Note: Descriptions are shown in the official language in which they were submitted.
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EXCITATORY AMINO ACID RECEPTOR ANTAGONISTS
BACKGROUND OF THE INVENTION
In the mammalian central nervous system (CNS), the transmission of nerve
impulses is controlled by the interaction between a neurotransmitter, that is
released by a
sending neuron, and a surface receptor on a receiving neuron, which causes
excitation of
this receiving neuron. L-Glutamate, which is the most abundant
neurotransmitter in the
CNS, mediates the major excitatory pathways in mammals, and is referred to as
an
excitatory amino acid (EAA). The receptors that respond to glutamate are
called
excitatory amino acid receptors (EAA receptors). See Watkins & Evans, Ann.
Rev.
Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev.
Pharmacol. Toxicol., 29, 36S (1989); Watkins, Krogsgaard-Larsen, and Honore,
Trans.
Pharnz. Sci., 11, 25 (1990). The excitatory amino acids are of great
physiological
importance, playing a role in a variety of physiological processes, such as
long-term
potentiation (learning and memory), the development of synaptic plasticity,
motor control,
respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types.
Receptors
2 0 that are directly coupled to the opening of cation channels in the cell
membrane of the
neurons are termed "ionotropic." This type of receptor has been subdivided
into at least
three subtypes, which are defined by the depolarizing actions of the selective
agonists N-
methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-propionic
acid
(AMPA), and kainic acid (KA). Molecular biological studies have established
that AMPA
2 5 receptors are composed of subunits (GluR1- GluR4), which can assemble. to
form
functional ion channels. Five kainate receptors have been identified which are
classified
as either High Affinity (I~A1 and KA2) or Low Affinity (composed of GIuRS,
GluR6,
and/or GluR~ subunits). Bleakman et al., Molecular Plzannacology, 49, No.4,
581,(1996).
The second general type of receptor is the G-protein coupled or second
messenger-linked
3 0 "metabotropic" excitatory amino acid receptor. This second type is coupled
to multiple
second messenger systems that lead to enhanced phosphoinositide hydrolysis,
activation
of phospholipase D, increases or decreases in cAMP formation, and changes in
ion
channel function. Schoepp and Conn, Trends in Phannacol. Sci., 14, 13 (1993).
Both types of excitatory amino acid receptor appear not only to mediate normal
synaptic
3 5 transmission along excitatory pathways, but also to participate in the
modification of '
synaptic connections during development and throughout life. Schoepp,
Bockaert, and
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Sladeczek, Trends in Pharrnacol. Sci., 11, 508 (1990); McDonald and Johnson,
Brain
Research Reviews, 15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors
leads to neuronal cell damage or loss by way of a mechanism known as
excitotoxicity.
This process has been suggested to mediate neuronal degeneration in a variety
of
neurological disorders and conditions. The medical consequences of such
neuronal
degeneration makes the abatement of these degenerative neurological processes
an
important therapeutic goal. For instance, excitatory amino acid receptor
excitotoxicity
has been implicated in the pathophysiology of numerous neurological disorders,
including
the etiology of cerebral deficits subsequent to cardiac bypass surgery and
grafting, stroke,
cerebral ischemia, spinal cord lesions resulting from trauma or inflammation,
perinatal
hypoxia, cardiac arrest, and hypoglycemic neuronal damage. In addition,
excitotoxicity
has been implicated in chronic neurodegenerative conditions including
Alzheimer's
Disease, Huntington's Chorea, inherited ataxias, Aff~S-induced dementia,
amyotrophic
lateral sclerosis, idiopathic and drug-induced Parkinson's Disease, as well as
ocular
damage and retinopathy. Other neurological disorders implicated with
excitotoxicity
and/or glutamate dysfunction include muscular spasticity including tremors,
drug
tolerance and withdrawal, brain edema, convulsive disorders including
epilepsy,
depression, anxiety and anxiety related disorders such as post-traumatic
stress syndrome,
2 0 tardive dyskinesia, , and psychosis related to depression, schizophrenia,
bipolar disorder,
mania, and drug intoxication or addiction. (see generally United States Patent
No.
5,446,051 and 5,670,516) Excitatory amino acid receptor antagonists may also
be useful
as analgesic agents and for treating or preventing various forms of headache,
including
cluster headache, tension-type headache, and chronic daily headache. In
addition,
2 5 published European Patent application W098/45720 reports that excitatory
amino acid
receptor excitotoxicity participates in the etiology of acute and chronic pain
states
including severe pain, intractable pain, neuropathic pain, post-traumatic
pain.
It is also known that trigeminal ganglia, and their associated nerve pathways,
are
associated with painful sensations of the head and face such as headache and,
in
3 0 particular, migraine. Moskowitz (Ceplaalalgia, 12, 5-7, (1992) proposed
that unknown
triggers stimulate the trigeminal ganglia which in turn innervate vasculature
within
cephalic tissue, giving rise to the release of vasoactive neuropeptides from
axons
innervating the vasculature. These neuropeptides initiate a series of events
leading to
neurogenic inflammation of the meninges, a consequence of which is pain. This
3 5 neurogenic inflammation is blocked by sumatriptan at doses similar to
those required to
treat acute migraine in humans. However, such doses of sumatriptan are
associated with
contraindications as a result of sumatriptan's attendant vasoconstrictive
properties.(see
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MacIntyre, P.D., et al., British Joun2al of Clinical Pharmacology, 34, 541-546
(1992);
Chester, A.H., et al., Cardiovascular Research, 24, 932-937 (1990); Conner,
H.E., et al.,
European Journal of Pharmacology, 161, 91-94 (1990)). Recently, it has been
reported
that all five members of the leainate subtype of ionotropic glutamate
receptors are
expressed on rat trigeminal ganglion neurons, and in particular, high levels
of GluRS and
KA2 have been observed. (Sahara et al., The Journal of Neuroscience, 17(17),
6611
(1997)). As such, migraine presents yet another neurological disorder which
may be
implicated with glutamate receptor excitotoxicity.
The use of a neuroprotective agent, such as an excitatory amino acid receptor
antagonist, is believed to be useful in treating or preventing all of the
aforementioned
disorders and/or reducing the amount of neurological damage associated with
these
disorders. For example, studies have shown that AMPA receptor antagonists are
neuroprotective in focal and global ischemia models. The competitive AMPA
receptor
antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f~quinoxaline) has
been
reported effective in preventing global and focal ischemic damage. Sheardown
et al.,
Science, 247, 571 (1900); Buchan et al., Neuroreport, 2, 473 (1991); LePeillet
et al.,
Brain Research, 571, 115 (1992). The noncompetitive AMPA receptor antagonists
GI~YI
52466 has been shown to be an effective neuroprotective agent in rat global
ischemia
models. LaPeillet et al., Brain Research, 571, 115 (1992). European Patent
Application
2 0 Publication No. 590789A1 and United States Patents No. 5,446,051 and
5,670,516
disclose that certain decahydroisoquinoline derivative compounds are AMPA
receptor
antagonists and, as such, are useful in the treatment of a multitude of
disorders conditions,
including pain and migraine headache. W098/45270 discloses that certain
decahydroisoquinoline derivative compounds are selective antagonists of the
iGluRS
2 5 receptor and are useful for the treatment of various types of pain,
including; severe,
chronic, intractable, and neuropathic pain
In accordance with the present invention, Applicants have discovered novel
compounds that are selective antagonists of the iGluRS receptor subtype and,
thus, could
be useful in treating the multitude of neurological disorders or
neurodegenerative
3 0 diseases, as discussed above. Such selective antagonists could address a
long felt need
for safe and effective treatments for neruological disorders, without
attending side effects.
The treatment of neurological disorders and neurodegenerative diseases is
hereby
furthered.
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SUMMARY OF THE INVENTION
The present invention provides a compound of Formula I
H O
N H
F
F H
Formula I
or a pharmaceutically acceptable salt or prodrug thereof.
In a preferred embodiment, the present invention provides a compound of
Formula
Ia
R10 O
- N OR2
F
F H
Formula Ia
wherein
R1 and R2 each independently represent hydrogen, (C1-CZO)alkyl, (C2-
C6)alkenyl,
2 0 (Cl-C6)alkylaryl, (Cl-C6)alkyl(C3-Clo)cycloalkyl, (C1-C6)alkyl-N,N-Cl-C6
dialkylamine, (C1-C6)alkyl-pyrrolidine, (C1-C6)alkyl-piperidine, or (Cl-
C6)alkyl-
morpholine, with the proviso that at least one of R1 and R~ are other than
hydrogen,
or a pharmaceutically acceptable salt thereof.
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In a particularly preferred embodiment, the present invention provides the
D- (-) -mandelic acid salt of Formula I or Formula Ia, wherein Formula I and
Formula Ia
are as defined hereinabove.
In another embodiment, the present invention provides a method of treating or
preventing a neurological disorder, or neurodegenerative condition, comprising
administering to a patient in need thereof an effective amount of a compound
of Formula I
or Formula Ia, or a pharmaceutically acceptable salt thereof. Examples of such
neurological disorders, or neurodegenerative conditions, include: cerebral
deficits
subsequent to cardiac bypass surgery and grafting; stroke; cerebral ischemia;
spinal cord
lesions resulting from trauma or inflammation; perinatal hypoxia; cardiac
arrest;
hypoglycemic neuronal damage; Alzheimer's Disease; Huntington's Chorea;
inherited
ataxias; AIDS-induced dementia; amyotrophic lateral sclerosis; idiopathic and
drug-
induced Parkinson's Disease; ocular damage and retinopathy; muscular
spasticity
including tremors; drug tolerance and withdrawal; brain edema; convulsive
disorders
including epilepsy; depression; anxiety and anxiety related disorders such as
post-
traumatic stress syndrome; tardive dyskinesia; psychosis related to
depression,
schizophrenia, bipolar disorder, mania, and drug intoxication or addiction;
headache,
including cluster headache, tension-type headache, and chronic daily headache;
migraine;
and acute and chxonic pain states including severe pain, intractable pain,
neuropathic pain,
2 0 and post-traumatic pain.
Specifically, the present invention provides a method of treating or
preventing
migraine comprising administering to a patient in need thereof an effective
amount of a
compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt
thereof.
More specifically, the present invention provides a method of treating or
2 5 preventing migraine comprising administering to a patient in need thereof
an effective
amount of the D- (-) -mandelic acid salt of Formula I or Formula Ia.
The present invention also provides a process for making a compound of Formula
Ia, comprising combining a compound of structure (2)
L90 ..,. ORa
H
(2)
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wherein RZ is as defined herein, Pg is a suitable nitrogen protecting group,
and Lg0 is a
suitable leaving group, with a suitable base in a suitable solvent, followed
by addition of a
compound of structure (3)
Ho'
wherein R1 is as defined herein, followed by oxidation to a compound of
structure (5)
R~
followed by halogenation and removal of the nitrogen protecting group.
