Note: Descriptions are shown in the official language in which they were submitted.
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GLYCINE TRANSPORT INHIBITORS
The present invention is concerned with the use of glycine transport
inhibiting a,a-di-
phenyl-1-piperidinebutanamides for the preparation of medicaments for treating
disorders of the central and peripheral nervous system, in particular
psychoses, pain,
epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head
trauma,
multiple sclerosis and the like. The invention further comprises novel
compounds, their
preparation and their pharmaceutical forms.
N,N Dimethyl-a,a-Biphenyl-1-piperidinebutanamides such as 4-(4-chlorophenyl)-4-
hydroxy-N,N-dimethyl-a,a-Biphenyl-1-piperidinebutanamide (loperamide,
ImodiumTM)
are well-known anti-diarrhoea) products. These compounds, their activity and
preparation were first disclosed in US-3,714,159.
The present invention is concerned with the use of glycine transport
inhibiting
compounds for the preparation of medicaments for treating disorders of the
central and
peripheral nervous system, said compounds having the formula
x (I)
N-R'
R2
the N-oxides, the stereochemically isomeric forms and the pharmaceutically
acceptable
addition salts thereof, wherein
R' and R2 each independently represent hydrogen or C~_4alkyl;
X represents a radical of formula
4
R
/C' R3 Ca); jC~ fib);
Rs
wherein the dotted line represents an optional bond;
wR3 represents a radical of formula
N
R6~~,,// \ i R8
~N~ ~ ~ ~a_1)
R~ (CHz)n
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R6 N~ j RS
\\-N ~ ~ (a-2)
R~~
wherein R6 and R' each represent hydrogen or both may be taken together
with the two carbon atoms to which they are attached to form a
phenyl ring;
Rg represents hydrogen or halo;
n is 1 or 2;
R4 represents hydrogen, hydroxy, C,.4alkyloxy, C~_4alkyloxyC,_4alkyl, or aryl-
C,_4alkyloxy;
RS represents diarylmethyloxyC,_4alkyl or a radical of formula
R9
N i
a R
B ~\ ~ \~2 (b-1) y to
N a4 ~ a3 _82~~ (b-2)
Rti O ~ (b_4)
w
-B3 ~ ~ (b_3) N /
R13
-CH2
-N (b-6)
R15
Ria (b_5) N~ Ri6
Y~ ~Ri7
Y
-B~--C I \ (b-~) O
1$ N ~ -B$-C-R1g (b-8)
R2a --.,-
wN \ ~ (b_10)
~N
N~ (b-9) \
R21
p R22
i
N
O (b-11) -NH ~ ~ ~ (b_12)
123 H_ 'R2a
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~N
(b-13)
~~ R2s
i
wherein B' represents -CH2, -CH(OH)-, -NH- , -CH2-NH_ or a direct bond;
B2 represents -NH-, -CH2- or a direct bond;
B3 represents -NR'2-, -CH2-, -C(=O)- or a direct bond;
B' represents -C'_4alkanediyl-NH- or -NH-C~_4aIkyl-;
B8 represents -NR'9-, -CH2- or -CH(aryl)-;
each Y independently represents O or S;
-a'=a2-a3=a4- represents a bivalent radical of formula
-CH=CH-CH=CH- (b-1-a) or
-N=CH-N=CH- (b-1-b);
wherein a hydrogen atom in radical (b-1-a) may be
replaced by hydroxy;
R9 represents C'_Qalkyl; or C'_4alkyl substituted with aryl, thienyl,
furanyl, furanyl substituted with hydroxyCl_4alkyl, or thiazolyl;
R'° represents aryl, arylamino, C'_aalkylamino, C1_4alkylthio;
R" represents hydrogen, C,_4alkyl, halo or trifluoromethyl;
R12 represents hydrogen or C~_4alkylcarbonyl;
R'3 represents hydrogen, C~_4alkyl or aryl;
R'4 represents hydrogen or halo;
R'S and R'6 each independently represent hydrogen or aryl;
R" represents hydrogen or C,_4alkyl;
R'8 represents aryl, 10,11-dihydro-SH-dibenz[b,f]azepin-5-yl or
C~_4alkyl optionally substituted with one or two substituents each
independently selected from C3_~cycloalkyl and aryl;
R'9 represents hydrogen, C,_4alkylcarbonyl or diarylCl_4alkyl;
R2°, R2', R22 and R23 each independently represent hydrogen,
C'_4alkyl or aryl;
R24 represents hydrogen or trifluoromethyl;
R25 represents hydrogen or halo; and
in case RS represents a radical of formula (b-3), then R' may also be
phenyl-C,_4alkylaminocarbonyl; and
R4 and RS may be taken together to form a spiro radical of formula
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0
N-R~
(b_14,
N
R27
wherein R26 and R2' each independently represent hydrogen, C,_4alkyl, aryl
or arylC,_4alkyl;
aryl represents phenyl, or phenyl substituted with 1 or 2 substituents
independently
selected from C1_4alkyl, halo, trifluoromethyl, hydroxy and C~_4alkyloxy.
