U.S. patent application number 10/291413 was filed with the patent office on 2003-07-10 for 1-(adamantyl) amidines and their use in the treatment of conditions generally associated with abnormalities in glutamatergic transmission.
This patent application is currently assigned to VERNALIS RESEARCH LIMITED. Invention is credited to Gillespie, Roger John, Snape, Michael Frederick, Ward, Simon Edward.
Application Number | 20030130354 10/291413 |
Document ID | / |
Family ID | 10823580 |
Filed Date | 2003-07-10 |
United States Patent
Application |
20030130354 |
Kind Code |
A1 |
Gillespie, Roger John ; et
al. |
July 10, 2003 |
1-(Adamantyl) amidines and their use in the treatment of conditions
generally associated with abnormalities in glutamatergic
transmission
Abstract
Use of a compound of the formula (1), wherein X is an alkylene
chain comprising 0, 1, 2, 3 or 4 carbon atoms; R.sup.1, R.sup.2 and
R.sup.3 are independently selected from hydrogen, alkyl and aryl;
R.sup.4, R.sup.5 and R.sup.6 are independently selected from
hydrogen, alkyl, aryl, halogen and alkoxy; and prodrugs thereof and
pharmaceutically acceptable salts thereof; in the manufacture of a
medicament for use in the treatment of a condition generally
associated with abnormalities in glutamatergic transmission.
Inventors: |
Gillespie, Roger John;
(Wilts, GB) ; Snape, Michael Frederick; (London,
GB) ; Ward, Simon Edward; (Reading, GB) |
Correspondence
Address: |
FOLEY AND LARDNER
SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
VERNALIS RESEARCH LIMITED
|
Family ID: |
10823580 |
Appl. No.: |
10/291413 |
Filed: |
November 12, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10291413 |
Nov 12, 2002 |
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09581340 |
Sep 11, 2000 |
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6500866 |
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09581340 |
Sep 11, 2000 |
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PCT/GB98/03715 |
Dec 11, 1998 |
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Current U.S.
Class: |
514/632 ;
564/225 |
Current CPC
Class: |
A61P 25/28 20180101;
C07C 257/14 20130101; A61P 43/00 20180101; C07C 257/16 20130101;
C07C 2603/74 20170501; A61P 25/00 20180101 |
Class at
Publication: |
514/632 ;
564/225 |
International
Class: |
A61K 031/155; C07C
257/16 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 12, 1997 |
GB |
GB 9726388.3 |
Claims
1. Use of a compound of the formula (1): 8Wherein X is an alkylene
chain comprising 0, 1, 2, 3 or 4 carbon atoms; R.sup.1, R.sup.2 and
R.sup.3 are independently selected from hydrogen, alkyl and aryl;
R.sup.4, R.sup.5 and R.sup.6 are independently selected from
hydrogen, alkyl, aryl, halogen and alkoxy; and prodrugs thereof and
pharmaceutically acceptable salts thereof; in the manufacture of a
medicament for use in the treatment of a condition generally
associated with abnormalities in glutamatergic transmission
2. Use of a compound according to claim 1 wherein X is an alkylene
chain comprising 1, 2, 3 or 4 carbon atoms and one or more carbon
atom(s) of the chain X is/are independently substituted by
substituent group(s) selected from allyl and aryl.
3. Use of a compound according to claim 2 wherein a substituted
carbon atom is substituted by one substituent group selected from
alkyl and aryl.
4. Use of a compound according to claim 2 wherein a substituted
carbon atom is substituted by two substituent groups independently
selected from allyl and aryl.
5. Use of a compound according to claim 2, 3 or 4 wherein the
substituent group(s) are selected from methyl, ethyl, phenyl and
benzyl.
6. Use of a compound according to claim 2, 3, 4 or 5 wherein one
carbon atom of the chain X is substituted.
7. Use of a compound according to claim 1 wherein X is
(CH.sub.2).sub.n where n=0 to 4.
8. Use of a compound according to any one of claims 1 to 7 wherein
X is an alkylene chain comprising 1 or 2 carbon atoms in the
chain.
9. Use of a compound according to claim 7 wherein n=0.
10. Use of a compound according to any preceding claim wherein
R.sup.1 and R.sup.2 are hydrogen and R.sup.3 is selected from
hydrogen, alkyl and aryl.
11. Use of a compound according to any preceding claim wherein
R.sup.1, R.sup.2 and R.sup.3 are hydrogen.
12. Use of a compound according to any one of claims 1 to 11
wherein at least one of R.sup.4, R.sup.5 and R.sup.6 is alkyl, aryl
halogen or alkoxy.
13. Use of a compound according to any one of claims 1 to 12
wherein R.sup.4 is selected from hydrogen, allyl and halogen.
14. Use of a compound according to any one of claims 1 to 13
wherein R.sup.5 is selected from hydrogen and alkyl.
15. Use of a compound according to any one of claims 1 to 14
wherein R.sup.6 is selected from hydrogen and alkyl.
16. Use of a compound according to claim 1 wherein X has 0 carbon
atoms; R.sup.1, R.sup.2 and R.sup.3 are hydrogen; R.sup.4 and
R.sup.5 are CH.sub.3; and R.sup.6 is hydrogen.
17. Use of a compound according to claim 1 wherein X has 0 carbon
atoms; R.sup.1, R.sup.2 and R.sup.3 are hydrogen; R.sup.4 is
methyl; and R.sup.5=R.sup.6=hydrogen or methyl
18. Use of a compound according to claim 2 wherein X has one carbon
atom and is substituted by an ethyl or benzyl group; and R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are hydrogen.
19. Use of a compound according to claim 1 wherein X has one carbon
atom and is unsubstituted; R.sup.1, R.sup.2 and R.sup.3 are
hydrogen; R.sup.4 and R.sup.5 are methyl and R.sup.6 is
hydrogen.
20. A compound of formula (1) as defined in any of claims 1 to 19
wherein at least one of R.sup.4, R.sup.5 and R.sup.6 is alkyl,
aryl, halogen or alkoxy, with the proviso that if R.sup.1, R.sup.2
and R.sup.3 are hydrogen and R.sup.4, R.sup.5 and R.sup.6 are
independently selected from hydrogen and C.sub.1-4 alkyl, then
either X is an alkylene chain comprising 2, 3 or 4 carbon atoms,
substituted or unsubstituted, or X is an alkylene chain of one
carbon atom substituted with one or two substituent group(s)
independently selected from alkyl and aryl and prodrugs and
pharmaceutically acceptable salts thereof.
21. A compound of formula (1) as defined in any of claims 1 to 19
wherein R.sup.4, R.sup.5 and R.sup.6 are hydrogen and either X is
an alkylene chain of 2, 3, or 4 carbon atoms, substituted or
unsubstituted, or X is an alkylene chain of 1 carbon atom
substituted with one or two substituent group(s) independently
selected from alkyl and aryl, or X is a CH.sub.2 group, with the
proviso that where X is a CH.sub.2 group then at least one of
R.sup.1, R.sup.2 and R.sup.3 are selected from alkyl and aryl, and
prodrugs and pharmaceutically acceptable salts thereof.
22. A compound of formula (2), (3), (4) or (5): 9and prodrugs and
pharmaceutically acceptable salts thereof
23. A compound according to any one of claims 20 to 22 for use in
therapy.
24. A pharmaceutical composition comprising a compound according to
any one of claims 20 to 22 in combination with a pharmaceutically
acceptable excipient
25. A method of treatment of a condition generally associated with
abnormalities in glutamatergic transmission comprising
administration to a patient in need of such treatment of a
pharmaceutically effective dose of a compound of formula (1) as
defined in any one of claims 1 to 19.
Description
[0001] The present invention relates to compounds and compositions
for use in the treatment of conditions generally associated with
abnormalities in glutamatergic transmission.
[0002] The excitatory neurotransmission underlying brain function
is primarily (about 80 percent) dependent on the action of
glutamate and other related neurotransmitters on specific receptors
activated by the excitatory amino acids. These receptors fall into
several categories, one of which is the glutamate receptor
specifically sensitive to the agonist N-methyl-D-aspartate (the
NMDA receptor). NMDA receptor subtypes are ubiquitously expressed
in mammalian brain and have unique properties underlying their role
in synaptic function and plasticity. In view of the central role of
these receptors in normal central nervous system function, numerous
suggestions have been made as to the utility of drugs acting at
this receptor to modulate the processes underlying various disease
states. The NMDA receptor has been studied with particular interest
in relation to its apparent involvement in the pathophysiology of
neurodegenerative diseases.
[0003] Non-competitive antagonists at this receptor should be
particularly advantageous in the treatment of diseases since such
compounds would have activity that should not be overcome by high
levels of endogenous agonists and would act equally well
independent of the endogenous agonist activating the receptor. This
is important since high levels of endogenous glutamnate can occur
in certain pathological processes and there are a variety of
different endogenous agonists that can act through a variety of
specific modulatory agonist binding sites on the receptor.