In addition, the present invention provides pharmaceutical compositions of
compounds of Formula I and Formula Ia, including the pharmaceutically
acceptable salts,
and hydrates thereof, useful for treating neurological disorders or
neurodegenerative
conditions, comprising, as an active ingredient, a compound of Formula I or
Formula Ia in
combination with a pharmaceutically acceptable carrier, diluent or excipient.
This
invention also encompasses novel intermediates, and processes for the
synthesis of the
compounds of Formula I and Formula Ia.
More specifically, the present invention provides pharmaceutical compositions
useful for treating or preventing migraine comprising, as an active
ingredient, the D- (-) -
mandelic acid salt of Formula I or Formula Ia, in combination with one or more
2 0 pharmaceutically acceptable carriers, diluents, or excipients.
The present invention also provides the use of a compound of Formula I or
Formula Ia for the manufacture of a medicament for treating or preventing a
neurological
disorder, or neurodegenerative condition.
More specifically, the present invention provides the use of a compound of
2 5 Formula I ox Formula Ia for the manufacture of a medicament for treating
or preventing
migraine.
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DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds functional as selective iGluRS
receptor
antagonists as well as pharmaceutically acceptable salts, prodrugs, and
compositions
thereof.
In addition, the present invention provides a method for the treatment of a
neurological disorder, or neurodegenerative condition. Particularly, the
present invention
provides a method fox the treatment of migraine which can be demonstrated by a
particular mechanism of action, inhibition of neurogenic dural protein
extravasation. By
treating a migraineur with a compound or composition which is a selective
antagonist of
the iGluRS receptor relative to other excitatory amino acid receptors, the
neurogenic
extravasation which mediates migraine is inhibited without the attending side
effects of
agents designed to optimize the 5-HTl-like mediated vasoconstrictive activity
of
sumatriptan.
It should be understood by the skilled artisan that all of the compounds
useful for
the methods of the present invention are available for prodrug formualtion. As
used
2 0 herein, the term "prodrug" refers to a compound of Formula I or which has
been
structurally modified such that in vivo the prodrug is converted, for example,
by
hydrolytic, oxidative, reductive, or enzymatic cleavage into the parent
compound (e.g. the
carboxylic acid (drug), or as the case may be the parent dicarboxylic acid )
as given by
Formula I. Such prodrugs may be, for example, metabolically labile ester or
diester
2 5 derivatives of the parent compounds having a carboxylic acid group. It is
to be
understood that the present invention includes any such prodrugs, such as
metabolically
labile ester or diester derivatives of compounds of the Formula I. In all
cases, the use of
the compounds described herein as prodrugs is contemplated, and often is
preferred, and
thus, the prodrugs of all of the compounds employed are encompassed in the
names of the
3 0 compounds herein. Preferred prodrugs include the diester derivatives of
Formula I.
Conventional procedures for the selection and preparation of suitable prodrugs
are well
known to one of ordinary skill in the art.
More specifically, examples of prodrugs of Formula I which are understood to
be
included within the scope of the present invention, are represented by Formula
Ia below:
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_g_
R10 O
OR2
F
F _ H
Formula Ia
wherein
R1 and R~ each independently represent hydrogen, (C1-C2o)alkyl, (CZ-
C6)alkenyl,
(C1-C6)alkylaryl, (C1-C6)alkyl(C3-Clo)cycloalkyl, (C~-C6)alkyl-N,N-C1-C6
dialkylamine, (CI-C6)alkyl-pyrrolidine, (C1-C6)alkyl-piperidine, or (C1-
C6)alkyl-
morpholine, with the proviso that at least one of R1 and R~ are other than
hydrogen,
or a pharmaceutically acceptable salt thereof.
It is understood that the selective iGluRS receptor antagonists of the present
invention
may exist as pharmaceutically acceptable salts and, as such, salts are
therefore included
within the scope of the present invention. The term "pharmaceutically
acceptable salt" as
used herein, refers to salts of the compounds provided by, or employed in the
present
invention which are substantially non-toxic to living organisms. Typical
pharmaceutically
acceptable salts include those salts prepared by reaction of the compounds of
the present
invention with a pharmaceutically acceptable mineral or organic acid or an
organic or
inorganic base. Such salts are known as acid addition and base addition salts.
It will be understood by the skilled reader that most or all of the compounds
used
in the present invention are capable of forming salts, and that the salt forms
of
2 0 pharmaceuticals are commonly used, often because they are more readily
crystallized and
purified than are the free bases. In all cases, the use of the pharmaceuticals
described
herein as salts is contemplated in the description herein, and often is
preferred, and the
pharmaceutically acceptable salts of all of the compounds are included in the
names of
them.
2 5 Acids commonly employed to form acid addition salts are inorganic acids
such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
phosphoric acid, and
the like, and organic acids such as p-toluenesulfonic acid, mandelic acid, 1,5-
naphthalenedisulfonic acid, methanesulfonic acid, oxalic acid, p-
bromophenylsulfonic
acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid,
and the like.
3 0 ~ Examples of such pharmaceutically acceptable salts are the sulfate,
pyrosulfate, bisulfate,
sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,
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metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate decanoate,
caprylate,
acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate,
heptanoate,
propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,
maleate, butyne-
1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate,
phenylpropionate, phenylbutyrate, citrate, lactate, cx-hydroxybutyrate,
glycolate, tartrate,
methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-
sulfonate,
mandelate, napadysilate and the like. Preferred pharmaceutically acceptable
acid addition
salts are those formed with mineral acids such as hydrochloric acid and
hydrobromic acid,
and those formed with organic acids such as D- (-) - mandelic acid, 1,5
naphthalenedisulfonic acid , malefic acid, and methanesulfonic acid.
Base addition salts include those derived from inorganic bases, such as
ammonium
or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and
the like. Such
bases useful in preparing the salts of this invention thus include sodium
hydroxide,
potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium
carbonate,
sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium
carbonate, and
the like. The potassium and sodium salt forms are particularly preferred. It
should be
recognized that the particular counterion forming a part of any salt of this
invention is
usually not of a critical nature, so long as the salt as a whole is
pharmacologically
2 0 acceptable and as long as the counterion does not contribute undesired
qualities to the salt
as a whole. It is further understood that such salts may exist as a hydrate.
As used herein, the term "stereoisomer" refers to a compound made up of the
same
atoms bonded by the same bonds but having different three-dimensional
structures which
are not interchangeable. The three-dimensional structures are called
configurations. As
2 5 used herein, the term "enantiomer" refers to two stereoisomers whose
molecules are
nonsuperimposable mirror images of one another. The term "chiral center"
refers to a
carbon atom to which four different groups are attached. As used herein, the
term
"diastereomers" refers to stereoisomers which are not enantiomers. In
addition, two
diastereomers which have a different configuration at only one chiral center
are referred to
3 0 herein as "epimers". The terms "racemate", "racemic mixture" or "racemic
modification"
refer to a mixture of equal parts of enantiomers.
The term "enantiomeric enrichment" as used herein refers to the increase in
the
amount of one enantiomer as compared to the other. A convenient method of
expressing
the enantiomeric enrichment achieved is the concept of enantiomeric excess, or
."ee",
3 5 which is found using the following equation:
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ee = El - Ez X 100
El + EZ
wherein El is the amount of the first enantiomer and EZ is the amount of the
second
enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such
as is present in
a racemic mixture, and an enantiomeric enrichment sufficient to produce a
final ratio of
50:30 is achieved, the ee with respect to the first enantiomer is 25%.
However, if the final
ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of
greater than
90°Io is preferred, an ee of greater than 95% is most preferred and an
ee of greater than
99°7o is most especially preferred. Enantiomeric enrichment is readily
determined by one
of ordinary skill in the art using standard techniques and procedures, such as
gas or high
performance liquid chromatography with a chiral column. Choice of the
appropriate
chiral column, eluent and conditions necessary to effect separation of the
enantiomeric
pair is well within the knowledge of one of ordinary skill in the art. In
addition, the
enantiomers of compounds of Formula I or Formula Ia can be resolved by one of
ordinary
skill in the art using standard techniques well known in the art, such as
those described by
J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and
Sons, Inc.,
1981.
The compounds of the present invention have one or more chiral centers and may
2 0 exist in a variety of stereoisomeric configurations. As a consequence of
these chiral
centers, the compounds of the present invention occur as racemates, mixtures
of
enantiomers and as individual enantiomers, as well as diastereomers and
mixtures of
diastereomers. All such racemates, enantiomers, and diastereomers are within
the scope
of the present invention.
2 5 The terms "R" and "S" are used herein as commonly used in organic
chemistry to
denote specific configuration of a chiral center. The term "R" (rectus) refers
to that
configuration of a chiral center with a clockwise relationship of group
priorities (highest
to second lowest) when viewed along the bond toward the lowest priority group.
The
term "S" (sinister) refers to that configuration of a chiral center with a
counterclockwise
3 0 relationship of group priorities (highest to second lowest) when viewed
along the bond
toward the lowest priority group. The priority of groups is based upon their
atomic
number (in order of decreasing atomic number). A partial list of priorities
and a
discussion of stereochemistry is contained in "Nomenclature of Organic
Compounds:
Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-
120.
3 5 The specific stereoisomers and enantiomers of compounds of Formula I and
Formula Ia can be prepared by one of ordinary skill in the art utilizing well
known
techniques and processes, such as those disclosed by Eliel and Wilen,
"Stereochemistry of
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Organic Compounds", John Wiley & Sons, Inc., 1994, Chapter 7, Separation of
Stereoisomers. Resolution. Racemization, and by Collet and Wilen,
"Enantiomers,
Racemates, and Resolutions", John Wiley & Sons, Inc., 1981. For example, the
specific
stereoisomers and enantiomers can be prepared by stereospecific syntheses
using
enantiomerically and geometrically pure, or enantiomerically or geometrically
enriched
starting materials. In addition, the specific stereoisomers and enantiomers
can be resolved
and recovered by techniques such as chromatography on chiral stationary
phases,
enzymatic resolution or fractional recrystallization of addition salts formed
by reagents
used for that purpose.
As used herein the term "Pg" refers to a suitable nitrogen protecting group.
Examples of a suitable nitrogen protecting group as used herein refers to
those groups
intended to protect or block the nitrogen group against undesirable reactions
during
synthetic procedures. Choice of the suitable nitrogen protecting group used
will depend
upon the conditions that will be employed in subsequent reaction steps wherein
protection
is required, and is well within the knowledge of one of ordinary skill in the
art.