The present invention also relates to a method of treating warm-blooded
animals
suffering from disorders of the central and peripheral nervous system, in
particular
psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease),
stroke,
head trauma, multiple sclerosis and the like. Said method comprises the
administration
of a therapeutically effective amount of a compound of formula (I) or a N
oxide form, a
pharmaceutically acceptable acid or base addition salt or a stereochemically
isomeric
form thereof in admixture with a pharmaceutical carrier.
As used in the foregoing definitions and hereinafter, halo is generic to
fluoro, chloro,
bromo and iodo; C3_7cycloalkyl is generic to cyclopropyl, cyclobutyl,
cyclopentyl,
cyclohexyl and cycloheptyl; C1_4alkyl defines straight and branched chain
saturated
hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example,
methyl,
ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the
like;
C1_4alkanediyl defines bivalent straight and branched chain saturated
hydrocarbon
radicals having from 1 to 4 carbon atoms such as, for example, 1;1-
methanediyl,
1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-
butanediyl and the
like.
The pharmaceutically acceptable addition salts as mentioned hereinabove are
meant to
comprise the therapeutically active non-toxic base and acid addition salt
forms which
the compounds of formula (I) are able to form. The acid addition salt form of
a
compound of formula (I) that occurs in its free form as a base can be obtained
by
treating said free base form with an appropriate acid such as an inorganic
acid, for
example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric,
phosphoric
and the like acids; or an organic acid, such as, for example, acetic,
hydroxyacetic,
propanoic, lactic, pyruvic, oxalic, malonic, succinic, malefic, fumaric,
malic, tartaric,
citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,
cyclamic,
salicylic, p-aminosalicyIic, pamoic and the like acids.
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The compounds of formula (I) containing acidic protons may be converted into
their
therapeutically active non-toxic base, i.e. metal or amine, addition salt
forms by
treatment with appropriate organic and inorganic bases. Appropriate base salt
forms
comprise, for example, the ammonium salts, the alkali and earth alkaline metal
salts,
e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like,
salts with
organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts,
and salts
with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt foams can be converted into the free forms by treatment
with an
appropriate base or acid.
The term addition salt as used hereinabove also comprises the solvates which
the
compounds of formula (I) as well as the salts thereof, are able to form. Such
solvates
are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those
com-
pounds of formula (I) wherein the piperidine nitrogen atom is oxidized to the
N oxide.
The term "stereochemically isomeric forms" as used herein defines all the
possible
stereoisomeric forms of the compounds of formula (I). Unless otherwise
mentioned or
indicated, the chemical designation of compounds denotes the mixture, and in
particular
the racemic mixture, of all possible stereochemically isomeric forms, said
mixture
containing all diastereomers and enantiomers of the basic molecular structure.
Stereochemically isomeric forms of the compounds of formula (I) and mixtures
of such
forms are obviously intended to be encompassed by formula (I).
In particular, the compounds of formula (I) and some of their intermediates
have at least
one stereogenic center in their structure. This stereogenic center may be
present in a R
or a S configuration, said R and S notation is used in correspondance with the
rules
described in Pure Appl. Chem., 1976, 45, 11-30.
Some of the compounds of formula (I) may also exist in their tautomeric forms.
Such
forms although not explicitly indicated in the above formula are intended to
be
included within the scope of the present invention.
Whenever used hereinafter, the term compounds of formula (I) is meant to
include also
the N-oxides, the pharmaceutically acceptable additian salts and all
stereoisomeric forms.
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The present compounds of formula (I) are deemed novel provided that when R4 is
hydrogen and RS is a radical of formula (b-1) wherein B~ is -CH2- and R9 is
4-fluorohenzyl, then -a'=a2-a3=a4- is other than -CH=CH-CH=CH-; and when R4 is
hydrogen and RS is a radical of formula (b-1) wherein B~ is -NH- and R9 is
4-methoxybenzyl, then -a'=a2-a3=a4- is other than -CH=N-CH=N-. The present
invention also relates to said novel compounds of formula (I) for use as a
medicine.
Suitably, RS is diarylmethyloxyC,.4alkyl or a radical of formula (b-2), (b-3),
(b-4), (b-
5), (b-6), (b-7), (b-8), (b-9), (b-10), {b-11), (b-12) or (b-13); or RS may be
taken
together with R4 to form a spiro radical of formula (b-14).