[0004] A number of NMDA antagonists have been disclosed which
operate by binding to the ion-channel of the NMDA receptor. The
advantage of channel blockers is that they operate only on the
"open" channel and therefore do not affect unactivated receptors.
In addition they are effective regardless of the mechanism of
receptor stimulation and their effect will not be diminished by
large concentrations of endogenous agonist.
[0005] Given that the NMDA receptor plays a primary role in normal
central nervous system function, it is not surprising that certain
drugs acting to block or antagonise the function of this receptor
affect normal function within the brain. This may be manifested as
central nervous system side effects such as hallucinations,
confusion, paranoia, aggression, agitation and catatonia. These
side effects can be described as a psychotic state and the drugs
that induce them are known as psychotomimetic NMDA antagonists.
Such side effects limit the utility of these compounds in treating
disease states. NMDA receptor antagonists that have efficacy in
treating central nervous system disorders but without such
psychotomimetic side effects would have a clear therapeutic
advantage. Thus, in view of the crucial role played by the NMDA
receptor in either the progression or expression of the disease
pathology and process, it is an object of this invention to provide
compounds for the treatment of central nervous system disorders
which modulate the activity of the NMDA receptor but which are
well-tolerated in the sense of having a markedly reduced propensity
to induce psychotomimetic side effects.
[0006] The present invention is particularly concerned with the
treatment of neurodegenerative disorders. There is a large body of
evidence to suggest that either an excitotoxic or slow excitotoxic
pathological over-activation of the NMDA receptor induces the death
of neurons in a variety of disorders such as ischaemic stroke,
other forms of hypoxic injury, haemorrhagic brain injury, traumatic
brain injury, Alzheimer's disease, Parkinson's disease,
Huntington's disease and other dementing diseases. There is thus
clear evidence that antagonism of the NMDA receptor will reduce or
prevent the neurodegeneration that underlies the disease process in
these and related conditions. There is also evidence to suggest
that a well tolerated compound will allow effective symptomatic
treatment of the manifestations of the disease process in these
disorders as well as reducing the primary underlying
neurodegeneration process. Also, it is known that disorders
previously described as involving acute neurodegeneration have
longer than expected elevations in glutamate release and
consequently require longer than expected treatment with NMDA
antagonists. There would therefore be a therapeutic advantage for
new drugs which are well tolerated and which can therefore be
administered chronically.
[0007] The published literature contains references to a number of
compounds and classes of compounds purported to be useful as NMDA
antagonists.
[0008] The compounds Amantadine and Memantine and related
anti-viral agents have been known for many years. 1
[0009] Patent applications have been filed directed to the use of
Memantine in the treatment of Parkinson's Disease in the 1970s and
as an NMDA antagonist in 1990 (see EP-A-0392059 and U.S. Pat. No.
5,061,703). Furthermore, International Patent application
WO94/05275 proposes the use of Amantadine and related compounds
such as Memantine in the treatment and prevention of non-ischaemic,
long term NMDA receptor-mediated neuronal degeneration. An increase
in affinity for the NMDA receptor due to substitution of the
adamantane ring of Memantine with alkyl groups was noted and
published by Kornhuber et al., Eur. J. Pharmacol., 1991, 206,
297-300, by Kroemer et al, J. Med. Chem., 1998, 41, 393-400 and by
Parsons et al., Neuropharmacology, 1995, 34, 1239-1258.
[0010] 1-(Adamantyl)amidines are disclosed as antivirals in
DE-A-2306784, JP-A-7391049, DD-A-151447 and GB-1478477.
1-(Adamantyl)acetamidine is disclosed in JP-A-120683 and
GB-1478477. 1-(Adamantyl)amidrazones are disclosed as insecticides
and acaricides in EP-A-0604798. N-substituted-1-(adamantyl)amidines
are disclosed by May et al., Arzneim. Forsch., 1978, 28, 732-735,
and the virostatic activities of the compounds reported.
N-substituted-1-(adamantyl)amidines as antivirals are disclosed by
Skwarski et al., Acta. Pol. Pharm., 1988, 45, 395-399.
[0011] The antiviral activities of adamantane derivatives including
1-(adamantyl)carbamidine and 1-(adamantyl)acetamidine are reported
by Inamoto et al., J. Med. Chem., 1975, 18, 713-721, where they are
compared with Amantadine.
[0012] As discussed above, psychotomimetic side-effects are
observed during the use of a number of well known NMDA channel
blockers and therefore it will be a considerable advantage to
identify clinically well-tolerated antagonists where such side
effects are minimised. Porter and Greenamyre (J. Neurochem. 1995,
64, 614-623; incorporated herein by reference) demonstrated that
well tolerated and psychotomimetic NMDA receptor channel blockers
could be differentiated on the basis of their relative affinities
for forebrain and cerebellar receptors irrespective of absolute
affinities. Selectivity for cerebellar NMDA receptors over
forebrain NMDA receptors is observed for well-tolerated compounds.
The basis of this observation may be related to different
populations of NMDA receptor subtypes in these brain regions.
[0013] The use of a number of the known NMDA antagonists such as
Dizocilpine, PCP, Cerestat and Ketamine gives rise to a number of
side effects which render these compounds unsuitable for use in
treatment. In particular, administration of the compounds is
associated with perceptual and cognitive disturbances of a kind
that resemble natural-occurring psychotic states.
[0014] In addition, the perceptual and cognitive side effects of
the compounds become more pronounced after the onset of puberty and
sexual maturation, and these compounds are therefore particularly
unsuitable for the treatment of adults. This developmental change
has been demonstrated empirically in both experimental animals and
in man, and is paralleled in experimental animals by brain
hypermetabolism.
[0015] In summary, there is a need for an NMDA antagonist which is
well tolerated and does not give rise to the side effects
associated with previous clinically investigated NMDA
antagonists.
[0016] A number of compounds have now been found that show affinity
for the NMDA receptor and are useful in the treatment of conditions
generally associated with abnormalities in glutamatergic
transmission such as stroke, traumatic brain injury and
neurodegenerative diseases such as Parkinson's and Alzheimer's
diseases. It has also been found that the compounds have a
surprisingly favourable ratio of cortex to cerebellar binding
affinity which indicates that these compounds should be well
tolerated in vivo.
[0017] According to the present invention there is provided use of
a compound of the formula (1): 2
[0018] wherein X is an alkylene chain comprising 0, 1, 2, 3 or 4
carbon atoms;
[0019] R.sup.1, R.sup.2 and R.sup.3 are independently selected from
hydrogen, alkyl and aryl;
[0020] R.sup.4, R.sup.5 and R.sup.6 are independently selected from
hydrogen, alkyl, aryl, halogen and alkoxy;
[0021] and prodrugs thereof and pharmaceutically acceptable salts
thereof;
[0022] in the manufacture of a medicament for use in the treatment
of a condition generally associated with abnormalities in
glutamatergic transmission.
[0023] As used herein, the term "alkyl" means a branched or
unbranched, cyclic or acyclic, saturated or unsaturated (e.g.
alkenyl or alkynyl) hydrocarbyl radical. Where cyclic, the alkyl
group is preferably C.sub.3 to C.sub.12, more preferably C.sub.5 to
C.sub.10, more preferably C.sub.5 to C.sub.7. Where acyclic, the
alkyl group is preferably C.sub.1 to C.sub.10, more preferably
C.sub.1 to C.sub.6, more preferably methyl, ethyl or propyl, more
preferably methyl or ethyl.
[0024] As used herein, the term "aryl" means an aromatic group,
such as phenyl or naphthyl, or a heteroaromatic group containing
one or more, preferably one, heteratom, such as pyridyl, pyrrolyl,
furanyl and thiophenyl. Preferably, the aryl group comprises
phenyl.