Commonly used nitrogen protecting groups are disclosed in Greene, "Protective
Groups
In Organic Synthesis," (John Wiley & Sons, New York (1981)). Suitable nitrogen
protecting groups comprise acyl groups such as formyl, acetyl, propionyl,
pivaloyl, t-
butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
phthalyl, o-
2 0 nitrophenoxyacetyl, .alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-
bromobenzoyl, 4-
nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-
toluenesulfonyl and
the like; carbamate forming groups such as benzyloxycarbonyl, p-
chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-
nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-
dimethoxybenzyloxycarbonyl,
2 5 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-
methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-
trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl,
.alpha.,.alpha.-
dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-
butyloxycarbonyl,
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,
methoxycarbonyl,
3 0 allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-
nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,
adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like;
alkyl
groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and
silyl groups
such as trimethylsilyl and the like. Preferred suitable nitrogen protecting
groups are
3 5 formyl, acetyl, methoxycarbonyl, benzoyl, pivaloyl, t-butylacetyl,
phenylsulfonyl, benzyl,
t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
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As used herein the term "(C1-C4)alkyl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but
is not
limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term "(CI-C6)alkyl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but
is not
limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-
pentyl, n-hexyl,
and the like.
As used herein the term "(C1-Clo)alkyl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes,
but is not
limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary
butyl, pentyl,
isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-
methyl-2-hexyl,
octyl, 4-methyl-3-heptyl and the like.
As used herein the term "(C1-C2o)alkyl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes,
but is not
limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
pentyl, isopentyl,
hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-
undecyl, n-
dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-
nonadecyl, n-
eicosyl and the like. It is understood that the terms "(Cl-C4)alkyl", "(C1-
C6)alkyl", and
"(C1-CIO)alkyl" are included within the definition of "(C1-C2o)alkyl".
2 0 As used herein, the terms "Me", "Et", "Pr", "iPr", "Bu" and "t-Bu" refer
to methyl,
ethyl, propyl, isopropyl, butyl and tart-butyl respectively.
As used herein, the term "(C1-C4)alkoxy" refers to an oxygen atom bearing a
straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon
atoms and
includes, but is not limited to methyoxy, ethyoxy, n-propoxy, isopropoxy, n-
butoxy, and
2 5 the like.
As used herein the term "(C1-C6)alkoxy" refers to an oxygen atom bearing a
straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon
atoms and
includes, but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-
butoxy, n-
pentoxy, n-hexoxy, and the like.
3 0 As used herein, the term "(CI-C6)alkyl(C1-C6)alkoxy" refers to a straight
or
' branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which
has a (C1-
C6)alkoxy group attached to the aliphatic chain.
As used herein, the terms "Halo", "Halide" or "Hal" refer to a chlorine,
bromine,
iodine or fluorine atom, unless otherwise specified herein.
3 5 As used herein the term "(Ca-C6)alkenyl" refers to a straight or branched,
monovalent, unsaturated aliphatic chain having from two to six carbon atoms.
Typical
Ca-C6 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, l-
methyl-1-
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propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-
butenyl,
2-pentenyl, and the like.
As used herein, the term "aryl" refers to a monovalent carbocyclic group
containing one or more fused or non-fused phenyl rings and includes, for
example,
phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and
the like.
The term "substituted aryl" refers to an aryl group substituted with one or
two moieties
chosen from the group consisting of halogen, hydroxy, cyano, nitro, (C1-
C6)alkyl, (C1-
C4)alkoxy, (C~-C6)alkyl(C3-C1o)cycloalkyl, (C1-C6)alkylaryl, (C1-
C6)alkoxycarbonyl,
protected carboxy, carboxymethyl, hydroxymethyl, amino, arninomethyl, or
trifluoromethyl.
As used herein, the term "(C1-C6)alkylaryl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an aryl
group
attached to the aliphatic chain. Included within the term "C1-C6 alkylaryl"
are the
following:
' _ ;
/ ~ ~ ~ / ' / ~ ' ~ /
and.the like.
As used herein, the term "aryl(Cl-C6 )alkyl" refers to an aryl group which has
a
straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon
atoms
attached to the aryl group. Included within the term "aryl(C1-C6 )alkyl" are
the following:
' ' ~ ~ '
and the like.
As used herein the term "(C3-Clo)cycloalkyl" refers to a saturated hydrocarbon
ring structure composed of one or more fused or unfused rings containing from
three to
ten carbon atoms. Typical C3-Clo cycloalkyl groups include cyclopropyl,
cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantanyl, and the like.
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As used herein, the term "C1-C6 alkyl(C3-Clo)cycloalkyl" refers to a straight
or
branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms.which
has a (C3-
Clo)cycloalkyl attached to the aliphatic chain. Included within the term "C1-
C6 alkyl(C3-
C10)cycloalkyl" are the following:
a
a
a
' r
' '
'
s a
a
i .
s a
a
' '
a s
s
and the like.
As used herein, the term "(Cl-C6) alkoxycarbonyl" refers to a carbonyl group
having a (C1-C6)alkyl group attached to the carbonyl carbon through an oxygen
atom.
Examples of this group include t-buoxycarbonyl, methoxycarbonyl, and the like.
As used herein the term "heterocycle" refers to a five- or six-membered ring,
which contains one to four heteroatoms selected from the group consisting of
oxygen,
sulfur, and nitorgen. The remaining atoms of the ring are recognized as carbon
by those
of skill in the art. Rings may be saturated or unsaturated. Examples of
heterocycle
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groups include thiophenyl, furyl, pyrrolyl, imidazolyl, pyrrazolyl, thiazolyl,
thiazolidinyl,
isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl,
tetrazolyl, pyridyl,
pyrimidyl, pyrazinyl, pyridiazinyl, triazinyl, imidazolyl, dihydropyrimidyl,
tetrahydropyrimdyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl,
pyrimidinyl,
imidazolidimyl, morpholinyl, pyranyl, thiomorpholinyl, and the like. The term
"substituted heterocycle" represents a heterocycle group substituted with one
or two
moieties chosen from the group consisting of halogen, hydroxy, cyano, nitro,
oxo, (C1-
C6)alkyl, (C1-C4)alkoxy, C1-C6 alkyl(C3-Clo)cycloalkyl, (Cl-C6)alkylaryl, (Cl-
C6)alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino,
aminomethyl, or trifluoromethyl.
As used herein the term "N,N-C1-C6 dialkylamine" refers to a nitrogen atom
substituted with two straight or branched, monovalent, saturated aliphatic
chains of 1 to 6
carbon atoms. Included within the term "N,N-C1-C6 dialkylamine" are -N(CH3)a, -
N(CH2CH3)2, -N(CH2CHZCH3)~, -N(CH2CHZCH2CH3)2, and the like.
As used herein the term "C1-C6alkyl-N,N-C1-C6dialkylamine" refers to straight
or
branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which
has an N,N-
C1-C6 dialkylamine attached to the aliphatic chain. Included within the term
"C1-Cs
alkyl-N,N-C1-C6 dialkylamine" are the following:
~ ,~~Nw '
~N ,~N~ , ~~N '
I ' ~ I
N .~', N~ '
' '
2 0 and the like.
As used herein the term "(Cl-C6)alkyl-pyrrolidine" refers to a straight or
branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a
pyrrolidine
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attached to the aliphatic chain. Included within the scope of the term "(C1-
C6)alkyl-
pyrrolidine" are the following:
,
'~ N
~ N , ~. N
, ~ ,
, ~ N
,~,!~/~ N , ,. NV , ,. ,
and the like.
As used herein the term "(Cl-C6)alkyl-piperidine" refers to a straight or
branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a
piperidine
attached to the aliphatic chain. Included within the scope of the term "(CI-
C6)alkyl-
piperidine" are the following:
~'~ N
, ~. N
~N
N
,, ,
~~ N~ ~ ~. N ~, ,
and the like.
As used herein the term "(C1-C6)alkyl-morpholine" refers to a straight or
branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which
has a
morpholine attached to the aliphatic chain. Included within the scope of the
term "C1-C6
alkyl-morpholine" are the following:
,:~N~ , ~O , ,~N
J '~ ,
o J
J . .. N
~~N ~~. N
, , ~ , , ,
arid the like.
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The designation " 'r"~ " refers to a bond that protrudes forward out of the
plane
of the page.
The designation " "' ~ ~ ~ t i I I " refers to a bond that protrudes backward
out of the
plane of the page.
As used herein the term "iGluRS" refers to the kainate ionotropic glutamate
receptor, subtype 5, of the larger class of excitatory amino acid receptors.
As used herein the term "migraine" refers a disorder of the nervous system
characterized by recurrent attacks of head pain (which are not caused by a
structural bxain
abnormalitiy such as those resulting from tumor or stroke), gasrointestinal
disturbances,
and possibly neurological symptoms such as visual distortion. Characteristic
headaches
of migraine usually last one day and are commonly accompanied by nausea,
emesis, and
photophobia.
Migraine may represent a "chronic" condition, or an "acute" episode. The term
"chronic", as used herein, means a condition of slow progress and long
continuance. As
such, a chronic condition is treated when it is diagnosed and treatment
continued
throughout the course of the disease. Conversely, the term "acute"means an
exacerbated
event or attack, of short course, followed by a period of remission. Thus, the
treatment of
migraine contemplates both acute events and chronic conditions. In an acute
event,
2 0 compound is administered at the onset of symptoms and discontinued when
the symptoms
disappear. As described above, a chronic condition is treated throughout the
course of the
disease.
As used herein the term "patient" refers to a mammal, such a mouse, gerbil,
guinea
pig, rat, dog or human. It is understood, however, that the preferred patient
is a human.
2 5 It is understood that the term "selective iGluRS receptor antagonist" as
used
herein, includes those excitatory amino acid receptor antagonists which
selectively bind to
the iGluRS kainate receptor subtype, relative to the iGluR2 AMPA receptor
subtype.
Preferably the selective iGluRS antagonist for use according to the methods of
the present
invention has a binding affinity at least 10 fold greater for iGluRS than for
iGluR2, more
3 0 preferably at least 100 fold greater. Selective iGluRS receptor
antagonists are readily
available to, or are readily prepared by, one of ordinary skill in the art
following
recognized procedures. For example, WO 98/45270 provides examples of selective
iGIuRS receptor antagonists and discloses methods for synthesis.
As used herein, the terms "treating", "treatment", or "to treat" each mean to
3 5 alleviate symptoms, eliminate the causation of resultant symptoms either
on a temporary
or permanent basis, and to prevent, slow the appearance, or reverse the
progression or
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severity of resultant symptoms of the named disorder. As such, the methods of
this
invention encompass both therapeutic and prophylactic administration.