An interesting group of compounds are those compounds of formula (I) wherein
R' and
R2 are methyl.
Particular compounds are those compounds of formula (I) wherein X represents a
radical
of formula (a), more in particular, a radical of formula (a) wherein R6 and R'
are taken
together with the two carbon atoms to which they are attached to form a phenyl
ring.
Other particular compounds are those compounds of formula (I) wherein X
represents a
radical of formula (b) wherein RS is a radical of formula (b-1), and
preferably, R9
represents C,_4alkyl substituted with aryl, especially wherein R9 is 4-
fluorobenzyl.
Yet other particular compounds are those compounds of formula (I) wherein X
represents a radical of formula (b) wherein R5 is a radical of formula (b-2),
and
preferably Y is S.
Preferred compounds are
4-( 11,12-dihydro-6H-benzimidazo[2,1-b] [3 ]benzazepin-6-yl)-N,N-dimethyl-a,a-
diphenyl-i-piperidinebutanamide;
4-[[1-[{4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]hydroxymethyl)-N,N-
dimethyl-
a,a-diphenyl-1-piperidinebutanamide; the N-oxides, the stereochemically
isomeric
forms and the pharmaceutically acceptable addition salts thereof.
In general, the compounds of formula (I) can be prepared according to reaction
procedures described in US 3,714,159, US-4,695,575 and US-5,008,268, more in
particular, by reacting an intermediate of formula (II) wherein 'W is an
appropriate
counter ion such as, for example, a halogen, or a functional derivative
thereof with an
intermediate of formula (III).
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_'7_
-~~- (I)
(II}
(an
Said reaction may be performed in a reaction-inert solvent such as, for
example,
methylisobutyl keton, N,N-dimethylacetamide or N,N dimethylformamide, in the
presence of a suitable base such as, for example, sodium carbonate, sodium
bicarbonate
or triethylamine, and optionally in the presence of potassium iodide.
In this and the following preparations, the reaction products may be isolated
from the
reaction medium and, if necessary, further purified according to methodologies
generally known in the art such as, for example, extraction, crystallization,
distillation,
IO trituration and chromatography.
The compounds of formula (I) can also be converted into each other following
art-
known procedures of functional group transformation.
The compounds of formula (I) may also be converted to the corresponding N-
oxide
forms following art-known procedures for converting a trivalent nitrogen into
its
N-oxide form. Said N-oxidation reaction may generally be carried out by
reacting the
starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine
or with an
appropriate organic or inorganic peroxide. Appropriate inorganic peroxides
comprise,
for example, hydrogen peroxide, alkali metal or earth alkaline metal
peroxides, e.g.
sodium peroxide, potassium peroxide; appropriate organic peroxides may
comprise
peroxy acids such as, for example, benzenecarboperoxoic acid or halo
substituted
benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,
peroxoalkanoic
acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl
hydroperoxide. Suitable
solvents are, for example, water, lower alkanols, e.g. ethanol and the like,
hydro-
carbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons,
e.g.
dichloromethane, and mixtures of such solvents.
Some of the compounds of formula (I) and some of the intermediates in the
present in-
vention may contain an asymmetric carbon atom. Pure stereochemically isomeric
forms of said compounds and said intermediates can be obtained by the
application of
art-known procedures. For example, diastereoisomers can be separated by
physical
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methods such as selective crystallization or chromatographic techniques, e.g,
counter
current distribution, liquid chromatography and the like methods. Enantiomers
can be
obtained from racemic mixtures by first converting said racemic mixtures with
suitable
resolving agents such as, for example, chiral acids, to mixtures of
diastereomeric salts
S or compounds; then physically separating said mixtures of diastereomeric
salts or
compounds by, for example, selective crystallization or chromatographic
techniques,
e.g. liquid chromatography and the like methods; and finally converting said
separated
diastereomeric salts or compounds into the corresponding enantiomers. Pure
stereochemically isomeric forms may also be obtained from the pure
stereochemically
isomeric forms of the appropriate intermediates and starting materials,
provided that the
intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of
formula (I) and intermediates involves liquid chromatography, in particular
liquid
1S chromatography using a chiral stationary phase.
Some of the intermediates and starting materials are known compounds and may
be
commercially available or may be prepared according to art-known procedures.
Glycine is an amino acid neurotransmitter in the central and peripheral
nervous system,
both at inhibitory and excitatory synapses. These distinct functions of
glycine are
mediated by two types of receptor, each of which is associated with a
different class of
glycine transporter. The inhibitory actions of glycine are mediated by glycine
receptors
that are sensitive to the convulsant alkaloid strychnine, and are therefore
referred to as
2S 'strychnine-sensitive.' Strychnine-sensitive glycine receptors are found
predominantly
in the spinal cord and brainstem.