[0025] The alkyl and aryl groups may be substituted or
unsubstituted, preferably unsubstituted. Where substituted, there
will generally be 1 to 3 substituents present, preferably 1
substituent. Substituents may include:
[0026] carbon containing groups such as
[0027] alkyl,
[0028] aryl, arylalkyl; (e.g. substituted and unsubstituted phenyl,
substituted and unsubstituted benzyl)
[0029] halogen atoms and halogen containing groups such as
[0030] haloalkyl (e.g. trifluoromethyl);
[0031] oxygen containing groups such as
[0032] alcohols (e.g. hydroxy, hydroxyalkyl,
(aryl)(hydroxy)alkyl),
[0033] ethers (e.g. alkoxy, alkoxyalkyl, aryloxyalkyl),
[0034] aldehydes (e.g. carboxaldehyde),
[0035] ketones(e.g. alkylcarbonyl, alkylcarbonylalkyl,
arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl)
[0036] acids (e.g. carboxy, carboxyalkyl),
[0037] acid derivatives such as esters (e.g. alkoxycarbonyl,
alkoxycarbonylalkyl, alkycarbonylyoxy, alkycarbonylyoxyalkyl)
[0038] and amides (e.g. aminocarbonyl, mono- or
dialkylaminocarbonyl, aminocarbonylalkyl, mono- or
dialkylaminocarbonylalkyl, arylaminocarbonyl);
[0039] nitrogen containing groups such as
[0040] amines (e.g. amino, mono- or dialkylamino, aminoalkyl, mono-
or dialkylaminoalkyl),
[0041] azides,
[0042] nitriles (e.g. cyano, cyanoalkyl),
[0043] nitro;
[0044] sulphur containing groups such as
[0045] thiols, thioethers, suphoxides, and sulphones (e.g.
alkylthio, alkylsulfinyl, alkylsufonyl, alkylthioalkyl,
alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl,
arylsulfonyl, arylthioalkyl, arylsulfinylalkyl,
arylsulfonylalkyl)
[0046] and heterocyclic groups containing one or more, preferably
one, heteroatom, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl,
pyrazolyl, thiazolyl, isothiazolyl, oxazolyl pyrrolidinyl,
pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,
tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl,
pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl,
benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl,
indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl,
coumarinyl, isocownarinyl, quinolyl, isoquinolyl, naphthridinyl,
cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl,
quinoxadinyl, chromenyl, chromanyl, isochromanyl and
carbolinyl).
[0047] As used herein, the term "alkoxy" means alkyl-O-- and
"alkoyl" means alkyl-CO--.
[0048] As used herein, the term "halogen" means a fluorine,
chlorine, bromine or iodine radical, preferably a bromine or
chlorine radical.
[0049] As used herein the term "conditions generally associated
with abnormalities in glutamatergic transmission" primarily
includes ischaemic stroke, haemorrhagic stroke, subarrachnoid
haemorrhage, subdural haematoma, coronary artery bypass surgery,
neurosurgery, traumatic brain injury, traumatic spinal injury,
Alzheimer's disease, Parkinson's disease, Huntington's disease,
Pick's disease, Lewy body disease, senile dementia, spongiform
encephalopathies, prion-protein induced neurotoxicity, peri-natal
asphyxia, demyelinating disease, multiinfarct dementia, dementia
pugilans, drug dependence, alcohol withdrawal, opiate withdrawal,
motor neurone disease, multiple sclerosis, acute and chronic pain
including neuropathic pain, cancer pain, trigeminal neuralgia,
migraine, primary and secondary hyperalgesia, inflammatory pain,
nociceptive pain, tabes dorsalis, phantom limb pain, spinal cord
injury pain, central pain, post-herpetic pain, HIV pain and
diabetic neuropathy. In addition, the term also includes the
following conditions: epilepsy, multiple system atrophy,
progressive supra-nuclear palsy, Friedrich's ataxia, autism,
fragile X syndrome, tuberous sclerosis, attention deficit disorder,
olivio-ponto-cerebellar atrophy, cerebral palsy, drug-induced optic
neuritis, peripheral neuropathy, myelopathy, ischaemic retinopathy,
glaucoma, cardiac arrest, encephalitis, depression, bi-polar
disorder, schizophrenia, psychosis, behaviour disorders, impulse
control disorders, pre-eclampsia, neuroleptic malignant syndrome,
chronic fatigue syndrome, anorexia nervosa, anxiety disorders,
generalised anxiety disorder, panic disorder, phobias, fresh water
drowning and decompression.
[0050] As used herein, the term "treatment" also includes
prophylactic treatment.
[0051] As used herein the term "pharmaceutically acceptable salt"
means any pharmaceutically acceptable salt of the compound of
formula (1). Salts may be prepared from pharmaceutically acceptable
non-toxic acids including inorganic and organic acids. Such acids
include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,
dichloroacetic, ethenesulfonic, fumaric, gluconic, glutamic,
hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic,
malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic,
p-toluenesulfonic and the like. Particularly preferred are
hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most
particularly preferred is the hydrochloride salt.
[0052] The compounds of formula (1) may exist in a number of
diastereomeric and/or enantiomeric forms. Reference in the present
specification to "a compound of formula (1)" is a reference to all
stereoisomeric forms of the compound and includes a reference to
the unseparated stereoisomers in a mixture, racemic or non-racemic,
and to each stereoisomer in its pure form.
[0053] The compounds of the present invention are active as NMDA
antagonists and are well tolerated in that side effects are
minimised. Experimental data are shown in Table 1.
[0054] In the compound of formula (1), preferably X is an alkylene
chain comprising 0, 1 or 2 carbon atoms, more preferably 0 carbon
atoms, in the chain.
[0055] In one embodiment of the invention, in the compound of
formula (1), where X is an alkylene chain comprising 1, 2, 3 or 4
carbon atoms, one or more of the carbon atom(s) in the chain X may
be independently substituted by substituent group(s) selected from
alkyl and aryl. Where substituted, a carbon atom may have one or
two substituents, preferably one. Preferred substituent groups are
selected from methyl, ethyl, phenyl and benzyl, preferably ethyl
and benzyl. Where X is substituted, it is preferred that only one
carbon atom in the chain is substituted.
[0056] In an alternative embodiment of the invention, in the
compound of formula (1), X is unsubstituted and has the formula
(CH.sub.2).sub.n where n=0 to 4, preferably n=0, 1 or 2 and more
preferably n=0.
[0057] In the compound of formula (1), preferably R.sup.1 and
R.sup.2 are hydrogen and R.sup.3 is selected from hydrogen, alkyl
and aryl. In a preferred embodiment, R.sup.1, R.sup.2 and R.sup.3
are hydrogen.
[0058] In the compound of formula (1), preferably at least one of
R.sup.4, R.sup.5 and R.sup.6 is alkyl, aryl, halogen or alkoxy.
Preferably R.sup.4 is selected from hydrogen, alkyl and halogen,
more preferably alkyl and more preferably methyl. Preferably
R.sup.5 is selected from hydrogen and alkyl, preferably hydrogen
and methyl. Preferably R.sup.6 is selected from hydrogen and alkyl
preferably hydrogen and methyl.
[0059] In a preferred embodiment, the compound of formula (1) is a
compound where X has 1 carbon atom (i.e. n=1) and is unsubstituted;
R.sup.1, R.sup.2 and R.sup.3 are hydrogen; R.sup.4 and R.sup.5 are
methyl; and R.sup.6 is hydrogen.
[0060] In a further preferred embodiment, the compound of formula
(1) is a compound where X has one carbon atom (i.e. n=1) and is
substituted by an ethyl or benzyl group; and R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are hydrogen
[0061] In a particularly preferred embodiment, the compound of
formula (1) is a compound of formula (1) where X has 0 carbon atoms
(i.e. n=0); R.sup.1, R.sup.2 and R.sup.3 are hydrogen; R.sup.4 and
R.sup.5 are CH.sub.3; and R.sup.6 is hydrogen.
[0062] In a further particularly preferred embodiment, the compound
of formula (1) is a compound where X has 0 carbon atoms (i.e.,
n=0); R.sup.1, R.sup.2 and R.sup.3 are hydrogen; R.sup.4 is methyl;
and R.sup.5=R.sup.6=hydrogen or methyl.
[0063] The present invention further provides a method of treatment
of conditions generally associated with abnormalities in
glutamatergic transmission comprising administering to a patient an
effective dose of a compound of formula (1) as defined above.
[0064] The present invention also provides a compound per se of the
formula (1) as defined above wherein at least one of R.sup.4,
R.sup.5 and R.sup.6 is alkyl, aryl, halogen or alkoxy, with the
proviso that if R.sup.1, R.sup.2 and R.sup.3 are hydrogen and
R.sup.4, R.sup.5 and R.sup.6 are independently selected from
hydrogen and C.sub.1-4 alkyl, then either X is an alkylene chain of
2-4 carbon atoms, substituted or unsubstituted, as defined above,
or X is an alkylene chain of 1 carbon atom substituted with one or
two, preferably one, substituent group(s) independently selected
from alkyl and aryl, and prodrugs and pharmaceutically acceptable
salts thereof
[0065] The present invention also provides a compound per se of the
formula (1) as defined above wherein R.sup.4, R.sup.5 and R.sup.6
are hydrogen and either X is an alkylene chain of 2-4 carbon atoms,
substituted or unsubstituted, as defined above, or X is an alkylene
chain of 1 carbon atom substituted with one or two, preferably one,
substituent group(s) independently selected from alkyl and aryl, or
X is a CH.sub.2 group, with the proviso that where X is a CH.sub.2
group then at least one of R.sup.1, R.sup.2 and R.sup.3 are
selected from alkyl and aryl, and prodrugs and pharmaceutically
acceptable salts thereof.