As used herein the term "effective amount" refers to the amount or dose of the
compound, upon single or multiple dose administration to the patient, which
provides the
desired effect in the patient under diagnosis or treatment. An effective
amount can be
readily determined by the attending diagnostician, as one skilled in the art,
by the use of
known techniques and by observing results obtained under analogous
circumstances. In
determining the effective amount or dose of compound administered, a number of
factors
are considered by the attending diagnostician, including, but not limited to:
the species of
mammal; its size, age, and general health; the degree of involvement or the
severity of the
migraine involved; the response of the individual patient; the particular
compound
administered; the mode of administration; the bioavailability characteristics
of the
preparation administered; the dose regimen selected; the use of concomitant
medication;
and other relevant circumstances.
A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of
each compound used in the present method of treatment. Preferably, daily doses
will be
about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to
about 25
mg/kg.
Oral administration is a preferred route of administering the compounds
employed
2 0 in the present invention whether administered alone, or as a combination
of compounds
capable of acting as a selective iGluRS receptor antagonist. Oral
administration, however,
is not the only route, nor even the only preferred route. Other preferred
routes of
administration include transdermal, percutaneous, intravenous, intramuscular,
intranasal,
buccal, or intrarectal routes. Where the selective iGluRS receptor antagonist
is
2 5 administered as a combination of compounds, one of the compounds may be
administered
by one route, such as oral, and the other may be administered by the
transdermal,
percutaneous, intravenous, intramuscular, intranasal, pulmonary, buccal, or
intrarectal
route, as particular circumstances require. The route of administration may be
varied in
any way, limited by the physical properties of the compounds and the
convenience of the
3 0 patient and the caregiver.
The compounds employed in the present invention may be administered as
pharmaceutical compositions and, therefore, pharmaceutical compositions
incorporating
compounds of Formula I or Formula Ia are important embodiments of the present
invention. Such compositions may take any physical form that is
pharmaceutically
3 5 acceptable, but orally administered pharmaceutical compositions are
particularly
preferred. Such pharmaceutical compositions contain, as an active ingredient,
an effective
amount of a compound of Formula I or Formula Ia, including the
pharmaceutically
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acceptable salts, prodrugs, and hydrates thereof, which effective amount is
related to the
daily dose of the compound to be~ administered. Each dosage unit may contain
the daily
dose of a given compound, or may contain a fraction of the daily dose, such as
one-half or
one-third of the dose. The amount of each compound to be contained in each
dosage unit
depends on the identity of the particular compound chosen for the therapy, and
other
factors such as the indication for which it is given. The pharmaceutical
compositions of
the present invention may be formulated so as to provide quick, sustained, or
delayed
release of the active ingredient after administration to the patient by
employing well
known procedures.
Compositions are preferably formulated in a unit dosage form, each dosage
containing from about 1 to about 500 mg of each compound individually or in a
single
unit dosage form, more preferably about 5 to about 300 mg (for example 25 mg).
The
term "unit dosage form" refers to a physically discrete unit suitable as
unitary dosages for
a patient, each unit containing a predetermined quantity of active material
calculated to
produce the desired therapeutic effect, in association with a suitable
pharmaceutical
carrier, diluent, or excipient.
The inert ingredients and manner of formulation of the pharmaceutical
compositions are conventional. The usual methods of formulation used in
pharmaceutical
science may be used here. All of the usual types of compositions may be used,
including
2 0 tablets, chewable tablets, capsules, solutions, parenteral solutions,
intranasal sprays or
powders, troches, suppositories, transdermal patches and suspensions. In
general,
compositions contain from about 0.5% to about 50% of the compounds in total,
depending on the desired doses and the type of composition to be used. The
amount of
the compound, however, is best defined as the "effective amount", that is, the
amount of
2 5 each compound which provides the desired dose to the patient in need of
such treatment.
The activity of the compounds employed in the present invention do not depend
on the
nature of the composition, hence, the compositions are chosen and formulated
solely for
convenience and economy.
Capsules are prepared by mixing the compound with a suitable diluent and
filling
3 0 the proper amount of the mixture in capsules. The usual diluents include
inert powdered
substances such as starches, powdered cellulose especially crystalline and
microcrystalline
cellulose, sugars such as fructose, mannitol and sucrose, grain flours, and
similar edible
powders.
Tablets are prepared by direct compression, by wet granulation, or by dry
3 5 granulation. Their formulations usually incorporate diluents, binders,
lubricants and
disintegrators as well as the compound. Typical diluents include, for example,
various
types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate,
inorganic salts
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such as sodium chloride and powdered sugar. Powdered cellulose derivatives are
also
useful. Typical tablet binders are substances such as starch, gelatin and
sugars such as
lactose, fructose, glucose and the like. Natural and synthetic gums are also
convenient,
including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the
like.
Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
Tablets are often coated with sugar as a flavor and sealant. The compounds may
also be formulated as chewable tablets, by using large amounts of pleasant-
tasting
substances such as mannitol in the formulation, as is now well-established
practice.
Instantly dissolving tablet-like formulations are also now frequently used to
assure that
the patient consumes the dosage form, and to avoid the difficulty in
swallowing solid
objects that bothers some patients.
A lubricant is often necessary in a tablet formulation to prevent the tablet
and
punches from sticking in the die. The lubricant is chosen from such slippery
solids as
talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable
oils.
Tablet disintegrators are substances which swell when wetted to break up the
tablet and release the compound. They include starches, clays, celluloses,
algins and
gums. More particularly, corn and potato starches, methylcellulose, agar,
bentonite, wood
cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar
gum, citrus
pulp and carboxymethylcellulose, for example, may be used, as well as sodium
lauryl
2 0 sulfate.
Enteric formulations are often used to protect an active ingredient from the
strongly acid contents of the stomach. Such formulations are created by
coating a solid
dosage form with a film of a polymer Which is insoluble in acid environments,
and
soluble in basic environments. Exemplary films are cellulose acetate
phthalate, polyvinyl
2 5 acetate phthalate, hydroxypropyl methylcellulose phthalate and
hydroxypropyl
methylcellulose acetate succinate.
When it is desired to administer the compound as a suppository, the usual
bases
may be used. Cocoa butter is a traditional suppository base, which may be
modified by
addition of waxes to raise its melting point slightly. Water-miscible
suppository bases
3 0 comprising, particularly, polyethylene glycols of various molecular
weights are in wide
use, also.
Transdermal patches have become popular recently. Typically they comprise a
resinous composition in which the drugs will dissolve, or partially dissolve,
which is held
in contact with the skin by a film which protects the composition. Many
patents have
3 5 appeared in the field recently. Other, more complicated patch compositions
are also in
use, particularly those having a membrane pierced with innumerable pores
through which
the drugs are pumped by osmotic action.
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The following table provides an illustrative list of formulations suitable for
use
with the compounds employed in the present invention. The following is
provided only to
illustrate the invention and should not be interpreted as limiting the present
invention in
any way.
Formulation 1
Hard gelatin capsules are prepared using the following ingredients:
~. 0
Quantity
(mg/capsule)
Active Ingredient 250
Starch, dried 200
Magnesium stearate 10
Total 460 mg
The above ingredients are mixed and filled into hard gelatin capsules in 460
mg
quantities.
2 5 Formulation 2
A tablet is prepared using the ingredients below:
Quantity
(mg/tablet)
Active Ingredient 250
3 5 Cellulose, microcrystalline 400
Silicon dioxide, fumed 10
Stearic acid 5
Total 665 mg
The components are blended and compressed to form tablets each weighing 665
mg.
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Formulation 3
An aerosol solution is prepared containing the following components:
Weight %
Active Ingredient 0.25
Ethanol 29.75
Propellant 22 70.00
(Chlorodifluoromethane)
Total 100.00
2 0 The active compound is mixed with ethanol and the mixture added to a
portion of
the Propellant 22, cooled to -30°C and transferred to a filling device.
The required
amount is then fed to a stainless steel container and diluted with the
remainder of the
propellant. The valve units are then fitted to the container.
2 5 Formulation 4
Tablets each containing 60 mg of active ingredient are made as follows:
3 0 Active Ingredient 60.0 mg
Starch 45.0 mg
Microcrystalline cellulose 35.0 mg
Polyvinylpyrrolidone 4.0 mg
Sodium carboxymethyl starch 4.5 mg
3 5 Magnesium stearate ~ 0.5 mg
Talc 1.0 m~
Total 150 mg
The active ingredient, starch, and cellulose are passed through a No. 45 mesh
U.S.
sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with
the
resultant powders which are then passed through a No. 14 mesh U.S. sieve. The
granules
so produced are dried at 50°C and passed through a No. 18 mesh U.S.
sieve. The sodium
carboxymethyl starch, magnesium stearate, and talc, previously passed through
a No. 60
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mesh U.S. sieve, are then added to the granules which, after mixing, are
compressed on a
tablet machine to yield tablets each weighing 150 mg.
Formulation 5
Capsules each containing 80 mg medicament are made as follows:
Active Ingredient ' 80 mg
Starch 59 mg
Microcrystalline cellulose 59 mg
Magnesium stearate 2 m~
Total 200 mg
The active ingredient, cellulose, starch, and magnesium stearate are blended,
passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg
quantities.
2 0 Formulation 6
Suppositories each containing 225 mg of active ingredient may be made as
follows:
2 5 Active Ingredient 225 mg
Saturated fatty acid glycerides 2,000 m~
Total 2,225 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended
in the saturated fatty acid glycerides previously melted using the minimum
heat necessary.
The mixture is then poured into a suppository mold of nominal 2 g capacity and
cooled.
3 5 Formulation 7
Suspensions each containing 50 mg of medicament per 5 ml dose are made as
follows:
4 0 Active Ingredient 50 mg
Sodium carboxymethyl cellulose 50 mg
Syrup 1.25 ml
Benzoic acid solution 0.10 ml
Flavor q.v.
45 Color q.v.
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Purified water to total 5 ml
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the
sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic
acid
solution, flavor and color are diluted with some of the water and added, with
stirring.
Sufficient water is then added to produce the required volume.
Formulation 8
An intravenous formulation may be prepared as follows:
Active Ingredient 100 mg
Mannitol 100 mg
5 N Sodium hydroxide 200 ml
Purified water to total 5 ml
2 0 It is understood by one of ordinary skill in the art that the procedures
as described
above can also be readily applied to a method of treating neurological
disorders or
neurodegenerative conditions, particularly migraine, comprising administering
to a patient
an effective amount of a compound of Formula I or Formula Ia.
Compounds of Formula I and Formula Ia can be prepared, for example, by
2 5 following the procedures set forth in Scheme I. These schemes are not
intended to limit
the scope of the invention in any way. All substituents, unless otherwise
indicated, are
previously defined. The reagents and starting materials are readily available
to one of
ordinary skill in the art. For example, certain necessary starting materials
can be prepared
by one of ordinary skill in the art following procedures disclosed in United
States Patents
3 0 Nos. 5,356,902 (issued October 18, 1994) and 5,446,051 (issued August 29,
1995).