Glycine functions in excitatory transmission by modulating the actions of
glutamate,
the major excitatory neurotransmitter in the nervous system (Johnson and
Ascher,
Nature, 325, S29-S31 (1987); Fletcher et al., Glvcine Transmission, (Otterson
and
Storm-Mathisen, eds., 1990), pp. 193-219). Specifically, glycine is an
obligatory co-
agonist at the class of glutamate receptor termed N-methyl-D-aspartate (NMDA)
receptor. NMDA receptors are widely distributed throughout the brain, with a
particularly high density in the cerebral cortex and hippocampal formation.
3S
Transporters take up neurotransmitter from the synapse, thereby regulating the
concentration and term of neurotransmitter in the synapse, which together
determine the
magnitude of synaptic transmission. By preventing the spread of
neurotransmitter to
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neighboring synapses, trarlsporters maintain the fidelity of synaptic
transmission. Last,
by re-uptake of released transmitter into the presynaptic terminal,
transporters allow for
transmitter reutilization. Neurotransmitter transport is dependent on
extracellular
sodium and the voltage difference across the membrane. Under specific
conditions, for
example during a seizure, transporters can function in reverse, releasing
neurotransmitter in a calciumindependent non-exocytotic manner (Attwell et
al.,
Neuron, 11, 401-407 (1993)). Modulation of neurotransmitter transporters thus
provides a means for modifying synaptic activity, which provides useful
therapy for the
treatment of disturbances of the central and peripheral nervous system.
Molecular cloning has revealed the existence of two classes of glycine
transporters,
termed GIyT-1 and GIyT-2. GIyT-1 is found predominantly in the forebrain, and
its
distribution corresponds to that of glutamatergic pathways and NMDA receptors
(Smith,
et al., Neuron. 8, 927-935 (1992)). At least three splice variants of GIyT-1
are known,
namely GIyT-la, GIyT-lb and GIyT-lc (Kim, et al., Molecular Pharmacolo y, 45,
608-
617 (1994)), each of which displays a unique distribution in the brain and
peripheral
tissues. GIyT-2, in contrast, is found predominantly in the brainstem and
spinal cord,
and its distribution corresponds closely to that of strychnine-sensitive
glycine receptors
(Liu et al., J Biological Chemistry , 268,. 22802-22808 (1993); Jursky and
Nelson,
Neurochemistry, 64, 10261033 (1995)). Thus, one can expect that by regulating
the
synaptic levels of glycine, GIyT-1 and GIyT-2 selectively modulate the
activity of
NMDA receptors and strychnine-sensitive glycine receptors, respectively.
Compounds that inhibit or activate glycine transporters would thus be expected
to alter
receptor function, and provide therapeutic benefits in a variety of disease
states. Thus,
inhibition of GIyT-2 could be used to diminish the activity of neurons having
strychnine-sensitive glycine receptors via increasing synaptic levels of
glycine, and so
diminish the transmission of pain-related (i.e., nociceptive) information in
the spinal
cord, which has been shown to be mediated by these receptors. Yaksh, Pain, 37,
111-123 (1989). Additionally, enhancing inhibitory glycinergic transmission
through
strychnine-sensitive glycine receptors in the spinal cord can be used to
decrease muscle
hyperactivity, which is useful in treating diseases or conditions associated
with
increased muscle contraction, such as spasticity, myacIonus, and epilepsy
{Truong et
al., Movement Disorders, 3 , 77-87 (1988); Becker, I~ASEB J, 4 2767-2774
(1990)).
Spasticity that can be treated via modulation of glycine receptors is
associated with
epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury,
dystonia, and other
conditions of illness and injury of the nervous system.
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NMDA receptors are involved in memory and Teaming (Rison and Stanton,
Neurosci.
Biobehav. Rev., 19, 533 552 (1995); Danysz at al., Behavioral Pharmacol , 6,
455-474
(1995)); and decreased function of NMDA-mediated neurotransmission appears to
contribute to the symptoms of schizophrenia (Olney and Farber, Archives
General
Psvchiatrv, 52, 998-1007 (1996). Thus, agents that inhibit GIyT-1 and thereby
increase
glycine activation of NMDA receptors can be used as novel antipsychotics and
anti-dementia agents, and to treat other diseases in which cognitive processes
are
impaired, such as attention deficit disorders and organic brain syndromes.