[0066] The present invention also provides compounds per se of
formulae (2), (3), (4) and (5): 3
[0067] and prodrugs and pharmaceutically acceptable salts
thereof.
[0068] The present invention also provides, for use in therapy:
[0069] (i) a compound of the formula (1) as defined above wherein
at least one of R.sup.4, R.sup.5 and R.sup.6 is alkyl, aryl,
halogen or alkoxy, with the proviso that if R.sup.1, R.sup.2 and
R.sup.3 are hydrogen and R.sup.4, R.sup.5 and R.sup.6 are
independently selected from hydrogen and C.sub.1-4 alkyl, then
either X is an alkylene chain of 2-4 carbon atoms, substituted or
unsubstituted, as defined above, or X is an alkylene chain of 1
carbon atom substituted with one or two, preferably one,
substituent groups independently selected from alkyl and aryl;
[0070] (ii) a compound of the formula (1) as defined above wherein
R.sup.4, R.sup.5 and R.sup.6 are hydrogen and either X is an
alkylene chain of 2-4 carbon atoms, substituted or unsubstituted,
as defined above, or X is an alkylene chain of 1 carbon atom
substituted with one or two, preferably one, substituent groups
independently selected from alkyl and aryl, or X is a CH.sub.2
group, with the proviso that where X is a CH.sub.2 group then at
least one of R.sup.1, R.sup.2 and R.sup.3 are selected from alkyl
and aryl; and
[0071] (iii) a compound of formula (2), (3), (4) or (5) as defined
above,
[0072] and prodrugs and pharmaceutically acceptable salts
thereof.
[0073] The present invention also provides a pharmaceutical
composition comprising:
[0074] (i) a compound of the formula (1) as defined above wherein
at least one of R.sup.4, R.sup.5 and R.sup.6 is alkyl, aryl,
halogen or alkoxy, with the proviso that if R.sup.1, R.sup.2 and
R.sup.3 are hydrogen and R.sup.4, R.sub.5 and R.sup.6 are
independently selected from hydrogen and C.sub.1-4 alkyl, then
either X is an alkylene chain of 2-4 carbon atoms, substituted or
unsubstituted, as defined above, or X is an alkylene chain of 1
carbon atom substituted with one or two, preferably one,
substituent group independently selected from alkyl and aryl;
or
[0075] (ii) a compound of the formula (1) as defined above wherein
R.sup.4, R.sup.5 and R.sup.6 are hydrogen and either X is an
alkylene chain of 2-4 carbon atoms, substituted or unsubstituted,
as defined above, or X is an alkylene chain of 1 carbon atom
substituted with one or two, preferably one, substituent groups
independently selected from alkyl and aryl, or X is a CH.sub.2
group, with the proviso that where X is a CH.sub.2 group then at
least one of R.sup.1, R.sup.2 and R.sup.3 are selected from alkyl
and aryl; or
[0076] (iii) a compound of formula (2), (3), (4) or (5) as defined
above,
[0077] and prodrugs and pharmaceutically acceptable salts thereof,
in combination with a pharmaceutically acceptable excipient.
[0078] According to a further aspect of the present invention there
is provided a method of preparing the compounds of the present
invention. Compounds of formula (1) may be prepared by conventional
synthetic routes; see for example DD-A-151447, U.S. Pat. No.
5,061,703, DE-A-2306784, GB-1478477, Skwarsli et al., Acta. Polon.
Pharm., (1988), 45, 395-399 and May et al., Arzneim. Forsch.,
(1978), 28, 732-735, the disclosures of which are incorporated
herein by reference.
[0079] The following reaction schemes describe examples of
synthetic routes for the preparation of compounds falling within
formula (1). The reaction schemes are included for the purpose of
exemplification only and are not intended to be limiting to the
invention.
[0080] Compounds of formula (1) may be synthesised by conventional
synthetic methods as illustrated in Scheme 1. 4
[0081] Amidines of formula 4 may be synthesised from nitrites of
formula 3 by conventional methods, for example by treatment with an
amine in the presence of trimethyl aluminium in a refluxing solvent
such as toluene for several days, or alternatively by treatment
with HCl in dry methanol at 0.degree. C. for several days followed
by treatment with NH.sub.3 at room temperature. Nitriles of formula
3 may be synthesised from carboxylic acids of formula 2 by
conventional methods, for example by treatment with
methanesulphonyl chloride in the presence of pyridine, followed by
treatment with NH.sub.3, followed by treatment with
methanesulphonyl chloride in the presence of pyridine. Carboxylic
acids of formula 2 are either commercially available or may be
synthesised by conventional methods such as those published in
Stetter et al., Chem. Ber., 1962, 95, 667-672, by Koch et al.,
Chem. Ber., 1963, 96, 213-219, by Stepanov et al., Zh. Obstrich.
Khim., 1964, 34, 579-584, by Stepanov et al., Zh. Org. Khim., 1965,
1, 280-283 and by Stepanov et al., Zh. Org. Khim., 1966, 2,
1612-1615.
[0082] An alternative route for the preparation of compounds of
formula (1) where X is CR.sup.7R.sup.8 wherein R.sup.7 and R.sup.8
are independently hydrogen or alkyl and wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined in formula
(1), also involving conventional methods, is illustrated in Scheme
2. 5
[0083] Amidines of formula 7 may be prepared from nitriles of
formula 6 as described above. Nitriles of formula 6 may be prepared
from nitriles of formula 5 by alkylation or dialkylation, for
example by treatment with a base such as LDA followed by treatment
with an alkyl halide. Further treatment with a base followed by a
second alkyl halide would give the dialkylated nitrile.
[0084] An alternative route for the preparation of compounds of
formula (1) where X is CHR.sup.9CH.sub.2 or CH.sub.2CHR.sup.10
wherein R.sup.9 and R.sup.10 are independently alkyl or aryl and
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are
as defined above, also involving conventional methods, is
illustrated in Scheme 3. 6
[0085] Amidines of formula 11 may be prepared from nitrites of
formula 10 as described above. Nitriles of formula 10 may be
prepared by reduction of unsaturated nitriles of formula 9, for
example by hydrogenation in the presence of a transition metal
catalyst such as palladium on carbon. Nitriles of formula 9 may be
prepared from ketones or aldehydes of formula 8 by conventional
methods such as the Horner-Emmons olefination reaction using an
appropriately substituted phosphonate in the presence of a base
such as sodium hydride. Ketones or aldehydes of formula 8 are
commercially available or may be synthesised by conventional
methods.
[0086] In addition, compounds of formula (1) where X is an alkylene
chain of 3 or 4 carbon atoms may be synthesised by conventional
methods as illustrated in Scheme 4. In Scheme 4, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above and
R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are independently selected
from hydrogen, alkyl and aryl. 7
[0087] Amidines of formula 16 and 17 may be synthesised from
nitriles of formula 15 and 12 respectively by the methods described
in Scheme 1. Nitriles of formula 15 may be synthesised from
nitriles of formula 14 by methods described in Scheme 3 or
alternatively from ketones of formula 13 by reduction to the
alcohol followed by tosylation or bromination, followed by cyanide
displacement. Nitriles of formula 14 may be synthesised from
ketones of formula 11 by methods described in Scheme 3. Ketones of
formula 13 may be synthesised from nitriles of formula 12 by the
addition of a Grignard reagent followed by hydrolytic work-up.
Nitriles of formula 12 may be prepared from ketones of formula 11
by the reduction, tosylation/bromination and cyanide displacement
sequence described above. Ketones of formula 11 may be prepared
from nitriles of formula 10 by Grignard reactions as described
above. Additional substituents may be introduced into the alkylene
chain X by methods analagous to those described in the above
schemes and by other conventional synthetic methods.
[0088] The compound of formula (1) may be administered in a form
suitable for oral use, for example a tablet, pellet, capsule,
aqueous or oily solution, suspension or emulsion; for topical use
including transmucosal and transdermal use, for example a cream,
ointment, gel, aqueous or oil solution or suspension, salve, patch
or plaster; for nasal use, for a example a snuff, nasal spray,
nasal powder or nasal drops; for vaginal or rectal use, for example
a suppository or pessary; for administration by inhalation, for
example a finely divided powder or a liquid aerosol; for
sub-lingual or buccal use, for example a tablet or capsule; for
ocular use, for example a sterile aqueous solution or sterile
ointment; or for parenteral use (including intravenous,
subcutaneous, intramuscular, intravascular or infusion), for
example a sterile aqueous or oil solution or suspension or
emulsion, or depot injection formulation. In general the above
compositions may be prepared in a conventional manner using
conventional excipients, using standard techniques, including
controlled release technologies, such as gelatin, lipid, gel depot,
liposome and microcapsule based systems well known to those skilled
in the art of pharmacy.
[0089] For oral administration, the compounds of the invention will
generally be provided in the form of tablets or capsules or as an
aqueous solution or suspension.