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Scheme I
H H H H H H
,. Step A ~~,,, Step B
'~ pRz ~ \ ~ ---
L9_Fk~l
\ Pg \ Pg R,o
H H
~NH
(1 ) (2)
(3)
Step C
P205, DMSO
a-~a2
(4)
Step D
Deoxofl uor
a-a~Cl-h-a, R.'f.
~ H H
~,,.
\~
Pg
F H
a F (6)
Step G
Step E
deprotect
Step F
F F
Formula I Formula la
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In Scheme I, step A, the 6-(hydroxymethyl)-2-(methoxycarbonyl)-
decahydroisoquinoline-3-carboxylate of compound (1) (wherein Pg is a suitable
nitrogen
protecting group as defined hereinabove, with methoxycarbonyl being preferred)
is treated
under standard conditions with a compound of formula Lg-Hal, wherein Lg is a
suitable
leaving group and Hal represents a chloro, bromo or iodo atom, to provide the
compound
of structure (2). For example, a solution of compound (1), dissolved in a
suitable organic
solvent such as dichloromethane and cooled to 0°C, is treated with an
excess of a suitable
organic base, such as triethylamine, followed by about 1 to 2 equivalents of a
compound
of formula Lg-Hal. Examples of Lg-Hal include m-nitrobenzenesulfonyl chloride,
p-
nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-
toluenesulfonyl
chloride, benzenesulfonyl chloride, methanesulfonyl chloride,
trifluoromethanesulfonyl
chloride, and the like. (In addition, one skilled in the art will appreciate
that a halo atom
itself, such as chloro, bromo, or iodo may also be used as a suitable leaving
group in place
of LgO.) The reaction mixture is warmed to room temperature and stirred for
about 5 to
20 hours. The compound (2) is then isolated using standard procedures. For
example, the
reaction mixture is washed with water, the organic layer separated and dried
over
anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide
crude
compound (2). Column chromatography is then performed with on silica gel with
a
suitable eluent such as 10-50% ethyl acetate/hexane to provide the purified
compound (2).
2 0 In Scheme I, Step B, compound (2) is treated under standard conditions
with a
pyrrolidine of structure (3) to provide the compound of structure (4). For
example,
compound (2) is mixed with about 1-1.5 equivalents of 4-hydroxy-L-proline
ethyl ester
(R3 is ethyl) and 1-1.5 equivalents of potassium carbonate and heated at
reflux in a
suitable solvent such as acetonitrile for about 60-70 hours. The reaction
mixture is cooled
2 5 to room temperature and solvents removed under vacuum. Compound (4) is
then isolated
using standard procedures such as extraction techniques. For example, the
reaction
mixture is partitioned between water and an organic solvent such as diethyl
ether, and the
aqueous layer extracted 2-6 times with diethyl ether. The organic layers are
combined,
dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum
to provide
3 0 compound (4). Compound (4) can then be purified by chromatography on
silica gel with
a suitable eluent such as 10-50% ethyl acetate/hexanes or methanol/chloroform.
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Alternatively in Step B, a pyrrolidine of structure (3) may be combined with a
suitable resin filter cake and the resulting mixture treated with the compound
of structure
(2) to provide the compound of structure (4). For example, Amberlite IRA 67
resin is
treated with water, then stirred and filtered and the filter cake washed with
a suitable
solvent such as acetone until the water content of the wash is less than about
5% by
weight. The filter cake is combined with 4-hydroxy-L-proline ethyl ester
hydrochloride
and acetone and the mixture stirred at RT for about 1-2 hrs. The mixture is
then filtered
and the filter cake washed again with acetone. This filtered solution of
hydroxyproline
ethyl ester may then be used directly. A slurry of Amberlite IRA 67 resin in
water is
stirred and the mixture filtered. The filter cake is washed with a suitable
solvent such as
acetone until the water content of the wash was less than about 5% by weight.
This
second filter cake may then be combined with the hydroxyproline ethyl ester
solution
from above and a solution of compound (2), and the mixture heated at reflux.
After about
24 hours, the reaction is cooled and filtered. The filter cake is washed with
dichloromethane (about 300 mL) and the combined filtrates are concentrated in
vacuo.
The residue may then be concentrated from dichloromethane several times to
provide
compound (4) as an oil to be used directly in the next step.
In Scheme I, Step C, compound (4) is oxidized under standard conditions to
give
2 0 the compound of structure (5). For example, a solution of dichloromethane
is treated with
phosphorus pentoxide an the reaction allowed to cool to about -10 °C.
Dimethyl sulfoxide
is added with stirnng and the reaction mixture is then treated with a solution
of compound
(4) dissolved in dichloromethane. The reaction is warmed to about 20-22
°C over a period
of about 4-5 hours, stirred for about 8-20 hours, cooled to about 0 °C
then treated with
2 5 triethylamine at such a rate so as to maintain the reaction temperature
below about 5°C.
The reaction is allowed to warm to R.T., stirred for about one hour, and then
added to a
solution of O.1M HCl at such a rate so as to maintain the reaction temperature
below
about 10°C. The compound (5) is then isolated using standard
procedures. For example,
additional dichloromethane is added to partition the reaction mixture. The
aqueous layer
3 0 is then extracted 2-6 times with dichloromethane and the organics
combined,washed with
1M NaHC03, dried over magnesium sulfate, then concentrated under vacuum to
provide
compound (5). The crude material may then be purified by chromatography on
silica gel
with a suitable eluent such as 10-50%ethyl acetate in toluene or
methanol/dichoromethane.
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In Scheme I, Step D, compound (5) is flourinated to provide the compound of
structure (6). For example, a solution of compound (5) in ethanol is dissolved
in a
suitable organic solvent such as 1,2-dichloroethane, treated with Deoxofluor
([Bis-(2-
methoxyethyl)amino]sulfur trifluoride) and stirred at R.T for about 20-25
hours. The
reaction mixture is then treated with a concentrated solution of NaHC03 and
stirred for
about 15 minutes. The layers are separated and the aqueous layer extracted 2-6
times with
toluene. The layers are separated and the organics combined, filtered, dried
over Na2S04 ,
and then concentrated under vacuum to provide the compound of structure (6).
The crude
material may then be purified by chromatography on silica gel with a sutiable
eluent such
as (50:50)toluenelheptane and or 10-50% ethyl acetate in toluene.
In Scheme I, Step E, the compound of structure (6) is deprotected under
standard
conditions well known in the art to provide the compound of Formula Ia. For
example,
when Pg is a methoxycarbonyl protecting group, compound (6) is dissolved in a
suitable
organic solvent such as dichloromethane under an atmosphere of nitrogen and
treated
with trimethylsilyl iodide. The reation mixture is allowed to warm to room
temperature
and stirred for 10-20 hours. The reaction is quenched by addition of saturated
aqueous
NaHC03. The aqueous layer is then extracted 2-6 times with dichloromethane.
The
organics are then combined, washed with a 1N solution of sodium thiosulfate,
dried over
magnesium sulfate, filtered, and concentrated under vacuum to provide the
compound of
2 0 Formula Ia. The material may then be purified by chromatography on silica
gel with a
suitable eluent such as methanol/dichoromethane, to provide the purified
compound of
Formula Ia.
In Scheme I, Step F, the compound of Formula Ia may be optionally hydrolyzed
to
the compound of Formula I under conditions well known in the art. For example,
the
2 5 compound of Formula Ia is dissolved in a suitable organic solvent such as
methanol, and
treated with an excess of a suitable base. Examples of suitable bases include
aqueous
lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like with
lithium
hydroxide being preferred. The reaction is stirred for about 10-20 hours. The
reaction
mixture is then neutralized to pH 6 with 1N HCl and concentrated under vacuum
to
3 0 provide the crude compound of Formula I. This material may then be then
purified by
techniques well known in the art, such as chromatography with a suitable
eluent .
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In Scheme I, Step G, compound (6) optionally may be concomitantly deprotected
and hydrolyzed to provide the compound of Formula I. For example, a solution
of
compound (6) dissolved in 6.0N HCl is heated at reflux for about 15-20 hours.
The
reaction mixture is then allowed to cool to room temperature and concentrated
under
vacuum to provide the compound of Formula I. The compound of Formula I may
then
purified by techniques well known in the art, such as cation exchange
chromatography
eluting with methanollwater followed by 2 N ammonia in methanol or ethanol to
provide
the purified compound of Formula I.
In addition, one skilled in the art will recognize that the compound of
Formula I
can be esterified under standard conditions to provide the compound of Formula
Ia. For
example, the compound of Formula I may be dissolved in a suitable organic
solvent such
as ethanol, and treated with an excess of a suitable acid. Examples of
suitable acids
include gaseous hydrochloric acid, aqueous sulfuric acid, p-toluene sulfonic
acid, and the
like with gaseous hydrochloric acid being a preferred acid. The reaction
mixture is heated
to reflux for a suitable time. The reaction mixture may then be concentrated ,
for example,
under vacuum to provide the crude compound,of Formula Ia. This material may
then be
purified by techniques well known in the art, such as canon exchange
chromatography
eluting with methanollwater followed by 2 N ammonia in ethanol to provide the
purified
compound of Formula Ia.
2 0 The Formula I and Formula Ia compounds of the present invention may be
chemically synthesized from a common intermediate, 6-hydroxymethyl-2-
methoxycarbonyl -decahydroisoquinoline-3-carboxylate. This intermediate, in
turn, may
be chemically synthesized from a 6-oxo-2-methoxycarbonyl -
decahydroisoquinoline-3-
carboxylic acid intermediate, the synthesis of which is described in United
States Patents
2 5 No. 4,902,695; No. 5,446,051, and No. 5,356,902 (the entire contents of
which are all
herein incorporated by reference.) '
Routes for the synthesis of the 6-(hydroxymethyl)-2-(methoxycarbonyl)-
decahydroisoquinoline-3-carboxylate intermediate, useful for the synthesis of
the
compounds of the present invention, are shown in Schemes IIa and lIb below.
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Scheme IIa
H N
o Std A H H
\oH .
HZN \ off
Ph3PCH3Br N
H / K-tart-OBU
H
(I-a)
O O
H H H N
..