Conversely,
over-activation of NMDA receptors has been implicated in a number of disease
states,
in particular the neuronal death associated with stroke, head trauma and
possibly
neurodegenerative diseases, such as Alzheimer's disease, mufti-infarct
dementia, AIDS
dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral
sclerosis or
other conditions in which neuronal cell death occurs. Coyle & Puttfarcken,
Science,
262, 689-695 (1993); Lipton and- Rosenberg, New Engl. J. of Medicine, 330, 613-
622
(1993); Choi, Neuron 1, 623-634 (1988). Thus, phamlacological agents that
increase
the activity of GIyT-1 will result in decreased glycine-activation of NMDA
receptors,
which activity can be used to treat these and related disease states.
Similarly, drugs that
directly block the glycine site on the NMDA receptors can be used to treat
these and
related disease states.
For administration purposes, the subject compounds may be formulated into
various
pharmaceutical compositions comprising a pharmaceutically acceptable carrier
and, as
active ingredient, a therapeutically effective amount of a novel compound of
formula
(I). To prepare the pharmaceutical compositions of this invention, an
effective amount
of the particular compound, in addition salx or in free acid or base form, as
the active
ingredient is combined in intimate admixture with a pharmaceutically
acceptable
carrier, which may take a wide variety of forms depending on the form of
preparation
desired for administration. These pharmaceutical compositions are desirably in
unitary
dosage form suitable, preferably, for administration orally, percutaneously,
or by
parenteral injection. For example, in preparing the compositions in oral
dosage form,
any of the usual pharmaceutical media may be employed, such as, for example,
water,
glycols, oils, alcohols and the like in the case of oral liquid preparations
such as
suspensions, syrups, elixirs and solutions; or solid earners such as starches,
sugars,
kaolin, lubricants, binders, disintegrating agents and the like in the case of
powders,
pills, capsules and tablets. Because of their ease in administration, tablets
and capsules
represent the most advantageous oral dosage unit form, in which case solid
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pharmaceutical carriers are obviously employed. For parenteral compositions,
the
carrier will usually comprise sterile water, at least in large part, though
other
ingredients, for example, to aid solubility, may be included. Injectable
solutions, for
example, may be prepared in which the carrier comprises saline solution,
glucose
solution or a mixture of saline and glucose solution. Injectable solutions
containing
compounds of formula (I) may be formulated in an oil for prolonged action.
Appropriate oils for this purpose are, for example, peanut oil, sesame oil,
cottonseed
oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty
acids and
mixtures of these and other oils. Injectable suspensions may also be prepared
in which
case appropriate liquid carriers, suspending agents and the like may be
employed. In the
compositions suitable for percutaneous administration, the carrier optionally
comprises
a penetration enhancing agent and/or a suitable wettable agent, optionally
combined
with suitable additives of any nature in minor proportions, which additives do
not cause
any significant deleterious effects on the skin. Said additives may facilitate
the
administration to the skin and/or may be helpful for preparing the desired
compositions.
These compositions may be administered in various ways, e.g., as a transdermal
patch,
as a spot-on or as an ointment. Addition salts of (I) due to their increased
water
solubility over the corresponding free base or free acid form, are obviously
more
suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical
composi-
tions in dosage unit form for ease of administration and uniformity of dosage.
Dosage
unit form as used in the specification and claims herein refers to physically
discrete
units suitable as unitary dosages, each unit containing a predetermined
quantity of
active ingredient calculated to produce the desired therapeutic effect, in
association
with the required pharmaceutical Garner. Examples of such dosage unit forms
are
tablets (including scored or coated tablets), capsules, pills, powder packets,
wafers,
injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the
like, and
segregated multiples thereof.
The following examples are intended to illustrate the present invention.
Exverimental part
Example A.1
A mixture of dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide
(0.01 mol), prepared as described in US 3,714,159, (~)-4-(11,12-dihydro-6H
benzimidazo[2,1-b][3]benzazepin-6-yl)-piperidine (0.01 mol), Na2CO3 (0.01 mol)
and
KI (10 mg) in methyl isobutyl keton (200mL) was stirred and refluxed
overnight. The
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solvent was evaporated and the residue taken up in water/CH2Cl2. The organic
layer
was separated and the water layer was extracted again with CH2C12. The
combined
organic layers were dried, filtered and the solvent evaporated. The residue
was purified
on a glass filter over silica gel (eluent : CH2Cl2/CHaOH 95/S to 90/10). The
pure
fractions were collected and evaporated. The residue was crystallized from
CH3CN,
yielding 0.88g (15%) of (~)-4-(11,12-dihydro-6H-benzimidazo[2,1-
b][3]benzazepin-6-
yl)-N,N dimethyl-a,a-diphenyl-1-piperidinebutanamide (comp. I; mp. 255.3
°C).