[0090] Tablets or pellets for oral use may include the active
ingredient mixed with pharmaceutically acceptable excipients such
as inert diluents, disintegrating agents, binding agents,
lubricating agents, sweetening agents, flavouring agents, colouring
agents and preservatives. Suitable inert diluents include sodium
and calcium carbonate, sodium and calcium phosphate, calcium
hydrogen phosphate, cellulose derivatives and lactose, while corn
starch and alginic acid are suitable disintegrating agents. Binding
agents may include starch, gelatin and polyvinyl-pyrrolidone
derivatives, while the lubricating agent, if present, will
generally be magnesium stearate, stearic acid or talc. If desired,
the tablets may be formulated or coated with a material such as
glyceryl monostearate or glyceryl distearate or polymethacrylate
polymers, cellulose derivatives or other pharmaceutically
acceptable polymer, to delay absorption in the gastrointestinal
tract.
[0091] Capsules for oral use include hard gelatin capsules in which
the active ingredient is mixed with a solid diluent, and soft
gelatin capsules wherein the active ingredient is mixed with water
or an oil such as peanut oil, liquid paraffin or olive oil.
[0092] For intramuscular, intraperitoneal, subcutaneous and
intravenous use, the compounds of the invention will generally be
provided in sterile aqueous solutions or suspensions or emulsions,
buffered to an appropriate pH and isotonicity. Suitable aqueous
vehicles include Ringer's solution and isotonic sodium chloride.
Aqueous suspensions according to the invention may include
suspending agents such as cellulose derivatives, sodium alginate,
polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such
as lecithin. Suitable preservatives for aqueous suspensions include
ethyl and n-propyl p-hydroxybenzoate.
[0093] Transdermal formulations include membrane permeation
systems, multi-laminate adhesive dispersion systems and matrix
dispersion systems. Transdermal delivery also includes the use of
electrically aided transport and skin penetration enhancers and
needle-free injection devices.
[0094] The preferred route of administration will be as an
intravenous infusion, preferably over a period of up to seven days,
or as an oral formulation, or as an intramuscular injection via a
styrette or as a subcutaneous injection.
[0095] It will be appreciated that the dosage levels used may vary
over quite a wide range depending upon the compound used, the
severity of the condition exhibited by the patient and the
patient's body weight. However, without commitment to a rigid
definition of dosages it may be stated that a daily dosage of the
active constituent (estimated as the free base) is 100 .mu.g to 800
mg. More particularly, the preferred compounds may be administered
at a preferred dose of 50-800 mg/day, in single or divided
doses.
[0096] The invention will now be described in detail. It will be
appreciated that the invention is described by way of example only
and modification of detail may be made without departing from the
scope of the invention.
EXPERIMENTAL
I Synthesis
Example 1
[0097] 3,5-Dimethyl-1-adamantanecarboximidamide hydrochloride
[0098] 3,5-Dimethyl-1-adamantanecarbonitrile
[0099] A solution of 3,5-dimethyl-1-adamantanecarboxylic acid (2.51
g, 12.1 mmol) in dry pyridine (40 mL) at 0.degree. C. was treated
dropwise with methanesulphonyl chloride (1.4 g, 12.2 mmol), stirred
for 2 h, saturated with ammonia gas, stirred for 5 min and the
excess ammonia removed in vacuo. The resulting suspension at
0.degree. C. was treated with methanesulphonyl chloride (11.8 g,
102 mmol), stirred overnight at room temperature, poured into cold
1-M HCl (200 mL) and extracted with EtOAc (3.times.40 mL). The
organic phase was washed with dilute HCl (50 mL), water (50 mL),
dried (MgSO.sub.4), concentrated in vacuo and the residue purified
by chromatography [SiO.sub.2; CH.sub.2Cl.sub.2] to give the product
(1.97 g, 86%) as a pale brown oil: IR .nu..sub.max (liquid
film)/cm.sup.-1 2922, 2849, 2235, 1455, 1359 and 1098; NMR
.delta..sub.H (400 MHz, CDCl.sub.3) 0.87 (6H, s), 1.19 (2H, s),
1.3-1.45 (4H, m), 1.55-1.75 (4H, m), 1.8-1.9 (2H, m) and 2.1-2.15
(1H, m).
[0100] 3,5-Dimethyl-1-adamantanecarboximidamide hydrochloride
[0101] A solution of 3,5dimethyl-1-adamantanecarbonitrile (1.95 g,
10.3 mmol) in MeOH (30 mL) at 0.degree. C. was saturated with HCl
gas over 30 min, left at 0.degree. C. for 5 days, concentrated in
vacuo, the residue triturated with EtOAc and filtered to give the
intermediate imidate hydrochloride salt (1.16 g, 44%) as a
hygroscopic solid. The solid (302 mg, 1.17 mmol) in MeOH (20 mL) at
0.degree. C. was saturated with ammonia gas, left at room
temperature for 4 days, concentrated to a small volume in vacuo,
treated with EtOAc and filtered to give the title compound (240 mg,
85%) as a white crystalline solid: mp 297-229.degree. C.; IR
.nu..sub.max (Nujol)/cm.sup.-1 3166, 1673, 1508, 1087 and 729; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 0.85 (6H, s), 1.20-1.50 (2H,
m), 1.30-1.40 (4H, m), 1.40-1.60 (4H, m), 1.69 (2H, m), 2.12 (2H,
m), 8.55 (2H, br s) and 8.90 (2H, br s); Anal. Calcd for
C.sub.13H.sub.23N.sub.2Cl- .0.1 H.sub.2O: C, 63.84; H, 9.56; N,
11.45. Found: C, 63.73; H, 9.34; N, 11.46.
Example 2
[0102] 3-Chloro-1-adamantanecarboximidamide hydrochloride
[0103] 3-Chloro-1-adamantanecarbonifrile
[0104] This was prepared from 3-chloro-1-adamantanecarboxylic acid
by the method of example 1 and the product isolated (2.12 g, 94%)
as a pale brown solid: mp 156-157.degree. C.; IR .nu..sub.max
(Nujol)/cm.sup.-1 2249, 2230, 1248, 1124, 972 and 734; NMR
.delta..sub.H (400 Mz, CDCl.sub.3) 1.64-1.73 (2H, m), 1.96-2.04
(4H, m), 2.07-2.16 (4H, m), 225-2.30 (2H, m) and 2.38 (2H, s);
Anal. Calcd for C.sub.11H.sub.14NCl: C, 67.52; H, 7.21; N, 7.15.
Found: C, 67.52; H, 7.18; N, 6.94.
[0105] 3-Chloro-1-adamantanecarboximidamide hydrochloride
[0106] This was prepared from 3chloro-1-adamantanecarbonitrile by
the method of example 1 and the title compound isolated (272 mg,
96%) as a white crystalline solid: mp 215-216.degree. C.; IR
.nu..sub.max (Nujol)/cm.sup.-1 3455, 3376, 3306, 3148, 1687, 1667,
1082, 837, 733 and 701; NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
1.55-1.65 (2H m), 1.80-1.90 (4H, m), 2.05-2.15 (4H, m), 2.25 (2H,
s), 2.28 (2H, s), 8.70 (2H, s) and 9.04 (2H, s); Anal. Calcd for
C.sub.11H.sub.18N.sub.2Cl.sub.2- .H.sub.2O.0.1NH.sub.4Cl: C, 48.48;
H, 7.54; N, 10.79. Found: C, 48.81; H, 7.63; N, 10.86.
Example 3
[0107] 3-Bromo-1-adamantanecarboxidamide hydrochloride
[0108] This was prepared from 3-bromo-1-adamantanecarbonitrile by
the method of example 1 and the title compound isolated (276 mg,
97%) as a white crystalline solid: mp 221-223.degree. C.; IR
.nu..sub.max (Nujol)/cm.sup.-1 3453, 3373, 3307, 3152, 1687, 1667,
1081, 825, 722, 699 and 679; NMR .delta..sub.H (400 Mz,
DMSO-d.sub.6) 1.60-1.70 (2H, m), 1.85-1.95 (4H, m), 2.21 (2H, s),
2.25-2.35 (4H, m), 2.50 (2H, s) and 8.8 (4H, br s); Anal. Calcd for
C.sub.11H.sub.18N.sub.2BrCl.H.sub.2O: C, 42.39; H, 6.47; N, 8.99.
Found: C, 42.17; H, 6.48; N, 9.08.