ORz Step C H~ ~~~ ORz
N N
R2-Br, Et3N \p9 1) BH3, THF \p9
ACN H 2) NaOH, H202 H
(ii) (1)
Scheme IIb
H N H H
Step A
~oH ' o~
-fir,, \
RzBr, Et3N N\p9
H ACN H
(i-b)
0
H N O Step C , H N
Ste[7 B H~'',~ ORz
--~ ~ \ ORz
N 1) BH3, THF
Ph3PCH3Br \ Pg H
K tart-OBu H 2) NaOH, H202
(ii) (1)
In Scheme IIa, Step A, 6-oxo-decahydroisoquinoline-3-carboxylic acid is
treated
with methyltriphenylphosphonium bromide to provide the 6-methylidine-
decahydroisoquinoline-3-carboxylic acid of compound (i-a). For example, a
slurry of 1
equivalent of 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid
and
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about 1.4 equivalents of methyltriphenylphosphonium bromide in THF and DMF is
stirred mechanically under an atmosphere of nitrogen and cooled to -10
°C. Potassium
tent-butoxide solution (2.4 equiv in THF) is added dropwise over a 10 minute
period. The
slurry is allowed to warm to room temperature and stirred thus for 2.5 hours
(complete by
TLC at this time). The reaction is partitioned between water and EtOAc and the
layers
are separated. The organic phase is extracted 2 times with water and the
aqueous portions
are combined and washed 2-6 times with dichloromethane. The aqueous solution
is made
acidic by addition of 6 M HCl solution and extracted 2-6 times with
dichloromethane.
These last three organic extracts are combined, dried with sodium sulfate and
concentrated under reduced pressure to provide the compound of structure (i-
a).
In Scheme IIa, Step B, the intermediate 6-methylidine-decahydroisoquinoline-3-
carboxylic acid (compound (i-a)) is esterified by reaction with a compound of
formula R2-
Br (where RZ is as herein defined) to provide the 6-methylidine-
decahydroisoquinoline-3-
carboxylate intermediate of compound (ii). For example 6-methylidine-2-
methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is dissolved in
acetonitrile and
treated with triethylamine and bromoethane. The reaction is heated at
50°C for about 3
hours, cooled and partitioned between 50:50 ethyl acetatelheptane and 1N HCL.
The
organic phase is isolated and washed 3 times with water, saturated sodium
bicarbonate,
brine, dried over anhydrous sodium sulfate, filtered, and concentrated under
vacuum to
2 0 provide the compound of structure (ii). This crude material is dissolved
in 10% ethyl
acetate/heptane and applied to a plug of silica gel (10 g in 10% ethyl
acetate/heptane).
The plug is eluted with, 10% ethyl acetate/heptane, 15% ethyl acetatelheptane,
and 25%
ethyl acetate/heptane. The eluents are combined and concentrated under vacuum
to
provide the purified compound of structure (ii).
2 5 In Scheme IIa, Step C, the 6-methylidine-decahydroisoquinoline-3-
carboxylate
intermediate (compound (ii)) is subjected to hydroboration, followed by
oxidation to
provide the 6-hydroxymethyl-decahydroisoquinoline-3-carboxylate intermediate
of
compound (1). For example, Ethyl-6-methylidine-2-methoxycarbonyl-
decahydroisoquinoline-3-carboxylate is dissolved in THF and cooled to about -
15°C
3 0 under an atmosphere of nitrogen with stirnng. A 1M solution of BH3~THF is
added
dropwise over 5-7 minutes and the reaction mixture is stirred for about 2
hours at -10 to
12°C. The reaction is then slowly treated with a suitable base, such as
lithium or sodium
hydroxide, and then treated slowly with 30% H202 over 15 minutes. The reaction
mixture
is allowed to warm to room temperature and then partitioned between ethyl
acetate and
3 5 50% saturated sodium chloride solution. The aqueous layer is extracted
with ethyl acetate
and the combined organics are washed with sodium bisulfite solution, brine,
dried over
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anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide
the
intermediate of compound (1).
Alternatively, the 6-hydroxymethyl-2-methoxycarbonyl-decahydroisoquinoline-3-
carboxylate intermediate (compund (1)) may be made according to the synthetic
route
described in Scheme IIb. In Scheme Ilb, Step A, 6-oxo-decahydroisoquinoline-3-
carboxylic acid is esterified by reaction with a compound of formula Ra-Br
(where R2 is
as herein defined) to provide the 6-oxo-decahydroisoquinoline-3-carboxylate
intermediate
of compound (i-b). For example 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-
carboxylic acid is dissolved in acetonitrile and treated with tiethylamine and
bromoethane.
The reaction is heated at 50°C for about 3 hours, cooled and
partitioned between 50:50
ethyl acetate/heptane and 1N HCL. The organic phase is isolated and washed 3
times
with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium
sulfate,
filtered, and concentrated under vacuum to provide the compound of structure
(i-b). This
crude material is dissolved in 10% ethyl acetate/heptane and applied to a plug
of silica gel
(10 g in 10% ethyl acetate/heptane). The plug is eluted with, 10% ethyl
acetate/heptane,
15% ethyl acetate/heptane, and 25% ethyl acetate/heptane. The eluents are
combined and
concentrated under vacuum to provide the purified compound of structure (i-b).
In Scheme IIb, Step B, the 6-oxo-decahydroisoquinoline-3-carboxylate
intermediate of compound (i-b) is treated with methyltriphenylphosphonium
bromide to
2 0 provide the 6-methylidine-decahydroisoquinoline-3-carboxylate of compound
(ii). For
example a slurry of 1 equivalent of 6-oxo-2-methoxycarbonyl-
decahydroisoquinoline-3-
carboxylate (compound (i-b)) and about 1.4 equivalents of
methyltriphenylphosphonium
bromide in THF and DMF is stirred mechanically under an atmosphere of nitrogen
and
cooled to -10 °C. Potassium tent-butoxide solution (2.4 equiv in THF)
is added dropwise
2 5 over a 10 minute period. The slurry is allowed to warm to room temperature
and stirred
thus for 2.5 hours (complete by TLC at this time). The reaction is partitioned
between
water and EtOAc and the layers are separated. The organic phase is extracted 2
times
with water and the aqueous portions are combined and washed 2-6 times with
dichloromethane. The aqueous solution is made acidic by addition of 6 M HCl
solution
3 0 and extracted 2-6 times with dichloromethane. These last three organic
extracts are
combined, dried with sodium sulfate and concentrated under reduced pressure to
provide
the compound of structure (ii).
In Scheme ICb, Step C, following the procedures as described in Scheme IIa,
Step
C above, the 6-methylidine-decahydroisoquinoline-3-carboxylate intermediate
(compound
3 5 (ii)) is subjected to hydroboration, followed by oxidation to provide the
6-hydroxymethyl-
decahydroisoquinoline-3-carboxylate intermediate of compound (1).
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The following preparations and examples illustrate the compounds and methods
of
the present invention. The reagents and starting materials are readily
available to one of
ordinary skill in the art. These examples are intended to be illustrative only
and are not to
be construed so as to limit the scope of the invention in any way. As used
herein, the
following terms have the meanings indicated: "i.v." refers to intravenously;
"p.o." refers
to orally; "i.p." refers to intraperitoneally; "eq" or "equiv." refers to
equivalents; "g"
refers to grams; "mg" refers to milligrams; "L" refers to liters; "mL" refers
to milliliters;
"~,L," refers to microliters; "mol" refers to moles; "mmol" refers to
millimoles; "psi"
refers to pounds per square inch; "mm Hg" refers to millimeters of mercury;
"min" refers
to minutes; "h" or "hr" refers to hours; "°C" refers to degrees
Celsius; "TLC" refers to
thin layer chromatography; "HPLC" refers to high performance liquid
chromatography;
"Rf" refers to retention factor; "RI" refers to retention time; "b" refers to
part per million
down-field from tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF"
refers to
N,N-dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "aq" refers to
aqueous;
"EtOAc" refers to ethyl acetate; "iPrOAc" refers to isopropyl acetate; "MeOH"
refers to
methanol; "MTBE" refers to tent-butyl methyl ether; "RT" refers to room
temperature;
"Ki" refers to the dissociation constant of an enzyme-antagonist complex and
serves as an
index of ligand binding; and ")D50" and "m100" refer to doses of an
administered
therapeutic agent which produce, respectively, a 50 °Io and 100%
reduction in a
2 0 physiological response.
Preparation 1
Preparation of [3S,4aR,6S,8aR]-6-methylidine-2-(methoxycarbonyl)-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
H H O
~~OH
N OMe
H
O
A slurry of methyltriphenylphosphonium bromide (12.4 g, 34.6 mmol) in THF (25
mL) is cooled to -10 to -12°C under an atmosphere of nitrogen and
treated with sodium
3 0 hexamethyldisilazide (35 mL of a 1M solution in THF) via syringe over 6 to
8 minutes
with stirnng. The reaction mixture is then stirred for 20 minutes at -10 to -
12°C and
added via cannula over 3-4 minutes to [3S,4aR,6S,8aR]-6-oxo-2-
(methoxycarbonyl)-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (10.0 g, 26.6
mmol),
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[which had previously been treated with sodium hexamethyldisilazide (27 mL of
1 M
solution in THF) at 0-3°C and stirred for 10 minutes] dissolved in DMF
(20 mL) and
cooled to 0-3°C under an atmosphere of nitrogen. This is followed by a
THF (3 mL) rinse
of the flask holding the Wittig reagent which is also added to the reaction
mixture. The
reaction mixture is then allowed to stir for 5 minutes at 0-3°C, then
allowed to warm to
room temperature, and stirred for an additional 3 hours. Ethyl acetate (100
mL) and water
(50 mL) are added with stirring and then the layers are separated. The organic
layer is
extracted with water (50 mL) and the combined aqueous portions are washed with
methylene chloride (5 X 75 mL). The aqueous isthen treated with 6M HCl (15 mL)
and '
extracted with methylene chloride (3 X 50 mL). The organic extracts are dried
over
anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide
the title
compound (6.59 g, 98%) as a yellow oil.
Alternative synthesis of [3S,4aR,6S,8aR]-6-methylidine-2-(methoxycarbonyl)-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
A slurry of [3S,4aR,6S,8aR]-6-oxo-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid (50.0 g, 0.133 mol, 1.0 equiv) and
methyltriphenylphosphonium bromide (66.4 g, 0.186 mol, 1.4 equiv) in THF (150
mL)
2 0 and DMF (25 mL) is stirred mechanically under an atmosphere of nitrogen
and cooled to
-10 °C. Potassium tart-butoxide solution (187 mL of 1.7 M in THF, 0.319
mol, 2.4
equiv) is added dropwise over a 10 minute period. A mild exotherm throughout
this
addition results in an increase of the reaction temperature to 6 °C.
The slurry is allowed
to warm to room temperature and stirred thus for 2.5 hours (complete by TLC at
this
2 5 time). Reaction is partitioned between water (250 mL) and EtOAc (250 mL)
and the
layers are separated. The organic phase is extracted with water (2 X 100 mL)
and the
aqueous portions are combined and washed with dichloromethane (5 X 300 mL).
The
aqueous solution is made acidic by addition of 6 M HCl solution (50 mL) and
extracted
with dichloromethane (3 X 150 mL). These last three organic extracts are
combined,
3 0 dried with sodium sulfate and concentrated under reduced pressure to
provide the title
compound as a yellow film (36.17 g). Estimated potency of the product by
proton NMR
is 89 wt% (remainder residual solvents) for a corrected yield of 32.2 g
(95.6%).