Example A.2
To a stirred mixture of 4-(3-bromo-2-oxopropyl)-N,N-dimethyl-a,a-diphenyl-1-
piperidinebutanamide monohydrobromide (13 g) in methanol (80 ml) was added
(2,6-
dimethylphenyl)thiourea (4.1 g) at 70 °C. Stirnng was continued for 1
hour at reflux
temperature. The solvent was evaporated and the residue was taken up in water.
Potassium carbonate was added untill a pH of about 9 and the mixture was
extracted
with ethylacetate. The organic phase was purified by acid base extraction,
dried,
filtered and the solvent evaporated. The residue was crystallized from
methanol. The
precipitate was filtered off, washed and dried, yielding 6.7 g (52 %) of 4-[[2-
[[2,6-
dimethylphenyl)amino]-4-thiazolyl]methyl)-N,N-dimethyl-a,a-diphenyl-1-
piperidine-
butanamide (comp. 47; mp. 210.5 °C).
In an analogous way were prepared
4-[[2-[[2,6-dichlorophenyl)amino]-4-thiazolyl]methyl]-N,N-dimethyl-a,a-
diphenyl-1-
piperidinebutanamide (comp. 48; mp. 207.0 °C);
N,N-dimethyl-4-[[2-(methylamino)-4-thiazolyl]methyl]-a,a-diphenyl-1-piperidine-
butanamide (comp. 49; mp. 188.3 °C).
Example A.3
To a stirred mixture of NaH (78 % dispersion; 0.55 g) in 1,4-dioxane (50 ml)
was
added 1-(4-fluorophenyl)-N,N dimethyl-4-oxo-a,a-Biphenyl-1,3,8-
triazaspiro[4,5]-
decane-8-butanamide (7.7 g). After stirring for 1 hour at room temperature,
the mixture
was heated to 60 °C and (chloromethyl)benzene (2.3 g) was added.
Stirnng was
continued overnight at 60 °C. the reaction mixture was poured out onto
water and the
mixture was extracted with CHCl3. The extract was washed with water, dried,
filtered
and the solvent evaporated. The residue was purified by column chromatography
over
silica gel using a mixture of CHC13 and 3 % methanol, saturated with gaseous
ammonia, as eluent.The pure fractions were collected and the solvent
evaporated. The
residue was triturated in n-hexane. The precipitate was filtered off and
dried, yielding 2
g of 1-(4-fluorophenyl)-N,N-dimethyl-4-oxo-a,a-Biphenyl-3-phenylmethyl-1,3,8-
triazaspiro[4,5]decane-8-butanamide (comp. 50; mp. 139.8 °C).
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Tables 1 and 2 list compounds which were prepared according to example A.1.
Some
compounds were prepared using a different base and/or solvent as regards the
ones used
in example A.I. Also, some compounds were prepared without using KI. The
reaction
conditions are mentioned in column "reaction conditions" in tables 1 and 2. In
said
column, MIK means methylisobutyl keton, DMA means N,N dimethylacetamide and
DMF means N,N-dimethylformamide.
Table 1
°' RS R4 Reaction conditions Physical properties
base / KI I solvent meltin oint : m . in °C
N
1 ~ ~ N -' H Na2C03 I KI / MIK mp. 255.3°C
2 <'N~~ I ~ H Na2C03 / KI / DMA mp. 173.7°C
~N
Br
N
3 ~ / N ~ ~ H Na2C0.3 / KI / MIK mp. 210.6°C
_.
0
4
H Na2C0~ I - I MIK
~N _
H Na2C03 / - / DMF mp. 239.0°C;
Ntt~ \ /
HZO (1:1); HCl (1:2)
6 ~ ~ H Et3N / - / DMF mp. 168.8°C; HBr ( 1:2)
~~s
N
,7 N
H Na2C03 / - / MIK mp. 196.4°C
/ 1
U
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°' RS R' Reaction conditions Physical properties
vo. base ! KI / solvent meltin oint : m . in °C
s ~ "~ ~ ~ ~=QH
N H NazC03 I - I MIK mp. 128.9°C; H20 (1:1)
-NH--<
N
H
H NazC03 I KI I M1K mp. 184.5°C
N ~ OH
-CHZ
~N I ~
°
10 ~ Hz \ ~ H NazCO 3 / KI / MIK mp. 161.4°C
N
CH2~~
N
11 CH, ~ ~ F
OH NazCO3 I KI I MIK mp. 170.5°C
N
-CH2 \\
N /
12 -cHZ / \ cH3 OH NazC03 I KI I MIK mp. 135°C
13 / \ c~ o-~'~'x Et3N / - / DMA mp. 161.3°C;
o HCl ( 1:1 ); H20 ( 1:1 )
_ II
14 CH-C-CHz-CH3
H NazC03 / - / MIK mp. 160.7°C;
ethanedioate (3:2)
15 ~ ~ ~ H NazC03 / KI / MIK mp. 265.4°C; HBr(2:1)
0
16
o H NazC03 I - I MIK mp. 139.1 °C
i Hy-CH3
17 -NH N \ H NazC03 I KI I MIK mp. 199.4°C
---y ''~l
N /
O _
18 -c-NH-cHZ ~ ~ -~ / ~ NazC03 I KI I MIK mp. 111.5-145°C;
_ H20 (2:1)
0
19 -C-NH-CH H
' ~ / NazCO~ I - I MIK mp. 188.8°C
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°' RS R' Reaction conditions Physical properties
~o. base l KI I solvent melon oint : m . in °C
20 -o-~-~H
Na2C03 / KI / MIK mp. 111.9°C ; HCl (2:1)
II
21 -NH-C-CH
H Na2C03 / - / MIK mp. 202-205°C
H
\ N
22 -NH~ ~>'-oF3 H Na2CO3 / KI / DMF mp. 192.4°C
N
\N~ N
23 / ~ H Na2CO 3 / KI / MIK mp. IS6.1°C
Ci
24 ~ I H I Na2CO3 I KI / MIK , mp. 208.9°C
(1:1)
s \
25 '°HZ-~~N ~ , OH Na2C03 I - I MIK mp. 257.4°C
26
i o~ H NaZCO~ / - / MIK mp. 176.2°C;
E)-2-butenedioate (I:1)
CH,_
27 ~ N H NazC03 / - / MIK mp. 142.7°C
0
N ~ /
28 / \ H Na2C03 I - I MIK mp. 198.0°C;
ethanedioate (I:I)
Cl I -O C
29 ~ H Na2C0~ / KI / MIK mp. 133.1-135.1 °C;
ethanedioate (2:S)
S
30 -~Z~N ~ / H NaHC03 / - / DMF m . 14 ° .
p 8.7 C,
s~ ethanedioate (1:2)
~~S-CH3
31 -~HZ ~ ~~N H NaHC03 / - I DMF mp. 121.8°C
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' Rs R4 Reaction conditionsPhysical properties
vo. base / KI / meltin oint :
c~ solvent m . in C
32 s H NaHC03 / - mp. 251.0C
/ DMF
cl
33 cHZ ~ / F OH Et3N / - / m . 1
DMF p 83.3 C
N /
~3
34 S
N~-r ~ / H NaHC03 / - mp. 257.3C
/ DMF
N
~3
35 i Z ~ / F H Et3N / - / m . 136.
DMF p S C,
N \ ethanedioate {
'IH~ 1:3)
OH N /
36 cHz ~
I H Na2C03 / - mp. 207.4C;
I DMF
N \ ethanedioate (
~ 1:2)
N
37 cHz ~ / F OCH3 Na2C03 / - m . 22 . .
I / DMF p 0 1 C,
N ~ (E)-2-butenedioate
{1:1)
N /
CI
38 s
ri,., ~ / OH NaHCO 3 / - mp. 183.7C;
/ DMF
N CI (2:1); ethanol
(1:1)
cl
39 s -
N,j ~ / OH NaHC03 I - mp. 198.7C
I DMF
N
cx,
S
~~
40 cH2 H Na2C03 / - p. 183.9C
m / DMA
N \
~~2
S
41 CHz
I ~ ~
H NazC03 / - mp. 201.4C;
/ DMA
'CH N \ (E)-2-butenedioate
(2:3)
N /
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' R5 R Reaction conditionsPhysical properties
~o. base / KI / meltin oint :
solvent m . in C
s
42 H Na2C03 / - mp. 177.8C;
cH, N ~ / DMF
(Z)-2-butenedioate
(1:2)
_
0
~
43 ~ ~ ~ ~
H Na2CO3 / KI m .
/ DMF p 190.5 C
_
53 i 2 ~ / F OH Na2C03 / - m . 164.
/ MIK p SC
N
-CHZ_NH
~
N
O
54 -~c-cH' CHZ-O-CH3Na2CO3 / - mp. 155.4C; HCI
/ MIK (1:1)
CF3
Table 2
f/ ~ p /CH3
N
\CH3
\CH~-CHZ_N\~R3
o.
R3 Reaction conditionsPhysical properties
vo. base / KI I melon oint : m
solvent . in C
N
~ Na2C03 l KI m
I MIK 206
6C
N p.
f .
;
r,... \ (E)-2-butenedioate
( 1:1 )
N
45 CN i Na2C03 / KI mp. 174.5C
-, \ / MIK
Also prepared according to example A.1 but without using KI was 1-(5-chloro-2-
methyl-phenyl)-N,N-dimethyl-4-oxo-a,a-Biphenyl-1,3,8-triazaspiro[4,5]decane-8-
butanamide (comp. 46; mp. 175.7°C).
Pharmacological example
Example B.l: Assay of transport via GIyTI transnorters
Subconfluent HEK 293 -GIyTl cells (i.e. a cell line which stably expresses
human
glycine transporter 1) were seeded in Cytostar-T plates at a concentration of
50,000
cells per well in 100 pl DMEM medium (Dulbecco's Modified Eagle Medium
supplemented with 10% foetal bovine serum, 1 mM Na-pyruvate, 2 mM glutamine,
100
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U penicillin/ml and 0.1 mg/ml streptomycin). The cells were incubated for 48
hours at
37°C, 5% C02, 95% humidity.
On day 3, the cells were washed using a Tecan PW96 microprocessor controlled
washer
S designed to wash all 96 wells of a microplate simultaneously with uptake
buffer (25
mM Hepes, 5.4 mM K-gluconate, 1.8 mM Ca-gluconate, 0.8 mM MgS04, 140 mM
NaCI, S mM glucose, 5 mM alanine, adjusted to pH 7.5 with 2M Tris). The Tecan
PW96 was programmed to wash the cells five times leaving 75 pI in each well.
The
test compounds were dissolved at different concentrations in the micromolar
range in
DMSO. 1 lrl Test solution was added to each well and the cells were incubated
for 5'
to 10' at ambient temperature. Then there was added 25 ~tl 30 ~.M
[U'4C]glycine
diluted in uptake buffer. The cells were incubated for 1 hour at ambient
temperature.
The plates were then sealed and [U'4C]glycine uptake was determined on a
Packard
microplate scintillation counter (TopCount). From the results obtained for the
various
concentrations of each test drug, the concentration giving 50 % inhibition
{ICso) of
glycine uptake was calculated. Calculated data for the test compounds
according to the
instant invention are shown in table 3 as pICso values (negative log values of
the ICso).
Compound 51 being 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-
N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide as disclosed in US-4,695,575
and
compound 52 being 4-[[9-[(4-methoxyphenyl)methyl]-9H-purin-8-yl]amino]-N,N-
dimethyl-a,a-diphenyl-1-piperidinebutanamide {E)-2-butenedioate (2:5) as
disclosed in
US-5,008,268 were also tested.
Table 3
Comp. PICso Comp. PICso
No. No.
1 7.28 28 6.56
2 6.80 29 6.10
3 6.77 30 6.63
4 6.49 31 6.17
6.43 32 6.12
6 6~1~ 33 6.21
7 6.16 34 6.35
8 6.05 35 7.22
9 6.13 36 6.25
10 6.62 37 6.90
11 6.89 38 6.04
12 6.15 39 6.23
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Comp. PICso Comp. PICso
No. No.
13 6.28 40 6.36
14 6.03 41 6.52
15 6.04 42 6.12
16 6.12 43 6.12
I7 6.13 44 6,70
18 6.03 45 6.00
19 6.29 46 6.27
20 6.39 47 6.79
21 6.08 48 6.54
22 6.03 49 6.12
23 6.03 50 6.60
24 6.08 51 6.91
25 6.36 52 6.47
26 6.10 53 6.39
27 6.26 54 6.61
C.
Composition
examples
The
following
formulation
exemplifies
a
typical
pharmaceutical
composition
suitable
for animal
systemic and
administration hu
to b
man
su
jects
in
accordance
with
the
present invention. "Active ingredient" (A.L) relates to a compound of formula
{I) or a
pharmaceutically acceptable addition salt thereof.
Example C.1 ~ film-coated tablets
Preparation of tablet core.A mixture of 100 of the A.L, 570 g lactose and 200
g starch
was mixed well and thereafter humidified with a solution of 5 g sodium dodecyl
sulfate
and 10 g polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture
was
sieved, dried and sieved again. Then there was added 100 g microcrystalline
cellulose
and 15 g hydrogenated vegetable oil. The whole was mixed well and compressed
into
tablets, giving 10.000 tablets, each comprising 10 mg of the active
ingredient.
Coating To a solution of 10 g methyl cellulose in 75 m1 of denaturated ethanol
there
was added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane.
Then there
were added 75 mI of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of
polyethylene glycol was molten and dissolved in 75 mI of dichloromethane. The
latter
solution was added to the former and then there were added 2.5 g of magnesium
octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color
suspension
and the whole was homogenated. The tablet cores were coated with the thus
obtained
mixture in a coating apparatus.