Example 4
[0109] 3-Ethyl-1-adamantanecarboximnidamide hydrochloride
[0110] This was prepared from 3-ethyl-1-adamantanecarbonitrile by
the method of example 1 and the title compound isolated (1.74 g,
94%) as a white crystalline solid: mp 210-212.degree. C.; IR
.nu..sub.max (Nujol)/cm.sup.-1 3266, 3070, 1665, 1089 and 734; NMR
.delta..sub.H (400 Mz, DMSO-d.sub.6) 0.79 (3H, t, J 7.75 Hz),
1.1-1.2 (2H, m), 1.35-1.45 (4H, m), 1.5-1.65 (4H, m), 1.7-1.85 (2H,
m), 2.09 (2H, s), 8.56 (2H, br s) and 8.92 (2H, br s); Anal. Calcd
for C.sub.13H.sub.23N.sub.2Cl: C, 64.31; H, 9.55; N, 11.53.Found:
C, 64.05; H, 9.95; N, 11.49.
Example 5
[0111] 3,5-Dimethyl-1-adamantaneacetimidamide hydrochloride
[0112] 3,5-Dimethyl-1-adamantaneacetonitrile
[0113] This was prepared from 3,5-dimethyl-1-adamantaneacetic acid
(Bott and Hellman, Angew. Chem. Int. Ed. Engl., 1966, 5,870, the
disclosure of which is incorporated herein by reference) by the
method of example 1 and the product isolated (833 mg, 88%) as a
pale brown oil: IR .nu..sub.max (liquid film)/cm.sup.-1 2900, 2843,
2244, 1455, 1360 and 1345; NMR .delta..sub.H (400 MHz, CDCl.sub.3)
0.84 (6H, s), 1.1-1.3 (6H, m), 1.32-1.35 (2H, m), 1.44-1.47 (2H,
m), 2.12 (2H, s) and 2.05-2.15 (1H, m).
[0114] 3,5-Dimethyl-1-adamantaneacetimidamide hydrochloride
[0115] This was prepared from 3,5-dimethyl-1-adamantaneacetonitrile
by the method of example 1 and the title compound isolated (778 mg,
100%) as a white crystalline solid: mp 252-253.degree. C.; IR
.nu..sub.max (Nujol)/cm.sup.-1 3384, 3076, 1691 and 722; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 0.81 (6H, s), 1.0-1.25 (6H,
m), 1.25-1.35 (4H, m), 1.38 (2H, s), 2.04 (1H, m), 2.17 (2H, s) and
8.76 (4H, br s); Anal. Calcd for
C.sub.14H.sub.25N.sub.2Cl.0.9H.sub.2O: C, 61.59; H, 9.89; N, 10.26.
Found: C, 61.69; H, 10.31; N, 10.19.
Example 6
[0116] N-Allyl-3,5-dimethyl-1-adamantanecarboximidamide
hydrochloride
[0117] This was prepared from 3,5-dimethyl-1-adamantanecarbonitrile
by the method of example 1 using allylamine (3 eq) instead of
ammonia. The title compound was isolated (46 mg, 42%) as a white
crystalline solid: mp 222-224.degree. C.; IR .nu..sub.max
(Nujol)/cm.sup.-1 3039, 1671, 1614, 993, 932, 810 and 722; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 0.85 (6H, s), 1.16-1.19 (2H,
m), 1.3-1.4 (4H, m), 1.48-1.6 (4H, m), 1.75 (2H, m), 2.14 (1H, m),
3.92 (2H, m), 5.10-5.20 (2H, m), 5.75-5.85 (1H, m), 8.7 (2H, br s)
and 9.0 (1H, br s); Anal. Calcd for C.sub.16H.sub.27N.sub.2Cl.- 0.2
H.sub.2O: C, 67.09; H, 9.64; N, 9.78. Found: C, 67.09; H, 9.56; N,
9.53.
Example 7
[0118] N-Allyl-1-adamantanecarboximidamide hydrochloride
[0119] This was prepared from 1-adamantanecarbonitrile by the
method of example 1 using allylamine (3 eq) instead of ammonia. The
title compound was isolated (298 mg, 90%) as a white crystalline
solid: mp 252-254.degree. C.; IR .nu..sub.max (Nujol)/cm.sup.-1
3185, 3031, 1678, 1613, 1257, 799, 751 and 717; NMR .delta..sub.H
(400, DMSO-d.sub.6) 1.65-1.70 (6H, m), 1.9-2.0 (6H, m), 2.04 (3H,
s), 3.95 (2H, m), 5.1-5.2 (2H, m), 5.75-5.85 (1H, m), 8.71 (1H, s),
8.79 (1H, s) and 9.15 (1H, s); Anal. Calcd for
C.sub.14H.sub.23N.sub.2Cl: C, 65.99; H, 9.10; N, 10.99. Found: C,
65.92; H, 9.04; N, 11.05.
Example 8
[0120] N-Ethyl-1-adamantanecarboximidamide hydrochloride
[0121] This was prepared from 1-adamantanecarbonitrile by the
method of example 1 using 2-M ethylamine in MeOH (3 eq) in place of
ammonia and the title compound isolated (175 mg, 55%) as a white
crystalline solid: mp 315.degree. C. (dec); IR .nu..sub.max
(Nujol)/cm.sup.-1 3191, 3030, 1682, 1616, 1354, 810 and 766; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 1.10 (3H, t, J 7.0 Hz),
1.6-1.7 (6H, m), 1.85-1.90 (6H, m), 2.0-2.05 (3H, m), 3.30 (2H,
pent, J 7.0 Hz), 8.67 (1H, s), 8.71 (1H, s) and 8.86 (1H, s); Anal.
Calcd for C.sub.13H.sub.23N.sub.2Cl: C, 64.31; H, 9.55; N, 11.54.
Found: C, 64.27; H, 9.56; N, 11.54.
Example 9
[0122] N-Benzyl-1-adamantanecarboximidamide hydrochloride
[0123] This was prepared from 1-adamantanecarbonitrile by the
method of example 1 using benzylamine (1.1 eq) in place of ammonia
and tie title compound isolated (357 mg, 90%) as a white
crystalline solid: mp 242-244.degree. C.; IR .nu..sub.max
(Nujol)/cm.sup.-1 3049, 1677, 1605, 1240, 759, 728 and 703; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 1.65-1.70 (6H, m), 1.9-2.0
(6H, m), 2.05 (3H, s), 4.58 (2H, s), 7.3-7.4 (5H, m), 8.80 (1H, s),
8.85 (1H, s), and 9.55 (1H, s); Anal. Calcd for
C.sub.18H.sub.25N.sub.2Cl: C,70.92; H, 8.27; N, 9.18. Found: C,
70.62; H, 8.21; N,9.18.
Example 10
[0124] N-(2-Dimethylaminoethyl)-1-adamantanecarboximidamide
dihydrochloride
[0125] This was prepared from 1-adamantanecarbonitrile by the
method of example 1 using N,N-dimethylethylenediamine (3 eq) in
place of ammonia and the title compound isolated (42 mg, 10%) as a
white crystalline solid: mp 293.degree. C. (dec); IR .nu..sub.max
(Nujol)/cm.sup.-1 3192, 2581, 2469, 1697, 1605 and 798; NMR
.delta..sub.H (400 MHZ, DMSO-d.sub.6) 1.65-1.75 (6H, m), 1.94 (6H,
s), 2.04 (3H, s), 2.81 (6H, s), 3.27 (2H, m), 3.72 (2H, m), 8.98
(1H, s), 9.04 (1H, s), 9.13 (1H, s) and 10 86 (1H, s); Anal. Calcd
for C.sub.15H.sub.29N.sub.3Cl.sub.2.0.25H.sub.2O: C, 55.12; H,
9.10; N, 12.86. Found: C, 55.23; H, 9.00; N, 12.89.
Example 11
[0126] 3-(3,5-Dimethyl-1-adamantyl)propanimidamide
hydrochloride
[0127] 3-(3,5-Dimethyl-1-adamantyl)propionitrile
[0128] A solution of 1-bromo-3,5dimethyladamantane (1.0 g, 4.11
mmol), acrylonitrile (436 mg, 8.22 mmol) and
1,1'-azobis(cyclohexanecarbonitrile- ) (50 mg, 0.21 mmol) in dry
toluene (12 mL) was treated with tri-n-butyltin hydride (1.44 g,
4.93 mmnol) at room temperature, refluxed for 3.5 h, cooled,
diluted with ether (30 mL), washed with 0.2-M NH.sub.4OH (30 mL),
water (10 mL), dried (MgSO.sub.4) and concentrated in vacuo. The
residue was purified by chromatography [SiO.sub.2,
CH.sub.2Cl.sub.2-hexane (0:100 to 100:0)] to give the product (771
mg, 86%) as a colourless oil: IR .nu..sub.max (liquid
film)/cm.sup.-1 2899, 2841, 2247, 1545 and 1359; NMR .delta..sub.H
(400 MHz, CDCl.sub.3) 0.81 (6H, s), 1.0-1.2 (6H, m), 1.25-1.35 (6H,
m), 1.53 (2H, t, J 4.2 Hz), 2.05-2.10 (1H, m) and 2.27 (2H, t J 4.2
Hz).
[0129] 3-(3,5-Dimethyl-1-adamantyl)propanimidamide
hydrochloride
[0130] This was prepared from
3-(3,5dimethyl-1-adamantyl)propionitrile by the method of example 1
and the title compound isolated (609 mg, 86%) as a white
crystalline solid: mp 246-248.degree. C.; IR .nu..sub.max
(Nujol)/cm.sup.-1 3076, 1681, 789 and 749; NMR .delta..sub.H (400
MHz, DMSO-d.sub.6) 0.80 (6H, s), 1.08 (6H, q, J 12.5 Hz), 1.28 (6H,
d J 2.6 Hz), 1.39 (2H, m), 2.02 (1H, m), 2.31 (2H, m), 8.65 (2H, br
s) and 8.99 (2H, br s); Anal. Calcd for
C.sub.15H.sub.25N.sub.2Cl.0.2 NH.sub.4Cl: C, 63.99; H, 9.95; N,
10.95. Found: C, 64.15; H, 9.98; N, 10.87.
Example 12
[0131] 3-Methyl-1-adamantanecarboximidamide hydrochloride
[0132] 3-Methyl-1-adamantanecarbonitrile
[0133] This was prepared from 3-methyl-1-adamantanecarboxylic acid
by the method of example 1 and the product (1.81 g, 80%) isolated
as a pale brown waxy solid: IR .nu..sub.max (Nujol)/cm.sup.-1 2923,
2853, 2233, 1456, 1377, 1360, 1343, 1161 and 1111; NMR
.delta..sub.H (400 MHz, CDCl.sub.3) 0.85 (3H, s), 1.45 (4H, m),
1.63 (2H, m), 1.74 (2H, s), 1.94 (4H, m), and 2.07 (2H, m).
[0134] 3-Methyl-1-adamantanecarboximidamide hydrochloride
[0135] This was prepared from 3-methyl-1-adamantanecarbonitrile by
the method of example 1 and the title compound (1.26 g, 95%)
isolated as a white crystalline solid: mp 255-257.degree. C.; IR
.nu..sub.max (Nujol)/cm.sup.-1 3222, 3084, 2923, 2853, 1674, 1502,
1456, 1376, 1087 and 737; NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
0.83 (3H, s), 1.42 (4H, m), 1.58 (4H, m), 1.77 (4H, m), 2.07 (2H,
m), 8.61 (2H, br s) and 8.99 (2H, br s); NMR .delta..sub.C (100 Mz,
DMSO-d.sub.6) 28.1, 30.2, 30.8, 34.9, 37.5, 42.7, 44.6 and
177.0.
Example 13
[0136] 3,5,7-Trimethyl-1-adamantanecarboximidamide
hydrochloride
[0137] 3,5,7-Trimethyl-1-adamantanecarbonitrile
[0138] This was prepared from
3,5,7-trimethyl-1-adamantanecarboxylic acid by the method of
example 1 and the product (2.01 g, 88%) isolated as a waxy solid:
IR .nu..sub.max (Nujol)/cm.sup.-1 2923, 2864, 2230, 1456, 1377,
1358, 1350, 1257, 1095 and 912; NMR .delta..sub.H (400 MHz,
CDCl.sub.3) 0.90 (9H, s), 1.12 (6H, m) and 1.60 (6H, s).
[0139] 3,5,7-Trimethyl-1-adamantanecarboximidamide
hydrochloride
[0140] This was prepared from
3,5,7-trimethyl-1-adamantanecarbonitrile by the method of example 1
and the title compound (0.98 g, 98%) isolated as a white
crystalline solid: mp 325.degree. C.; IR .nu..sub.max
(Nujol)/cm.sup.-1 3266, 3094, 2923, 2854, 1666, 1517, 1454, 1376,
1365, 1113, 1098 and 741; NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
0.86 (9H, s), 1.09 (6H, m), 1.44 (6H, s), 8.59 (2H, br s) and 8.99
(2H, br s); NMR .delta..sub.C (100 MHz, DMSO-d.sub.6) 30.0, 31.8,
40.9, 43.5, 49.2 and 176.7.
Example 14
[0141] 3-(4-Nitrophenyl)-1-adamantanecarboximidamide
hydrochloride
[0142] 3-(4-Nitrophenyl)-1-adamantanecarbonitrile
[0143] This was prepared from
3-(4-nitrophenyl)-1-adamantanecarboxylic acid by the method of
example 1 and the product (0.92 g, 93%) isolated as a pale brown
solid: IR .nu..sub.max (Nujol)/cm.sup.-1 2923, 2854, 2235, 1594,
1516, 1458, 1377, 1353, 1111 and 858; NMR .delta..sub.H (400 MHz,
CDCl.sub.3) 1.79 (2H, m), 1.94 (4H, m), 2.11 (4H, m), 2.21 (2H, s),
2.30 (2H, m), 7.49 (2H, m) and 8.20 (2H, m).
[0144] 3-(4-Nitrophenyl)-1-adamantanecarboximidamide
hydrochloride
[0145] This was prepared from
3-(4-nitrophenyl)-1-adamantanecarbonitrile by the method of example
1 and the title compound (0.22 g, 77%) isolated as a white
crystalline solid: mp 256-259.degree. C.; IR .nu..sub.max
(Nujol)/cm.sup.-1 3448, 3365, 3314, 3160, 3074, 2923, 2854, 1686,
1664, 1608, 1596, 1512, 1455, 1377, 1351, 741 and 697; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 1.72 (2H, m), 1.93 (8H, m),
2.09 (2H, s), 2.25 (2H, m), 7.75 (2H, m), 8.21 (2H, m), 8.73 (2H,
br s) and 8.93 (2H, br s).
Example 15
[0146] 2-(1-Adamantyl)butanimidamide hydrochloride
[0147] 2-(1-Adamantyl)butanenitrile
[0148] A solution of diisopropylamine (0.45 mL, 3.2 mmol) in dry
THF (15 mL) at -78.degree. C. was treated with n-BuLi (1.6-M, 2 mL,
3.2 mmol), stirred at -78.degree. C. for 15 min, treated with a
solution of 2-(1-adamantyl)acetonitrile (0.5 g, 2.9 mmol) in dry
THF (5 mL) and stirred at -78.degree. C. for 1 h. Ethyl iodide
(0.26 mL, 3.2 mmol) was added dropwise, the solution stirred at
-78.degree. C. for 2 h, allowed to warm to room temperature,
treated with NH.sub.4Cl solution (20 mL), extracted with EtOAc
(3.times.10 mL), the extracts washed with brine (10 mL), dried
(MgSO.sub.4) and concentrated in vacuo to give the product (0.56 g,
97%) as a pale brown solid: mp 53-54.degree. C.; IR .nu..sub.max
(Nujol)/cm.sup.-1 2914, 2231, 1455, 1378, 1366, 1346, 1317, 1091
and 979;.NMR .delta..sub.H (400 MHz, CDCl.sub.3) 1.11 (3H, t, J 7.4
Hz), 1.49 (1H, m), 1.74-1.64 (13H, m) and 2.06 (4H, m); Anal. Calcd
for C.sub.14H.sub.21N.0.1H.sub.2O: C, 81.97; H, 10.42; N, 6.83.
Found: C, 81.92; H, 10.68; N, 6.74.
[0149] 2-(1-Adamantyl)butanimidamide hydrochloride
[0150] A suspension of NH.sub.4Cl (1.38 g, 26 mmol) in dry toluene
(8 mL) at 0.degree. C. was treated dropwise with 2-M
trimethylaluminium in toluene (13 mL, 26 mmol), allowed to warm to
room temperature and stirred for 2 h. This solution was added to a
solution of 2-(1-adamantyl)butaneni- trile (0.44 g, 2.2 mmol) in
dry toluene (10 mL) and the resulting solution refluxed for 4 days,
cooled to room temperature and poured into a slurry of SiO.sub.2 (5
g) and CHCl.sub.3 (10 mL). The slurry was filtered, the filtrate
treated with Na.sub.2SO.sub.4, concentrated in vacuo and the
residue loaded on to the top of a silica column and purified by
chromatography [SiO.sub.2; EtOAc--MeOH (9:1 to 4:1)] to give the
title compound (0.38 g, 68%) as a white solid: mp 223.degree. C.
(dec); IR .nu..sub.max (Nujol)/cm.sup.-1 3332, 3157, 3071, 2925,
2852, 1666, 1510, 1462, 1377 and 724; NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 0.81 (3H, t, J 7.2 Hz), 1.39 (2H, m), 1.56-1.69 (11H,
br m), 1.96 (3H, m), 2.13 (1H, m) and 9.08 (4H, br m); NMR
.delta..sub.C (100 MHz, DMSO-d.sub.6) 11.8, 17.0, 27.8, 34.1, 36.2,
39.5, 56.0 and 171.0.
Example 16
[0151] 2-(1-Adamantyl)-3-phenylpropanimidamide hydrochloride
[0152] This was prepared from
2-(1-adamantyl)-2-phenylpropanenitrile by the method of example 15
and the title compound (0.11 g, 46%) isolated as a white
crystalline solid: mp 147-148.degree. C.; IR .nu..sub.max
(Nujol)/cm.sup.-1 3250 br, 2923, 2852, 1679, 1495, 1456, 1377,
1346, 1313, 1084, 739 and 699; NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 1.51 (3H, m), 1.66 (6H, m), 1.79 (3H, m), 2.01 (3H,
m), 2.60 (1H, m), 2.96 (2H, m), 7.24 (5H, m), 8.60 (1H, br s), 8.78
(1H, br s), 8.92 (1H, br s) and 9.05 (1H, br s).
Example 17
[0153] 3-(1-Adamantyl)-2-phenylpropanimidamide hydrochloride
[0154] 3-(1-Adamantyl)-2-phenylpropenenitrile
[0155] A solution of diethyl 1-cyano-1-phenylmethylphosphonate
(10.97 g, 43.3 mmol) in dry THF (60 mL) at 0.degree. C. was treated
with NaH (60% dispersion in oil, 1.7 g, 43.3 mmol), stirred at
0.degree. C. for 40 min, warmed to room temperature for 20 min,
treated with a solution of 1-adamantanecarboxaldehyde (3.56 g, 21.7
mmol) in dry THF (10 mL) and heated at 60.degree. C. for 16 h. The
reaction mixture was cooled, treated with water (50 mL), extracted
with EtOAc (3.times.20 mL), the extracts washed with brine (40 mL),
dried (MgSO.sub.4) and concentrated in vacuo. The resulting brown
oil was purified by chromatography [SiO.sub.2, heptane-EtOAc (9:1)]
and recrystallised (heptane) to give the product (1.62 g, 28%) as a
white solid: mp 107-108.degree. C.; IR .nu..sub.max
(Nujol)/cm.sup.-1 2924, 2852, 2218, 1497, 1448, 1377, 1343, 1101,
910, 762, 750 and 689; NMR .delta..sub.H (400 MHz, CDCl.sub.3) 1.76
(6H, m), 1.99 (6H, m), 2.07 (3H, m), 6.50 (1H, s), 7.37 (3H, m) and
7.51 (2H, m); Anal. Calcd for C.sub.19H.sub.21N: C, 86.65; H, 8.04;
N, 5.32. Found: C, 86.58; H, 8.09; N, 5.33.
[0156] 3-(1-Adamantyl)-2-phenylpropanenitrile
[0157] A solution of 3-(1-adamantyl)-2-phenylpropenenitrile (600
mg, 2.28 mmol) in EtOAc (30 mL) was treated with 10% Pd/C (70 mg),
hydrogenated at 50 psi for 16 h, filtered through SiO.sub.2 and
concentrated in vacuo. The residue was purified by chromatography
[SiO.sub.2, EtOAc-heptane (1:1)] and the resulting solid
recrystallised (heptane) to give the product (552 mg, 91%) as a
white crystalline solid: mp 83-84.degree. C.; IR .nu..sub.max
(Nujol)/cm.sup.-1 2912, 2852, 2239, 1497, 1453, 1377, 1355, 1346,
1105, 749, 713 and 696; NMR .delta..sub.H (400 MHz, CDCl.sub.3)
1.50 (1H, dd, J 14.3, 3.2 Hz), 1.63 (9H, m), 1.72 (3H, m), 1.94
(1H, dd, J 14.3, 10.4 Hz), 2.01 (3H, m), 3.79 (1H, dd, J 10.4, 3.2
Hz) and 7.35 (5H, m); Anal. Calcd for C.sub.19H.sub.23N: C, 85.99;
H, 8.73; N, 5.28. Found: C, 85.96; H, 8.90; N, 5.27.
[0158] 3-(1-Adamantyl)-2-phenylpropanimidamide hydrochloride
[0159] This was prepared from
3-(1-adamantyl)-2-phenylpropanenitrile by the method of example 15
and the title compound (92 mg, 60%) isolated as a pale brown solid:
mp 253.degree. C. (dec); IR .nu..sub.max (Nujol)/cm.sup.-1 3243,
2918, 2853, 1680, 1496, 1455, 1377, 1105, 1080, 754, 721 and 705;
NMR .delta..sub.H (400 MHz, DMSO-d.sub.6) 1.40 (3H, m), 1.55 (7H,
m), 1.68 (3H, m), 1.92 (3H, m), 2.15 (1H, m), 4.05 (1H, m), 7.31
(1H, m), 7.40 (2H, m), 7.52 (2H, m) and 9.01 (4H, br s).
Example 18
[0160] 3-(1-Adamantyl)-3-phenylpropanimidamide hydrochloride
[0161] This was prepared from
3-(1-adamantyl)-3-phenylpropanenitrile by the method of example 15
and the title compound (130 mg, 50%) isolated as a pale yellow
solid: mp 249.degree. C. (dec); IR .nu..sub.max (Nujol)/cm.sup.-1
3400-2800 br, 2957, 1684, 1455, 1407, 1377, 772 and 704; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 1.37 (3H, m), 1.51 (6H, m),
1.60 (3H, m), 1.92 (3H, m), 2.91 (3H, m), 7.25 (5H, m), 8.50 (2H,
br s) and 9.00 (2H, br s).
II NMDA Receptor Binding
[0162] The NMDA receptor contains several distinct binding domains
that can regulate opening of the cationic channel. The
phencyclidine (PCP) site of the NMDA receptor can be radiolabeled
with
[.sup.3H]-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin-
e hydrogen maleate, [.sup.3H-MK-801]. The following describes the
procedure for determining the affinity of compounds for the PCP
site in rat cortical or cerebellar membranes.
[0163] Frozen rat cortex or cerebellum, homogenized in 10 volumes
of ice cold 0.32 M. sucrose is centrifuged at 1,000 g for 12 min
and the supernatant stored on ice whilst the pellet was
resuspended, rehomogenized and recentrifuged twice more. The three
final supernatants were pooled and centrifuged at 30,000 g for 40
min at 4.degree. C. to yield P.sub.2 pellets. These were
resuspended in ice-cold distilled water, and centrifuged at 30,000
g for 50 min at 4.degree. C. Following three further washes in
distilled water, the P.sub.2 pellets were stored at -20.degree. C.
for at least 18 h. On the day of the assay, membrane pellets were
thawed at room temperature, resuspended in ice-cold distilled water
and centrifuged at 30,000 g for 20 min. The pellets were
resuspended in 50 mM tris-HCl (pH:7.4) and recentrifuged twice more
before being resuspended in tris-HCl for immediate use in the
assay. Binding assays were performed at equilibrium in a total
volume of 200 .mu.l, containing, [.sup.3H]-MK-801 (5 nM final
conc.), 10 .mu.M glutamate, 10 .mu.M glycine, 160 .mu.l of membrane
preparation and additional drugs where appropriate. Non-specific
binding was determined using MK-801 (10 .mu.M). The assay was
incubated for 120 min at room temperature. The incubation was
terminated by rapid filtration through Whatman GF/B filters
(pre-soaked in 0.1% PEI solution). The assay tubes and filters were
washed five times with 1 ml of ice cold assay buffer. The filters
were placed in poly-Q mini vials with approximately 5 ml of
scintillation fluid. The vials are then shaken and left for at
least 8 hours before being counted on a liquid scintillation
counter. To determine the free ligand concentration 3 aliquots (20
.mu.M) of the [.sup.3H]-NM-801 working solution were also counted.
Concentration response data for drugs was analysed using a 4
parameter equation fitted by non linear regression. This yielded
the half maximally effective drug concentration (IC.sub.50) and
Hill coefficient.
[0164] The data obtained from these assays are presented in Table
1. The data clearly demonstrate that the compounds of the invention
are active as NMDA antagonists and have favourable ratios of
cortical to cerebellar binding affinity indicating that the
compounds will be well-tolerated in vivo.
1TABLE 1 Binding Affinities at Cortical and Cerebellar NMDA
Receptors IC.sub.50(.mu.M) IC.sub.50(.mu.M) Compound Cortex
Cerebellum Ratio Example 1 28 6 4.7 Example 2 291 Example 3 188 105
1.8 Example 4 122 56 2.2 Example 5 82 56 1.5 Example 6 31 Example 7
698 297 2.4 Example 8 1000 Example 9 754 388 1.9 Example 10 1000
Example 11 78 48 1.6 Example 12 96 36 2.7 Example 13 43 18 2.4
Example 14 406 234 1.7 Example 15 144 46 3.1 Example 16 52 27 1.9
Example 17 16 Example 18 27
* * * * *