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Preparation 2
Preparation of [3S,4aR,6S,8aR]-Ethyl-6-methylidine-2-(methoxycarbonyl)-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
H H O
~~ OEt
N OMe
H
[3S,4aR,6S,8aR]-6-methylidine-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid (6.59 g, 26.0 mmol, prepared in
preparation 1) is
dissolved in acetonitrile (26 mL) and treated with triethylamine (7.25 mL, 52
mmol) and
bromoethane (5.82 mL, 78 mmol). The reaction is heated at 50°C fox
about 3 hours,
cooled and partitioned between 50:50 ethyl acetate/heptane (100 ml) and 1N HCL
(75
mL). The organic phase is isolated and washed with water (3 X 30 mL),
saturated sodium
bicarbonate (30 mL), brine (30 mL), dried over anhydrous sodium sulfate,
filtered, and
concentrated under vacuum to provide the crude title compound as an amber oil.
This
crude material is dissolved in 10% ethyl acetate/heptane (15 mL) and applied
to a plug of
silica gel (10 g in 10% ethyl acetate/heptane). The plug is eluted with 10%
ethyl
acetate/heptane (10 mL), 15% ethyl acetate/heptane (15 mL), and 25% ethyl
acetate/heptane (90 mL). The eluents are combined and concentrated under
vacuum to
provide the purified titled compound (6.84 g, 91 %) as a colorless oil.
2 0 Pr~aration 3
Preparation of [3S,4aR,6S,8aR]-Ethyl-6-(hydroxymethyl)-2-(methoxycarbonyl)-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
H H H O
HO~ ~~' OEt
N OMe
H
O
[3S,4aR,6S,8aR]-Ethyl-6-methylidine-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylate (2.0 g, 7.11 mrnol, prepared in
preparation 2) is
dissolved in THF (10 mL) and heptane (2 ~,) and cooled to about -15°C
under an
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atmosphere of nitrogen with stirring. A 1M solution of BH3~THF in THF (3.91
mL, 3.91
mmol) is added dropwise over 5-7 minutes and the reaction is stirred for about
2-4 hours
at -10 to -14°C. The reaction is treated with ethanol (1.25 mL) over 2
minutes then
allowed to warm to 20°C. The reaction is then treated slowly with 1M
LiOH solution
(3.91 mL), followed by slow addition of 30% H2O2 (1.2 mL addition at such a
rate that
the reaction temperature remains below 30°C). The reaction mixture is
allowed stir at
room temperature for 30-45 minutes and then partitioned between ethyl acetate
(12 mL)
and 10% sodium bisulfite solution (14 mL). The organic layer is washed with
10%
sodium bisulfite solution (16 mL), brine (8 mL), dried over anhydrous sodium
sulfate,
filtered, and concentrated under vacuum to provide the title compound (2.01 g)
as a
colorless oil.
EXAMPLE 1
3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-
difluoropyrrolidinyl)methyl)-l,
2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate ~ D-(-)-
mandelic acid
Et0 O
Et
~ D - (-) - mandelic acid
F
F H
A. Preparation of
O Chiral
--N
O w ~ .O H O
S.O~-,,,
O r
N~O~
H O
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A solution of [3S,4aR,6S,8aR]-Ethyl-6-(hydroxymethyl)-2-(methoxycarbonyl)-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (37.5 g, 0.125 mol)
and
triethylamine (35.0 mL, 0.25 mol) in EtOAc (94 mL) is added dropwise to a
solution of p-
nitrobenzenesulfonyl chloride (28.6 g, 0.125 mol) in EtOAc (94 mL) maintained
at 0-2° C
(addition time: 30.min.). Reaction is allowed to warm to RT and stirred for
about 2.5 hr
then quenched by addition of water (100 mL), 1M HCl (100 mL) and brine (20
mL). The
layers are separated and the organic phase washed with 1M NaHC03 solution (150
mL),
brine (150 mL) and dried over MgS04. Concentration in vacuo provides the title
compound as an oil (58.9 g, 97%). 1H NMR (CDC13) 88.41 (2H, d), 8.05 (2H, d),
4.38 (t,
1H), 4.17 (m, 2H), 3.97 m, 2H), 3.69 (s, 3H), 3.39 (m, 2H), 2.12 (m, 1H), 1.85
(m, 3H),
1.55 (m, 5H), 1.25 (m, 5H).
B. Preparation of
Chiral
O " !
O\
Amberlite IRA 67 resin (334.7 g) is treated with water (about 680 mL) and
stirred.
The mixture is filtered and the filter cake is washed with acetone until the
water content
of the wash is less than 5% by weight. This filter cake is combined with
hydroxyproline
2 0 ethyl ester HCI, 72.7 g, 0.372 mol) and acetone (700 mL) and the mixture
stirred at RT
for about 1-2 hrs. The mixture is filtered and the filter cake is washed with
acetone (300
mL). This filtered solution of hydroxyproline ethyl ester is used directly. A
slurry of
Amberlite IRA 67 resin (465 g) in water (about 900 mL) is stirred and then the
mixture is
filtered. The filter cake is washed with acetone until the water content of
the wash is less
2 5 than 5% by weight. This filter cake is combined with the hydroxyproline
ethyl ester
solution from above and a solution of the compound from Step A above (100 g,
0.206
mol) in EtOAc (about 150 mL) and the mixture is heated at reflux. After about
24 hours,
the reaction is cooled and filtered. The filter cake is washed with
dichloromethane (about
300 mL) and the combined filtrates are concentrated ifz vacuo and the residue
is
3 0 concentrated from dichloromethane several times to provide the title
compound as an oil
to be used directly in the next step.
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C. Preparation of
O O~ O Chiral
H
N~~~''' O
N~O
O H
O~
Dichloromethane (about 230 mL) is treated with phosphorous pentoxide (117.2 g,
0.825 mol) and the mixture is cooled to about -10° C. Dimethyl
sulfoxide (96.8 g, 1.24
mol) is added to the mixture at such a rate that the reaction temperature
remains at about -
10° C. The reaction is stirred at about -10° C and treated with
a solution of the compound
of Step B above in dichloromethane (about 230 mL) at such a rate that the
reaction
temperature remains below about -10° C. The reaction is warmed to about
20-22° C over
a few hours (4-5) and stirred overnight then cooled to about 0° C and
treated with
triethylamine (83.5 g, 0.825 mol) at such a rate that the reaction temperature
remains
below 5° C. The reaction is allowed to warm to RT and stirred fox 1
hour. The reaction is
added to a O.1M HCl solution (about 460 mL pre-cooled to about 0-5° C)
at such a rate
that the reaction temperature remains below 10° C. Additional
dichloromethane (about
460 mL) is added and the mixture is stirred briefly and the layers separated.
The aqueous
portion is extracted with dichloromethane (about 460 mL) and the combined
organic
extracts are washed with 1M NaHC03 (about 460 mL). The layers are separated
and the
organic layer is dried over magnesium sulfate and concentrated in vacuo. The
crude
2 0 product is purified by chromatography using Silica Gel 60 and 35% EtOAc in
toluene to
provide the title compound as an oil (36.9 g, 41 % from 504476). 1H NMR
(CDCl3) 54.39
(t, 1H), 4.18 (m, 4H), 3.72 (m, 1H), 3.70 (s, 3H), 3.40 (m, 3H), 3.00 (d, 1H),
2.40-2.69
(m, 4H), 2.08 (m, 1H), 1.45-1.95 (m, 9H), 1.30 (m, 6H), 1.10 (m, 1H).
30
D. Preparation of
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Chiral
O
O H O
N~'~~,,.
N O~ ,
F F H O
A solution of the compound from Step C above (8.98 g, 0.0205 mol) and ethanol
(0.227 mL, 0.0039 mol) in 1,2-dichloroethane (43 mL) is treated with
Deoxofluor ([Bis-
(2-methoxyethyl)amino~sulfur trifluoride, 6.5 mL, 0.0353 mol) and the reaction
is stirred.
at RT for about 21 hours. The reaction is treated with a saturated solution of
NaHCO3 in
water (60 mL) and the mixture is then stirred for 15 min. The layers are
separated and the
aqueous portion is extracted with toluene (about 45 mL). The layers are
separated and the
toluene and 1,2-dicloroethane solutions combined and dried over Na2S04. The
drying
agent is filtered and the filter cake is washed with toluene (about 30 mL).
The filtrate is
concentrated irz vacuo and the residue is dissolved in 50:50 toluene : heptane
(about 17
mL) and the solution is then applied to a Silica Gel 60 column (43 g in 50:50
toluene
heptane). Column is eluted with 50:50 toluene : heptane (about 230 mL),
toluene (about
430 mL), 10% EtOAc in toluene (about 240 mL) and 20% EtOAc in toluene (about
86
mL). Fractions of eluent containing pure compound are combined and
concentrated in
vacuo to provide the title compound as a syrup (5.79 g, 61%). 1H NMR (CDCl3)
b4-.35
(m, 1H), 4.20 (m, 4H), 3.70 (s, 3H), 3.40 (m, 4H), 2.78 (m, 1H), 2.40-2.65 (m,
3H), 2.30
(m, 1H), 2.15 (m, 1H), 1.70-1.95 (m, 4H), 1.45-1.65 (m, 4H), 1.30 (m, 6H),
1.10 (m, 2H).
2 0 E. Preparation of 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-
difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-
decahydroisoquinoline-3-
carboxylate (free base)
Chiral
Preparation of 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-
difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-
decahydroisoquinoline-3-
carboxylate ~ D=(-)-mandelic acid salt
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Chiral
O O
H O
W',,,.
N
F N
F H
O
O
O
A solution of the compound of Step D above (9.7 g, 0.021 mol) in
dichloromethane
(about 70 mL) and toluene (about 30 mL) is cooled to 0-5° C and treated
with
iodotrimethylsilane (12.7 g, 0.063 mol) dropwise. The reaction is allowed to
warm to RT
and is stirred for about 16 hours then is concentrated in vacuo. The residue
is
concentrated from MTBE (methyl t-butyl ether) several times then is dissolved
in MTBE
(about 70 mL) and toluene (about 30 mL) and is washed with saturated NaHCO3
(about
100 mL), 1N sodium thiosulfate (about 100 mL), and water (about 100 mL). The
organic
layer is concentrated in vacuo and the residue is concentrated from MTBE
several times
and then is dissolved in toluene (about 22 mL) and then is treated with a
solution of D-(-)-
mandelic acid (2.75 g, 0.181 mol) in MTBE (about 33 mL). The mixture is
stirred at RT
for about 2 hours then is cooled to about -15° C and stirred for about
2 hours. The D-(-)-
mandelic acid salt is collected by filtration, washed with cold MTBE (about 73
mL at
about -15° C) and is dried to a crystalline solid (8.25 g, 71 %). 1H
NMR (DMSOd6)
X7.16-7.38 (m, 5H), 4.72 (s, 1H), 4.12 (m, 4H), 3.65 (m, 1H), 3.51 (m, 1H),
3.33 (m, 1H),
2.25-2.91 (m, 8H), 1.85 (m, 2H), 1.70 (m, 2H), 1.34-1.86 (m, 5H), 1.15-1.38
(m, 7H),
0.81 (m, 1H).
