15
a
_ -
Re denotes a hydrogen atom or
E denotes the group -C (R'R1°) - whilst
R' denotes a hydrogen atom and
Rl° together with the adjacent group R8 denotes a carbon-
carbon bond,
whilst, unless otherwise stated, alkyl groups contained in the
groups mentioned above may each contain 1 to 3 carbon atoms
and a halogen atom mentioned above may be a fluorine, chlorine
or bromine atom,
the enantiomers, diastereomers, the mixtures thereof and the
salts thereof, particularly the physiologically acceptable
acid addition salts thereof.
Particularly preferred are the compounds of general formula I,
wherein
m denotes the number 1,
n denotes the number 1,
A denotes a single bond or a straight-chained or branched Cl_3
alkylene group,
X denotes an oxygen or sulphur atom,
Y denotes an oxygen or sulphur atom,
R1 denotes a straight-chained or branched C1_3-alkyl group,
RZ denotes a straight-chained or branched C1_3-alkyl group, or
Rl and R~'together with the nitrogen atom denote a piperidino
or morpholino group,
CA 02309388 2000-OS-15
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R3 to R6 denote hydrogen atoms,
R' denotes a cyclohexyl group or a phenyl group optionally
substituted by a halogen atom or by an alky3., alkoxy or
trifluoromethyl group,
E denotes a sulphur atom, a methylene group, a carbonyl or
sulphinyl group and
Re denotes a hydrogen atom or
E denotes the group -G (R9R1°) -, wherein
R' denotes a hydrogen atom and
R1° together with the adjacent group R° denotes a carbon-
carbon bond,
the enantiomers, diastereomers, the mixtures thereof and the
salts thereof, particularly the physiologically acceptable
acid addition salts thereof.
Most particularly preferred are the compounds of general
formula I wherein
m denotes the number 1,
n denotes the number 1,
A denotes a single bond or a methylene group,
X denotes an oxygen or sulphur atom,
Y denotes an oxygen or sulphur atom,
R1 and RZ each denote a methyl group,
CA 02309388 2000-OS-15
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R' to R6 denote hydrogen atoms ,
R' denotes a phenyl group optionally substituted by a fluorine
or chlorine atom or by a methyl group,
E denotes a sulphur atom, a methylene or carbonyl group and
R8 denotes a hydrogen atom or
E denotes the group -C (R9R1°) -, wherein
R9 denotes a hydrogen atom and
R1° together with the adjacent group R8 denotes a carbon-
carbon bond,
the mixtures and salts thereof, particularly the
physiologically acceptable acid addition salts thereof,
but particularly the compounds
(1) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)-
phenylthio]piperidine,
(2) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)ben-
zoyl]piperidine,
(3) N-benzyloxycarbonyl-4-[4-(dimethylaminomethyl)phenylthio]-
piperidine,
(4) N-(4-chlorophenoxy)carbonyl-4-[4-(dimethylaminomethyl)phe-
nylthio]piperidine,
(5) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)ben-
zyl]piperidine,
(6) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)ben-
zylidene]piperidine,
CA 02309388 2000-OS-15
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- 12 -
(7) N-(4-chlorophenoxy)thiocarbonyl-4-[4-
(dimethylaminomethyl)-benzyl]piperidin,
(8) N-(4-chlorophenoxy)carbonyl-4-,[4-(dimethylaminomethyl)-
benzyl]piperidine,
(9) N-benzyloxycarbonyl-4-[4-(dimethylaminomethyl)benzyl]-
piperidine,
(10) 4-[4-(dimethylaminomethyl)benzyl]-N-(4-methylphenoxy)-
carbonylpiperidin,
(il) 4-[4-(dimethylaminomethyl)benzyl]-N-(4-methylphenoxy)-
thiocarbonylpiperidine and
( 12 ) 4 - [4 - ( dimethylaminomethyl ) benzyl ] -N- ( 4 - f luorphenoxy) -
carbonylpiperidine,
the mixtures and the salts thereof, particularly the
physiologically acceptable acid addition salts thereof, such
as the hydrochlorides, methanesulphonates or tartrates
thereof.
The compounds of general formula I may be prepared for example
by the following methods:
a) reacting a compound of general formula
R8
R3 (CH2)" ~
E /N-H (II) ,
R' ~ (CH2)m
~N~-~ T
4 R5 Re
R
R2
wherein
CA 02309388 2000-OS-15
a
' - 13 -
m, n, E with the exception of the sulphinyl group, R1 to R6 and
Re are as hereinbefore defined, with a compound of general
f ormul a
z Y~A~ R
(III),
X
wherein
A, X, Y and R' are as hereinbefore defined and Z denotes a
leaving group, e.g. a halogen atom such as a chloine, bromine
or iodine atom.
The reaction is carried out under Schotten-Baumann or Einhorn
conditions, i.e. the components are reacted in the presence of
at least one equivalent of an auxiliary base at temperatures of
between -50°C and +120°C, preferably -10°C and
+30°C, and
optionally in the presence of solvents. Preferred auxiliary
bases are alkali and alkaline earth metal hydroxides, e.g.
sodium hydroxide, potassium hydroxide or barium hydroxide,
alkali metal carbonates, e.g. sodium carbonate, potassium
carbonate or caesium carbonate, alkali metal acetates, e.g.
sodium or potassium acetate, and tertiary amines, e.g.
pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine,
N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-di-
azabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene,
whilst preferred solvents include, for example, diethylether,
methylene chloride, dichloromethane, ethyl acetate, toluene,
tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide,
dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof; if
alkali or alkaline earth metal hydroxides, alkali metal
carbonates or acetates are used as auxiliary bases, water may
also be added to the reaction mixture as a cosolvent.
b) In order to prepare compounds of general formula (I),
wherein X and Y each denote a sulphur atom and m, n, A, E and
R1 to R8 are as hereinbefore defined with the proviso that R'
does not~represent an optionally substituted phenyl or
naphthyl group if A denotes a single bond:
CA 02309388 2000-OS-15
- 14 -
reacting compounds of general formula (II), wherein m, n and E
with the exception of the sulphinyl group, Rl to R6 and R' are
as hereinbefore defined, with carbon disulphide and
subsequently with an alkylating agent of general formula
(IV)
wherein
A and R' are as hereinbefore defined, with the proviso that R'
does not represent an optionally substituted phenyl or
naphthyl group if A denotes a single bond, and Zl denotes a
leaving group, e.g. a halogen atom, such as the chlorine,
bromine or iodine atom, an alkylsulfonyloxy group with 1 to 10
carbon atoms in the alkyl moiety, a phenylsulphonyloxy or
naphthylsuphonyloxy group optionally mono-, di- or
trisubstituted by chlorine or bromine atoms, by methyl or
nitro groups, whilst the substituents may be identical or
different.
The reaction is appropriately carried out by first converting
a compound of general formula (II) into the lithium salt in a
suitable solvent, e.g. in tetrahydrofuran, dioxane, hexane or
toluene, e.g. using n-butyllithium at a temperature of from
-20 to -10°C, and then reacting it with carbon disulphide.
Then a compound of general formula (IV) is added in a suitable
solvent, e.g. in tetrahydrofuran, dimethylformamide,
dimethylsulphide or a mixture thereof and the reaction is
carried out at 20-60°C.
c) In order to prepare compounds of general formula (I)
wherein E denotes a sulphinyl group:
Oxidation of a compound of general formula (I) wherein m, n,
A, X, Y,' and R1 to RB are as hereinbefore defined and E denotes
a sulphur atom, preferably with sodium metaperiodate.
CA 02309388 2000-OS-15
' 15 -
The oxidation is conveniently carried out with one equivalent
of the oxidising agent used, e.g. with sodium metaperiodate in
aqueous methanol or ethanol at -15 to 25°C.
The compounds of general formula I prepared by the above
methods can be purified and isolated by methods known per se,
e.g. by crystallisation, distillation or chromatography.
Moreover, the compounds of general formula I obtained may
optionally be resolved into their enantiomers and/or
diastereomers.
Thus, for example, the compounds of general formula I obtained
which occur as racemates may be separated by methods known per
se (cf. Allinger N. L. and Eliel E. L. in "Topics in
Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their
optical antipodes and compounds of general formula I with at
least 2 asymmetric carbon atoms may be resolved into their
diastereomers on the basis of their physical-chemical
differences using methods known per se, e.g. by chromatography
and/or fractional crystallisation, and, if these compounds are
obtained in racemic form, they may subsequently be resolved
into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation
on chiral phases or by recrystallisation from an optically
active solvent or by reacting with an optically active
substance which forms salts or derivatives such as e.g. esters
or amides with the"racemic compound, particularly acids and
the activated derivatives or alcohols thereof, and separating
the diastereomeric mixture of salts or derivatives thus
obtained, e.g. on the basis of their differences in
solubility, whilst the free antipodes may be released from the
pure diastereomeric salts or derivatives by the action of
suitablelagents. Optically active acids in common use are e.g.
the D- and L-forms of tartaric acid or dibenzoyltartaric acid,
CA 02309388 2000-OS-15
a
- 16 -
di-o-tolyltartaric acid, malic acid, mandelic acid,
camphorsulphonic acid, glutamic acid, aspartic acid or quinic
acid. An optically active.alcohol may be for example (+) or
(-)-menthol and an optically active acyl group in amides, for
example, may be a (+)-or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into
the salts thereof, particularly for pharmaceutical use into
the physiologically acceptable salts with inorganic or organic
acids. Acids which may be used for this purpose include for
example hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acid, fumaric acid, auccinic acid, lactic acid,
citric acid, tartaric acid or malefic acid.
The starting compounds of general formula II wherein E denotes
a carbonyl group may be prepared by the methods described in
DE 44 07 136 Al (pp. 4-5).
The starting compounds of general formula II wherein E denotes
a methylene group or the group -C(R9R1°)-, wherein R9 denotes a
hydrogen atom and Rl° together with the adjacent group R8
denotes a carbon-carbon bond, can be prepared by the methods
described in DE 44 07 138 A1 (5/1144)(pp. 7-8).
Compounds of general formula II wherein E denotes an oxygen or
sulphur atom may be prepared by the following reaction plan:
CA 02309388 2000-OS-15
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R~ ~~ Rs CH
R E ~. O ~S. ( z)" ~
R~ ~ ~ ~ O N-R»
~N/ ~ . ~ H (CH2)m/
R4 R Rs
R2 (V) (VI )
Rs
R3 (CHZ)" ~
E N- R~~ --~. (II)
R ~C ~ (CH2)m/
~N/
R4 R5 Rs
Rz
(VII)
The reaction of a compound of formula V wherein R' to RS are as
hereinbefore defined and E denotes an oxygen or sulphur atom
with a compound of formula VI wherein m, n, R6 and RB are as
hereinbefore defined, R11 denotes a protecting group, for
y example the tert.butyloxycarbonyl group, and R12 denotes an
alkyl group, yields a corresponding compound of formula VII
which is converted by the cleaving of the protecting group R1~
into a compound of formula II.
Compounds of general formula II wherein E denotes a methylene
group, an oxygen or sulphur atom, R3 to RS and R8 denote
hydrogen atoms, R6 denotes a hydrogen atom or an alkyl group
and the phenyl group is 1,4-disubstituted may be prepared by
the two methods shown in the following reaction plan:
z
s
CA 02309388 2000-OS-15
- 1.~ -
Re
(CHZ)n \
E ~N-R~~ (VIII) .
(CH2)m
RB
.Re (CH2)n \ O RB (CHZ)n \
~~E ~N-R" ~ ~ E /N-R~~
CI~ ~ (CH2)m CI (CH2)m
(IX) Re (XI) Re
a
Re (CH2)n \ O R (CH~n \
E N-Rtt ~ ~ E ~N-R"
R~- \ \ ~ (CH~m~ Rt- \ (CHZ)m
Rz Re Rz Re
(X) (XII)
(II) (II)
On the one hand a compound of formula VIII wherein Rl' denotes
a protecting group, preferably a 2,2,2-trichloroethoxycarbonyl
group, is converted by chloromethylation into a compound of
formula IX. Aminolysis with an amine of formula R1RZNH yields a
compound of formula X which is converted by cleaving the
protecting group into a compound of formula II.
On the other hand, a compound of formula VIII wherein R11
denotes a protecting group, preferably the trifluoroacetyl
group, may be converted by a Friedel-Crafts reaction with
oxalylchloride in the presence of aluminium chloride into a
compound of formula XI. Aminolysis with an amine of formula
R1RZNH yields a compound of formula XII which is converted by
CA 02309388 2000-OS-15
7
.f
- 19 -
reduction with lithium aluminium hydride and cleaving of the
protecting group into a compound of formula II.
Compounds of formula II wherein E denotes an oxygen or sulphur
atom, R3 to RS and R8 denote hydrogen atoms, R6 denotes a
hydrogen atom or an alkyl group, may also be prepared by the
following method:
Rs
(CHZ)n ~ R~~+ _
E /N- R~~ 2/N=CH2 Hal
Br (CHa)m R
Rs
(XI I I ) (~)
R$
(CH2)n ~
E N- R~~ --~~ (II)
(CH2)m~
R~~N~R2 Rs
i (XV)
A compound of formula XIII wherein Rll denotes a protecting
group, preferably a trityl group, is first converted into the
lithium compound and then reacted with a compound of formula
XIV wherein Hal denotes a chlorine, bromine or iodine atom to
form a compound of formula XV. Cleaving the protecting group
yields a compound of formula II.
The compounds of general formula I have valuable biological
properties. They are inhibitors of cholesterol biosynthesis,
particularly inhibitors of the enzyme
2,3-epoxysqualene-lanosterol-cyclase. In view of their
biological properties they are suitable for treating diseases
y .
CA 02309388 2000-OS-15
- 20 -
in which cholesterol biosynthesis is implicated, particularly
for the treatment and prophylaxis of hypercholesterolaemia,
hyperlipoproteinaemia and hypertriglyceridaemia and the
resultant atheroscleotic vascular changes with their sequelae
such as coronary heart disease, cerebral isehaemia,
Claudicatio intermittens, gangrene et al.
For treating these diseases the compounds of general formula I
may be used either on their own for monotherapy or in
conjunction with other cholesterol- or lipid-lowering
substances, whilst'the compounds may preferably be
administered as an oral preparation, and optionally also in
the form of suppositories as a rectal formulation. The
following are possible combination partners:
- bile acid-binding resins such as cholestyramine, cholestipol
and others,
- compounds which inhibit cholesterol absorption such as e.g.
sitosterol and neomycin,
compounds which interfere with cholesterol biosynthesis by a
mechanism other than inhibition of
2,3-epoxysqualene-lanosterol-cyclase such as e.g.
HMG-CoA-reductase inhibitors such as lovastatin, simvastatin,
pravastatin, fluvastatin, atorvastatin, cerivastatin and
others,
- squalene-epoxidase inhibitors such as NB 598 and analogous
compounds and
- squalene-synthetase inhibitors such as compounds from the
class of the isoprenoid-(phosphinylmethyl)phosphonates and
squalestatin.
Other possible combination partners still to be mentioned are
the fibrates, such as clofibrate, bezafibrate, gemfibrozil and
CA 02309388 2000-OS-15
' - 21 -
others, nicotinic acid, the derivatives and analogues thereof
such as acipimox, and probucol.
Furthermore the compounds of general formula I are suitable
for the treatment of diseases connected with excessive cell
proliferation. Cholesterol is an essential ingredient of cells
and must be present in sufficient quantities for cell
proliferation, i.e. cell division. The inhibition of cell
proliferation by inhibiting cholesterol biosynthesis is
described with reference to the smooth muscle cells with the
HMG-CoA-reductase inhibitor of the mevinolin type lovastatin,
as mentioned hereinbefore.
Examples of diseases connected with excessive cell prolifer-
ation are primarily tumour diseases. In cell culture and
in-vivo experiments it has been.shown that the lowering of the
serum cholesterol or intervention in cholesterol biosynthesis
by means of HMG-CoA-reductase inhibitors reduces tumour growth
(Lancet 339, 1154-1156 [1992]). The compounds of formula I
according to the invention are therefore potentially suitable
for treating tumour diseases on the basis of their inhibitory
effect on cholesterol biosynthesis. They may be used on their
own or in support of known therapeutic principles.
Other examples are hyperproliferative skin diseases such as
psoriasis, basal cell carcinomas, plate epithelial carcinomas,
keratosis and keratinisation disorders. The term "psoriasis"
used here denotes a hyperproliferatively inflammatory skin
disease which changes the regulatory mechanism of the skin. In
particular, lesions are formed which contain primary and
secondary changes in the proliferation in the epidermis,
inflammatory reactions of the skin and the expression of
regulatory molecules such as lymphokines and inflammatory
factors. Psoriatic skin is morphologically characterised by an
increased turnover of epidermis cells, thickened epidermis,
abnormal~keratinisation of inflammatory cell infiltrates into
the dermis layer and polymorphonuclear leukocyte infiltration
CA 02309388 2000-OS-15
- 22 -
into the epidermis, causing an increase in the basal cell
cycle. Additionally, hyperkeratotic and parakeratotic cells
are present. The terms "keratosis", "basal cell carcinomas",
"plate epithelial carcinomas" and "keratinisation disorders"
relate to hyperproliferative skin diseases ~in which the
regulating mechanism for the proliferation and differentiation
of the skin cells has been disrupted.
The compounds of formula I are effective as antagonists of
skin hyperproliferation, i.e. as agents which inhibit the
hyperproliferation of human keratinocytes. The compounds are
consequently suitable as agents for treating hyperprolifer-
ative skin diseases such as psoriasis, basal cell carcinomas,
keratinisation disorders and keratosis. For treating these
diseases the compounds of formula I may be administered either
orally or topically, and may be used either on their own in
the form of monotherapy or in combination with known active
substances.
Hyperproliferative vascular diseases such as stenoses and
vascular occlusions based on the proliferation of smooth
muscle cells and caused by surgical procedures such as PTCA
(percutaneous transluminal coronary angioplasty) or bypass
operations should also be mentioned. As mentioned hereinbefore
this cell proliferation is known to be suppressed by
HMG-CoA-reductase inhibitors of the mevinoline type, such as
lovastatin. In view of their inhibitory activity on
cholesterol biosynthesis the compounds of general formula I
are also suitable for the treatment and prophylaxis of these
diseases, and may be used either on their own or in
conjunction with known active:.substances such as intravenously
administered heparin, preferably by oral administration.
Another possible use of the compounds of general formula I
according to the invention is the prophylaxis and treatment of
gallstone problems. The formation of gallstones is triggered
by the cholesterol concentration in the bile exceeding the
CA 02309388 2000-OS-15
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maximum solubility of the cholesterol in the bile fluid,
causing the cholesterol to be precipitated in the form of
gallstones. Lipid-lowering substances from the fibrate class
lead to increased precipitation of neutral steroids through
the bile and increase the tendency to form gallstones.
Hy contrast, cholesterol biosynthesis inhibitors such as lova-
statin or pravastatin do not result in increased gallstone
formation; on the contrary they may bring about a reduction in
the cholesterol concentration in the bile and hence lower the
so-called lithogenic index, a measurement of the probability
of gallstone formation. This is described in Gut 31, 348-350
[1990] and in Z. Gastroenterol. 2~, 242-245 [1991] .
Moreover, the efficacy of lovastatin in dissolving gallstones,
particularly in conjunction with ursodeoxycholic acid, is
described in Gastroenterology 102, No. 4, Pt. 2, A 319 [1992].
In view of their mode of activity the compounds of general
formula I are therefore also important in the prevention and
treatment of gallstone problems. They may be used either on
their own or in conjunction with known therapies such as, for
example, treatment with ursodeoxycholic acid or shockwave
lithotripsy, and are preferably administered orally.
Finally, the compounds of general formula I are suitable for
the treatment of infections caused by pathogenic fungi such as
e.g. Candida albicans, Aspergillus niger, Trichophyton menta-
grophytes, Penicillium sp., Cladosporium sp. and others. As
mentioned earlier, the end product of sterol biosynthesis in
the fungal organism is not cholesterol, but ergosterol which
is essential for the integrity and function of the fungal cell
membranes. Inhibiting ergosterol biosynthesis therefore leads
to growth disorders and possibly the death of the fungal
organisms.
For treating mycoses the compounds of general formula I may be
administered either orally or topically. They may be used
CA 02309388 2000-OS-15
- 24 -
either on their own or in conjunction with known antimycotic
active substances, particularly with those which interfere in
other stages of sterol biosynthesis, such as for example the
squalene-epoxidase inhibitors terbinafine and naftifine or the
lanosterol-14a-demethylase inhibitors of the azole type such
as ketoconazole and fluconazole.
Another possible use of the compounds of general formula I is
their application in poultry rearing. Lowering the cholesterol
content of eggs by administering the HMG-CoA-reductase
inhibitor lovaatatin to laying hens has been described (FASEB
Journal 4_, A 533, Abstracts 1543 [1990]). The production of
low-cholesterol eggs is of interest as the cholesterol loading
of the body can be reduced without changing eating habits by
means of eggs with a reduced cholesterol content. In view of
their inhibitory activity on cholesterol biosynthesis the
compounds of general formula I can also be used in poultry
rearing to produce low-cholesterol eggs, the substances
preferably being given to the hens as a feed additive.
The biological activity of compounds of general formula I was
determined by the following methods:
I. Measuring the inhibition of 14C-acetate incorporation into
the steroids which can be precipitated with digitonin:
The inhibitory effect was investigated using the method
described in J. Lipid. Res. 37, 148-157 1996) at test
concentrations of 10-8 and 10-9 mol/1.
By way of example, the test results for the following
compounds (A) to (M) of general formula I and the comparison
substances (U), (V) and (W) at these test concentrations are
given:
(A) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)-
phenylthio]piperidine-hydrochloride;
CA 02309388 2000-OS-15
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(B) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)ben-
zoyl]piperidine-hydrochloride,
(C) N-benzyloxycarbonyl-4-[4-(dimethylaminomethyl)phenylthio]-
piperidine-hydrochloride,
(D) N-(4-chlorophenoxy)carbonyl-4-[4-(dimethylaminomethyl)-
phenylthio]piperidine-hydrochloride,
(E) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)-
benzyl]piperidine-hydrochloride,
(F) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)-
benzyliden]piperidine-hydrochloride,
(G) N- (4-chlorophenoxy) thiocarbonyl-4- [4-
(dimethylaminomethyl)-benzyl]piperidine-hydrochloride,
(H) N-(4-chlorophenoxy)carbonyl-4-[4-(dimethylaminomethyl)-
benzyl]piperidine-hydrochloride,
(I) N-benzyloxycarbonyl-4-[4-(dimethylaminomethyl)benzyl]-
piperidine-hydrochloride,
(K) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) -
carbonylpiperidine-hydrochloride,
(L) 4- [4- (dimethylaminomethyl)benzyl] -N- (4-methylphenoxy) -
thiocarbonylpiperidine-hydrochloride,
(M) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-fluorphenoxy) -
carbonylpiperidine-hydrochloride,
CA 02309388 2000-OS-15
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(U) 1-(4-chlorobenzoyl)-4-[4-(2-oxazolin-2-yl)-benzylideneJ
-piperidine (EP-A-0 596 326, p. 16, compound A therein; J.
Lipid. Res. 38, 564-575 [199'7J) ,
(V) trans-N-(4-chlorobenzoyl)-N-methyl-[4-(4--dimethylamino)-
methyl)phenyl]cyclohexylamine (DE-A-44 38 020; J. Lipid. Res.
37, 148-157 [1996.]) and
(W) traps-O-(p-tolylacetyl)-4-(4-dimethylaminomethylphenyl)-
cyclohexanol (WO 95/29148, p. 28, compound I therein).
The percentages by which the above compounds inhibit the 14,v._
acetate incorporation are shown in Table 1.
Table 1:
~~ r ~co~ri ou~:d ~~ lQ :mod. :~; ~~~~.0 ~'.mol= ~.
~~:,~ ~~ ~~ :.,
P. ~ ~~ ~ ~ . ~ t ~~ . , / 3
~
(A) -85 -53
(B) -85 -47
(C) -78 -57
(D) -86 -55
(E) -87 -47
(F) -84 -45
(G) -83 -56
(H) -80 -45
(I) -85 -47
(K) -82 -49
(L) -88 -64
(M) -84 i -59
(U) -54 -07
(V) -59 -23
(W) -72 -21
The IC50 values of cornpounds H, I, F~; and M were determined.
These are given together with the IC'S0 value~~ of compounds U,
V and W in Table 2.
CA 02309388 2000-OS-15
- 27 -
Table 2:
s ~~mm ~;Comp,~und'~~~~'~,a~ ~~~~~(nmdl/~13~
~,>
(H) 0.8
(I) 1.2
(K) 1.4
(M) 1.5
(U) 5.5
(V) 3.8
-
(W) 9.6
(
Table 2 shows that the compounds according to the invention
are significantly superior to the comparison :substances
described earlier.
II. Measuring the in-vivo act:ivity in the rat after oral
administration
Inhibiting the enzyme 2,3-epoxysqualene-lanosterol-cyclase
causes an increase in the 2,3-epoxisqualene levels in the
liver and plasma. The quantity of 2,:3-epoxysqualene formed
therefore serves as a direct measurement of the potency on t:he
animal as a whole. The amounts were determined using the
method described in J. Lipid. Res. 38, 564-575, [1997 after t
- 3 or 8 hours after administration of the substance in
concentrations of c = 0.01, 0.03, 0.1, 0.3 and 1.0 mg/kg.
Table 3 which follows gives t:he results obtained for the
abovementioned substances A, B, C, D, E, G, H, I and K by way
of example.
CA 02309388 2000-OS-15
- 28 -
Tab. 3: 2,3-epoxysqualene concentration [~g/g]
In the liver (rat)
,,
,g : r - rv ~1 ~ .~ ' ,. ' ~' ~ ~.'~ .~~.
". J 1 ~r ~~,.~ ~ Y9 ,~ ~5~
.~ ,< ,pa ; .. ~ '~,'~ ~'t
'~ P 1. ~,... -t.- .rim:'
~ - , Ti'i ',?Y~'~~.
c~
A 2.0 1.2 9.3 9.8
B 4.5 5.8 39.2 42.0
_
O 0.5 1.3 0.5 1.8 3.8 2.0
:6 3.0
D 1.3 1.0 1.4 1.8
E 0.9 1.0 5.6 4.4
G 10.3 11.5 87.4 134.2
H 1.0 0.8 56.3 20.7
I 1.0 26.1 10.0
~
K 0.4 0.4 24.0 5.5
In the control animals there were nc> measurable 2,3-
epoxisqualene levels under these conditions.
III. Lipid reduction in the normolipaemic golden hamster
This was determined using the method described in J. Lipid.
Res. 38, 564-575, (1997). At the end of the experiment the
total cholesterol, (3-lipoprotein-cholesterol and HDL-
cholesterol were determined and compared with the values of a
control group which were fed without. any test. substance.
The lipid-lowering activity of the abovementi-oned compound H
was tested.
The results are shown :in Table 4.
CA 02309388 2000-OS-15
- 29 -
Table 4:
-a . .."e..'~,~x. ~V W .azrs'r~r~~, n~,. 'aro? r
s'o- ~ot' , .", ;~ %°~ ~ °: ~ Las c5 ~ ~ ~ &.~°~~.~HD "~
e; ~~.$~: ;
~. ~ ~~ s r ~, t ~ *-
';,. a , .~. ~ ~ ~~~'~ ~ ~ ~~~haT~' ste'. ~ ,[~]"
~.ivt,::'.. ~ ° '° ist .~ 7,e
8".'~'~'=.ai,.t'.~~.'i~t.,'.;"~''fin.~.' v"e'h
d k~~ .h'' ~i . ~ r..4,:~ .h .°~5:;..r '.bt..u.,nf, .~.ad..
.'~d..._.,.Yy~Yt" ~.3r.~
n'~" .'.~~y~x' er
H 6.5 -8.3 -13.0 -3.4
19.9 -11.0 -13.2 -8.2
62.3 -32.1 -33.7 -28.5
I 47.1 -23.1 -32.9 -1'7.6
K 54.2 -6.8 -21.2 2.3
M 57.5 -26.8 -31.6 -20.4
Under these conditions the compounds exhibited no toxic
effects.
IV. Determining the fungistatic activity
The fungistatic activity was determined by the series dilution
test (microtitre system). Sabouraud broth was used as tt:e
nutrient medium. The inoculum amounted to about 104 to 105
CFU/ml (CFU = colony-forming units); the incubation period was
2 to 4 days at 26°C.
The lowest concentration which allows no visible growth
(minimum inhibitory concentration MIC) was determined.
The abovementioned compounds A, B, D, E, F, H, I, K, L and M
were tested. The results are assembled in the following Tab:Le
5. The MIC is given in ~,g/ml.
The following test pathogens were used:
CA 02309388 2000-OS-15
- 30 -
Test pathogen Abbreviation
Cand. albicans A'rCC 102?,l Cand.
Sacch. carlsbergensis ATCC 9080 - Sacc.
Rhod. rubra 49 Rhod.
Asp. Asp.
niger
ATCC
16404
Trich. mentagrophytes ATCC 9129 Trich.
Pen. Pen.
notatum
CBS
19746
Table 5:
~..
>~ _ v "..
wir ;~ '' z : s
TE ~" a~r k.~..
. - ., h~.. 6'~
r 'S~, ~ . ~9:k. !F-~~' -lLkC.:
8
~F., u. ~
:Test., 2 . i,'a
....: ~'. < x
x. g, :..
a.j ~ ~r . b ~~'; ~
;~ ,.~ ry "Y
a'; '~ . t ~ ~" G ~ ax ~n
':.. ' ~~" 'a: ~ ~ ",
w . ~', " ~.~ ~ k ,a
'it~. t .-'- ... F . . ~a:~..
, x . 9r e, . lure ' k~,-~,~~.b .~:-..-
''fit ~ E a,.,~.,..XN rr .. ~ ~., G
. , ",, r ,ate., ~' %Y ~
~7 a ':ari w .5.>r
~y ~. ..
~', ~ P .
' . ~,
.." '>.
r" ..~
~'-.
>:
i1. .
a f
ep ;qs
. '. ngF.
. ,n
.g~~ d,~~;2~
~'.a
.~ ,
a. z~..
-,~ n"..
r ae
, ~< ~~ f,.r~,i =,-~2;F: ~i ,'.
.;. 9 -, a . ~,x .... a ~ ., '~ ~~r' $cs ~k'=;4,"~o
~r ~a#,~.."'' . ~ . ",r.3. , ,Y a d
:d .x - y w x z. _ ~ '~', i
r. ~ : ~~ ~- ,. .a ~ N..
' r , ~'Y ~ . ~ r& ." x
y.#~ ~~ ~ .. ~ a.x~srr r 'x
q,;~' ~ ~ ~.~: .< y-~~
' Y ~ . ~
, t , . e>. ..
>.p.x " ~~~a~'w:.. ~ . ~.~~ a. ..,.F'.%';
~t, ' :~~ x=. ~.
'::,3 ,,.dz~.~i~.n sn's .F ~
, :" > ~b'siv:: kYn..~~'~~~
R ' ~ ~~, s &~'
w. , ~ .-ze v, kAaC7.S, . 2;"
Y. .1-?:
.,w~~s:,
r~":,~~~.'~x. ~: ..,
, ~ s:.:z'',$Tz.
A 16 8 16 8 1 4
B 64 32 16 32 2 8
D 64 128 64 256 16 128
E 16 16 4 8 1 1
F 16 16 4 8 2 4
H 64 128 16 32, 1 64
I 256 512 64 64 4 128
K 64 512 64 64 8 256
L 32 64 8 64 1 32
M 128 512 32 64 2 512
For pharmaceutical use the compounds of general formula I may
be incorporated in the conventional pharmaceutical
preparations for oral, rectal and topical administration in a
manner known per se.
Formulations for oral administration include for example plain
and coated tablets and capsules. For rectal administration
suppositories may be used. The daily dose is between 0.1 and
200 mg for a person with a body weight of 60 kg, but the
preferred daily dose is front 1 to 100 mg for a person weighing
CA 02309388 2000-OS-15
x
' - 31 -
60 kg. The daily dose is preferably divided into 1 to 3
individual doses.
For topical application the compounds may be administered in
preparations containing about 1 to-1000 mg, particularly 10 to
300 mg of active substance per day. The daily dose is
preferably divided into l,to 3 individual doses.
Topical formulations include gels, creams, lotions, ointments,
powders, aerosols and other conventional formulations for
applying medicaments to the skin. The amount of active
substance for topical.use is 1 to 50 mg per gram of
formulation, but preferably 5 to 20 mg per gram of
formulation. Apart from application to the skin the topical
formulations of the present invention may also be used in the
treatment of mucous membranes accessible to topical treatment.
For example, the topical formulations may be applied to the
mucous membranes of the mouth, lower colon, etc.
For use in poultry rearing for the production of low-
cholesterol eggs the active substances of general formula I
are administered to the animals by the usual methods as an
additive to suitable feedstuffs. The concentration of the
active substances in the finished feed is normally 0.01 to 1%,
.,
but preferably 0.05 to 0.5%.
The active substances may be added to the feed as they are.
Thus, the feeds for laying hens according to the invention
contain, in addition to the active substance and optionally a
conventional vitamin-mineral mixture, maize, soya bean flour,
meat meal, edible fat and soya oil, for example. To this feed
is added one of the abovementioned compounds of formula I as
active substance in a concentration of from 0.01 to 1%, but
preferably 0.05 to 0.5%.
CA 02309388 2000-OS-15
- 32 -
The following Examples serve to illustrate the invention more
fully. The Rf values given were determined on ready-made
plates obtained from E.Merck of Darmstadt on:
a) aluminium oxide F-254 (type E)
b) silica gel 60 F-254
Examples of the preparation of the starting materials:
Example A
4-[4-(Dimethylaminomethyl)phenylthio]piperidine
To a solution of 7.18 g (71 mmol) of 4-hydroxypiperidine in
100 ml dimethylformamide are added first 19.6 g (142 mmol) of
powdered potassium carbonate and then 19.8 g (71 mmol) of
tritylchloride. The mixture is stirred for 22 hours at ambient
temperature, diluted with ethyl acetate to twice the volume,
washed with water and saturated saline solution, dried with
magnesium sulphate and concentrated by evaporation. The
residue is recrystallised from ethyl acetate/petroleum ether
_ (1:4, v:v). 17.65 g (72.4 % of theory) of 4-hydroxy-N-
tritylpiperidine are obtained as colourless crystals, melting
point 157-158°C.
5.77 g of this product are dissolved in 60 ml methylene
chloride, 2.6 g of methanesulphonic acid chloride are added
and 3.4 g of triethylamine are slowly added dropwise. The
mixture is stirred for 1 hour at 0°C, diluted with ether,
washed with ice water (4x), dried with magnesium sulphate and
concentrated by evaporation. 7.58 g of 4-methanesulphonyloxy-
N-tritylpiperidine is obtained as a colourless foam.
The product is dissolved in 30 ml of tetrahydrofuran and added
dropwise to a solution of the sodium salt of 4-bromothiophenol
(prepared from 3.18 g of 4-bromothiophenol and 0.81 g of 55~
CA 02309388 2000-OS-15
- 33 -
sodium hydride in 35 ml tetrahydrofuran). It ~~s heated to
boiling for 1 hour, cooled, then taken up in ethyl acetate,
washed with water and saturated saline solution, dried with
magnesium sulphate and concentrated by evaporation. 5.28 g of
4-(4-bromophenylthio)-N-tritylpiperidine are obtained as
colourless crystals, melting point 174-175°C.
2.57 g (5mmol) of this product are dissolved :i_n 30 ml
tetrahydrofuran and at -70°C 4 ml (6.4mmol) of a 1.6-molar
solution of n-butyllithium in n-hexane are added dropwise.
After 1.5 hours at -70°C, 1.1 g (6.4 mmol) of
N,N-dimethyl-methylenei_mmonium-iodide are added, the cooling
bath is removed and the mixture is stirred overnight. The
solvent is evaporated, the residue z_s triturated with water
and extracted with ethyl acetate. The organic phase is dried
with magnesium sulphate, concentrated by evapc:~ration and the
residue is purified by column chromatography (aluminium oxide,
ethyl acetate/petroleum ether = 1:10, v:v). 0.9 g 4-[4-
(dimethylaminomethyl)phenylthio]-N-trityl-piperidine are
obtained as colourless crystals, melting point 163°C.
This product is dissolved in :30 ml methylene chloride anrl 10
ml ethereal hydrochloric acid are added. After 1 hour at
ambient temperature the mixture is concentrated by
evaporation, combined with ether and the precipitate is
suction filtered. This is dissolved in a little water, ether
is added and the mixture is adjusted to pH 11 with 6N-sodium
hydroxide solution. The ether phase is separated off, the
aqueous phase is again extracted with ether and the combined
extracts are dried with magne:~ium sulphate. 500 mg of 4-[4-
(dimethylaminomethyl)phenylthio]piperidine are obtained as
colourless crystals, melting point 52°C.
CA 02309388 2000-OS-15
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Example B
4-[4-(Piperidinomethyl)phenylthio~piperidine
10.1 g (0.1 mol) of 4-hydroxypiperidine and 11 g (0.11 mol) of
triethylamine are placed in 200 ml ethyl acetate and 250 ml
tetrahydrofuran and a solution of 23.3 g (0.11 mol) of 2,2;2-
trichloroethyl chloroformate is added dropwise at 0-4°C. The
mixture is stirred for 1 hour at 0°C and for 1 hour at ambient
temperature. The precipitate is suction filtered, the filtrate
is combined at -12 to -14°C with 12 g (0.105 mol) of
.. methanesulphonic acid chloride and at -8 to -12°C 12 8 .(0:12
mol) of triethylamine in 50 ml tetrahydrofuran are added
dropwise. It is stirred for 40 minutes at -10°C, the cooling
bath is removed and the mixture is stirred for 30 minutes.
After washing with water and saturated saline solution it is
dried with magnesium sulphate, concentrated by evaporation,
the residue is triturated with diisopropylether and suction
filtered. 32.4 g (91.5 % of theory) of 4-methanesulphonyloxy-
N-2,2,2-trichlorethoxycarbonylpiperidine are obtained as
colourless crystals, melting point 93°C.
17.7 g (50 mmol) of this product in 30 ml dimethylformamide
are added dropwise at ambient temperature to a solution of
potassium thiophenoxide (prepared from 6 g thiophenol and
6.2 g potassium-tert. butoxide in 50 ml dimethylformamide at
20-60°C). The jelly formed is combined with 100 ml
dimethylformamide, heated to 60°C and after the addition of
30 ml methanol left to stand overnight at ambient temperature.
After the addition of 800 ml water the mixture is extracted
with ether, the ether extract is washed with water, dried with
magnesium sulphate and concentrated by evaporation. After
purification by column chromatography (silica gel, petroleum
ether/ethyl acetate = 5:1, v:v) 11 g (64.3 % of theory) of 4-
phenylthio-N-2,2,2-trichlorethoxycarbonylpiperidine are
obtained as a colourless oil.
CA 02309388 2000-OS-15
_ 35 _
9 g (25 mmol) of this product, 6 g paraformaldehyde and 5.6 g
(42 mmol) of zinc chloride are placed in 300 ml methylene
chloride. At 20-22°C, hydrogen chloride is introduced for 30
minutes. After one hour hydrogen chloride is again piped in
for 10 minutes and then the mixture is stirred overnight. The
reaction mixture is stirred into 300 ml of a 1-molar disodium
hydrogen phosphate solution, the methylene chloride phase is
separated off and the aqueous phase extracted with methylene
chloride. The organic phases are combined, washed with water,
dried with magnesium sulphate and concentrated by evaporation.
After purification by column chromatography (silica gel, ethyl
acetate/petroleum ether = 1:10, v:v) 4.5 g (43--:2 % of theory)
of 4- [4- (chloromethyl) phenylthio] -N-2, 2, 2-
trichloroethoxycarbonylpiperidine are obtained as a colourless
oil.
2.1 g (5mmo1) of this product and 1.3 g (15 mmol) of
piperidine are refluxed in 10 ml tetrahydrofuran and 10 ml
ethanol for 2.5 hours. After evaporation, the residue is
triturated with water and extracted with ether. The ether
phase is washed with water, dried with magnesium sulphate and
concentrated by evaporation. 2.5 g of 4-[4-
(piperidinomethyl)phenylthio]-2,2,2-trichloro-
ethoxycarbonylpiperidine are obtained as a crude product.
2.4 g of this product are dissolved in 3.5 ml acetic acid and
18 ml of water and 5 g of zinc powder are added (vigorous
foaming). The mixture is stirred for 20 hours at ambient
temperature and for 1 hour at 50°C. After the addition of 20
ml of water a layer of 100 ml ether is added, the mixture is
made strongly alkaline with 6N-sodium hydroxide solution and
stirred for 20 minutes. The ether is separated off and the
aqueous phase extracted 3 x with ether. The combined extracts
are dried with magnesium sulphate and concentrated by
evaporation. 1.3 g of 4-[4-(piperidinomethyl)phenylthio]-
piperidine are obtained as a colourless powder.
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Rt value: 0.69 (aluminium oxide, methylene chloride/methanol =
10:1, v:v) .
Example C
4-[4-(dimethylaminomethyl)benzyl]piperidine
100 g (0.57 mol) of 4-benzylpiperidine in 220 ml methanol are
combined with 88 g (0.68 mol) of methyl trifluoroacetate at 20
to 35°C. After 2 hours the mixture is concentrated by
evaporation. After crystallisation of the residue from
petroleum-ether, 117 g (76 % of theory) of 4-benzyl-N-
trifluoracetylpiperidine are obtained as colourless crystals.
113 g (0.848 mol) of aluminium chloride in 600 ml of
dichloroethane are combined with 114 g (0.9 mol) of
oxalylchloride. At -4 to +4°C 114 g of the above product are
added dropwise to 300 ml of dichloroethane (development of
gas). The mixture is stirred for 2.5 hours at ambient
temperature and then at -25°C 300 ml of a 40% aqueous
dimethylamine solution is added quickly (temperature rises to
35°C). The jelly formed is diluted with 100 ml dichloroethane,
-.~ stirred for 20 minutes and diluted with chloroform to improve
phase separation. It is washed with water, 2N sodium hydroxide
solution, water, 2N hydrochloric acid and again with water.
The organic phase is dried with magnesium sulphate,
concentrated by evaporation and the residue triturated with
ether. 111 g (80 % of theory) of 4-[4-(dimethylaminocarbonyl)-
benzyl]-N-trifluoracetylpiperidine are obtained as colourless
crystals.
64 g of this product in 350 ml tetrahydrofuran are added
dropwise at 0 to 3°C to 70 ml of a 20 % solution of lithium
aluminium hydride in ether, diluted with 250 ml ether. This is
stirred'for 20 minutes at 0°C and then refluxed for 1 hour. At
0 to 15°C 40 ml 4N-sodium hydroxide solution are added
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dropwise (vigorous foaming), stirred for 30 minutes at ambient
temperature, suction filtered and the filter residue is washed
with ether. The combined ether phases are dried with magnesium
sulphate and concentrated by evaporation. 46 g (99 % of
theory) of 4-[4-(dimethylaminomethyl)benzyl]piperidine are
obtained as a colourless, slowly crystallising oil.
Rf value: 0.56 (aluminium oxide, methylene chloride/methanol =
10:1, v:v).
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Examples of the preparation of the end products:
Examgle 1
N-(benzylthio)thiocarbonyl-4-[4-(dimethylam,~nomethyl)phenyl-
thio]piperidine-hydrochloride
A mixture of 237 mg (0.83 mmol) of 4-[4-(dimethylaminomethyl)-
phenylthio]piperidine, 200 mg (2 mmol) of triethylamine and
1 ml ethanol are combined at ambient temperature with 150 mg
(2 mmol) of carbon disulphide. The precipitate formed is
dissolved by~the addition of. 1 ml of triethylamine and 2.5 ml
of dimethylformamide. After 1 hour at ambient temperature 160
mg (0.94 mmol) of benzylbromide are added, it is stirred
overnight at ambient temperature and then heated to 60°C for 3
hours. After the addition of 50 ml water the mixture is
extracted with ethyl acetate, the organic phase is dried with
magnesium sulphate and concentrated by evaporation. After
purification of the residue by column chromatography
(aluminium oxide, petroleum ether/ethyl acetate = 4:1, v:v)
210 mg of the title compound are obtained as a colourless oil,
which is converted into the hydrochloride with ethereal
hydrochloric acid.
Rg value of the free base: 0.83 (aluminium oxide, ethyl
acetate/petroleum ether = 3:1, v:v).
1H-NMR spectrum (200 MHz,DMSO-d6), signals at ppm:
1.4-1.6 (m, 2H), 2.0-2.15 (m, 2H), 2.55 (d, 6H), 3.5-3.65 (t,
2H), 3.7-3.85 (m, 1H ), 4.2 (d, 2H), 4.3-4.4 (m, 1H), 4.5 (s,
2H), 4.95-5.15 (m, 1H), 7.2-7.6 (m, 9H)
The following are obtained analogously:
(1) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)-
benzoyl]piperidine-hydrochloride,
from 4-[4-(dimethylaminomethyl)benzoyl]piperidine and
benzylbromide; colourless powder; Rt value of the free base:
0.65 (aluminium oxide, ethyl acetate)
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(2) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)-
benzylidene]piperidine-hydrochloride,
from 4-[4-(dimethylaminomethyl)benzylidene]piperidine and
benzylbromide; colourless powder; melting point: 190°C
(3) N-(benzylthio)thiocarbonyl-4-[4-(dimethylaminomethyl)-
benzyl]piperidine-hydrochloride,
from 4-[4-(dimethylaminomethyl)benzyl]piperidine and
benzylbromide; colourless powder; Rf value of the free base:
0.26 (aluminium oxide, petroleum ether/ethyl acetate = 10:1,
v:v)
Example 2
N-benzyloxycarbonyl-4-[4-(dimethylaminomethyl)phenylthio]-
piperidine
250 mg (lmmol) of 4- [4- (dimethylaminomethyl) -
phenylthio]piperidine in 20 ml tetrahydrofuran are combined
with 2 ml 2N sodium hydroxide solution and 5 ml water. At
ambient temperature 200 mg (1.2 mmol) of benzyl chloroformate
in 5 ml tetrahydrofuran are slowly added dropwise. After 1.5
hours at ambient temperature some benzyl chloroformate and
sodium hydroxide solution are again added. After the addition
of 100 ml ether the mixture is washed with saturated saline
solution, the organic phase is dried with magnesium sulphate
and concentrated by evaporation. The product obtained after
purification by column chromatography (aluminium oxide,
petroleum ether/ethyl acetate = 4:1, v:v) is converted into
the hydrochloride with ethereal hydrochloric acid. 190 mg
(45.1 % of theory) of the title compound are obtained as a
colourless powder, melting point 144°C.
1H-NMR spectrum (200 MHz,DMSO-d6), signals at ppm:
1.3-1.5 (m, 2H), 1.85-2.0 (m, 2H), 2.65 (s, 6H), 2.95-3.15 (t,
2H), 3.5-3.65 (m, 1H ), 3.8-4.0 (m, 2H), 4.2 (s, 2H), 5.05 (s,
2H), 7.3-7.6 (m, 9H)
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The following are obtained analogously:
(1) N-(4-chlorophenylthio)thiocarbonyl-4-[4-(dimethylamino-
methyl)phenylthio]piperidine-hydrochloride,-
.. from 4-[4-(dimethylaminomethyl)phenylthio]piperidine and 4-
chlorophenyl chlorodithioformate; colourless powder; melting
point: 178°C
(2) 4-[4-(dimethylaminornethyl)phenylthio]-N-phenoxycarbonyl-
piperidine-hydrochloride,
from 4-[4-(dimethylaminomethyl)phenylthio]piperidine and
phenyl chloroformate; colourless powder;
melting point: 161°C
(3) N-(4-chlorophenoxy)carbonyl-4-[4-(dimethylaminomethyl)-
phenylthio]piperidine-hydrochloride,
from 4-[4-(dimethylaminomethyl)phenylthio]piperidine and 4-
chlorophenyl chloroformate; colourless powder;
melting point:169°C
(4) 4-[4-(dimethylaminomethyl)phenylthio]-N-(phenylthio)thio-
carbonylpiperidine-hydrochloride,
from 4-[4-(dimethylaminomethyl)phenylthio]piperidine and
phenyl chlorodithioformate; colourless powder;
Rt value of the free base: 0.57 (aluminium oxide, petroleum
ether/ethyl acetate = 4:1, v:v)
(5) N-4- (4-chlorophenoxy) thiocarbonyl-4- [4- (dimethylamino-
methyl)benzyl]piperidine-hydrochloride,
from 4-[4-(dimethylaminomethyl)benzyl]piperidine and O-4-
chlorophenyl chlorothioformate; colourless powder;
melting point :150°C
(6) N-(4-chlorophenoxy)carbonyl-4-[4-(dimethylaminomethyl)-
benzyl]piperidine,
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from 4-[4-(dimethylaminomethyl)benzyl]piperidine and 4-
chlorophenyl chloroformate;
melting point of the free base: 104°C;
The hydrochloride was obtained by treating with hydrochloric
acid. Colourless powder; melting point: 156°C;
The methanesulphonate was obtained by treating the free base
with methanesulphonic acid in an ethyl acetate-ether mixture.
Colourless powder; melting point: 152°C.
The tartrate was obtained by treating the free base with L-
tartaric acid in a methanol-ethyl acetate mixture.
Colourless powder; melting point: 147°C
(7) N-(4-chlorophenylthio)carbonyl-4-[4-(dimethylaminomethyl)-
benzyl]piperidine-hydrochloride,
from 4-[4-(dimethylaminomethyl)benzyl]piperidine and S-4-
chlorophenyl chlorothioformate; colourless powder;
melting point: 190-191°C
(8) N-benzyloxycarbonyl-4-[4-(piperidinomethyl)phenylthio]-
piperidine-hydrochloride,
from 4-[4-(piperidinomethyl)phenylthio]piperidine and benzyl
" chloroformate; colourless powder; melting point: 186°C
(9) N-phenoxycarbonyl-4-[4-(piperidinomethyl)phenylthio]-
piperidine-hydrochloride,
from 4-[4-(piperidinomethyl)phenylthio]piperidine and phenyl
chloroformate; colourless powder;
melting point: 204°C
(10) N-4-chlorophenoxycarbonyl-4-[4-(piperidinomethyl)phenyl-
thio]piperidine-hydrochloride,
from 4-[4-(piperidinomethyl)phenylthio]piperidine and 4-
chlorophenyl chloroformate; colourless powder;
melting point: 182°C
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(11) N-benzyloxycarbonyl-4-[4-(dimethylaminomethyl)benzyl]-
piperidine,
from 4-[4-(dimethylaminomethyl)benzyl]piperidine and benzyl
chloroformate;
melting point of the free base: 63°C;
The hydrochloride was obtained by treating with hydrochloric
acid. Colourless powder; melting point: 132°C;
The methanesulphonate was obtained by treating the free base
with methanesulphonic acid in an ethyl acetate-ether mixture.
Colourless powder; melting point: 140°C.
The tartrate was obtained by treating the free base with L-
tartaric acid in a methanol-ethyl acetate mixture."
Colourless powder; melting point: 125°C
(12) 4-[4-(dimethylaminomethyl)benzyl]-N-(4-methylphenoxy)-
carbonylpiperidine,
from 4-[4-(dimethylaminomethyl)benzyl]piperidine and 4-
methylphenyl chloroformate;
melting point of the free base: 80°C;
'~ The hydrochloride was obtained by treating with hydrochloric
acid. Colourless powder; melting point: 185°C;
The methanesulphonate was obtained by treating the free base
with methanesulphonic acid in an ethyl acetate-ether mixture.
Colourless powder; melting point: 165°C.
The tartrate was obtained by treating the free base with L-
tartaric acid in a methanol-ethyl acetate mixture.
Colourless powder; melting point: 162°C
(13) 4-E4-(dimethylaminomethyl)benzyl]-N-(4-methylphenoxy)-
thiocarbonylpiperidine-hydrochloride,
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from 4-[4-(dimethylaminomethyl)benzyl]piperidine and O-4-
methylphenyl chlorothioformate; colourless powder;
melting point: 184°C
(14) 4-[4-(dimethylaminomethyl)benzyl]-N-(4-fluorphenoxy)car-
bonylpiperidine-hydrochloride,
from 4-[4-(dimethylaminomethyl)benzyl]piperidine and 4-
fluorophenyl chloroformate; colourless powder;
Rg value of the free base: 0.61 (aluminium oxide, petroleum
ether/ethyl acetate = 6:1, v:v)
Example 3
N-benzyloxycarbonyl-4-[4-(dimethylaminomethyl)phenyl-
sulphinyl]piperidine-hydrochloride
90.7 mg (0.215 mmol) of N-benzyloxy-4-[4-
(dimethylaminomethyl)-phenylthio]piperidine hydrochloride are
dissolved in a mixture of 1 ml methanol and 1 ml water and
first 18.6 mg (0.226 mmol) of anhydrous sodium acetate and
then 48.4 mg (0.226 mmol) of sodium metaperiodate are added.
The mixture is stirred for 6 hours at ambient temperature,
diluted with water, covered with ethyl acetate and saturated
,; with sodium carbonate. The organic phase is separated off, the
aqueous phase extracted with ethyl acetate, the organic phases
are combined, washed with saturated saline solution, dried
with magnesium sulphate and concentrated by evaporation. The
residue is dissolved in a little methylene chloride, combined
with ethereal hydrochloric acid and the solvent is evaporated.
The residue is triturated with ether, the solvent is
evaporated and the residue is dried in a high vacuum. 85 mg
(90.5 % of theory) of the title compound are obtained as a
colourless powder.
Rf value of the free base: 0.43 (aluminium oxide, ethyl
acetate/petroleum ether = 1:1, v:v).
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1H-NMR spectrum (200 MHz,DMSO-d6), signals at ppm:
1.3-1.6 (m, 3H), 1.8-2.0 (m, 1H), 2.65 (s, 6H), 2.7-3.1 (m,
3H), 3.95-4.15 (t, 2H), 4.35 (s, 2H), 5.05 (s, 2H), 7.3 (s,
5H), 7.65-7.85 (q, 4H)
The following is obtained analogously:
(1) 4-[4-(dimethylaminomethyl)phenylsulphinyl]-N-phenoxy-
carbonylpiperidine-hydrochloride,
from 4-[4-(dimethylaminomethyl)phenylthio]-N-phenoxycarbonyl-
piperidine-hydrochloride and sodium metaperiodate; colourless
powder; Rr value of the free base: 0.4 (aluminium oxide, ethyl
acetate/petroleum ether = 1:1, v:v).
,.