.
EXAMPLE 2
Preparation of 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-
difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-
decahydroisoquinoline-3-
2 5 ' carboxylate ~ 1,5-naphthalene disulfonic acid
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Et0 O
\N
~ 1,5 -naphthalenedisulfonic acid
tetrahydrate
F
F H
A solution of 1,5-naphthalenedisulfonic acid tetrahydrate (1.1 g, 3.05 mmol)
in
refluxing ethanol (about 5 mL) is treated with a solution of 3S, 4aR, 6S, 8aR
Ethyl 6-
(((ZS)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-l, 2, 3, 4, 4a, 5,
6, 7, 8, 8a-
decahydroisoquinoline-3-carboxylate (the free base diester compound from
Example 1,
Step E above) (1.2 g, 3.0 mmol) in ethanol (about 5 mL) and the mixture is
heated at
reflux until crystals began to form (about 5 minutes). Reaction is cooled and
allowed to
stand at RT for about 3 days. Product is collected by filtration, washed with
ethanol (3 X
5 mL) and~dried (2.0 g, 96%). Product can be recrystallized from water or
methanol.
EXAMPLE 3
Preparation of 3S, 4aR, 6S, 8aR 6-(((2S)-2-(Carboxylic acid)-4,4-
difluoropyrrolidinyl)methyl)-l, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-
decahydroisoquinoline-3-
carboxylic Acid ~ dihydrochloride
H O
~N OH
2 HCI
F
F H
Preparation of 3S, 4aR, 6S, 8aR 6-(((2S)-2-(Carboxylic acid)-4,4-
difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-
decahydroisoquinoline-3-
carboxylic Acid (free base)
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H O
'N OH
F
F H
A mixture of the compound from Example 1, Step D above (16.3 g, 0.0353 mol)
and 6M HCl (170 mL) is heated to reflux and the distillate from the reaction
(about 15
mL) is collected over a period of 3 hours. The reaction is cooled and washed
with
dichloromethane (2 X 50 mL) then is treated with activated charcoal (about 8
g) and is
then stirred at 60° C for 30 min. The mixture is cooled and filtered
through a pad of
Hyflo. The Filter cake is washed with water (about 50 mL) and the aqueous
filtrates are
combined and concentrated in vacuo to a solid (14.2 g). This solid (8.61 g,
61% of the
amount obtained) is concentrated from 2-propanol then is treated with 2-
propanol (about'
43 mL) and the mixture is heated at 50° C for 1 hour. The mixture is
cooled to about 0° C
and stirred for 30 min. Solid is collected by filtration, washed with cold 2-
propanol (20
mI,), and dried to a white powder (7.5 g), which is the dihydrochloride salt
of the title
compound. This powder (2.5 g, 33.3% of the amount obtained) is treated with 1N
NaOH
solution (11.9 mL) and the solution is then concentrated in vacuo. The residue
is
concentrated from EtOH then is treated with 50:50 EtOH:EtOAc. The mixture is
warmed
to about 35°C, then is cooled to RT and stirred for l.hour , then is
filtered. The filter
cake is washed with 50:50 EtOH:EtOAc (5 mL) and the combined filtrates are
2 0 concentrated to a foam. The foam is concentrated from EtOAc then is
treated with
EtOAc (10 mL) and stirred. The free base of the title compound is collected by
filtration
and is dried to a powder (1.96 g, potency corrected). Yield calculation for
free base: 1.96
g divided by 0.333 divided by 0.61 = 9.65 g or 79%. 1H NMR (D2O + DCl) 04.55
(t,
1H), 4.07 (m, 1H), 3.83 (m, 1H), 3.65 (rn, 1H), 3.25 (m, 1H), 2.95 (m, 4H),
2.59 (m, 1H),
1.89 (m, 3H), 1.77 (m, 1H), 1.65 (m, 1H), 1.46 (m, 3H), 1.35 (d, 1H), 1.20 (m,
1H), 0.84
(m, 1H).
EXAMPLE 4
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To establish that the iGluRS receptor subtype is mediating neurogenic protein
extravasation, a functional characteristic of migraine, the binding affinity
of the panel
compounds to the iGluRS receptor is first measured using standard methods. For
example, the activity of compounds acting at the iGluRS receptor antagonists
can be
determined by radiolabelled ligand binding studies at the cloned and expressed
human
iGluRS receptor (Korczak et al., 1994, Recept. Channels 3; 41-49), and by
whole cell
voltage clamp electrophysiological recordings of currents in acutely isolated
rat dorsal
root ganglion neurons (Bleakman et al., 1996, Mol. Pharmacol. 49; 581-585).
The
selectivity of compounds acting at the iGluRS receptor subtype can then be
determined by
comparing antagonist activity at the iGluRS receptor with antagonist activity
at other
AMPA and kainate receptors. Methods useful for such comparison studies
include:
receptor-ligand binding studies and whole-cell voltage clamp
electrophysiological
recordings of functional activity at human GIuRI, GluR2,GluR3 and GluR4
receptors
(Fletcher et al., 1995, Recept. Channels 3; 21-31); receptor-ligand binding
studies and
whole-cell voltage clamp electrophysiological recordings of functional
activity at human
GluR6 receptors (Hoo et al., Recept. Channels 2;327-338); and whole-cell
voltage clamp
electrophysiological recordings of functional activity at AMPA receptors in
acutely
isolated cerebellar Purkinje neurons (Bleakman et al., 1996, Mol. Pharmacol.
49; 581-
585) and other tissues expressing AMPA receptors (Fletcher and Lodge, 1996,
Pharmacol.
2 0 Ther. 70; 65-89).
A. iGluRS antagonist binding affinity profiles
Cell lines (HEK293 cells) stably transfected with human iGluR receptors are
employed. Displacement of 3[H] AMPA by increasing concentrations of antagonist
is
2 5 measured on iGluRl , iGIuR2, iGluR3, and iGluR4 expressing cells, while
displacement
of 3[H] kainate (KA) is measured on iGluRS, iGluR6, iGluR7, and KAZ-expressing
cells. Estimated antagonist binding activity (Ki) in p.M, for example, is
determined for
Compounds of Formula I or Formula Ia. As an indicia of selectivity, the ratio
of binding
affinity to the iGluR2 AMPA receptor subtype, versus the binding affinity to
iGluRS
3 0 kainate receptor subtype (Ki at iGluR2 / Ki at ,iGluRS), is also
determined. Compounds
provided by the present invention display a greater binding affinity for
iGluRS (lower Ki)
than that for iGluR2 , preferably at least 10 fold greater for iGluRS than
that for iGluR2,
and more preferably at least 100 fold.
EXAMPLE 5
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The following animal model may be employed to determine the ability of the
compounds of Formula I or Formula Ia to inhibit protein extravasation, an
exemplary
functional assay of the neuronal mechanism of migraine.
Animal Model of Dural Protein Extravasation
A. Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles River
Laboratories (225-325 g) are anesthetized with sodium pentobarbital
intraperitoneally
(65 mg/kg or 45 mg/kg respectively) and are placed in a stereotaxic frame
(David
Kopf Instruments) with the incisor bar set at -3.5 mm for rats or -4.0 mm for
guinea
pigs. Following a midline sagital scalp incision, two pairs of bilateral holes
are drilled
through the skull (6 mm posterially, 2.0 and 4.0 mm laterally in rats; 4 mm
posteriorly
and 3.2 and 5.2 mm laterally in guinea pigs, all coordinates referenced to
bregma).
Pairs of stainless steel stimulating electrodes, insulated except at the tips
(Rhodes
Medical Systems, Inc.), are lowered through the holes in both hemispheres to a
depth
of 9 mm (rats) or 10.5 mm (guinea pigs) from dura.
B. The femoral vein is exposed and a dose of the test compound is injected
intravenously
(i.v.) at a dosing volume of 1m1/Kg or, in the alternative, test compound is
2 0 administered orally (p.o) via gavage at a volume of 2.Oml/Kg .
Approximately 7
minutes post i.v. injection, a 50 mg/Kg dose of Evans Blue, a fluorescent dye,
is also
injected intravenously. The Evans Blue complexes with proteins in the blood
and
functions as a marker for protein extravasation. Exactly 10 minutes post-
injection of
the test compound, the left trigeminal ganglion is stimulated for 3 minutes at
a current
2 5 intensity of 1.0 mA (5 Hz, 4 msec duration) with a Model 273 potentiostat/
galvanostat (EG&G Princeton Applied Research).
C. Fifteen minutes following stimulation, the animals are euthanized by
exsanguination
with 20 mL of saline. The top of the skull is removed to facilitate the
collection of the
3 0 dural membranes. The membrane samples are removed from both hemispheres,
rinsed with water, and spread flat on microscopic slides. Once dried, the
tissues are
coverslipped with a 70% glycerol/water solution.
D. A fluorescence microscope (Zeiss) equipped with a grating monchromator and
a
3 5 spectrophotometer is used to quantify the amount of Evans Blue dye in each
sample.
An excitation wavelength of approximately 535 nm is utilized and the emission
intensity at 600 nm is determined. The microscope is equipped with a motorized
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stage and also interfaced with a personal computer. This facilitates the
computer-
controlled movement of the stage with fluorescence measurements at 25 points
(500
mm steps) on each dural sample. The mean and standard deviation of the
measurements are determined by the computer.
E. The extravasation induced by the electrical stimulation of the trigeminal
ganglion has
an.ipsilateral effect (i.e. occurs only on the side of the dura in which the
trigeminal
ganglion is stimulated). This allows the other (unstimulated) half of the dura
to be
used as a control. The ratio ("extravasation ratio") of the amount of
extravasation in
the dura from the stimulated side, over the amount of extravasation in the
unstimulated side, is calculated. Control animals dosed with only with saline,
yield an
extravasation ratio of approximately 2.0 in rats and apprximately 1.8 in
guinea pigs.
In contrast, a compound which completely prevents the extravasation in the
dura from
the stimulated side yields an extravasation ratio of approximately 1Ø
F . Dose-response curves may be generated for each of the compounds of Formula
I and
Formula Ia and the dose that inhibits the extravasation by 50% (ID50) or 100%
0100) Can then be approximated. The compound 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-
2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7,
8, 8a-
decahydroisoquinoline-3-carboxylate ~ dihydrochloride provides an ID100 of
approximately 0.01 ng/Kg when administerd orally to rats.
30
What is claimed is:
