U.S. patent application number 12/574201 was filed with the patent office on 2010-04-15 for excitatory amino acid receptor antagonists.
Invention is credited to Jose Antonio Martinez-Perez, Thomas Michael Wilson.
Application Number | 20100094014 12/574201 |
Document ID | / |
Family ID | 32714995 |
Filed Date | 2010-04-15 |
United States Patent
Application |
20100094014 |
Kind Code |
A1 |
Martinez-Perez; Jose Antonio ;
et al. |
April 15, 2010 |
EXCITATORY AMINO ACID RECEPTOR ANTAGONISTS
Abstract
The present invention provides novel compounds of Formula (I)
and Formula (I(a)), or the pharmaceutically acceptable salts
thereof; methods for treating neurological disorders and
neurodegenerative diseases, particularly pain and migraine,
comprising administering a compound of Formula (I) or Formula
(I(a)); and processes for preparing compounds of Formula (I) or
Formula (I(a)).
Inventors: |
Martinez-Perez; Jose Antonio;
(S.S. de los Reyes, ES) ; Wilson; Thomas Michael;
(Speedway, IN) |
Correspondence
Address: |
ELI LILLY & COMPANY
PATENT DIVISION, P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Family ID: |
32714995 |
Appl. No.: |
12/574201 |
Filed: |
October 6, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11302869 |
Dec 14, 2005 |
7601738 |
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12574201 |
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10450667 |
Dec 1, 2003 |
7205313 |
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PCT/US01/45857 |
Dec 19, 2001 |
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11302869 |
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Current U.S.
Class: |
546/147 |
Current CPC
Class: |
C07D 401/14 20130101;
C07D 409/14 20130101; C07D 217/26 20130101; C07D 417/14 20130101;
C07D 401/12 20130101 |
Class at
Publication: |
546/147 |
International
Class: |
C07D 217/06 20060101
C07D217/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 5, 2001 |
EP |
01500004.5 |
Claims
1-47. (canceled)
48. A compound of the formula ##STR00086## wherein Pg represents
methoxycarbonyl or t-butoxycarbonyl.
49. The compound according to claim 48 that is
(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-tert-butoxy-
carbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid.
50. The compound according to claim 48 that is
(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-methoxycarb-
onyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
Description
[0001] This is a continuation of U.S. application Ser. No.
11/302,869, filed Dec. 14, 2005, which is a continuation of U.S.
application Ser. No. 10/450,667, filed Jun. 13, 2003, which is a
371 (national filing) of PCT/US01/45857, filed Dec. 19, 2001, which
claims priority to European Patent Application EP01500004.5, filed
Jan. 5, 2001
BACKGROUND OF THE INVENTION
[0002] 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, 365 (1989);
Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. 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.
[0003] Excitatory amino acid receptors are classified into two
general types. Receptors 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),
.alpha.-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA),
and kainic acid (KA). Molecular biological studies have established
that AMPA receptors are composed of subunits
(GluR.sub.1-GluR.sub.4), which can assemble to form functional ion
channels. Five kainate receptors have been identified which are
classified as either High Affinity (KA1 and KA2) or Low Affinity
(composed of GluR.sub.5, GluR.sub.6, and/or GluR.sub.7 subunits).
Bleakman et al., Molecular Pharmacology, 49, No. 4, 581,
(1996).
[0004] The second general type of receptor is the G-protein coupled
or second messenger-linked "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 Pharmacol. Sci., 14, 13 (1993). Both types of excitatory
amino acid receptor appear not only to mediate normal synaptic
transmission along excitatory pathways, but also to participate in
the modification of synaptic connections during development and
throughout life. Schoepp, Bockaert, and Sladeczek, Trends in
Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain
Research Reviews, 15, 41 (1990).
[0005] 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, AIDS-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, tardive
dyskinesia, and psychosis related to depression, schizophrenia,
bipolar disorder, mania, and drug intoxication or addiction (see
generally U.S. Pat. Nos. 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, published International Patent application
WO 98/45720 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.
[0006] 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 particular, migraine.
Moskowitz (Cephalalgia, 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 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 MacIntyre, P. D., et al., British
Journal 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 kainate
subtype of ionotropic glutamate receptors are expressed on rat
trigeminal ganglion neurons, and in particular, high levels of
GluR.sub.5 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.
[0007] 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 GKYI 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 Publication No. 590789A1 and
U.S. Pat. Nos. 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. WO 98/45270 discloses that certain decahydroisoquinoline
derivative compounds are selective antagonists of the iGluR.sub.5
receptor and are useful for the treatment of various types of pain,
including; severe, chronic, intractable, and neuropathic pain.
[0008] In accordance with the present invention, Applicants have
discovered novel compounds that are antagonists of the iGluR.sub.5
receptor subtype and, thus, could be useful in treating the
multitude of neurological disorders or neurodegenerative diseases,
as discussed above. Such 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.
SUMMARY OF THE INVENTION
[0009] The present invention provides a compound of Formula I
##STR00001##
wherein
[0010] Z represents a sulfur or oxygen atom;
[0011] R.sup.1 represents hydrogen, CN,
(C.sub.1-C.sub.4)alkyl-CO.sub.2H, CO.sub.2H, or tetrazole;
[0012] R.sup.2 represents hydrogen, halo, aryl, substituted aryl,
CO.sub.2H, tetrazole, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkylaryl, heterocycle, substituted heterocycle,
CF.sub.3, NHR.sup.3, or O--R.sup.4;
[0013] R.sup.3 represents hydrogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkylaryl, or aryl;
[0014] R.sup.4 represents (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.4)alkylaryl, (C.sub.1-C.sub.4)alkyl-heterocycle,
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.1-C.sub.4)alkyl(substituted)aryl, aryl, or heterocycle;
and
[0015] W, X, and Y each independently represent hydrogen, halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkoxy, aryl, substituted
aryl, CO.sub.2H, CO(NH.sub.2), CF.sub.3, NH-aryl, NH.sub.2, or
NO.sub.2, or optionally, X and R.sup.2 together, or W and X
together, or Y and R.sup.2 together, along with the carbon atoms to
which they are attached, form a benzo-fused group;
[0016] with the proviso that where Z is sulfur, then R.sup.1 is
hydrogen, CO.sub.2H, or tetrazole, R.sup.2 is hydrogen, Halo,
(C.sub.1-C.sub.4)alkyl, or CO.sub.2H, and W, X, and Y are each
hydrogen, Halo, (C.sub.1-C.sub.6)alkyl, CO.sub.2H, or
CO(NH.sub.2);
[0017] or a pharmaceutically acceptable salt or prodrug
thereof.
[0018] 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 a
pharmaceutically acceptable salt or prodrug 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 chronic pain states
including severe pain, intractable pain, neuropathic pain, and
post-traumatic pain.
[0019] More specifically, the present invention provides a method
of treating or preventing pain or migraine comprising administering
to a patient in need thereof an effective amount of a compound of
Formula I, or a pharmaceutically acceptable salt or prodrug
thereof.
[0020] In addition, the present invention provides pharmaceutical
compositions of compounds of Formula I, including the
pharmaceutically acceptable salts, prodrugs, and hydrates thereof,
comprising, a compound of Formula I 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.
[0021] Specifically, The present invention also provides a process
for making compounds of Formula I(a):
##STR00002##
[0022] wherein, [0023] Z represents oxygen [0024] R.sup.5, R.sup.8,
and R.sup.10 each independently represents hydrogen,
(C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkylaryl,
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.1-C.sub.6)alkyl-N,N--C.sub.1-C.sub.6 dialkylamine,
(C.sub.1-C.sub.6)alkyl-pyrrolidine,
(C.sub.1-C.sub.6)alkyl-piperidine, or
(C.sub.1-C.sub.6)alkyl-morpholine; with the proviso that where
R.sup.7 is CO.sub.2R.sup.10; or W', X', or Y' is CO.sub.2R.sup.8,
then at least one, but no more than two of R.sup.5, R.sup.8, and
R.sup.10 is other than hydrogen; [0025] R.sup.6 represents
tetrazole; [0026] R.sup.7 represents hydrogen, halo, aryl,
substituted aryl, CO.sub.2R.sup.10, tetrazole,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylaryl, heterocycle,
substituted heterocycle, CF.sub.3, NHR.sup.3, or OR.sup.4; [0027]
R.sup.3 represents hydrogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkylaryl, or aryl; [0028] R.sup.4 represents
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkylaryl,
(C.sub.1-C.sub.4)alkyl-heterocycle,
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.1-C.sub.4)alkyl(substituted)aryl, aryl, or heterocycle; and
[0029] W', X' and Y' each independently represent hydrogen, halo,
(C.sub.1-C.sub.6)alkyl, CO.sub.2R.sup.8, or CO(NH.sub.2); or
optionally, X' and R.sup.7 together, or W' and X' together, or Y'
and R.sup.7 together, along with the carbon atoms to which they are
attached, form a benzo-fused group; comprising combining a compound
of structure (10):
##STR00003##
[0030] wherein Pg is a suitable nitrogen protecting group,
with a suitable base in a suitable solvent, followed by addition of
a compound of structure (11b):
##STR00004##
[0031] wherein Pg is a suitable nitrogen protecting group; [0032]
R.sup.2 represents hydrogen, halo, aryl, substituted aryl,
CO.sub.2H, tetrazole, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkylaryl, heterocycle, substituted heterocycle,
CF.sub.3, NHR.sup.3, or OR.sup.4; [0033] R.sup.3 and R.sup.4 are as
defined above, and [0034] W, X, and Y each independently represent
hydrogen, halo, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkoxy,
aryl, substituted aryl, CO.sub.2H, CO(NH.sub.2), CF.sub.3, NH-aryl,
NH.sub.2, or NO.sub.2, or optionally, X and R.sup.2 together, or W
and X together, or Y and R.sup.2 together, along with the carbon
atoms to which they are attached, form a benzo-fused group;
followed by esterification to a compound of structure (12b)
[0034] ##STR00005## [0035] wherein Pg, R.sup.5, R.sup.7, W', X',
and Y' are as defined above; followed by removal of the nitrogen
protecting groups, and precipitation with a suitable acid.
[0036] In a further embodiment, the present invention provides yet
another process for synthesizing a compound of Formula I(a):
##STR00006## [0037] wherein, [0038] Z represents oxygen; [0039]
R.sup.5, R.sup.8, and R.sup.10 each independently represents
hydrogen, (C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkylaryl,
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.1-C.sub.6)alkyl-N,N--C.sub.1-C.sub.6 dialkylamine,
(C.sub.1-C.sub.6)alkyl-pyrrolidine,
(C.sub.1-C.sub.6)alkyl-piperidine, or
(C.sub.1-C.sub.6)alkyl-morpholine; with the proviso that where
R.sup.7 is CO.sub.2R.sup.10; or W', X', or Y' is CO.sub.2R.sup.8,
then at least one, but no more than two of R.sup.5, R.sup.8, and
R.sup.10 is other than hydrogen; [0040] R.sup.6 represents
tetrazole; [0041] R.sup.7 represents hydrogen, halo, aryl,
substituted aryl, CO.sub.2R.sup.10, tetrazole,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylaryl, heterocycle,
substituted heterocycle, CF.sub.3, NHR.sup.3, or OR.sup.4; [0042]
R.sup.3 represents hydrogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkylaryl, or aryl; [0043] R.sup.4 represents
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkylaryl,
(C.sub.1-C.sub.4)alkyl-heterocycle,
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.1-C.sub.4)alkyl(substituted)aryl, aryl, or heterocycle; and
[0044] W', X' and Y' each independently represent hydrogen, halo,
(C.sub.1-C.sub.6)alkyl, CO.sub.2R.sup.8, or CO(NH.sub.2); or
optionally, X' and R.sup.7 together, or W' and X' together, or Y'
and R.sup.7 together, along with the carbon atoms to which they are
attached, form a benzo-fused group; comprising combining a compound
of structure (10):
[0044] ##STR00007## [0045] wherein Pg is a suitable nitrogen
protecting group, with a suitable base in a suitable solvent,
followed by addition of a compound of structure (11a):
[0045] ##STR00008## [0046] wherein, [0047] R.sup.2 represents
hydrogen, halo, aryl, substituted aryl, CO.sub.2H, tetrazole,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylaryl, heterocycle,
substituted heterocycle, CF.sub.3, NHR.sup.3, or OR.sub.4; [0048]
R.sup.3 and R.sup.4 are as defined above, and [0049] W, X, and Y
each independently represent hydrogen, halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkoxy, aryl, substituted
aryl, CO.sub.2H, CO(NH.sub.2), CF.sub.3, NH-aryl, NH.sub.2, or
NO.sub.2, or optionally, X and R.sup.2 together, or W and X
together, or Y and R.sup.2 together, along with the carbon atoms to
which they are attached, form a benzo-fused group; followed by
deprotection of the nitrogen group, precipitation with a suitable
acid, and crystallization of the hydrate salt of structure
(12e):
##STR00009##
[0050] wherein R2, W, X, and Y are as defined above;
followed by treatment with a suitable alcohol in the presence
suitable acid to effect the one step esterification and
crystallization of Formula I(a).
[0051] The present invention also provides the use of a compound of
Formula I of Formula I(a) for the manufacture of a medicament for
treating or preventing a neurological disorder, or
neurodegenerative condition.
[0052] More specifically, the present invention provides the use of
a compound of Formula I or Formula I(a) for the manufacture of a
medicament for treating or preventing pain or migraine.
DETAILED DESCRIPTION OF THE INVENTION
[0053] The present invention provides compounds functional as
iGluR.sub.5 receptor antagonists as well as pharmaceutically
acceptable salts, prodrugs, and compositions thereof. These
compounds are useful in treating or preventing neurological
disorders, or neurodegenerative diseases, particularly pain and
migraine. As such, methods for the treatment or prevention of
neurological disorders, or neurodegenerative diseases, are also
provided by the present invention.
[0054] In addition, 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 formulation. As used herein,
the term "prodrug" refers to a compound of Formula I 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 (drug)) as given
by Formula I. Such prodrugs may be, for example, metabolically
labile mono- or di-ester derivatives of the parent compounds having
a carboxylic acid group(s). 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. 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 provided are encompassed in the names of the
compounds herein. Conventional procedures for the selection and
preparation of suitable prodrugs are well known to one of ordinary
skill in the art.
[0055] More specifically, examples of prodrugs of Formula I which
are understood to be included within the scope of the present
invention, are represented by Formulas Ia below:
##STR00010##
wherein
[0056] Z is as defined hereinabove;
[0057] R.sup.5 represents hydrogen, (C.sub.1-C.sub.20)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkylaryl,
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.1-C.sub.6)alkyl-N,N--C.sub.1-C.sub.6 dialkylamine,
(C.sub.1-C.sub.6)alkyl-pyrrolidine,
(C.sub.1-C.sub.6)alkyl-piperidine, or
(C.sub.1-C.sub.6)alkyl-morpholine;
[0058] R.sup.6 represents hydrogen, CN,
(C.sub.1-C.sub.4)alkyl-CO.sub.2R.sup.9, CO.sub.2R.sup.9, or
tetrazole;
[0059] R.sup.7 represents hydrogen, halo, aryl, substituted aryl,
CO.sub.2R.sup.10, tetrazole, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkylaryl, heterocycle, substituted heterocycle,
CF.sub.3, NHR.sup.3, or O--R.sup.4;
[0060] R.sup.3 and R.sup.4 are as defined hereinabove;
[0061] W', X' and Y' each independently represent hydrogen, halo,
(C.sub.1-C.sub.6)alkyl, CO.sub.2R.sup.8, or CO(NH.sub.2); or
optionally, X' and R.sup.7 together, or W' and X' together, or Y'
and R.sup.7 together, along with the carbon atoms to which they are
attached, form a benzo-fused group;
[0062] with the proviso that where Z is sulfur, then R.sup.6 is
hydrogen, CO.sub.2R.sup.9 or tetrazole, R.sup.7 is hydrogen, Halo,
(C.sub.1-C.sub.4)alkyl, or CO.sub.2R.sup.10, and W', X', and Y' are
each independently hydrogen, Halo, (C.sub.1-C.sub.6)alkyl,
CO.sub.2R.sup.9 or CO(NH.sub.2);
[0063] R.sup.8, R.sup.9, and R.sup.10 each independently represent
hydrogen, (C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkylaryl,
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.1-C.sub.6)alkyl-N,N--C.sub.1-C.sub.6 dialkylamine,
(C.sub.1-C.sub.6)alkyl-pyrrolidine,
(C.sub.1-C.sub.6)alkyl-piperidine, or
(C.sub.1-C.sub.6)alkyl-morpholine;
[0064] with the further proviso that where R.sup.6 is
(C.sub.1-C.sub.4)alkyl-CO.sub.2R.sup.9 or CO.sub.2R.sup.9; or
R.sup.7 is CO.sub.2R.sup.10; or W', X', or Y' is CO.sub.2R.sup.8,
then at least one, but no more than two of R.sup.5, R.sup.8,
R.sup.9, and R.sup.10 other than hydrogen;
[0065] or a pharmaceutically acceptable salt thereof.
[0066] It is understood that the iGluR.sub.5 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.
[0067] 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 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.
[0068] 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, methanesulfonic acid,
oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic
acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable salts are the sulfate,
pyrosulfate, bisulfate, sulfite, bisulfate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, bromide, iodide, hydroiodide, dihydroiodide,
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, .alpha.-hydroxybutyrate,
glycolate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate 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
maleic acid, mandelic acid, p-toluenesulfonic acid, and
methanesulfonic acid.
[0069] 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 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.
[0070] 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 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 herein as "epimers". The
terms "racemate", "racemic mixture" or "racemic modification" refer
to a mixture of equal parts of enantiomers.
[0071] 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",
which is found using the following equation:
e e = E 1 - E 2 E 1 + E 2 .times. 100 ##EQU00001##
wherein E.sup.1 is the amount of the first enantiomer and E.sup.2
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% is preferred, an ee of greater than 95% is most preferred and
an ee of greater than 99% 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 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.
[0072] The compounds of the present invention have one or more
chiral centers and may 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.
[0073] 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
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.
[0074] The specific stereoisomers and enantiomers of compounds of
Formula I 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 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.
[0075] 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-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,
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-butoxycarbonyl,
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,
methoxycarbonyl, 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 formyl, acetyl, methyoxycarbonyl, benzoyl, pivaloyl,
t-butylacetyl, phenylsulfonyl, benzyl, t-butyoxycarbonyl (Boc) and
benzyloxycarbonyl (Cbz).
[0076] As used herein the term "(C.sub.1-C.sub.4)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.
[0077] As used herein the term "(C.sub.1-C.sub.6)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.
[0078] As used herein the term "(C.sub.1-C.sub.10)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.
[0079] As used herein the term "(C.sub.1-C.sub.20)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 "(C.sub.1-C.sub.4)alkyl",
"(C.sub.1-C.sub.6)alkyl", and "(C.sub.1-C.sub.10)alkyl" are
included within the definition of "(C.sub.1-C.sub.20)alkyl".
[0080] As used herein, the terms "Me", "Et", "Pr", "iPr", "Bu",
"iBu", and "t-Bu" refer to methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, and tert-butyl respectively.
[0081] As used herein, the term "(C.sub.1-C.sub.4)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 the like.
[0082] As used herein the term "(C.sub.1-C.sub.6)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.
[0083] As used herein, the term
"(C.sub.1-C.sub.6)alkyl(C.sub.1-C.sub.6)alkoxy" refers to a
straight or branched, monovalent, saturated aliphatic chain of 1 to
6 carbon atoms which has a (C.sub.1-C.sub.6)alkoxy group attached
to the aliphatic chain.
[0084] As used herein, the terms "Halo", "Halide" or "Hal" refer to
a chlorine, bromine, iodine or fluorine atom, unless otherwise
specified herein.
[0085] As used herein the term "(C.sub.2-C.sub.6)alkenyl" refers to
a straight or branched, monovalent, unsaturated aliphatic chain
having from two to six carbon atoms. Typical C.sub.2-C.sub.6
alkenyl groups include ethenyl (also known as vinyl),
1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl,
2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl,
and the like.
[0086] 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, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.1-C.sub.6)alkylaryl, (C.sub.1-C.sub.6)alkoxycarbonyl,
protected carboxy, carboxymethyl, hydroxymethyl, amino,
aminomethyl, trifluoromethyl, or trifluoromethoxy.
[0087] As used herein, the term "(C.sub.1-C.sub.6)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 "C.sub.1-C.sub.6
alkylaryl" are the following:
##STR00011##
and the like.
[0088] As used herein, the term
"(C.sub.1-C.sub.4)alky(substituted)laryl" refers to a straight or
branched, monovalent, saturated aliphatic chain of 1 to 6 carbon
atoms which has a "substituted ary" group attached to the aliphatic
chain
[0089] As used herein, the term "aryl(C.sub.1-C.sub.6)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(C.sub.1-C.sub.6)alkyl"
are the following:
##STR00012##
and the like.
[0090] As used herein the term "(C.sub.3-C.sub.10)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 C.sub.3-C.sub.10 cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, adamantanyl, and the like.
[0091] As used herein, the term "C.sub.1-C.sub.6
alkyl(C.sub.3-C.sub.10)cycloalkyl" refers to a straight or
branched, monovalent, saturated aliphatic chain of 1 to 6 carbon
atoms which has a (C.sub.3-C.sub.10)cycloalkyl attached to the
aliphatic chain. Included within the term "C.sub.1-C.sub.6
alkyl(C.sub.3-C.sub.10)cycloalkyl" are the following:
##STR00013## ##STR00014##
and the like.
[0092] As used herein, the term "(C.sub.1-C.sub.6) alkoxycarbonyl"
refers to a carbonyl group having a (C.sub.1-C.sub.6)alkyl group
attached to the carbonyl carbon through an oxygen atom. Examples of
this group include t-butoxycarbonyl, methoxycarbonyl, and the
like.
[0093] 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 nitrogen. 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 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,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkoxy, C.sub.1-C.sub.6
alkyl(C.sub.3-C.sub.10)cycloalkyl, (C.sub.1-C.sub.6)alkylaryl,
(C.sub.1-C.sub.6)alkoxycarbonyl, protected carboxy, carboxymethyl,
hydroxymethyl, amino, aminomethyl, trifluoromethyl, or
trifluoromethoxy. Further, the heterocycle group can be optionally
fused to one or two aryl groups to form a benzo-fused group.
Examples of substituted heterocycle include
1,2,3,4-tetrahydrodibenzeofuranyl, 2-methylbezylfuranyl, and 3,5
dimethylisoxazolyl, and the like.
[0094] As used herein, the term "benzo-fused group" refers to a
phenyl group fused to an aromatic radical or a heterocycle group.
Included within the term "benzo-fused group" are the following:
##STR00015##
and the like, wherein all substituents are as previously defined
hereinabove.
[0095] As used herein, the term "triazole-fused group" refers to a
triazole group fused to an aromatic radical or a heterocycle group.
Included within the term "triazole-fused group" are the
following:
##STR00016##
and the like, wherein all substituents are as previously
defined.
[0096] As used herein the term "N,N--C.sub.1-C.sub.6 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--C.sub.1-C.sub.6 dialkylamine"
are --N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3).sub.2,
--N(CH.sub.2CH.sub.2CH.sub.3).sub.2,
--N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.2, and the like.
[0097] As used herein the term
"C.sub.1-C.sub.6alkyl-N,N--C.sub.1-C.sub.6dialkylamine" refers to
straight or branched, monovalent, saturated aliphatic chain of 1 to
6 carbon atoms which has an N,N--C.sub.1-C.sub.6 dialkylamine
attached to the aliphatic chain. Included within the term
"C.sub.1-C.sub.6 alkyl-N,N--C.sub.1-C.sub.6 dialkylamine" are the
following:
##STR00017##
and the like.
[0098] As used herein the term "(C.sub.1-C.sub.6)alkyl-pyrrolidine"
refers to a straight or branched, monovalent, saturated aliphatic
chain of 1 to 6 carbon atoms which has a pyrrolidine attached to
the aliphatic chain. Included within the scope of the term
"(C.sub.1-C.sub.6)alkyl-pyrrolidine" are the following:
##STR00018##
and the like.
[0099] As used herein the term "(C.sub.1-C.sub.6)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
"(C.sub.1-C.sub.6)alkyl-piperidine" are the following:
##STR00019##
and the like.
[0100] As used herein the term "(C.sub.1-C.sub.6)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
"C.sub.1-C.sub.6 alkyl-morpholine" are the following:
##STR00020##
and the like.
[0101] The designation refers to a bond that protrudes forward out
of the plane of the page.
[0102] The designation refers to a bond that protrudes backward out
of the plane of the page.
[0103] As used herein the term "iGluR.sub.5" refers to the kainate
ionotropic glutamate receptor, subtype 5, of the larger class of
excitatory amino acid receptors.
[0104] 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 brain abnormality such as
those resulting from tumor or stroke), gastrointestinal
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.
[0105] 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, 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.
[0106] 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.
[0107] The term "iGluR.sub.5 receptor antagonist" or "iGluR.sub.5
antagonist", as used herein, refers to those excitatory amino acid
receptor antagonists which bind to, and antagonize the activity of,
the iGluR.sub.5 kainate receptor subtype. As a preferred
embodiment, the present invention further provides selective
iGluR.sub.5 receptor antagonists. "Selective iGluR.sub.5 receptor
antagonist" or "selective iGluR.sub.5 antagonist" as used herein,
includes those excitatory amino acid receptor antagonists which
selectively bind to, and antagonize, the iGluR.sub.5 kainate
receptor subtype, relative to the iGluR.sub.2 AMPA receptor
subtype. Preferably, the "selective iGluR.sub.5 antagonists" for
use according to the methods of the present invention have a
binding affinity at least 10 fold greater for iGluR.sub.5 than for
iGluR.sub.2, more preferably at least 100 fold greater. WO 98/45270
provides examples of selective iGluR.sub.5 receptor antagonists and
discloses methods for synthesis.
[0108] As used herein, the terms "treating", "treatment", or "to
treat" each mean to 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
severity of resultant symptoms of the named disorder. As such, the
methods of this invention encompass both therapeutic and
prophylactic administration.
[0109] 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
disease 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.
[0110] 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.
[0111] Oral administration is a preferred route of administering
the compounds employed in the present invention whether
administered alone, or as a combination of compounds capable of
acting as an iGluR.sub.5 receptor antagonist. Oral administration,
however, is not the only route, nor even the only preferred route.
Other preferred routes of administration include transdermal,
percutaneous, pulmonary, intravenous, intramuscular, intranasal,
buccal, or intrarectal routes. Where the iGluR.sub.5 receptor
antagonist is 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,
pulmonary, intravenous, intramuscular, intranasal, 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 patient and
the caregiver.
[0112] The compounds employed in the present invention may be
administered as pharmaceutical compositions and, therefore,
pharmaceutical compositions incorporating compounds of Formula I
are important embodiments of the present invention. Such
compositions may take any physical form that is pharmaceutically
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, including the pharmaceutically 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.
[0113] 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.
[0114] 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 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 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.
[0115] Capsules are prepared by mixing the compound with a suitable
diluent and filling 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.
[0116] Tablets are prepared by direct compression, by wet
granulation, or by dry 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 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.
[0117] 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.
[0118] 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.
[0119] 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 sulfate.
[0120] 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 acetate phthalate, hydroxypropyl
methylcellulose phthalate and hydroxypropyl methylcellulose acetate
succinate.
[0121] 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 comprising, particularly, polyethylene glycols of
various molecular weights are in wide use, also.
[0122] 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
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.
[0123] 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
[0124] Hard gelatin capsules are prepared using the following
ingredients:
TABLE-US-00001 Quantity (mg/capsule) Active Ingredient 250 Starch,
dried 200 Magnesium stearate 10 Total 460 mg
[0125] The above ingredients are mixed and filled into hard gelatin
capsules in 460 mg quantities.
Formulation 2
[0126] A tablet is prepared using the ingredients below:
TABLE-US-00002 Quantity (mg/tablet) Active Ingredient 250
Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic
acid 5 Total 665 mg
[0127] The components are blended and compressed to form tablets
each weighing 665 mg.
Formulation 3
[0128] An aerosol solution is prepared containing the following
components:
TABLE-US-00003 Weight % Active Ingredient 0.25 Ethanol 29.75
Propellant 22 70.00 (Chlorodifluoromethane) Total 100.00
[0129] The active compound is mixed with ethanol and the mixture
added to a portion of the Propellant 22, cooled to -30.degree. 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.
Formulation 4
[0130] Tablets each containing 60 mg of active ingredient are made
as follows:
TABLE-US-00004 Active Ingredient 60.0 mg Starch 45.0 mg
Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg
Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc
1.0 mg Total 150 mg
[0131] 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.degree. 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 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
TABLE-US-00005 [0132] Capsules each containing 80 mg medicament are
made as follows: Active Ingredient 80 mg Starch 59 mg
Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200
mg
[0133] 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.
Formulation 6
[0134] Suppositories each containing 225 mg of active ingredient
may be made as follows:
TABLE-US-00006 Active Ingredient 225 mg Saturated fatty acid
glycerides 2,000 mg Total 2,225 mg
[0135] 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
allowed to cool.
Formulation 7
[0136] Suspensions each containing 50 mg of medicament per 5 ml
dose are made as follows:
TABLE-US-00007 Active Ingredient 50 mg Sodium carboxymethyl
cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor
q.v. Color q.v. Purified water to total 5 ml
[0137] 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
[0138] An intravenous formulation may be prepared as follows:
TABLE-US-00008 Active Ingredient 100 mg Mannitol 100 mg 5 N Sodium
hydroxide 200 ml Purified water to total 5 ml
[0139] 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 pain and migraine, comprising
administering to a patient an effective amount of a compound of
Formula I.
[0140] Compounds of Formula I and Formula I(a) can be chemically
prepared, for example, by following the synthetic routes set forth
in the Schemes below. However, the following discussion is not
intended to be limiting to the scope of the present invention in
any way. For example, the specific synthetic steps for the routes
described herein may be combined in different ways, or with steps
from different schemes, to prepare the compounds of Formula I and
Formula I(a). All substituents, unless otherwise indicated, are as
previously defined. The reagents and starting materials are readily
available to one of ordinary skill in the art. For example, certain
starting materials can be prepared by one of ordinary skill in the
art following procedures disclosed in U.S. Pat. No. 5,356,902
(issued Oct. 18, 1994) and U.S. Pat. No. 5,446,051 (issued Aug. 29,
1995) and U.S. Pat. No. 5,670,516 (issued Sep. 23, 1997) the entire
contents, all of which, are herein incorporated by reference. Other
necessary reagents and starting materials for the below procedures
may be made by procedures which are selected from standard
techniques of organic and heterocyclic chemistry, techniques which
are analogous to the syntheses of known structurally similar
compounds, and the procedures described in the Examples, including
novel procedures.
[0141] Compounds of Formula I, wherein Z represents an oxygen atom,
may be synthesized according to Scheme I.
##STR00021## ##STR00022##
[0142] In Scheme I, step A, the compound of structure (1) is
treated with a trialkylsilyl iodide (Alk.sub.3SiI) and the
resulting amine, without isolation, is protected under standard
conditions to provide the compound of structure (2). For example,
when a protecting group other than methoxycarbonyl is desired, a
solution of
ethyl-6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate,
dissolved in a suitable organic solvent such as dichloromethane at
room temperature, is treated with about 4 equivalents of a compound
of formula Alk.sub.3SiI such as trimethylsilyl iodide,
triethylsilyl iodide, tributylsilyl iodide, and the like, with
trimethylsilyl iodide being most preferred. The reaction mixture is
stirred for about 10 to 20 hours, quenched with ethanol and
concentrated under vacuum. The resulting solid, for example, is
then dissolved in a suitable organic solvent such as
dichloromethane and treated with an excess of a suitable organic
base, such as triethylamine, followed by about 1 equivalent of, for
example, di-tert-butyl dicarbonate. The reaction mixture is stirred
at room temperature for 10 to 20 hours. The compound (2) is then
isolated using standard procedures. For example, the reaction
mixture is concentrated under vacuum, suspended in ethyl acetate
and filtered. The filtrate is washed with diluted hydrochloric acid
and water, the organic layer separated and dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum to provide
concentrated compound (2). Column chromatography may then be
performed on silica gel with a suitable eluent such as 25% ethyl
acetate/hexane to provide the purified compound (2). Note, where
the desired protecting group (Pg) is methoxycarbonyl, the compound
of structure (1) may be used directly in Step B below.
[0143] In Scheme I, Step B, compound (2) is reduced under standard
conditions with a suitable reducing reagent in the presence of a
suitable Lewis acid catalyst, to provide the compound of structure
(3). For example, ethyl
6-oxo-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylate
(compound (2) of Step A above) is mixed with about 1 equivalent of
a Lewis acid catalyst, such as cerium trichloride, in a suitable
organic solvent such as ethanol. The resulting solution is cooled
to -78.degree. C. and about 1 to 2 equivalents of a reducing
reagent, such as sodium borohydride, is added and the mixture is
warmed slowly to room temperature. After 4 to 8 hours, a suitable
acid, such as acetic acid, is added at 0.degree. C. and the
resulting mixture is stirred for about 1 to 2 hours at room
temperature and concentrated under vacuum. The compound (3) 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 ethyl acetate, and the aqueous layer is
extracted 2-4 times with ethyl acetate. The organic layers are
combined, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum to provide a mixture of compound (3) and
compound (4). Both compounds are then purified by chromatography on
silica gel with a suitable eluent such as 70% ethyl
acetate/hexanes.
[0144] In Scheme I, Step C, compound (4) is treated with a compound
of structure (5) in the presence of a phosphine and a dialkyl
azadicarboxylate to give the compound of structure (6). For
example, a solution of
ethyl-6-hydroxy-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylate-
, about 1-1.5 equivalents of compound of structure (5) (wherein U
represents hydrogen, CN, (C.sub.1-C.sub.4)alkyl-CO.sub.2R.sup.9, or
CO.sub.2R.sup.9) about 0-1.5 equivalents of an organic base such as
pyridine, and about 1-1.5 equivalents of a phosphine such as
triphenylphosphine in tetrahydrofuran is treated with about 1-1.5
equivalents of a dialkyl azadicarboxylate such as diethyl
azodicarboxylate. The reaction is then stirred at 25-70.degree. C.
for 15-48 hours. The solvents are removed under vacuum to provide
the compound of structure (6). Compound (6) is then purified by
chromatography on silica gel with a suitable eluent such as diethyl
ether/hexanes or ethyl acetate/hexanes.
[0145] In Scheme I, Step D(a), the compound of structure (6) is
deprotected under standard conditions well known in the art to
provide the compound of structure (8). For example, compound (6) is
treated with an organic solvent such as ethyl acetate saturated
with HCl at room temperature for about 3 to 5 hours. The mixture is
then concentrated under vacuum to provide the compound of structure
(8) wherein U is as defined in Step C. This material may then be
purified by techniques well known in the art, such as titration
with organic solvents and/or cation exchange chromatography,
eluting with MeOH/water, followed by 2N ammonia in MeOH, to provide
the purified compound of structure (8) wherein U is as defined in
Step C.
[0146] In Scheme I, Step D, the compound of structure (6) is
hydrolyzed under standard conditions to give the compound of
structure (7) wherein R.sup.1 is other than tetrazole, but
otherwise as defined hereinabove. For example, compound (6) is
dissolved in a suitable organic solvent or solvents mixture, such
as methanol, ethanol, tetrahydrofuran and/or ethyl acetate, 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 10-36 hours. The
reaction mixture is then concentrated under vacuum, diluted with
water and washed with ethyl acetate. The aqueous layer is made
acidic to pH 3-4 with 10% HCl and extracted with ethyl acetate.
These organic phases are combined, dried over sodium sulfate,
filtered, and concentrated under vacuum to provide the compound (7)
wherein R.sup.1 is other than tetrazole, but otherwise as defined
hereinabove. The material may then be purified by chromatography on
silica gel with a suitable eluent such as ethyl
acetate/hexanes/acetic acid, to provide the purified compound.
[0147] In Scheme I, where it is desired that the compound of
structure (7) contain a tetrazole at R.sup.1, compound (6) (wherein
U for the purposes of this step is nitrile) is treated with a
compound of Alk.sub.3SnN.sub.3 in Step E to give the compound of
structure (6a). This is followed by hydrolysis in Step F, to
provide the compound of structure (7) (wherein R.sup.1 is
tetrazole). For example, compound (6) (wherein U is nitrile) is
treated with about 3 to 5 equivalents of azido-tri-n-butyl stannane
at about 70 to 100.degree. C. for about 12 to 16 hours under an
atmosphere of nitrogen to give the compound of structure (6a).
Compound (6a) is then hydrolyzed, concentrated, and the resulting
compound (7) (wherein R.sup.1 is tetrazole) may then be purified,
all of which occur under standard conditions well known in the art
as described in Step D above.
[0148] As an alternative to Steps D and F above, the compounds of
structure (6) and (6a) may be selectively hydrolyzed under standard
conditions known in the art to provide a compound of structure
(7a):
##STR00023##
[0149] For example, compound (6) may be hydrolyzed to provide
compounds of (7a) wherein R.sup.6 is as defined hereinabove, other
than tetrazole, whereas compound (6a) may be hydrolyzed to provide
compounds of (7a) wherein R.sup.6 is tetrazole. Compound (7a) can
then be deprotected under standard conditions to provide the
compound of structure (9):
##STR00024##
[0150] Methods for the selective hydrolysis of compounds of
structure (6) and (6a) are well known in the art.
[0151] In Scheme I, Step G, the compound of structure (7) is
deprotected under standard conditions well known in the art to
provide the compound of Formula I. For example, compound (7) is
treated with an organic solvent, such as ethyl acetate, saturated
with hydrogen chloride at room temperature for about 3 to 5 hours.
The mixture is then concentrated under vacuum to provide the
compounds of Formula I. This material may then be purified by
techniques well known in the art, such as tritration with organic
solvents and/or cation exchange chromatography eluting with
methanol/water, followed by 2 N ammonia in methanol, to provide the
purified compound of Formula I.
[0152] As an alternative to the sequence of Steps D and G, and as
an alternative to the sequence of steps F and G, the compounds of
structure (6) and (6a), respectively, may be concomitantly
hydrolyzed and deprotected as provided below to provide the
compounds of Formula I.
##STR00025##
[0153] In Scheme II, compound (6) or (6a) is deprotected and
hydrolyzed concomitantly under standard conditions to provide the
compounds of Formula I. For example, in Scheme II, Step A-1, a
solution of compound (6), dissolved in 6N HCl, is heated to reflux
(90-95.degree. C.) for about 15-20 hours. The reaction mixture is
then allowed to cool to room temperature and concentrated in vacuo
to provide the compound of Formula I wherein R.sup.1 is as defined
hereinabove, other than tetrazole. The compound of Formula I can
then be purified by techniques well known in the art, such as
cation exchange chromatography eluting with methanol/water followed
by 2N ammonia in methanol or ethanol to provide the purified
compound of Formula I wherein R.sup.1 is as defined other than
tetrazole. In Scheme II, Step A-2, a solution of compound (6a) is
treated as described above in Step A-1 to provide the compound of
Formula I wherein R.sup.1 is tetrazole. This material may then be
purified by techniques well known in the art, such as cation
exchange chromatography eluting with methanol/water followed by 2N
ammonia in methanol or ethanol to provide the purified compound of
Formula I wherein R.sup.1 is tetrazole.
[0154] In Scheme I, Step H, the compound of Formula I may be
nonselectively or selectively esterified to provide the compounds
of Formula Ia. For example, the compound of Formula I is dissolved
in a suitable organic solvent, such as ethanol, isobutanol, or
2-ethylbutanol, and treated with an excess of a dehydrating agent
such as thionyl chloride. The reaction mixture is heated to about
120.degree. C. for about 1 to 2 hours. The reaction mixture is then
concentrated under vacuum to provide the crude compound of Formula
Ia. This material may then be precipitated with diethyl ether and
filtered to provide the purified compound. Alternatively in Step H,
the compound of Formula I can be esterified by dissolving in a
suitable organic solvent such as ethanol, and treating 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
preferred. The reaction mixture is heated to reflux (78-85.degree.
C.) for about 15-25 hours. The reaction mixture is then
concentrated under vacuum to provide the crude compound of Formula
Ia. This material can then be purified by techniques well known in
the art, such as cation exchange chromatography eluting with
methanol/water followed by 2N ammonia in ethanol to provide the
purified compound.
[0155] Compounds of Formula I, wherein Z represents an oxygen atom
and R.sup.1 represents tetrazole may alternatively be synthesized
according to the procedures set forth in Scheme III.
##STR00026## ##STR00027##
[0156] In Scheme III, step A, the compound of structure (2) (as
previously described in Scheme I above), is hydrolyzed to the
compound of structure (9) under standard conditions well known in
the art. For example, ethyl
6-oxo-2-(tert-butoxycarbonyl)-decahydroisoquinoline-3-carboxylate
is dissolved in a suitable organic solvent or solvents mixture,
such as methanol, ethanol, tetrahydrofuran and/or ethyl acetate,
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 20-24 hours at room
temperature. The reaction mixture is then concentrated under
vacuum, diluted with water and washed with ethyl acetate. The
aqueous layer is made acidic to pH 3-4 with 10% HCl and extracted
with ethyl acetate. These organic phases are combined, dried over
sodium sulfate, filtered, and concentrated under vacuum to provide
the compound of structure (9).
[0157] In Scheme III, Step B, compound (9) is reduced with a
suitable reducing reagent, such as lithium or sodium selectride, to
provide the compound of structure (10). For example,
6-oxo-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylic acid
is dissolved in a suitable organic solvent such as tetrahydrofuran.
The resulting solution is cooled to about 0.degree. C. and about 2
equivalents of lithium selectride, dissolved in tetrahydrofuran, is
added. The reaction mixture is warmed slowly to room temperature.
After about 2 to 3 hours, a suitable acid, such as 1N hydrochloric
acid, and sodium chloride are added and the resulting mixture is
filtered. The compound (10) is then isolated using standard
procedures such as extraction techniques. For example, the aqueous
layer is extracted 2-4 times with ethyl acetate. The organic layers
are combined, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum to provide the crude compound (10).
Compound (10) may then be purified by chromatography on silica gel
with a suitable eluent such as 60% ethyl acetate/hexanes.
[0158] In Scheme III, Step C, compound (10) is treated with a
compound of structure (11) in the presence of a suitable base to
provide the compound of structure (12). For example, a solution of
6-hydroxy-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylic
acid, dissolved in an organic solvent such as tetrahydrofuran, is
treated at 0.degree. C. with about 2-2.5 equivalents of a suitable
base such as potassium tert-butoxide. The resulting mixture is
stirred at room temperature for about 20 to 40 minutes, cooled to
0.degree. C. and treated with about 1-1.5 equivalents of compound
(11) (where R.sup.2, W, X, and Y are as defined hereinabove). The
reaction is then stirred at room temperature for about 15-24 hours.
The reaction mixture is then diluted with water and washed with
ethyl acetate. The aqueous layer is made acidic to pH 3-4 with 10%
HCl and extracted with ethyl acetate. These organic phases are
combined, dried over sodium sulfate, filtered, and concentrated
under vacuum to provide the compound of structure (12). Compound
(12) may then be purified by chromatography on silica gel with a
suitable eluent such as ethyl acetate/hexanes
[0159] In Scheme III, Step D, compound (12) is treated with a
compound of formula Alk.sub.3SnN.sub.3, wherein Alk is an alkyl
group such as Me, Et, Bu, and the like, and the resulting compound
is deprotected without further treatment to the compound of Formula
I, wherein R.sup.1 is tetrazole, under standard conditions well
known in the art. For example, compound (12) is treated with about
3 to 5 equivalents of azido tri-n-butyl stannane at 70 to
100.degree. C. for about 12 to 76 hours under an atmosphere of
nitrogen. The mixture is then treated with an organic solvent, such
as ethyl acetate, saturated with hydrogen chloride at room
temperature for about 3 to 5 hours. The mixture is then
concentrated under vacuum to provide the compound of Formula I,
wherein R.sup.1 is tetrazole. This material may then be purified by
techniques well known in the art, such as trituration with organic
solvents and/or cation exchange chromatography eluting with
methanol/water followed by 2 N ammonia in methanol to provide the
purified compound.
[0160] In Scheme III, Step E, the compound of Formula I is
nonselectively, or selectively, esterified to provide the compound
of Formula Ia, wherein R.sup.6 is tetrazole. For example, the
compound of Formula I is dissolved in a suitable base, such as
ethanol, isobutanol, or 2-ethylbutanol, and treated with an excess
of a dehydrating agent, such as thionyl chloride. The reaction
mixture is heated to 120.degree. C. for about 1-2 hours. The
reaction mixture is then concentrated under vacuum to provide the
crude compound of Formula Ia, wherein R.sup.7 is tetrazole. This
material is precipitated with diethyl ether and filtered to provide
the purified compound of Formula Ia. Alternatively, in Step E, the
compound of Formula I can be esterified by dissolving in a suitable
organic solvent such as ethanol, and treating 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 preferred. The
reaction mixture is heated to reflux (78-85.degree. C.) for about
15-25 hours. The reaction mixture is then concentrated under vacuum
to provide the crude compound of Formula Ia. This material can then
be purified by techniques well known in the art, such as cation
exchange chromatography eluting with methanol/water followed by 2N
ammonia in ethanol to provide the purified compound.
[0161] One of ordinary skill in the art will understand that the
nitrile group of structure (11) (see Scheme III above) can be
converted to a protected tetrazole group prior to treatment of
compound (10) with compound (11) and, thus, provide yet another
route of synthesis for compounds of Formula I wherein R.sup.1 is
tetrazole. This alternate route is provided in Scheme IV(a) and
IV(b) below:
##STR00028##
[0162] In Scheme IV(a), Step A, the compound of structure (11) is
treated under standard conditions to provide the compound of
structure (11a). For example, a solution of trimethyl aluminum in
toluene is added to a round bottomed flask under nitrogen and the
solution cooled to about -7 degrees Celsius. Azidotrimethylsilane
(about 3.86 mol) is then added via cannula such that the internal
temperature of the reaction is maintained at no greater than about
3 degrees Celsius. To this mixture, the compound of structure (11)
is added dropwise in a solution of toluene. The reaction is slowly
warmed to RT and then heated to about 90 degrees Celsius. The
reaction is heated at 90 degrees for about 13 hours before cooling
to RT. The reaction is then cooled to about 0 degrees Celsius in an
ice bath, then slowly transferred via cannula to a solution of 6N
aqueous HCl and ethyl acetate, pre-cooled to about -5 degrees
Celsius. The internal temperature during the quench is maintained
at no greater than about 5 degrees. After addition, the flask is
allowed to warm to room temperature. The reaction is then diluted
with ethyl acetate to dissolve any solids, the layers are
separated, and the aqueous layer extracted with ethyl acetate. The
organics are combined, washed with brine, dried over anhydrous
sodium sulfate, and concentrated using standard techniques well
known in the art to provide the concentrated compound of structure
(11a)
[0163] In Scheme IV(a), Step B, the compound of structure (11a) is
protected with a suitable nitrogen protecting group under standard
conditions to provide the compound of structure (11b). For example,
to a slurry of compound (11a) and 4,4'-dimethoxybezhydrol in
glacial acetic acid, is added concentrated sulfuric acid. Upon
addition, the reaction becomes red and homogenous and an endotherm
of about 3 to 4 degrees Celsius is observed. After about 15
minutes, the product of structure (11b) begins to crystallize,
resulting in a slight exotherm of less than about 10 degrees. After
about 1 hour, the product is isolated using standard techniques,
such as filtration, washed with water, and then with isopropyl
alcohol. The product of compound (11b) is dried and concentrated
under vacuum to provide the concentrated compound of structure
(11b).
##STR00029##
[0164] In Scheme IV(b), Step A, the compound of structure (10)
(from Scheme III above) is treated with the compound of structure
(11b) from Scheme IV(a), Step B above, to provide the compound of
structure (12a). For example, to a solution of sodium hydride in
dry dimethyl sulfoxide, is added compound (10) dropwise as a
solution of dimethyl sulfoxide. During addition, a cooling bath is
used to maintain the reaction temperature at or below about 25
degrees Celsius. The reaction is stirred for about 15 minutes at
ambient temperature and then compound (11b) is added in one portion
as a solid. The reaction slurry is stirred at RT for about 20
minutes before heating to about 40 degrees Celsius for about 2.5-3
hours. The reaction is quenched by addition of 1N aqueous HCl
solution, water, and ethyl acetate. The layers are separated and
the aqueous layer is extracted with ethyl acetate. The combined
organics are washed with water and about a 10% solution of aqueous
sodium chloride solution. The organic layer is then dried over
anhydrous sodium sulfate and concentrated under vacuum to provide
the crude compound of structure (12a). This material may then be
purified using standard techniques such as chromatography on silica
gel, eluting with a suitable eluent such as 1% MeOH in methylene
chloride, followed by 5% MeOH in methylene chloride to afford the
purified product of compound (12a)
[0165] As one of ordinary skill in the art will recognize, the
compound of structure (12a) may then be deprotected using, for
example TMSI (iodotrimethylsilane) in methylene chloride, to
provide the compound of Formula I, wherein R.sup.1 is tetrazole.
Alternatively, the compound of structure (12a) may be esterified
under standard conditions well known in the art, followed by
deprotection, to provide the compound of Formula Ia, wherein
R.sup.6 is tetrazole.
[0166] Scheme IV(a) and IV(b), above, provide procedures for the
synthesis of Formula I and I(a) compounds where R.sup.1 or R.sup.6
is tetrazole, wherein the protected hydroxy acid of compound (10)
is treated with the protected aryl tetrazole of compound 11(b) in a
nucleophilic aromatic substitution reaction to provide the compound
of structure 12(a). As discussed, compound 12(a) can then be
esterified and/or deprotected, all under standard conditions, to
provide the compounds of Formula I(a) or Formula I. Scheme IV(c)
provides a general synthetic route for these procedures.
##STR00030##
[0167] In Scheme IV(c), Step A, the compound of structure 12(a) is
esterified under standard conditions to provide the compound of
structure 12(b) wherein R.sup.6 is tetrazole. For example, compound
12(a), dissolved in a suitable solvent such as DMF, is treated with
a compound of the formula R.sup.5-LG where LG represents a suitable
leaving group such as a halide. For example R.sup.5 is as defined
previously and LG represents a chloro or bromo atom. The reaction
is heated until complete (confirmed for example by TLC and HPLC).
For example, heating at 80.degree. C. under nitrogen for about 1
hour. The reaction is then cooled to ambient temperature and
submitted to standard extractive workup techniques know to the
skilled artisan to provide purified compound 12(b), wherein R.sup.6
is tetrazole.
[0168] In Scheme IV(c), Steps B and C, the compound of structure
12(a) or 12(b) is deprotected under standard conditions to provide
Formula I or Formula I(a) wherein R.sup.1 or R.sup.6 is tetrazole.
For example, to a solution of compound 12(a) or 12(b) is added
anisole and trifluoroacetic acid (TFA). The solution is stirred
until the reaction is complete. For example stirring for 6 hours at
room temperature. The product, compound 12(c) or 12(d), can be
isolated by standard workup conditions.
[0169] Compounds 12(c) and 12(d) are further deprotected in Step C
to provide the final products of Formula I or I(a) (wherein R.sup.1
or R.sup.6 is tetrazole). For example, compound 12(c) or 12(d) is
combined with TMSI in CH.sub.2Cl.sub.2 and the reaction is stirred
until complete. The Final compounds of Formula I or I(a) wherein
R.sup.1 or R.sup.6 is tetrazole may be isolated after standard
workup conditions.
[0170] Surprisingly, and as a further embodiment of the present
invention, Applicants have discovered alternative nucleophilic
aromatic substitution procedures for the synthesis of Formula I or
Formula I(a) (wherein R.sup.1 or R.sup.6 is tetrazole) that offer
additional advantages over the procedures described in Schemes
IV(a)-IV(c). These additional procedures are generally provided in
Scheme IV(d), below.
##STR00031##
[0171] In Scheme IV(d), Step A, compound (10) is treated with an
unprotected aryl tetrazole of structure 11(a) to provide the
compound of structure 12(c). For example, to a solution of a
suitable base, such as potassium tert-butoxide, in a suitable
solvent, such as THF, is added the compound of structure (10) and
the unprotected aryl tetrazole of structure 11(a). The reaction is
heated until complete. For example, the reaction is heated to about
65.degree. C. for about 4 hours. The compound 12(c) is isolated by
standard workup techniques.
[0172] In Scheme IV(d), Step B, compound 12(c) is deprotected to
provide the compound of Formula I wherein R.sup.1 is tetrazole. For
example, to a solution of a suitable base, such as 85% KOH in
water, compound 12(c) is added and the mixture is heated to about
100.degree. C. until the reaction is complete. The mixture is
cooled then added to a suitable acid, such as HCl, to provide the
precipitated acid salt of Formula I, wherein R.sup.1 is tetrazole.
The acid salt of Formula I (R.sup.1 is tetrazole) can purified by
standard recrystallization techniques and isolated as the salt or a
solvate thereof such as the hydrate.
[0173] In Scheme IV(d), Step C, Formula I is esterified with a
compound of the formula R.sup.5--OH under standard conditions. For
example, a mixture of the hydrate salt of Formula I (Step B above),
a suitable acid such as p-toluenesulfonic acid monohydrate, a
compound of formula R.sup.5--OH, and water is heated to about
140.degree. C. until complete. The ester salt of Formula I(a) where
R6 is tetrazole is isolated by standard techniques and may be
purified by standard recrystallization techniques.
[0174] Compounds of Formula I, wherein Z represents a sulfur atom,
may be synthesized according to Scheme V.
##STR00032##
[0175] In Scheme V, step A, the compound of structure (3) 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
(13). For example, a solution of
ethyl-6-hydroxy-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate,
dissolved in a suitable organic solvent such as dichloromethane and
cooled to 0.degree. 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 include m-nitrobenzenesulfonyl chloride,
p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride,
p-toluenesulfonyl chloride, benzenesulfonyl chloride,
methanesulfonyl chloride, trifluoromethanesulfonyl chloride, and
the like, with methanesulfonyl chloride being a preferred compound.
The reaction mixture is warmed to room temperature and stirred for
about 3 to 20 hours. The compound of structure (13) is then
isolated using standard procedures. For example, the reaction
mixture is washed with water, the organic layer separated, washed
with aqueous saturated solution of ammonium chloride, and dried
over anhydrous sodium sulfate, filtered, and concentrated under
vacuum to provide concentrated compound (13). If desired, column
chromatography may then be performed with on silica gel with a
suitable eluent such as 10-50% ethyl acetate/hexane to provide the
purified compound (13).
[0176] In Scheme V, Step B, compound (13) is treated with an aryl
thiol of structure (14) to provide the compound of structure (15).
For example, ethyl
methanesulfonyloxy-2-methoxycarbonyl-decahydroisoquinoline-3-carbox-
ylate is mixed with about 1-2.5 equivalents of substituted aryl
thiol (wherein U represents hydrogen, CN,
(C.sub.1-C.sub.4)alkyl-CO.sub.2R.sup.9, or CO.sub.2R.sup.9 and
where all other substituents are as defined hereinabove) and about
1-2.5 equivalents of potassium carbonate and heated at reflux in a
suitable solvent such as acetone for about 24-48 hours. The
reaction mixture is cooled to room temperature and compound (15) 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 ethyl acetate, and the
aqueous layer extracted 2-4 times with ethyl acetate. The organic
layers are combined, dried over anhydrous sodium sulfate, filtered,
and concentrated under vacuum to provide concentrated compound
(15). Compound (15) may then be purified by chromatography on
silica gel with a suitable eluent such as ethyl
acetate/hexanes.
[0177] In Scheme V, Step C, compound (15) is concomitantly
deprotected and hydrolyzed under standard conditions to provide the
compound of Formula I wherein R.sup.1 is other than tetrazole, but
otherwise as defined hereinabove. For example, a solution of
compound (15) dissolved in 6M HCl is heated to reflux for about
20-50 hours. The reaction mixture is then allowed to cool to room
temperature and concentrated in vacuo to provide the compound of
Formula I wherein R.sup.1 is other than tetrazole, but otherwise as
defined hereinabove. The compound of Formula I may then be purified
by techniques well known in the art, such as cation exchange
chromatography eluting with methanol/water followed by 2 N ammonia
in methanol or ethanol to provide the purified compound.
[0178] In Scheme V, Step D, where it is desired that the compound
of Formula I contain a tetrazole at R.sup.1, compound (15), wherein
U is nitrile, is treated under standard conditions with a compound
of formula Alk.sub.3SnN.sub.3, wherein Alk is an alkyl chain, to
provide the compound of structure (16). For example, when U is a
nitrile group, compound (15) is treated with about 2 to 5
equivalents of azido tri-n-butyl stannane at 70 to 100.degree. C.
for about 72-120 hours under an atmosphere of nitrogen to give
compound (16). Purification of compound (16) may be achieved by
standard flash chromatography using silical gel and a suitable
eluent.
[0179] In Scheme V, Step E, compound (16) is concomitantly
deprotected and hydrolyzed under standard conditions to provide the
compound of Formula I, wherein R.sup.1 is tetrazole. For example, a
solution of compound (16), dissolved in 6M HCl, is heated to reflux
for about 20-50 hours. The reaction mixture is then allowed to cool
to room temperature and concentrated in vacuo to provide the
compound of Formula I wherein R.sup.1 is tetrazole. The compound of
Formula I may then be purified by techniques well known in the art,
such as cation exchange chromatography eluting with methanol/water,
followed by 2 N ammonia in methanol or ethanol to provide the
purified compound of Formula I wherein R.sup.1 is tetrazole.
[0180] In Scheme V, Step F, the compound of Formula I is esterified
under standard conditions well known in the art to provide the
compound of Formula Ia. For example, the compound of Formula I is
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 preferred. The reaction mixture is heated to reflux
(78-85.degree. C.) for about 15-24 hours. The reaction mixture is
concentrated 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 cation exchange chromatography eluting with
methanol/water, followed by 2 N ammonia in ethanol to provide the
purified compound of Formula Ia.
[0181] The Formula I compounds of the present invention may be
chemically synthesized, for example, from a
6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate
intermediate, or a
6-hydroxy-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylate
intermediate, or a
6-hydroxy-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate
intermediate. These intermediates, in turn, may be synthesized from
a 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid,
the synthesis of which is described in U.S. Pat. No. 4,902,695, No.
5,446,051, and No. 5,356,902 (the contents of which are all herein
incorporated by reference). A route for the synthesis of the
6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate
intermediate, useful for the synthesis of the compounds of the
present invention, is shown in Scheme VI below. Synthesis of the
6-hydroxy-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylate
intermediate is provided in Preparation 1 (infra), while synthesis
of the
6-hydroxy-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate is
provided, for example, essentially as described in. Scheme I (Steps
A and B) and as provided in U.S. Pat. No. 4,902,695, No. 5,446,051,
and No. 5,356,902.
##STR00033##
[0182] In Scheme VI, Step A,
6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylic acid (Pg is as
herein defined above) is esterified by reaction with a compound of
formula R.sup.5--Br (where R.sup.5 is as herein defined) to provide
the 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylate intermediate
of compound (2). For example
6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is
dissolved in acetonitrile and treated with triethylamine and
bromoethane. The reaction is heated at 50.degree. 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
ethyl 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate,
a compound of structure (2). This crude material may then be
purified under standard conditions well known in the art. For
example, the 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 (2).
[0183] The following preparations and examples further illustrate
the invention and represent typical synthesis of the compounds of
Formula I as described generally above. The reagents and starting
materials are readily available to one of ordinary skill in the
art. 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; ".mu.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; ".degree. C." refers to degrees Celsius; "TLC" refers to
thin layer chromatography; "HPLC" refers to high performance liquid
chromatography; "R.sub.f" refers to retention factor; "R.sub.t"
refers to retention time; ".delta." 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 tert-butyl methyl ether; "PPh.sub.3" refers to
triphenylphosphine; "DEAD" refers to diethyl azodicarboxylate; "RT"
refers to room temperature; "K.sub.i" refers to the dissociation
constant of an enzyme-antagonist complex and serves as an index of
ligand binding; and "ID.sub.50" and "ID.sub.100" refer to doses of
an administered therapeutic agent which produce, respectively, a
50% and 100% reduction in a physiological response.
Preparation 1
Ethyl(3S,4aS,6R,8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a--
decahydroisoquinoline-3-carboxylate
##STR00034##
[0184] A.
Ethyl(3S,4aS,6R,8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5-
,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0185] To a -78.degree. C. solution of
(3S,4aS,8aR)6-oxo-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydrois-
oquinoline-3-carboxylic acid (6.88 g, 21.14 mmol) (see Preparation
2, Steps A and B, below and Scheme III, Step A generally) and
cerium trichloride heptahydrate (7.9 g, 21.2 mmol) in absolute
ethyl alcohol (90 mL), under nitrogen sodium borohydride (1.24 g,
32.73 mmol) was added in portions. The resulting mixture was slowly
warmed up to room temperature over 5 hours. The reaction mixture
was cooled down to 0.degree. C. and acetic acid (50% in water, 25
mL) was carefully added. The resulting mixture was stirred for 1
hour at room temperature and the solvent was removed in vacuo. To
the resulting material water and ethyl acetate were added and the
phases separated. Aqueous layer was extracted with ethyl acetate
(3.times.). The combined organic phases were dried, filtered and
concentrated in vacuo. Flash chromatography (silicagel, 70% ethyl
acetate/hexane) gave
ethyl(3S,4aS,6S,8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-
-decahydroisoquinoline-3-carboxylate (2.4 g, 35%) and the title
compound (4.15 g, 60%)
[0186] Ion Electrospray Mass Spectrum M+Na: 350.2
Example 1
Preparation of
(3S,4aS,6S,8aR)6-(3-Carboxy-naphthalen-2-yloxy)-1,2,3,4,4a,5,6,7,8,8a-dec-
ahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00035##
[0187] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(3-ethoxycarbonyl-naphthalen-2-yloxy)-2-tert-butoxy-
carbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0188] A solution of the material from preparation 1 (120 mg, 0.37
mmol), triphenylphosphine (145 mg, 0.55 mmol), ethyl
3-hydroxy-naphthalen-2-carboxylate (111 mg, 0.55 mmol) in
tetrahydrofuran (1.9 mL), was treated with diethylazodicarboxylate
(0.090 mL, 0.55 mmol) at room temperature for 16 h. Flash
chromatography (silicagel, 50% diethyl ether/hexane) gave 103 mg of
the title intermediate (55%).
B. Preparation of
(3S,4aS,6S,8aR)6-(3-Carboxy-naphthalen-2-yloxy)-1,2,3,4,4a,5,6,7,8,8a-dec-
ahydroisoquinoline-3-carboxylic acid hydrochloride
[0189] To a solution of the material from step A (103 mg, 0.20
mmol) in tetrahydrofuran (0.5 mL) hydrochloric acid (3N, 1 mL) was
added. The resulting mixture was stirred at 80.degree. C. for 10 h
and concentrated in vacuo to give a solid that was triturated with
ethyl acetate, diethyl ether and cold acetone to afford the desired
amino acid (57 mg, 70%).
[0190] Mass Spectrum (Fast Atom Bombardment) M-HCl+1: 370.2
[0191] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 8.35 (s, 1H); 7.83 (t,
J=7.9 Hz, 2H); 7.48 (m, 3H); 4.63 (m, 1H); 4.10 (m, 1H); 3.40 (m,
1H); 3.15 (m, 1H); 2.26-1.55 (m, 10H).
Example 2
Preparation of
(3S,4aS,6S,8aR)6-(4-carboxy-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decah-
ydroisoquinoline-3-carboxylic acid hydrochloride
##STR00036##
[0192] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(4-ethoxycarbonyl-biphenyl-3-yloxy)-2-tert-butoxyca-
rbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0193] Following the procedures as described in Example 1, step A,
a solution of the material from preparation 1 (2.02 g, 8.3 mmol),
triphenylphosphine (3.15 g, 12.0 mmol), ethyl
3-hydroxy-biphenyl-4-carboxylate (2.63 g, 8.02 mmol) in
tetrahydrofuran (42 mL), was treated with diethylazodicarboxylate
(1.89 mL, 12.0 mmol) at room temperature for 20 h. Flash
chromatography (silicagel, 30% diethyl ether/hexane) gave 2.76 g of
the title intermediate (62%).
[0194] Mass Spectrum (Fast Atom Bombardment) M+Na: 574.2
B. Preparation of
(3S,4aS,6S,8aR)6-(4-carboxy-biphenyl-3-yloxy)-2-tert-butoxycarbonyl-1,2,3-
,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0195] To a solution of the material from step A (400 mg) in
absolute ethanol (2 mL) a solution of lithium hydroxide (2.5 N, 2
mL) was added. The resulting mixture was stirred at room
temperature for 72 hours. The ethanol was removed in vacuo and the
mixture extracted with ethyl acetate (2.times.). The aqueous phase
was made acidic by addition of hydrochloric acid (10%, pH=3-4) and
extracted with ethyl acetate (3.times.). The resulting organic
phases were combined, dried and concentrated in vacuo to afford,
after flash chromatography (silicagel, 50% ethyl acetate/hexane/5%
acetic acid), to give the title compound (350 mg, 95%)
[0196] Mass Spectrum (Fast Atom Bombardement) M+1: 496.2
C. Preparation of
(3S,4aS,6S,8aR)6-(4-carboxy-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decah-
ydroisoquinoline-3-carboxylic acid hydrochloride
[0197] The material from step B (350 mg, 0.71 mmol) was treated
with ethyl acetate saturated with hydrogen chloride (7 mL) for 4
hours at room temperature. The mixture was concentrated in vacuo to
afford, after trituration with ethyl acetate and diethyl ether, the
desired amino acid (250 mg, 82%).
[0198] Ion Electrospray Mass Spectrum M-HCl+1: 396.2
[0199] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 7.90 (d, J=8.1 Hz,
1H); 7.78 (m, 2H); 7.53-7.27 (m, 5H); 4.60 (m, 1H); 4.08 (dd,
J=12.0, 3.3 Hz, 1H); 3.37 (m, 1H); 3.12 (dd, J=12.7, 4.3 Hz, 1H);
2.18-1.59 (m, 10H).
Example 3
Preparation of
ethyl(3S,4aS,6S,8aR)6-(4-ethoxycarbonyl-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,-
7,8,8a-decahydroisoquinoline-3-carboxylate hydrochloride
##STR00037##
[0200] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(4-ethoxycarbonyl-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,-
7,8,8a-decahydroisoquinoline-3-carboxylate hydrochloride
[0201] Following the procedures as described in Example 2C,
material from Example 2A (2.25 g, 4.08 mmol) treated with ethyl
acetate saturated with hydrogen chloride (50 mL) gave a solid that
was washed with hexane to afford the title compound (1.9 g,
95%).
[0202] Ion Electrospray Mass Spectrum M-HCl+1: 452.2
[0203] Analysis calcd. for: C27H33NO5.1 HCl. 0.8 H2O: C 64.55, H
7.14, N 2.79; Found: C 64.64, H 7.34, N 3.00.
Example 4
Preparation of
(3S,4aS,6S,8aR)6-(2-carboxy-5-chloro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decah-
ydroisoquinoline-3-carboxylic acid hydrochloride
##STR00038##
[0204] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(5-chloro-2-ethoxycarbonyl-phenoxy)-2-tert-butoxyca-
rbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0205] Following the procedures as described in Example 1, step A,
a solution of the material from preparation 1A (120 mg, 0.37 mmol),
triphenylphosphine (145 mg, 0.55 mmol), ethyl
4-chloro-2-hydroxy-benzoate (80 mg, 0.40 mmol) in tetrahydrofuran
(1.9 mL), was treated with diethylazodicarboxylate (0.090 mL, 0.55
mmol) at 70.degree. C. for 24 h. Flash chromatography (silicagel,
40% diethyl ether/hexane) gave 132 mg of the title intermediate
(71%).
[0206] Mass Spectrum (Fast Atom Bombardment) M+1: 510.3
B. Preparation of
(3S,4aS,6S,8aR)6-(2-carboxy-5-chloro-2-phenoxy)-2-tert-butoxycarbonyl-1,2-
,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0207] Following the procedures as described in Example 2B, a
solution of the material from step A (132 mg, 0.26 mmol) in
tetrahydrofuran (1.2 mL) and absolute ethanol (0.5 mL) was treated
with a solution of lithium hydroxide (2.5 N, 1 mL) at room
temperature for 24 h to give the title compound (118 mg, 100%).
[0208] Mass Spectrum (Fast Atom Bombardment) M+Na: 476.2
C. Preparation of
(3S,4aS,6S,8aR)6-(2-carboxy-5-chloro-2-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-dec-
ahydroisoquinoline-3-carboxylic acid hydrochloride
[0209] Following the procedures as described in Example 2C,
material from step B (118 mg, 0.26 mmol) treated with ethyl acetate
saturated with hydrogen chloride (1 mL) gave the desired amino acid
(98 mg, 97%).
[0210] Mass Spectrum (Fast Atom Bombardment) M-HCl+1: 354.1
[0211] Analysis calcd. for: C17H202NO5.1 HCl. 0.5 H2O: C, 51.14; H,
5.55; N, 3.51; Found: C, 51.3; H, 5.90; N, 3.82.
Example 5
Preparation of
ethyl(3S,4aS,6S,8aR)6-(5-chloro-2-ethoxycarbonyl-phenoxy)-1,2,3,4,4a,5,6,-
7,8,8a-decahydroisoquinoline-3-carboxylate hydrochloride
##STR00039##
[0212] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(5-chloro-2-ethoxycarbonyl-phenoxy)-1,2,3,4,4a,5,6,-
7,8,8a-decahydroisoquinoline-3-carboxylate hydrochloride
[0213] Following the procedures as described in Example 2 step C,
material from Example 4, step A (1.25 g, 2.45 mmol) treated with
ethyl acetate saturated with hydrogen chloride (20 mL) gave the
title compound (930 mg, 93%).
[0214] Ion Electrospray Mass Spectrum M-HCl+1: 410.2
[0215] .sup.1H NMR (CDCl.sub.3, 200.13 MHz): 9.85 (br s, 2H); 7.64
(d, J=8.2 Hz, 1H); 6.90 (m, 2H); 5.28 (br s, 1H); 4.24 (m, 5H);
3.91 (br s, 1H); 3.42, 3.26 (2 br s, 2H); 2.65-1.78 (m, 10H);
1.32-1.18 (m, 6H).
Example 6
Preparation of
(3S,4aS,6S,8aR)6-(2-carboxy-4,5-difluoro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-d-
ecahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00040##
[0216] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(2-ethoxycarbonyl-4,5-difluoro-phenoxy)-2-tert-buto-
xycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0217] Following the procedures as described in Example 1, step A,
a solution of the material from preparation 1A (100 mg, 0.31 mmol),
triphenylphosphine (121 mg, 0.46 mmol), ethyl
4,5-difluoro-2-hydroxy-benzoate (78 mg, 0.39 mmol) in
tetrahydrofuran (1.6 mL), was treated with diethylazodicarboxylate
(0.072 mL, 0.46 mmol) at room temperature for 36 h. Flash
chromatography (silicagel, 40% diethyl ether/hexane) gave 115 mg of
the title intermediate (73%).
[0218] Ion Electrospray Mass Spectrum M+Na: 534.2
B. Preparation of
(3S,4aS,6S,8aR)6-(2-carboxy-4,5-difluoro-2-phenoxy)-2-tert-butoxycarbonyl-
-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0219] Following the procedures as described in Example 2B, a
solution of the material from step A (99 mg, 0.21 mmol) in absolute
ethanol (1 mL) was treated with a solution of lithium hydroxide
(2.5 N, 1 mL) at room temperature for 48 h to give the title
compound (87 mg, 100%).
[0220] Mass Spectrum (Fast Atom Bombardment) M+Na: 478.2
C. Preparation of
(3S,4aS,6S,8aR)6-(2-carboxy-4,5-difluoro-2-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-
-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0221] Following the procedures as described in Example 2 step C,
material from step B (77 mg, 0.17 mmol) treated with ethyl acetate
saturated with hydrogen chloride (2 mL) gave, after washing the
solid with diethyl ether and acetone, the desired amino acid (98
mg, 97%).
[0222] Mass Spectrum (Fast Atom Bombardment) M-HCl+1: 356.1
[0223] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 7.70 (t, J=9.9 Hz,
1H); 7.21 (dd, J=6.6, 5.8 Hz, 1H); 4.44 (m, 1H); 4.07 (br d, J=14.4
Hz, 1H); 3.35 (m, 1H); 3.16 (dd, J=12.5, 3.7 Hz, 1H); 2.23-1.49 (m,
10H).
Example 7
Preparation of
(3S,4aS,6S,8aR)6-(2-carboxy-4-chloro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decah-
ydroisoquinoline-3-carboxylic acid hydrochloride
##STR00041##
[0224] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(2-ethoxycarbonyl-4-chloro-phenoxy)-2-tert-butoxyca-
rbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0225] Following the procedures as described in Example 1, step A,
a solution of the material from preparation 1 (120 mg, 0.37 mmol),
triphenylphosphine (145 mg, 0.55 mmol), ethyl
2-hydroxy-5-chloro-benzoate (73 mg, 0.366 mmol) in tetrahydrofuran
(2 mL), was treated with diethylazodicarboxylate (0.090 mL, 0.55
mmol) at room temperature for 16 h. Flash chromatography (silica
gel, diethyl ether-hexane 1:2) gave 106 mg (57% yield) of the title
compound.
[0226] Mass Spectrum (Fast Atom Bombardment) M+1:511.1
B. Preparation of
(3S,4aS,6S,8aR)6-(2-carboxy-4-chloro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decah-
ydroisoquinoline-3-carboxylic acid hydrochloride
[0227] A solution of the material from step A (106 mg, 0.20 mmol)
in tetrahydrofuran (1 mL) was treated with 3N HCl (3 mL) and heated
at 80.degree. C. overnight. The crude was concentrate in vacuo and
washed with ethyl acetate (2.times.) to afford 25 mg (31% yield) of
the title compound.
[0228] Mass Spectrum (Fast Atom Bombardment) M-HCl+1: 354.1
[0229] Analysis calculated for C17H21Cl2NO5: % C, 52.32; % H, 5.42;
% N, 3.59. Found: % C, 52.39; % H, 5.61; % N, 3.60.
Example 8
Preparation of
(3S,4aS,6S,8aR)6-(2-carboxy-4-nitro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahy-
droisoquinoline-3-carboxylic acid hydrochloride
##STR00042##
[0230] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(2-ethoxycarbonyl-4-nitro-phenoxy)-2-tert-butoxycar-
bonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0231] Following the procedures as described in Example 1A, a
solution of the material from preparation 1A (120 mg, 0.37 mmol),
triphenylphosphine (145 mg, 0.55 mmol), ethyl
2-hydroxy-5-nitro-benzoate (77 mg, 0.366 mmol) in tetrahydrofuran
(2 mL), was treated with diethylazodicarboxylate (0.090 mL, 0.55
mmol) at room temperature for 16 h. Flash chromatography (silica
gel, diethyl ether-hexane 1:2) gave 120 mg (63% yield) of the title
compound.
[0232] Mass Spectrum (Fast Atom Bombardment) M+1:521.3
B. Preparation of
(3S,4aS,6S,8aR)6-(2-carboxy-4-nitro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahy-
droisoquinoline-3-carboxylic acid hydrochloride
[0233] Following the procedures as described in Example 7, step B,
compound from step A (106 mg, 0.23 mmol) afforded 50 mg (54% yield)
of the title compound.
[0234] Mass Spectrum (Fast Atom Bombardment) M-HCl+1: 365.1
[0235] Analysis calculated for C17H21ClN2O7: % C, 50.94; % H, 5.28;
% N, 6.99. Found: % C, 50.88; % H, 5.35; % N, 6.80.
Preparation 2
(3S,4aS,6S,8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decah-
ydroisoquinoline-3-carboxylic acid
##STR00043##
[0236] A.
Ethyl(3S,4aS,8aR)6-oxo-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,-
8a-decahydroisoquinoline-3-carboxylate
[0237] To a solution of
ethyl(3S,4aS,8aR)6-oxo-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroi-
soquinoline-3-carboxylate (3.54 g, 12.5 mmol) in methylene chloride
(100 mL) under nitrogen, iodotrimethylsilane (10.0 g, 50 mmol) was
added in one portion at room temperature. The reaction mixture was
stirred overnight and quenched with ethanol (20-30 mL). The
solution was concentrated in vacuo and dried for 3 hours under
reduced pressure. The resulting solid was dissolved in methylene
chloride (100 mL) and triethylamine (7 mL, 50 mmol) was added.
After stirring for 15 minutes a solution of
di-tert-butyl-dicarbonate (2.73 g, 12.5 mmol) in methylene chloride
(10 mL) was added. The resulting mixture was stirred overnight at
room temperature and concentrated in vacuo. The resulting solid was
suspended in ethyl acetate and filtered. The filtrate was washed
with 1N hydrochloric acid and brine. The organic phase was dried,
filtered and concentrated in vacuo. Flash chromatography
(silicagel, 25% ethyl acetate/hexane) gave pure product as an
colorless oil (3.69 g, 92%).
B.
(3S,4aS,8aR)6-oxo-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydro-
isoquinoline-3-carboxylic acid
[0238] To a solution of ester from preparation 2A (9.7 g, 29.81
mmol) in absolute ethanol (130 mL) a solution of lithium hydroxide
(2.5 N, 132 mL) was added. The resulting mixture was stirred at
room temperature for 22 h. The ethanol was removed in vacuo and the
resulting mixture was washed with ethyl acetate (.times.2). The
aqueous phase was made acidic by addition of 10% hydrochloric acid
(pH=3-4) and extracted with ethyl acetate (.times.3). The resulting
organic phases were combined, dried and concentrated in vacuo to
afford the title compound (8.85 g, 100%)
C.
(3S,4aS,6S,8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-de-
cahydroisoquinoline-3-carboxylic acid
[0239] To an ice-cooled solution of ketone from preparation 2B
(11.34 g, 38.14 mmol) in dry tetrahydrofuran (50 mL) under nitrogen
a solution of L-Selectride (1 M in tetrahydrofuran, 76 mL) was
added dropwise. The resulting mixture was allowed to reach room
temperature for 2 h and quenched with 1N hydrochloric acid (78 mL).
To the resulting mixture sodium chloride was added to saturate the
aqueous phase. After filtration the aqueous phase was extracted
with ethyl acetate. The combined organic phases were dried and
concentrated in vacuo. Flash chromatography (silicagel, ethyl
acetate-hexane 4:3) afforded the desired alcohol (8.5 g, 74%)
Example 9
Preparation of
(3S,4aS,6S,8aR)6-[3-Chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00044##
[0240] A. Preparation of
(3S,4aS,6S,8aR)6-(3-chloro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4-
,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0241] To an ice-cooled solution of the material from preparation 2
(400 mg, 1.34 mmol) in dry tetrahydrofuran (5.6 mL) under nitrogen
a solution of potassium tert-butoxide (1M in tetrahydrofuran, 3.0
mL) was slowly added. The resulting suspension was stirred at room
temperature for 25 min and again cooled to 0-5.degree. C. before
the addition of 2-chloro-6-fluorobenzonitrile (249 mg, 1.60 mmol).
The reaction mixture was stirred a room temperature overnight,
diluted with water and washed with ethyl acetate (.times.2). The
aqueous phase was made acidic (pH=3-4) with 10% hydrochloric acid
and extracted with ethyl acetate (.times.2). The resulting organic
phases were combined, dried and concentrated in vacuo. Flash
chromatography (silicagel, 75% ethyl acetate/hexane/2.5% acetic
acid) gave the desired compound as a white solid (460 mg, 79%).
[0242] Ion Electrospray Mass Spectrum M+1-t-butylOCO: 335.2
B. Preparation of
(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-tert-butoxy-
carbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid
[0243] A mixture of the nitrile from Example 9, step A (3.03 g, 6.9
mmol) and azidotri-n-butylstannane (7.6 mL, 28 mmol) was stirred
under nitrogen at 85.degree. C. for 60 h. The mixture was diluted
with ethyl acetate (20 mL) and sodium hydroxide (2.5N, 25 mL) was
added. The resulting mixture was stirred for 1 h. The aqueous layer
was washed with ethyl acetate (2.times.) and concentrated in vacuo.
Flash chromatography (silicagel, 55% ethyl acetate/hexane/1% acetic
acid) gave the desired tetrazol as an oil (1.18 g, 35%).
[0244] Ion Electrospray Mass Spectrum M+1: 478.1
C. Preparation of
(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0245] A suspension of the protected decahydroisoquinoline from
step B (400 mg, 0.84 mmol) in ethyl acetate saturated with hydrogen
chloride (5 mL) was stirred for 4 h at room temperature. The
mixture was extracted with water (1.times.). The aqueous layer was
washed with ethyl acetate (2.times.) and concentrated in vacuo to
afford a white solid (320 mg, 92%).
[0246] Ion Electrospray Mass Spectrum M-HCl+1: 378.1
[0247] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 7.54 (t, J=8.3 Hz,
1H); 7.22 (t, J=8.1 Hz, 2H); 4.47 (m, 1H); 4.00 (dd, J=12.6, 3.5
Hz, 1H); 3.21 (t, J=12.6 Hz, 1H); 3.06 (dd, J=12.7, 4.7 Hz, 1H);
2.21-1.59 (m, 10H).
Example 10
Preparation of
2-Ethyl-butyl(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]--
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
hydrochloride
##STR00045##
[0249] To a suspension of the compound from Example 9, step C (800
mg, 2.18 mmol) in 2-ethylbutanol (50 mL), thionyl chloride (1.75
mL, 24 mmol) was added dropwise. The resulting solution was stirred
at 120.degree. C. for 2 h. The solvent was removed in vacuo and
diethyl ether was added. The resulting solid was filtered and
washed with diethyl ether) to give the desired material (711 mg,
70%).
[0250] Ion Electrospray Mass Spectrum M-HCl+1: 462.3
[0251] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 7.53 (t, J=8.0 Hz,
1H); 7.24 (d, J=8.2 Hz, 1H); 7.19 (d, J=8.0 Hz, 1H); 4.45 (br s,
1H); 4.22 (dd, J=10.8, 5.7 Hz, 1H); 4.14 (m, 2H); 3.23 (t, J=12.6
Hz, 1H); 3.11 (d, J=9.6 Hz, 1H); 2.19-1.36 (m, 15H); 0.91 (t, J=7.5
Hz, 6H).
Example 11
Preparation of
(3S,4aS,6S,8aR)6-[3-methoxy-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5-
,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00046##
[0252] A. Preparation of
(3S,4aS,6S,8aR)6-(3-methoxy-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,-
4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0253] Following the procedures as described in Example 9, step A,
material from preparation 2 (400 mg, 1.34 mmol) in tetrahydrofuran
(5.6 mL) was treated with a solution of potassium tert-butoxide (1
M in tetrahydrofuran, 3.0 mL) and 6-methoxy-2-fluorobenzonitrile
(242 mg, 1.60 mmol) to give, after flash chromatography (silicagel,
75% ethyl acetate/hexane/2.5% acetic acid), 429 mg of the title
compound (74%).
[0254] Ion Electrospray Mass Spectrum M+1-t-butylOCO: 331.3
B. Preparation of
(3S,4aS,6S,8aR)6-[3-methoxy-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5-
,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0255] Following the procedures as described in Example 9, step B,
compound from step A (429 mg, 0.92 mmol) was treated with
azidotri-n-butylstannane (0.8 mL, 3.6 mmol) at 85.degree. C. for 62
h to give 50 mg of an oil that was directly submitted to the next
reaction. As for Example 2, step C, the above material was treated
with ethyl acetate saturated with hydrogen chloride (2.5 mL) to
give the desired amino acid (17 mg, 5%, two steps).
[0256] Ion Electrospray Mass Spectrum M-HCl+1: 374.2
[0257] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 7.50 (t, J=8.5 Hz,
1H); 6.82 (dd, J=12.0, 8.5 Hz, 2H); 4.43 (m, 1H); 4.02 (dd, J=12.3,
3.6 Hz, 1H); 3.81 (s, 3H); 3.22 (d, J=12.8 Hz, 1H); 3.07 (dd,
J=12.8, 4.3 Hz, 1H); 2.14-1.29 (m, 10H).
Example 12
Preparation of
(3S,4aS,6S,8aR)6-[3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00047##
[0258] A. Preparation of
(3S,4aS,6S,8aR)6-(3-fluoro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4-
,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0259] Following the procedures as described in Example 9, step A,
material from preparation 2 (300 mg, 1 mmol) in tetrahydrofuran
(4.2 mL) was treated with a solution of potassium tert-butoxide (1
M in tetrahydrofuran, 2.2 mL) and 2,6-difluorobenzonitrile (209 mg,
1.5 mmol) to give 377 mg of the title compound (90%).
[0260] Ion Electrospray Mass Spectrum M+Na: 441.2
B. Preparation of
(3S,4aS,6S,8aR)6-[3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-tert-butoxy-
carbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid
[0261] Following the procedures as described in Example 9, step B,
compound from step A (370 mg, 0.88 mmol) was treated with
azidotri-n-butylstannane (1.0 mL, 3.6 mmol) at 90.degree. C. for 31
h to give the desired compound (120 mg, 29%).
[0262] Ion Electrospray Mass Spectrum M+1: 462.3
C. Preparation of
(3S,4aS,6S,8aR)6-[3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0263] Following the procedures as described in Example 9, step C,
material from step B (120 mg, 0.26 mmol) treated with ethyl acetate
saturated with hydrogen chloride (3 mL) gave the desired amino acid
(60 mg, 64%).
[0264] Ion Electrospray Mass Spectrum M-HCl+1: 362.2
[0265] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 7.57 (dt, J=8.3, 6.7
Hz, 1H); 7.13 (d, J=8.9 Hz, 1H); 6.97-6.88 (m, 1H); 4.59-4.49 (m,
1H); 4.05 (dd, J=12.1, 4.3 Hz, 1H); 3.38-3.25 (m, 1H); 3.11 (dd,
J=12.9, 4.6 Hz, 1H); 2.27-1.39 (m, 10H).
Example 13
Preparation of
(3S,4aS,6S,8aR)6-[4-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00048##
[0266] A. Preparation of
(3S,4aS,6S,8aR)6-(4-fluoro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4-
,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0267] Following the procedures as described in Example 9, step A,
material from preparation 2 (300 mg, 1 mmol) in tetrahydrofuran
(4.2 mL) was treated with a solution of potassium tert-butoxide (1
M in tetrahydrofuran, 2.2 mL) and 2,5-difluorobenzonitrile (209 mg,
1.5 mmol) to give 344 mg of the title compound (82%).
[0268] Ion Electrospray Mass Spectrum M+Na: 441.2
B. Preparation of
(3S,4aS,6S,8aR)6-[4-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-tert-butoxy-
carbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid
[0269] Following the procedures as described in Example 9, step B,
compound from step A (344 mg, 0.82 mmol) was treated with
azidotri-n-butylstannane (0.9 mL, 3.3 mmol) at 90.degree. C. for 24
h to give the desired compound (249 mg, 66%).
[0270] Ion Electrospray Mass Spectrum M+1: 462.3
C. Preparation of
(3S,4aS,6S,8aR)6-[4-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0271] Following the procedures as described in Example 9, step C,
material from step B (249 mg, 0.54 mmol) treated with ethyl acetate
saturated with hydrogen chloride (2.5 mL) gave the desired compound
(70 mg, 36%)
[0272] Ion Electrospray Mass Spectrum M-HCl+1: 362.2
[0273] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 7.70 (dt, J=8.4, 1.9
Hz, 1H); 7.33 (dd, J=5.9, 1.5 Hz, 2H); 4.54 (m, 1H); 4.02 (dd,
J=12.2, 4.2 Hz, 1H); 3.42-3.30 (m, 1H); 3.14 (dd, J=12.8, 4.4 Hz,
1H); 2.17-1.52 (m, 10H).
Example 14
Preparation of
(3S,4aS,6S,8aR)6-[4-methyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00049##
[0274] A. Preparation of
(3S,4aS,6S,8aR)6-(4-methyl-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4-
,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0275] Following the procedures as described in Example 9, step A,
material from preparation 2 (170 mg, 0.57 mmol) in tetrahydrofuran
(2.4 mL) was treated with a solution of potassium tert-butoxide (1
M in tetrahydrofuran, 1.2 mL) and 5-methyl-2-fluorobenzonitrile (85
mg, 0.62 mmol) to give, after flash chromatography (silicagel, 60%
ethyl acetate/hexane/2.5% acetic acid), 187 mg of the title
compound (79%).
[0276] Ion Electrospray Mass Spectrum M+1: 415.2
B. Preparation of
(3S,4aS,6S,8aR)6-[4-methyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0277] Following the procedures as described in Example 9, step B,
compound from step A (147 mg, 0.36 mmol) was treated with
azidotri-n-butylstannane (0.44 mL, 1.5 mmol) at 90.degree. C. for
64 h to give a solid (80 mg, 49%) that was directly submitted to
the next reaction. The solid was treated with ethyl acetate
saturated with hydrogen chloride (1 mL) and hydrochloric acid (1
mL) to give the desired amino acid (37 mg, 29%, two steps)
[0278] Ion Electrospray Mass Spectrum M-HCl+1: 358.3
[0279] .sup.1H NMR (CD.sub.3OD, 500 MHz): 7.79 (s, 1H); 7.35 (d,
J=7.1 Hz, 1H); 7.18 (d, J=8.6 Hz, 1H); 4.54 (m, 1H); 4.07 (d,
J=11.1 Hz, 1H); 3.40 (t. J=12.9 Hz, 1H); 3.14 (d, J=9.5 Hz, 1H);
2.34 (s, 3H); 2.32-1.57 (m, 10H).
Example 15
Preparation of
(3S,4aS,6S,8aR)6-[5-bromo-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6-
,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00050##
[0280] A. Preparation of
(3S,4aS,6S,8aR)6-(5-bromo-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,-
4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0281] Following the procedures as described in Example 9, step A,
material from preparation 2 (350 mg, 1.17 mmol) in tetrahydrofuran
(4.9 mL) was treated with a solution of potassium tert-butoxide (1
M in tetrahydrofuran, 2.6 mL) and 5-methyl-2-fluorobenzonitrile
(281 mg, 2.34 mmol) to give, after flash chromatography (silicagel,
70% ethyl acetate/hexane/2.5% acetic acid), 470 mg of the title
compound (72%).
[0282] Ion Electrospray Mass Spectrum M+Na: 501.0
B. Preparation of
(3S,4aS,6S,8aR)6-[5-bromo-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-tert-butoxyc-
arbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid
[0283] Following the procedures as described in Example 9, step B,
compound from step A (468 mg, 0.98 mmol) was treated with
azidotri-n-butylstannane (1.1 mL, 3.92 mmol) at 85.degree. C. for
30 h to give the desired compound (380 mg, 74%).
[0284] Ion Electrospray Mass Spectrum M+1: 522.1
C. Preparation of
(3S,4aS,6S,8aR)6-[5-bromo-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6-
,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0285] Following the procedures as described in Example 9, step C,
material from step B (378 mg, 0.72 mmol) treated with ethyl acetate
saturated with hydrogen chloride (6 mL) gave the desired amino acid
(290 mg, 95%)
[0286] Ion Electrospray Mass Spectrum M-HCl+1: 422.0
[0287] Analysis calcd. for: C17H20BrN5O3.1 HCl. 1.5 H2O: C, 42.03;
H, 4.98; N, 14.42; Found: C, 41.75; H, 4.59; N, 14.02.
Example 16
Preparation of
(3S,4aS,6S,8aR)6-[3,5-difluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4-
a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
##STR00051##
[0288] A. Preparation of
(3S,4aS,6S,8aR)6-(3,5-difluoro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2-
,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0289] Following the procedures as described in Example 9, step A,
material from preparation 2 (150 mg, 0.50 mmol) in tetrahydrofuran
(2.0 mL) was treated with a solution of potassium tert-butoxide (1
M in tetrahydrofuran, 1.1 mL) and 2,4,6-trifluorobenzonitrile (102
mg, 0.65 mmol) to give, after flash chromatography (silicagel, 50%
ethyl acetate/hexane/0.5% acetic acid), 75 mg of the title compound
(35%).
[0290] Ion Electrospray Mass Spectrum M+Na: 459.2
B. Preparation of
(3S,4aS,6S,8aR)6-[3,5-difluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4-
a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
[0291] To the compound from step A (75 mg, 0.17 mmol), toluene (0.2
mL) and azidotri-n-butylstannane (140 .mu.L, 0.51 mmol) were added
at room temperature. The reaction mixture was allowed to stir at
100.degree. C. for four days. Then, it was cooled at room
temperature and treated with a 1N solution of hydrogen chloride in
ethyl acetate (5 mL). The reaction mixture was allowed to stir at
room temperature for 2 hours. The resulting white solid was washed
with ethyl acetate and ethyl ether to give, after purification by
HPLC [YMC C18, 2.times.5 cm, (A) water/0.05% trifluoroacetic acid,
(B) acetonitrile/0.05% trifluoroacetic acid; 10 mL/min, 5-40% B in
15 min] the desired amino acid (6 mg, 9%, two steps).
[0292] Ion Electrospray Mass Spectrum M-HCl+1: 380.2
[0293] .sup.1H-NMR (MeOH-d4, 200.15 MHz): 7.02 (dd, J=11.0, 1.6 Hz,
1H); 6.87-6.76 (m, 1H); 4.59-4.39 (m, 1H); 4.02 (dd, J=12.6, 3.8
Hz, 1H); 3.21-3.05 (m, 2H); 2.20-1.78 (m, 8H); 1.49-1.29 (m,
2H).
Example 17
Preparation of
(3S,4aS,6S,8aR)6-[4-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00052##
[0294] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(4-chloro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,-
2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0295] To a solution of the material from preparation 1 (120 mg,
0.37 mmol), triphenylphosphine (145 mg, 0.55 mmol) and
5-chloro-2-hydroxy-benzonitrile (136 mg, 0.89 mmol) in dry
tetrahydrofuran (1.9 mL) under nitrogen, neat
diethylazodicarboxylate (0.090 mL, 0.55 mmol) was added dropwise at
room temperature. The reaction mixture was stirred overnight at
room temperature and concentrated in vacuo. Flash chromatography
(silicagel, 25% ethyl acetate/hexane) gave 61 mg of the desired
compound (36%).
[0296] Ion Electrospray Mass Spectrum M+1: 463.2
B. Preparation of
(3S,4aS,6S,8aR)6-(4-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy)-2-tert-butoxy-
carbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid
[0297] A mixture of the material from step A (120 mg, 0.26 mmol)
and azidotri-n-butylstannane (0.21 mL, 0.78 mmol) was stirred under
nitrogen at 50.degree. C. for 76 h and at 70.degree. C. overnight.
The reaction mixture was directly treated with ethanol (2 mL) and
lithium hydroxide aqueous solution (40%, 2.5 mL) and stirred at
room temperature for 24 h. The reaction mixture was diluted with
water and washed with ethyl acetate (2.times.). The aqueous layer
was made acidic by addition of hydrochloric acid (10%, till pH=5-6)
and extracted with ethyl acetate (3.times.). The combined organic
phases were dried and concentrated in vacuo to afford the title
compound as a foam (98 mg, 79%, two steps).
[0298] Ion Electrospray Mass Spectrum M+1: 478.2
C. Preparation of
(3S,4aS,6S,8aR)6-[4-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0299] The material from step B (95 mg, 0.2 mmol) was treated with
hydrochloric acid (5N, 1.5 mL) at room temperature for 5 h to give,
after trituration with ethyl acetate and diethyl ether, the desired
amino acid (37 mg, 49%)
[0300] Ion Electrospray Mass Spectrum M-HCl+1: 378.1
[0301] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 7.95 (d, J=2.6 Hz,
1H); 7.54 (dd, J=9.0, 2.6 Hz, 1H); 7.32 (d, J=9.0 Hz, 1H); 4.59 (m,
1H); 4.14 (dd, J=13.4, 2.7 Hz, 1H); 3.22 (dd, J=13.0, 4.4 Hz, 1H);
2.21-1.65 (m, 10H).
Example 18
Preparation of
(3S,4aS,6S,8aR)6-[5-methyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00053##
[0302] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(5-methyl-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,-
2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0303] To a solution of the material from preparation 1 (200 mg,
0.61 mmol), triphenylphosphine (192 mg, 0.73 mmol),
4-methyl-2-hydroxy-benzonitrile (89 mg, 0.67 mmol) and dry pyridine
(0.055 mL, 0.67 mmol) in dry tetrahydrofuran (3.1 mL) under
nitrogen, neat diethylazodicarboxylate (0.115 mL, 0.73 mmol) was
added dropwise at 0.degree. C. The reaction mixture was stirred for
48 h at room temperature and concentrated in vacuo. A solution of
the material in methylene chloride was washed with sodium hydroxide
aqueous solution (0.5 M, .times.2), dried and evaporated in vacuo.
Flash chromatography (silicagel, 25% ethyl acetate/hexane) gave 86
mg of the desired compound (32%).
[0304] Ion Electrospray Mass Spectrum M+1-t-butylOCO: 343.3
B. Preparation of
(3S,4aS,6S,8aR)6-[5-methyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0305] Following the procedures as described in Example 17, step B
the material from step A (70 mg, 0.15 mmol) was treated with
azidotri-n-butylstannane (0.125 mL, 0.45 mmol) at 85.degree. C. for
76 h and then treated with ethanol (1.5 mL) and lithium hydroxide
aqueous solution (40%, 2 mL) for 48 h to afford a material (33 mg)
that was directly submitted to the next reaction. The above
material was treated with ethyl acetate saturated with hydrogen
chloride (2 mL) at room temperature for 4 h to give, after
trituration with ethyl acetate and diethyl ether, the title
compound (17 mg, 65%, three steps)
[0306] Ion Electrospray Mass Spectrum M+1: 358.3
[0307] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 7.86 (d, J=7.9 Hz,
1H); 7.14 (s, 1H); 6.96 (d, J=7.9 Hz, 1H); 4.89 (m, 1H); 4.09 (dd,
J=12.3, 3.7 Hz, 1H); 3.42 (t, J=13.0 Hz, 1H); 3.15 (dd, J=12.9, 4.1
Hz, 1H); 2.43 (s, 3H); 2.21-1.51 (m, 10H).
Example 19
Preparation of
(3S,4aS,6S,8aR)6-[5-methoxy-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5-
,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00054##
[0308] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(5-methoxy-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1-
,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0309] Following the procedures as described in Example 18, step A,
a solution of the material from preparation 1, triphenylphosphine,
4-methoxy-2-hydroxy-benzonitrile (100 mg, 0.67 mmol) and pyridine
in tetrahydrofuran, was treated with diethylazodicarboxylate at
room temperature for 24 h. Flash chromatography (silicagel, 35%
ethyl acetate/hexane) gave 150 mg of the desired compound
(54%).
[0310] Ion Electrospray Mass Spectrum M+Na: 481.1
B. Preparation of
(3S,4aS,6S,8aR)6-[5-methoxy-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5-
,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0311] Following the procedures as described in Example 17, step B
the material from step A (125 mg, 0.27 mmol) was treated with
azidotri-n-butylstannane (0.225 mL, 0.82 mmol) at 85.degree. C. for
45 h and then treated with ethanol (2 mL) and lithium hydroxide
aqueous solution (40%, 2.5 mL) for 48 h to afford an oil (79 mg)
that was directly treated with ethyl acetate saturated with
hydrogen chloride (2 mL) to give the title compound (45 mg, 41%,
three steps)
[0312] Ion Electrospray Mass Spectrum M+1: 374.2
[0313] Analysis calcd. for: C18H23N5O4.1.7 HCl.0.2 CH3CH2OH: C,
49.71; H, 5.87; N, 15.75; Found: C, 50.05; H, 5.52; N, 15.51.
Example 20
Preparation of
(3S,4aS,6S,8aR)6-[2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a--
decahydroisoquinoline-3-carboxylic acid
##STR00055##
[0314] A. Preparation of
ethyl(3S,4aS,6S,8aR)6-(2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,-
5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0315] Following the procedures as described in Example 18, step A,
a solution of the material from preparation 1 (400 mg, 1.22 mmol),
triphenylphosphine (384 mg, 1.46 mmol), 2-hydroxy-benzonitrile (160
mg, 1.34 mmol) and pyridine (0.11 mL, 1.34 mmol) in tetrahydrofuran
(6.1 mL), was treated with diethylazodicarboxylate (0.23 mL, 1.46
mmol) at room temperature for 43 h. Flash chromatography
(silicagel, 35% ethyl acetate/hexane) gave 264 mg of the desired
intermediate (51%).
[0316] Mass Spectrum (Fast Atom Bombardment) M+1: 429.3
B.
(3S,4aS,6S,8aR)6-[2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8-
a-decahydroisoquinoline-3-carboxylic acid
[0317] The intermediate from step A (45 mg, 0.105 mmol), was
treated with azidotributyltin (0.17 mL, 0.626 mmol) and heated at
80.degree. C. for three days. The mixture was concentrated in vacuo
and treated with 2.5 M lithium hydroxide solution (3 mL) and heated
at 50.degree. C. overnight. Then the mixture was extracted with
ethyl acetate and the aqueous phase was separated and treated with
ethyl acetate saturated with hydrogen chloride and extracted. The
aqueous phase was concentrated in vacuo, the product was dissolved
in water and then Dowex resin (2.0 g) was added and stirred for 1
h. The resin was washed with water and 50 mL 1:1
tetrahydrofuran/water. The resin was collected, a 10% solution
pyridine-water was added and the mixture was stirred for 2 hours,
filtered and the filtrate was collected. The resin was washed with
water (10 mL) and the combined pyridine-water filtrate was
concentrated in vacuo to give 18 mg (50% yield) of the title
compound.
[0318] Mass Spectrum (Fast Atom Bombardment) M+1: 344.2
[0319] .sup.1H NMR (CD.sub.3OD, 200.13 MHz): 7.54 (m, 1H),7.33 (m,
1H); 7.13 (m, 2H); 4.12 (m, 1H); 3.22 (m, 1H); 2.95 (m, 1H); 2.59
(m, 1H); 2.10-1.39 (m, 10H).
Example 21
Preparation of
(3S,4aS,6S,8aR)6-[5-Benzyloxy-3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1-
,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
##STR00056##
[0320] A. 4-Benzyloxy-2,6-difluorobenzonitrile
[0321] To a suspension of 2,4,6-trifluorobenzonitrile (314 mg, 2.00
mmol) and potassium carbonate (828 mg, 6.00 mmol) in dry
N,N-dimethylformamide (3 mL) at 100.degree. C. was added a solution
of benzyl alcohol (216 mg, 2.00 mL) in dry N,N-dimethylformamide (1
mL) using a syringe pump over 4 h and the resulting mixture was
stirred at 100.degree. C. for 1 h. The reaction mixture was stirred
at room temperature overnight and water and ethyl acetate were
added and the phases separated. The organic phase was washed with
1.2 M hydrochloric acid (3.times.) and the combined organic phases
were back-extracted with ethyl acetate (3.times.). The organic
phases were dried (sodium sulfate), filtered, concentrated in vacuo
and the residue was purified by flash chromatography (silica gel,
hexanes-ethyl acetate 15:1) to give a white solid, mixture of
regioisomers. The title product was obtained as a white solid (51
mg, 10%) by HPLC purification (reversed phase).
[0322] Ion Electrospray Mass Spectrum M+18: 263.
B. Preparation of
ethyl(3S,4aS,6S,8aR)6-(5-benzyloxy-3-fluoro-2-cyano-phenoxy)-2-tert-butox-
ycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0323] Following the procedures as described for Example 9, step A,
reaction of material from step A (51 mg, 0.21 mmol) with
Preparation 1 (52 mg, 0.18 mmol) and potassium tert-butoxide (0.40
mL, 0.40 mmol) in tetrahydrofuran (2 mL) gave, after flash
chromatography (silica gel, hexanes-ethyl acetate-acetic acid:
1:1:0.01) the desired product as a white solid (58 mg) in 61%
yield.
[0324] Ion Electrospray Mass Spectrum M+Na: 547
C. Preparation of
(3S,4aS,6S,8aR)6-[5-Benzyloxy-3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1-
,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
[0325] As for Example 9, step B, the reaction between material from
step B (58 mg, 0.11 mmol) and azido tributyltin (8 equiv, 292 mg,
0.88 mmol) at 90.degree. C. for 5 d gave the desired tetrazol. The
crude product was dissolved in 1 M hydrogen chloride/ethyl acetate
solution (5 mL) and the mixture was stirred at room temperature 2 h
and filtered. The solid was washed with ethyl, dried and purified
by solid-phase extraction to give pure amino acid as a pale yellow
solid (25 mg, 45%) and small amount (7 mg, 13%) slightly
impure.
[0326] Ion Electrospray Mass Spectrum M+1: 568.
Preparation 3
Preparation of
ethyl(3S,4aS,6R,8aR)6-methanesulfonyloxy-2-methoxycarbonyl-1,2,3,4,4a,5,6-
,7,8,8a-decahydroisoquinoline-3-carboxylate
##STR00057##
[0328] To an ice-cooled solution of
ethyl(3S,4aS,6R,8aR)6-hydroxy-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-dec-
ahydroisoquinoline-3-carboxylate (760 mg, 2.66 mmol) in dry
dichloromethane (10 mL) under nitrogen, triethylamine (0.60 mL, 4.3
mmol) and methanesulfonyl chloride (0.33 mL, 4.3 mmol) were added.
The resulting mixture was stirred overnight at room temperature and
a saturated solution of ammonium chloride was added (10 mL). The
layers were separated and the aqueous layer extracted with
dichloromethane (10 mL.times.2). The combined organic phases were
washed with 1 N hydrochloric acid (10 mL), dried over sodium
sulfate and concentrated in vacuo to give the title compound as an
oil (0.965 g, 100%).
[0329] Ion Electrospray Mass Spectrum M+1: 364
Example 22
Preparation of
(3S,4aS,6S,8aR)6-((3-carboxy-2-naphthalenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-d-
ecahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00058##
[0330] A. Methyl
3-(((trifluoromethane)sulfonyl)oxy)-2-naphthoate
[0331] To a solution of methyl 3-hydroxy-2-naphthoate (500 mg, 2.47
mmol) and 4-(N,N-dimethylamino)pyridine (603 mg, 4.94 mmol) in
dichloromethane (25 mL) at 0.degree. C. under nitrogen,
trifluoromethanesulfonic anhydride (677 mg, 0.404 mL, 2.97 mmol)
was added dropwise and the reaction mixture was stirred for 10 min
at 0.degree. C. and then at room temperature until no starting
material is left according to TLC (hexane-ethyl acetate 9:1) (a
second addition of 0.1-0.2 equiv of trifluoromethanesulfonic
anhydride might be required). The reaction mixture was treated with
saturated aqueous solution of ammonium chloride and the phases
separated. The organic phase was washed twice with saturated
aqueous solution of ammonium chloride and the aqueous were phases
back-extracted with dichloromethane. The combined organic phases
were washed with brine, treated with a spoon of silica gel to
remove traces of N,N-dimethylaminopyridine, dried with anhydrous
sodium sulfate, filtered and concentrated in vacuo, to afford the
desired triflate in quantitative yield (845 mg) as a white solid.
The product was used without further purification.
[0332] Electronic Impact Mass Spectrum M+: 334.
[0333] Analysis Calculated for C.sub.13H.sub.9F.sub.3O.sub.5S: C,
46.71; H, 2.71 Found: C, 46.54; H, 2.66
B. Methyl 3-mercapto-2-naphthoate
[0334] To a carefully deoxygenated solution of the compound from
step A (200 mg, 0.60 mmol) in dry benzene (2 mL) under nitrogen at
room temperature, a solution of tetrakistriphenylphosphine
palladium (0) (0.05 equiv, 34 mg, 0.03 mmol) and sodium
triisopropilsilanethiolate in dry tetrahydrofuran [1.3 equiv,
prepared from triisopropilsilanethiol (148 mg, 0.78 mmol) and
sodium hydride (95%, 20 mg, 0.78 mmol) in tetrahydrofuran (2 mL) at
0.degree. C. 5-10 min, then 5-10 min at room temperature] was added
and the reaction mixture was warmed to reflux (bath temp 90.degree.
C.) for 1.5 h. The reaction mixture was cooled down and
concentrated in vacuo. The crude residue was dissolved in
tetrahydrofuran (5 mL) and treated with tetrabutylammonium fluoride
(1 M solution in tetrahydrofuran, 1 equiv, 0.6 mL, 0.6 mmol) at
0.degree. C. and stirred for 45 min. Glacial acetic acid (0.5 mL)
was added and the reaction mixture stirred at 0.degree. C. for 15
min. Diethyl ether and water were added and the phases separated.
The aqueous phase was extracted twice with diethyl ether and the
organic phases dried (sodium sulfate-magnesium sulfate) filtered
and concentrated in vacuo. Flash chromatography (silica gel,
hexane-ethyl acetate 25:1) gave the desired thiol as a white solid
(91 mg, 69%).
[0335] Electronic Impact Mass Spectrum M+: 218.
C.
Ethyl(3S,4aS,6S,8aR)6-((3-methoxycarbonyl-2-naphthalenyl)thio)-2-methox-
ycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0336] To a solution of decahydroisoquinoline mesylate from
preparation 3 (76 mg, 0.21 mmol) in acetone (0.5 mL), potassium
carbonate solid (29 mg, 0.21 mmol) was added under nitrogen,
followed by addition of a solution of thiol from step B (45 mg,
0.21 mmol) in acetone (0.5 mL) under nitrogen, and the resulting
yellow suspension stirred under reflux for 7 h. More potassium
carbonate solid (29 mg, 0.21 mmol) and more thiol from step B (45
mg, 0.21 mmol) in acetone (0.5 mL) were added and the mixture
stirred under reflux overnight. The reaction mixture was cooled
down and concentrated in vacuo. Flash chromatography (silica gel,
hexane-ethyl acetate 2.5:1) gave the desired product (36.5 mg, 36%
yield).
[0337] .sup.1H NMR (CDCl.sub.3, 200.15 MHz): 8.39 (s, 1H); 7.83 d,
J=7.8 Hz, 1H); 7.74 (d, overlapping, 1H); 7.72 (s, 1H); 7.58-7.41
(m, 2H); 4.74 (dd, J=5.8, 3.4 Hz, 1H); 4.16 (q, 7.2 Hz, 2H); 3.96
(s, 3H); 3.70 (s, 3H); 3.68 (m, 2H); 3.30 (br d, J=11 Hz, 1H); 2.45
(m, 1H); 2.2-1.7 (m, 8H); 1.45 (m, 1H); 1.24 (t, J=7.1 Hz, 3H).
D.
(3S,4aS,6S,8aR)6-((3-Carboxy-2-naphthalenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-
-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0338] The alkylated decahydroisoquinoline derivative from step C
(36 mg, 0.075 mmol) was treated with 6M hydrochloric acid under
reflux for 35 h. The solution was concentrated in vacuo and water
added and concentrated in vacuo (3.times.), followed by addition of
acetone and concentration in vacuo (3.times.), to give an off-white
solid (30 mg, 96% yield).
[0339] M.p.>183.degree. C. with dec.
[0340] Fast Atom Bombardment Mass Spectrum M-Cl+1: 386.
[0341] Analysis Calculated for C.sub.21H.sub.24NO.sub.4S.2H.sub.2O:
C, 55.08; H, 6.16; N, 3.06 Found: C, 55.08; H, 6.34; N, 3.19
Example 23
Preparation of
(3S,4aS,6S,8aR)6-(2-(1(2)H-tetrazolylphenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-d-
ecahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00059##
[0342] A.
Ethyl(3S,4aS,6S,8aR)6-((2-cyanophenyl)thio)-2-methoxycarbonyl-1,-
2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0343] Following the procedures for Example 22, Step C,
decahydroisoquinoline mesylate from preparation 3 (102 mg, 0.28
mmol) in acetone (0.5 mL), potassium carbonate solid (38 mg, 0.28
mmol, twice) and 2-mercaptobenzonitrile (38 mg, 0.286 mmol, twice)
gave, after flash chromatography (hexanes-ethyl acetate 2:1), the
desired product as an oil (64 mg) in 57% yield.
[0344] Electronic Impact Mass Spectrum M+: 402.
B.
(3S,4aS,6S,8aR)6-(2-(1(2)H-Tetrazolylphenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-
-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0345] The alkylated decahydroisoquinoline from step A (122 mg,
0.30 mmol) and azidotributyltin (199 mg, 0.60 mmol) were stirred at
80.degree. C. for 2 days. More azidotributyltin (242 mg, 0.73 mmol)
was added and the reaction stirred at 80.degree. C. 3 more days.
Diethyl ether and hexane were added and the oil was washed twice
and dried in vacuo. The residue was treated with 6M HCl under
reflux for 1.5 days. The reaction mixture was elaborated as in
example 22, Step D to give the title compound in 98% yield as a
pale beige solid.
[0346] Fast Atom Bombardment Mass Spectrum M+1: 360
[0347] Analysis Calculated for
C.sub.17H.sub.22ClN.sub.5O.sub.2S.3H.sub.2O: C, 45.38; H, 6.27; N,
15.56 Found: C, 45.18; H, 5.82; N, 15.35
Example 24
Preparation of
(3S,4aS,6S,8aR)6-((2-carboxy-5-methylphenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-d-
ecahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00060##
[0348] A. Ethyl
4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate
[0349] Following the procedures for Example 22, Step A, ethyl
4-methylsalicylate (500 mg, 2.77 mmol),
4-(N,N-dimethylamino)pyridine (676 mg, 5.54 mmol) and
trifluoromethanesulfonic anhydride (938 mg, 0.447 mL, 3.32 mmol)
gave the desired triflate as a pale orange oil (760 mg, 88% yield).
The product was used without further purification.
[0350] Electronic Impact Mass Spectrum M+: 312.
[0351] Analysis Calculated for C.sub.11H.sub.11F.sub.3O.sub.5S: C,
42.31; H, 3.55 Found: C, 42.89; H, 3.84
B. Ethyl 2-mercapto-4-methylbenzoate
[0352] To a solution of the triflate from step A (500 mg, 1.60
mmol) and tetrakistriphenylphosphine palladium(0) (0.05 equiv, 92
mg, 0.08 mmol) in dry benzene (2 mL) under nitrogen at room
temperature, a solution of sodium triisopropilsilanethiolate in dry
tetrahydrofuran [1.3 equiv, prepared from triisopropilsilanethiol
(396 mg, 2.08 mmol) and sodium hydride (95%, 52 mg, 2.08 mmol) in
tetrahydrofuran (2 mL) as in Example 22, Step B] was added and the
reaction mixture was warmed to reflux (bath temp 90.degree. C.) for
3.5 h. The reaction mixture was cooled down to 0.degree. C. and
tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 1.5
equiv, 3.1 mL, 3.1 mmol) and glacial acetic acid (3.5 equiv, 437
mg, 0.405 mL, 7.28 mmol) were added and the reaction mixture
stirred at 0.degree. C. for 20 min. Work-up as in Example 22, Step
B gave, after flash chromatography (silica gel, hexane-ethyl
acetate 25:1), the desired thiol as an oil (220 mg, 70%). The
product was kept under nitrogen at -18.degree. C.
[0353] Electronic Impact Mass Spectrum M+: 196.
C.
Ethyl(3S,4aS,6S,8aR)6-((2-ethoxycarbonyl-5-methylphenyl)thio)-2-methoxy-
carbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0354] Following the procedures for Example 22, Step C,
decahydroisoquinoline mesylate from preparation 3 (145 mg, 0.40
mmol), potassium carbonate solid (65 mg, 0.46 mmol, twice) and
thiol from step B (90 mg, 0.42 mmol, twice) gave, after flash
chromatography (silica gel, hexane-ethyl acetate 3:1) the desired
product (107 mg, 57% yield)
[0355] Electronic Impact Mass Spectrum M+: 463.
D.
(3S,4aS,6S,8aR)6-((2-Carboxy-5-methylphenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-
-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0356] Following the procedures for Example 22, Step D, extensive
hydrolysis of material from step C (54 mg, 0.12 mmol) with 6M
hydrochloric acid (3 mL) gave the title product (39 mg, 84%
yield).
[0357] M.p.>177.degree. C. (dec).
[0358] Fast Atom Bombardment Mass Spectrum M-HCl+1: 350.
[0359] .sup.1H NMR (CD.sub.3OD, 200.15 MHz,): 7.78 (d, J=7.9 Hz,
1H); 7.29 (s, 1H); 7.03 (d, J=7.7 Hz, 1H); 4.01 (m, 1H); 3.5-3.2
(m, 2H); 3.09 (br d, J=10.3 Hz, 1H); 2.37 (s, 3H); 2.3-1.6 (m, 8H);
1.4 (m, 2H).
Example 25
Preparation of
(3S,4aS,6S,8aR)6-((2-carboxy-5-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-d-
ecahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00061##
[0360] A. Ethyl 2-mercapto-4-Chlorobenzoate
[0361] 4-Chloro-2-mercaptobenzoic acid (2.9 g, 15.4 mmol) was
dissolved in ethanol (200 mL) and concentrated sulfuric acid (9 mL)
was added. The solution was stirred at 80-85.degree. C. overnight.
The solvent was evaporated in vacuo. The residue was dissolved with
200 mL of diethyl ether and washed with water (100 mL) and sodium
bicarbonate saturated solution (2.times.100 mL). The organic layer
was dried, filtered and concentrated in vacuo. Flash chromatography
(silica gel, 15% ethyl acetate/hexane) gave 2.5 g of the title
compound (75%).
[0362] Electronic Impact Mass Spectrum M+: 216.
B.
Ethyl(3S,4aS,6S,8aR)6-((2-ethoxycarbonyl-5-chlorophenyl)thio)-2-methoxy-
carbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0363] To the intermediate from step A (70 mg, 0.32 mmol) a
solution of the material from preparation 3 (78 mg, 0.21 mmol) in
acetone (2 mL) was added, followed by addition of anhydrous
potassium carbonate solid (50 mg, 0.36 mmol). The resulting yellow
suspension was stirred under reflux for 24 h. More anhydrous
potassium carbonate (50 mg, 0.36 mmol) and more thiol from step A
(70 mg, 0.32 mmol) in acetone (0.5 mL) were added and the mixture
stirred under reflux for 20 h. The reaction was cooled down and
quenched with a saturated solution of ammonium chloride (1 mL). The
mixture was extracted with ethyl acetate (10 mL) and the organic
layer was dried, filtered and concentrated in vacuo. Flash
chromatography (silica gel, 60% diethyl ether/hexane) gave the
title compound as an oil in 67% yield.
[0364] Electronic Impact Mass Spectrum M+1: 485
C.
(3S,4aS,6S,8aR)6-((2-Carboxy-5-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-
-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0365] The intermediate from step B (30 mg, 0.06 mmol) was treated
with 6M hydrochloric acid under reflux for 60 h. The solution was
cooled down and concentrated in vacuo, followed by washing the
resulting solid with acetone (3.times.5 mL), to give an off-white
solid (17 mg, 68%)
[0366] Fast Atom Bombardment Mass Spectrum M+1: 370
[0367] Analysis calculated for
C.sub.17H.sub.21Cl.sub.2NO.sub.4S.1.5 H.sub.2O: C, 47.12; H, 5.58;
N, 3.23. Found: C, 47.12; H, 5.51; N, 3.39.
Example 26
Preparation of
(3S,4aS,6S,8aR)6-((2-carboxy-4-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-d-
ecahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00062##
[0368] A. Ethyl
5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)benzoate
[0369] To a solution of 5-chlorosalicylic acid ethyl ester (500 mg,
2.49 mmol) and 2,6-lutidine (534 mg,0.58 mL, 4.98 mmol) in
dichloromethane at 0.degree. C., trifluoromethanesulfonic anhydride
(773 mg,0.46 mL, 2.74 mmol) was added dropwise and the reaction was
stirred 6 h at room temperature. More trifluoromethanesulfonic
anhydride (0.25 mL) and 2,6-lutidine (1.1 mL) were added and the
reaction stirred at room temperature overnight. More
trifluoromethanesulfonic anhydride (0.35 mL) and 2,6-lutidine (0.40
mL) and 4-(N,N-dimethylamino)pyridine (44 mg, 0.36 mmol) were added
and the reaction was stirred at room temperature overnight. The
reaction mixture was treated with 1.2M hydrochloric acid and the
phases were separated. The aqueous phase was back-extracted with
dichloromethane and the combined organic phases were washed with
brine, dried with anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by flash
chromatography (silica gel, hexane-ethyl acetate 65:1) to give the
triflate as a pale yellow oil (547 mg, 66% yield).
[0370] Electronic Impact Mass Spectrum M+: 332.
B. Ethyl 2-mercapto-5-chlorobenzoate
[0371] To a solution of the triflate from step A (100 mg, 0.30
mmol) in dry toluene (2 mL) under nitrogen at room temperature, a
solution of tetrakistriphenylphosphine palladium (0) (0.10 equiv,
35 mg, 0.03 mmol) and sodium triisopropilsilanethiolate in dry
tetrahydrofuran (1.0 equiv, prepared from triisopropilsilanethiol
(190 mg, 10 mmol) and sodium hydride (95%, 24 mg, 10 mmol) in
tetrahydrofuran (2 mL) as in Example 22, Step B) was added and the
reaction mixture was warmed at 90.degree. C. (bath temp.) for 4 h.
The reaction mixture was cooled down and concentrated in vacuo.
Flash chromatography (silica gel, hexane-ethyl acetate 40:1) gave
92 mg of a mixture of triisopropylsilylarylthiol and free arylthiol
contaminated with small amounts of triphenylphosphine, which was
used without further purification in next step.
[0372] Electronic Impact Mass Spectrum M+-triisopropylsilyl:
216
C.
Ethyl(3S,4aS,6S,8aR)6-((2-ethoxycarbonyl-4-chlorophenyl)thio)-2-methoxy-
carbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0373] To a solution of the mixture from step B in
N,N-dimethylformamide (0.5 mL), tetrabutylammonium fluoride (1 M
solution in tetrahydrofuran, 0.12 mL, 0.12 mmol) was added and the
reaction mixture was stirred for 1 h at room temperature. A
solution of material from preparation 3 (50 mg, 0.13 mmol) in
N,N-dimethylformamide (0.5 mL) was then added and the resulting
mixture was stirred at 60.degree. C. overnight. Ethyl acetate and
water were added and the phases were separated. The organic phase
was washed successively with 1.2 M hydrochloric acid, brine, dried
(sodium sulfate) and concentrated in vacuo. The residue was
purified by flash chromatography (silical gel, hexane-diethyl ether
2:3) to give the desired product in 17% yield.
[0374] Electronic Impact Mass Spectrum M+-3 carboxylates: 279
D.
(3S,4aS,6S,8aR)6-((2-Carboxy-4-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-
-decahydroisoquinoline-3-carboxylic acid hydrochloride
[0375] Following the procedures for Example 22, Step D, the
decahydroisoquinoline derivative from step C (10 mg, 0.021 mmol)
gave an off-white solid (4 mg, 47% yield).
[0376] .sup.1H NMR (CD.sub.3OD, 200.15 MHz): 7.84 (br s, 1H); 7.48
(br s, 2H); 4.01 (br d, J=12 Hz, 1H); 3.5-3.0 (m, 3H); 2.3-1.7 (m,
8H); 1.5-1.2 (m, 2H).
[0377] Fast Atom Bombardment Mass Spectrum M-HCl+1: 370
Example 27
Preparation of
Ethyl(3S,4aS,6S,8aR)6-((2-ethoxycarbonyl-5-chlorophenyl)thio)-1,2,3,4,4a,-
5,6,7,8,8a-decahydroisoquinoline-3-carboxylate hydrochloride
##STR00063##
[0379] Material from Example 25 (1.78 g, 4.39 mmol) was suspended
in saturated hydrogen chloride solution in ethanol (100 mL) and the
reaction mixture was heated at reflux overnight. The solvent was
concentrated in vacuo. The solid was triturated with ethyl ether
and was filtered to afford 1.75 g (86%) of the title compound.
[0380] Ion Electrospray Mass Spectrum M-HCl+1: 425
Preparation 4
4-Benzyl-2-fluoro-benzonitrile
##STR00064##
[0381] A. Trifluoro-methanesulfonic acid 4-cyano-3-fluoro-phenyl
ester
[0382] To a solution of 16.0 g (116.6 mmol) of
2-fluoro-4-hydroxybenzonitrile and 50.0 g (140.0 mmol) of
N-phenyltrifluoromethanesulfonimide in 250 mL of dichloromethane is
added N,N-diisopropylethylamine and the mixture is stirred for 16
hr at room temperature. The mixture is then washed with 10% aqueous
sodium bisulfate. The organic portion is separated and the aqueous
portion is extracted three times with dichloromethane. The combined
organic portions are dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. Chromatography (silica gel, 50%
chloroform/hexane) of the residue affords 26.7 g (85%) of the title
compound.
[0383] Field Desorption Mass Spectrum: M=269.
B. 4-Benzyl-2-fluoro-benzonitrile
[0384] To a room temperature solution of 1.5 g (5.57 mmol) of the
triflate from Step A above, 0.32 g (0.56 mmol) of
bis(dibenzylideneacetone)palladium and
1,1'-bis(diphenylphosphino)-ferrocene in 15 mL of tetrahydrofuran
is added to 12.25 mL (6.13 mmol) of a 0.5 M solution of benzylzinc
bromide in tetrahydrofuran via syringe. The mixture is heated to
65.degree. C. for 16 hr and cooled to room temperature. The mixture
is poured into saturated ammonium chloride and extracted two times
with ethyl acetate. The combined organic portions are dried
(MgSO.sub.4), filtered, and concentrated in vacuo. Chromatography
(Biotage, 100% toluene) of the residue affords 0.76 g (65%) of the
title compound.
[0385] Field Desorption Mass Spectrum: M=211.
Example 28
(3S,4aS,6S,8aR)6-[5-Benzyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6-
,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00065##
[0387] Following the procedures as described in Example 9 using
0.45 g (1.51 mmol) of material from Preparation 2 and 0.32 g (1.51
mmol) of material from Preparation 4 affords 0.13 g (21% overall
yield) of the title compound.
[0388] Electrospray Mass Spectrum: M+1=434.
Preparation 5
2-Fluoro-4-thiophen-2-yl-benzonitrile
##STR00066##
[0390] To a degassed solution of 2.5 g (9.3 mmol) of the triflate
from Preparation 4, Step A above, 1.3 g (10.4 mmol) thiophene and
1.4 g (10.4 mmol) of potassium carbonate in 24 mL of toluene is
added to 0.4 g (0.37 mmol) of tetrakis (triphenylphosphine)
palladium(0). The mixture is heated to 90.degree. C. for 5.5 hr and
cooled to room temperature. The mixture is then diluted with ethyl
acetate and washed with water. The organic portion is separated and
the aqueous portion is extracted two times with ethyl acetate. The
combined organic portions are dried over MgSO.sub.4, filtered, and
concentrated in vacuo. Chromatography (silica gel, 10% ethyl
acetate/hexane) of the residue affords 1.2 g (79%) of the title
compound.
[0391] Field Desorption Mass Spectrum: M=203.
Example 29
(3S,4aS,6S,8aR)6-[5-(2-thienyl)-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4-
a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
##STR00067##
[0392] A.
(3S,4aS,6S,8aR)6-[5-(2-thienyl)-2-cyano]-phenoxy-2-methoxycarbon-
yl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid
[0393] Following the procedures as described in Step A of Example
9, using 1.0 g (3.9 mmol) of
(3S,4aS,6S,8aR)6-hydroxy-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydr-
oisoquinoline-3-carboxylic acid (prepared as described in U.S. Pat.
Nos. 4,902,695, 5,446,051, and No. 5,356,902) and 0.8 g (3.9 mmol)
of material from Preparation 5, affords 0.84 g (49%) of the title
compound.
[0394] Electrospray Mass Spectrum: M+NH.sub.4.sup.+=458.
B.
(3S,4aS,6S,8aR)6-[5-(2-thienyl)-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-meth-
oxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid
[0395] A solution of 0.84 g (1.9 mmol) of material from Part A and
1.6 g (4.8 mmol) of azidotributyltin, in just enough
tetrahydrofuran to dissolve the nitrile, is heated to 95.degree. C.
for 48 hr and the tetrahydrofuran is allowed to evaporate from the
mixture. The mixture is cooled to room temperature and 8 mL of
methanol is added. To this mixture is added 0.8 mL of 5 N sodium
hydroxide and the mixture is stirred for 1.5 hr. The mixture is
concentrated in vacuo and partitioned between water and diethyl
ether. The organic portion is separated and the aqueous portion is
washed once with diethyl ether. The aqueous portion is acidified
(pH2) with 10% aqueous sodium bisulfate and extracted four times
with ethyl acetate. The combined organic portions are dried
(MgSO.sub.4), filtered, and concentrated in vacuo. The resulting
solid is suspended in ethyl acetate and stirred for 16 hr. The
suspension is filtered and dried in vacuo to afford 0.57 g (62%) of
the title compound.
[0396] Electrospray Mass Spectrum: M+1=484.
C.
(3S,4aS,6S,8aR)6-[5-(2-thienyl)-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,-
4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
[0397] To a suspension of 0.56 g (1.32 mmol) of material from Part
B in 8 mL of chloroform is added 0.75 mL (5.28 mmol) of
iodotrimethylsilane. The mixture is stirred for 3 hr and 0.19 mL
(1.32 mmol) more of iodotrimethylsilane is added. The mixture is
stirred for 16 hr more and concentrated in vacuo. Water is added
and the mixture is concentrated in vacuo two times. The resulting
solid is suspended in water, filtered, and rinsed with acetone then
diethyl ether. A precipitate forms in the filtrate and is filtered
and dried in vacuo. The solids are combined, suspended in 10 mL of
5 N hydrochloric acid, and stirred for 16 hr. The suspension is
filtered and rinsed with water, acetone, and then diethyl ether.
The solid is dried in vacuo to afford 0.13 g (21%) of the title
compound.
[0398] Electrospray Mass Spectrum: M+1=426.
Preparation 6
3,2'-Difluoro-biphenyl-4-carbonitrile
##STR00068##
[0400] The material from Preparation 4, Step A (2.5 gm, 9.3 mmol),
2-Fluorophenylboronic acid (1.82 gm, 13.0 mmol), and powdered
potassium carbonate (1.93 gm, 13.9 mmol) are combined with toluene
(25 mL). The solution is stirred under a nitrogen atmosphere and
degassed. Tetrakis(triphenylphosphine)palladium(0) (1.07 gm, 0.93
mmol) is added with a toluene rinse (5 mL), and the solution is
degassed and heated at 90.degree. C. overnight. The reaction is
diluted with ethyl acetate and washed with distilled water
(2.times.). The separated aqueous layer is back extracted with
ethyl acetate (3.times.). The combined organics are dried
(magnesium sulfate), filtered, and concentrated to give crude oil
(3.14 gm). Chromatography (0 to 50% chloroform in hexane) affords
the product as a white solid: 1.97 gm (98.5%). MS (m/z, EI+):
215.3.
Example 30
(3S,4aS,6S,8aR)6-[2'-Fluoro-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,4-
,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
##STR00069##
[0401] A.
(3S,4aS,6S,8aR)6-(4-Cyano-2'-fluoro-biphenyl-3-yloxy)-1,2,3,4,4a-
,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid
2-tert-butyl ester
[0402] The material from Preparation 6 (0.36 gm, 1.67 mmol) is
added to a 0.degree. C. solution of material from Preparation 2
(0.50 gm, 1.67 mmol) and potassium tert-butoxide (1.0 M in
tetrahydrofuran, 5.01 mL) in anhydrous tetrahydrofuran (6 mL),
after the solution is stirred at 0.degree. C. for 20 minutes. The
reaction is stirred for 24 hrs at room temperature, and potassium
tert-butoxide (1.0 M in tetrahydrofuran, 0.84 mL) is added at
0.degree. C. The reaction is then stirred at room temperature for a
few hours, and then diluted with aqueous sodium bisulfate (10%
aq.). The separated aqueous layer is extracted with ethyl acetate
(3.times.). The combined organics are dried (magnesium sulfate),
filtered, and concentrated in vacuo to give crude material (1.10
gm). Chromatography (0-30% ethyl acetate in hexane with 2% acetic
acid) gives the title product: 0.37 gm (45%). MS (m/z, ES+):
495.2.
B.
(3S,4aS,6S,8aR)6-[2'-Fluoro-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,-
3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
[0403] To a solution of material from Step A (0.34 gm, 0.69 mmol)
in anhydrous tetrahydrofuran (0.8 mL) is added azidotributyltin
(0.68 gm, 2.05 mmol). The reaction is stirred under nitrogen at
95.degree. C. for 3 days. The reaction is diluted in a small volume
of dichloromethane and chromatographed (40% ethyl acetate in hexane
containing 3% acetic acid to give the desired product.
C.
(3S,4aS,6S,8aR)6-[2'-Fluoro-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,-
3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
[0404] To a solution of material from Step B in ethyl acetate (3.5
mL) is added a solution of hydrogen chloride (2 M in ethyl acetate,
3.5 mL). The reaction is stirred at room temperature under nitrogen
overnight. The precipitated solid is filtered, washed with ethyl
acetate (2.times.) and then with diethyl ether (2.times.), and
dried in a vacuum oven to give final product: 0.179 gm (55%
combined Steps B&C yield). MS (m/z, ES+): 438.2.
Example 31
(3S,4aS,6S,8aR)6-[4'-Methyl-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,4-
,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
##STR00070##
[0406] Following the procedures as described in Preparation 6 and
Example 30, above, and using Trifluoro-methanesulfonic acid
4-cyano-3-fluoro-phenyl ester (0.64 gm, 2.37 mmol) and
4-Methylphenylboronic acid (0.45 gm, 3.33 mmol) affords 0.301 gm
(38% overall yield) of the title compound. MS (m/z, ES+):
434.2.
Example 32
(3S,4aS,6S,8aR)6-[5-Naphthalen-2-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,-
4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
##STR00071##
[0408] Following the procedures as described in Preparation 6 and
Example 30, above, and using Trifluoro-methanesulfonic acid
4-cyano-3-fluoro-phenyl ester (0.55 gm, 2.04 mmol) and
2-Naphthaleneboronic acid (0.49 gm, 2.86 mmol) affords 0.069 gm
(6.6% overall yield) of the title compound. MS (m/z, ES+):
470.3
Example 33
(3S,4aS,6S,8aR)6-[2'-Methoxy-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,-
4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
##STR00072##
[0410] Following the procedures as described in Preparation 6 and
Example 30, Step A, above, and using Trifluoro-methanesulfonic acid
4-cyano-3-fluoro-phenyl ester (0.59 gm, 2.2 mmol) and
2-Methoxyphenylboronic acid (0.47 gm, 3.1 mmol) affords 0.41 gm
(45% yield) of the N-boc protected title compound. MS (m/z, ES+):
470.3 The final title product is isolated by the procedures
described in Example 30, Step B.
[0411] MS (m/z, ES+): 450.2
Preparation 7
2-Hydroxy-4-pyrazol-1yl-benzonitrile
##STR00073##
[0412] A. Preparation of 2-Benzyloxy-4-fluoro-benzonitrile
[0413] To 2.5 mL benzyl alcohol in 80 mL THF is added 1.87 g NaH.
After one hour stirring at room temperature, 5.0 g of
2,4-Difluorobenzonitrile is added. After stirring one hour, the
reaction is quenched with excess water and concentrated in vacuo.
The residue is redissolved in ethyl acetate and washed with water,
brine, dried over sodium sulfate, filtered and concentrated in
vacuo. The product is recrystallized in carbon tetrachloride to
give 3.24 g (39.7%) of the title compound.
[0414] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.6-7.55 (dd, 1H),
7.5-7.32 (m, 5H), 6.78-6.7 (m, 2H), 5.2 (s, 2H).
B. Preparation of 2-Benzyloxy-4-pyrazol-1-yl-benzonitrile
[0415] To 0.180 g pyrazole in 5 mL DMF is added 0.105 g NaH. After
stirring 50 minutes at room temperature, 0.200 g of the material
from Step A, above, is added all at once with 5 mL DMF. After 2
hours at room temperature, the reaction is quenched with water and
Concentrated in vacuo. The residue is redissolved in ethyl acetate
and washed with water, brine, dried over sodium sulfate, filtered
and concentrated in vacuo. Flash chromatography eluting with
toluene provides 0.181 g (74.8%) of the title compound.
[0416] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92 (s, 1H), 7.75
(s, 1H), 7.67-7.65 (d, 1H), 7.6 (s, 1H), 7.52-7.47 (d, 2H),
7.45-7.4 (t, 2H), 7.4-7.34 (d, 1H), 7.25-7.2 (d, 1H), 6.55 (s, 1H),
5.3 (s, 2H).
C. Preparation of 2-Hydroxy-4-pyrazol-1-yl-benzonitrile
[0417] To 0.395 g of the material from Step B, above, dissolved in
10 mL THF, is added a catalytic amount of 10% Pd/C and excess
ammonium formate. The reaction is heated to 50.degree. C. for 45
minutes. Upon cooling, celite is added. The reaction is then
gravity filtered and concentrated in vacuo. The residue is
redissolved in ethyl acetate and washed with water, brine, dried
over sodium sulfate, filtered and concentrated in vacuo to give
0.152 g of the final title compound (57.1%).
[0418] .sup.1H NMR (400 MHz, DMSO-d) .delta. 8.35 (s, 1H), 7.75 (s,
1H), 7.61-7.59 (d, 1H), 7.4 (s, 1H), 7.35-7.3 (d, 1H), 6.55 (s,
1H).
Example 34
(3S,4aS,6S,8aR)6-[5-Pyrazol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,-
5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
##STR00074##
[0419] A. Preparation of
(3S,4aS,6S,8aR)6-(2-Cyano-5-pyrazol-1-yl-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-d-
ecahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester
3-ethyl ester
[0420] To 0.145 g of the material from Preparation 7, 0.256 g of
Ethyl(3S,4aS,6S,8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-
-decahydroisoquinoline-3-carboxylate (prepared essentially as
described in Preparation 1), and 0.308 g triphenylphosphine are
added to 0.18 mL diethylazodicarboxylate. After stirring at room
temperature overnight, the reaction is concentrated in vacuo. Flash
chromatography eluting with a stepwise gradient from 5-25% Ethyl
acetate/toluene provides 0.226 g of the title compound (58.4%
yield).
[0421] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.9 (m, 1H), 7.8
(m, 1H), 7.7-7.6 (dd, 1H), 7.4 (m, 1H), 7.25-7.18 (m, 1H), 7.18-7.1
(d, 1H), 6.5-6.4 (m, 1H), 4.95-4.65 (m, 2H), 4.2-4.05 (m, 2H),
3.9-3.7 (m, 1H), 3.25-3.0 (m, 1H), 2.75-2.5 (m, 1H), 2.17-2.07 (d,
1H), 2.07-1.9 (m, 3H), 1.9-1.75 (m, 2H), 1.75-1.55 (m, 2H),
1.45-1.3 (m, 9H), 1.3-1.15 (m, 3H).
[0422] MS m/z: 395.3 (m.sup.+-99).
B.
(3S,4aS,6S,8aR)6-[5-Pyrazol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,-
4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid
2-tert-butyl ester 3 ethyl ester
[0423] To 0.220 g of the material from Step A, above, is added 0.5
mL azidotributyltin and 0.5 mL toluene. The reaction is heated to
90.degree. C. for two days. The residue is dissolved in ethyl
acetate and washed with water, brine, dried over sodium sulfate,
filtered and concentrated in vacuo. Flash chromatography eluting
with 2% MeOH/CHCl.sub.3 provides 0.142 g of the title compound
(59.4% yield).
[0424] .sup.1H NMR (400 MHz, d-MeOH) .delta. 8.35 (s, 1H),
7.81-7.79 (d, 1H), 7.73 (s, 1H), 7.61 (s, 1H), 7.5-7.46 (d, 1H),
6.55 (s, 1H), 4.95-4.89 (bm, 1H), 4.45-4.29 (bm, 1H), 4.15-4.03 (q,
2H), 3.75-3.65 (d, 1H), 3.1-2.9 (bm, 1H), 2.25-2.15 (d, 1H),
2.0-1.92 (d, 1H), 1.85-1.53 (m, 6H), 1.43 (s, 9H), 1.38-1.1 (m,
4H), 0.92-0.84 (t, 1H).
C.
(3S,4aS,6S,8aR)6-[5-Pyrazol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,-
4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid
2-tert-butyl ester
[0425] To 0.129 g of the material from Step B, above, dissolved in
10 mL MeOH is added 0.72 mL 1N NaOH. The reaction is heated to
50.degree. C. overnight. 0.72 mL 1N NaOH is then added and heated
for four more hours. Upon completion, the reaction is concentrated
in vacuo, redissolved in water and acidified to pH 3, extracted
with ethyl acetate, washed with brine, dried over sodium sulfate,
filtered and concentrated in vacuo. Flash chromatography eluting
with 10% MeOH/CHCl.sub.3 provides 0.040 g of the title compound
(32.8% yield), which is used directly in the following step.
D.
(3S,4aS,6S,8aR)6-[5-Pyrazol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,-
4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
[0426] To 0.040 g of the material from Step C, above, dissolved in
5 mL CH.sub.2Cl.sub.2, is added 3 mL 2M HCl in diethyl ether. After
stirring four hours at ambient temperature, the reaction is
concentrated in vacuo.
[0427] .sup.1H NMR (400 MHz, d-MeOH) .delta. 8.4 (s, 1H), 8.06-8.04
(d, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.52-7.49 (d, 1H), 6.58 (s,
1H), 4.75-4.65 (bm, 1H), 4.05-3.96 (d, 1H), 3.16-3.08 (dd, 1H),
2.33-1.88 (m, 10H), 1.66-1.5 (m, 1H).
[0428] MS m/z: 410.2 (m+1).
Preparation 8
2-Hydroxy-4-indol-yl-benzonitrile
##STR00075##
[0429] A. Preparation of 2-Benzyloxy-4-indol-1-yl-benzonitrile
[0430] Using indole, the title compound is prepared according to
the procedures described in Preparation 7, step B and provides 0.39
g (91.1% yield).
[0431] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.73-7.63 (m, 2H),
7.6-7.37 (m, 5H), 7.3-7.07 (m, 6H), 6.71-6.68 (d, 1H), 5.3 (s,
2H).
B. Preparation of 2-Hydroxy-4-indol-1-yl-benzonitrile
[0432] Using the material from Step A, above, the title compound is
prepared according to the procedures described in Preparation 7,
step C and provides 0.188 g (66.7% yield).
[0433] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.65-7.54 (m, 3H),
7.27-7.1 (m, 5H), 6.67 (d, 1H).
Example 35
(3S,4aS,6S,8aR)6-[5-indol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,-
6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
##STR00076##
[0434] A.
(3S,4aS,6S,8aR)6-(2-Cyano-5-indol-1-yl-phenoxy)-1,2,3,4,4a,5,6,7-
,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl
ester 3-ethyl ester
[0435] Using the material from Preparation 8, above, the title
compound is prepared according to the procedures described in
Example 34, step A and provides 0.233 g (53.4% yield).
[0436] MS m/z: 444.3 (m.sup.--99).
B.
(3S,4aS,6S,8aR)6-[5-indol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a-
,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid
2-tert-butyl ester 3-ethyl ester
[0437] Using the material from Step A, above, the title compound is
prepared according to the procedures described in Example 34, step
B and provides 0.19 g (76% yield).
[0438] MS m/z: 585.2 (M.sup.--1).
C.
(3S,4aS,6S,8aR)6-[5-indol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a-
,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid
2-tert-butyl ester
[0439] Using the material from Step B, above, the title compound
was prepared according to the procedures described in Example 34,
step C and provides 0.100 g (58.5% yield).
[0440] MS m/z: 557.3 (M.sup.--1).
D.
(3S,4aS,6S,8aR)6-[5-indol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a-
,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
[0441] Using the material from Step C, above, the title compound is
prepared according to the procedures described in Example 34, step
D and provides 0.078 g (92.9% yield).
[0442] .sup.1H NMR (400 MHz,d-MeOH) .delta. 8.14-8.11 (d, 1H),
7.64-7.6 (d, 2H), 7.55 (s, 1H), 7.43 (s, 1H), 7.37-7.35 (d, 1H),
7.22-7.18 (t, 1H), 7.15-7.1 (t, 1H), 6.7 (s, 1H), 4.74-4.64 (m,
1H), 4.03-4.0 (d, 1H), 3.37-3.3 (t, 1H), 3.15-3.1 (dd, 1H),
2.18-1.93 (m, 5H), 1.85-1.68 (m, 3H), 1.68-1.55 (m, 2H).
[0443] MS m/z: 459.2 (m.sup.-+1).
Preparation 9
2-Hydroxy-4-pyrrol-1-yl-benzonitrile
##STR00077##
[0444] A. Preparation of 2-Benzyloxy-4-pyrrol-1-yl-benzonitrile
[0445] Using pyrrole, the title compound is prepared according to
the procedures described in Preparation 7, step B and provides
0.457 g (94.6% yield).
[0446] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.57-7.56 (d, 1H),
7.46-7.44 (d, 2H), 7.4-7.35 (t, 2H), 7.34-7.3 (d, 1H), 7.01-6.98
(m, 3H), 6.94 (s, 1H), 6.34 (s, 2H), 5.23 (s, 2H).
B. Preparation of 2-Hydroxy-4-pyrrol-1-yl-benzonitrile
[0447] Using the material from Step A, above, the title compound is
prepared according to the procedures described in Preparation 7,
step C and provides 0.213 g (70.5% yield).
[0448] .sup.1H NMR (400 MHz,d-MeOH) .delta. 7.54-7.51 (d, 1H), 7.7
(s, 2H), 7.05-7.02 (d, 1H), 6.96 (s, 1H), 6.28 (s, 2H).
Example 36
(3S,4aS,6S,8aR)6-[5-Pyrrol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5-
,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
##STR00078##
[0449] A.
(3S,4aS,6S,8aR)6-(2-Cyano-5-pyrrol-1-yl-phenoxy)-1,2,3,4,4a,5,6,-
7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl
ester 3-ethyl ester
[0450] Using the material from Preparation 9, above, the title
compound is prepared according to the procedures described in
Example 34, step A and provides 0.216 g (38% yield).
[0451] MS m/z: 394.2 (M.sup.+-99).
B.
(3S,4aS,6S,8aR)6-[5-Pyrrol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4-
a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid
2-tert-butyl ester 3-ethyl ester
[0452] Using the material from Step A, above, the title compound is
prepared according to the procedures described in Example 34, step
B and provides 0.074 g (35% yield) which is used directly in the
following step.
C.
(3S,4aS,6S,8aR)6-[5-Pyrrol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4-
a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid
2-tert-butyl ester
[0453] Using the material from Step B, above, the title compound is
prepared according to the procedures described in Example 34, step
C and provides 0.014 g, (22.6% yield) which is used directly in the
following step.
D.
(3S,4aS,6S,8aR)6-[5-Pyrrol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4-
a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride
[0454] Using the material from Step C, above, the title compound is
prepared according to the procedures described in Example 34, step
D and provides 0.012 g (97.5% yield).
[0455] .sup.1H NMR (400 MHz, d-MeOH) .delta. 8.0-7.98 (d, 1H),
7.35-7.3 (d, 3H), 7.3-7.24 (d, 1H), 6.32 (s, 2H), 4.78-4.69(m, 1H),
4.0-3.96 (dd, 1H), 3.37-3.3 (t, 1H), 3.14-3.08 (dd, 1H), 2.33-2.25
(m, 1H), 2.2-1.74 (m, 7H), 1.64-1.5 (m, 1H), 1.26 (s, 1H).
[0456] MS m/z: 409.3 (M.sup.++1), 407.3 (M.sup.--1).
Preparation 10
(3S,4aS,6S,8aR)6-hydroxy-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydro-
isoquinoline-3-carboxylic acid
##STR00079##
[0458] To a slurry of 17.3 g of
(3S,4aS,8aR)6-oxo-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoqui-
noline-3-carboxylic acid (46 mmol) in 240 mL of tetrahydrofuran is
added 106 mL if 1.0 M L-Selectride in tetrahydrofuran. The mixture
is stirred for 1 hour at room temperature, then quenched with 130
mL of 1.4 M hydrochloric acid. The layers are separated and the
aqueous phase extracted with 50 mL of tert-butyl methyl ether. The
organic phases are combined and extracted with 75 mL of saturated
aqueous sodium carbonate. The aqueous phase is washed twice with 30
mL portions of tert-butyl methyl ether then acidified to pH 1 with
6 M hydrochloric acid. The product is extracted into 75 mL of
tert-butyl methyl ether. The organic mixture is dried with sodium
sulfate, and concentrated to 8.17 g of yellow solid. The product is
crystallized from 20 mL of tert-butyl methyl ether to provide 6.92
g of the title compound (59% yield).
Preparation 11
6-Chloro-2-fluoro-benzotetrazole
##STR00080##
[0460] To a 12 L round bottomed flask under nitrogen was added
trimethyl aluminum (1930 mL of a 2M solution in toluene, 3.86 mol).
The flask is cooled to -7.degree. C. before adding
azidotrimethylsilane (512.5 mL, 3.86 mol) via cannula such that the
internal temperature is maintained at less than 3.degree. C. To
this flask is added 6-chloro-2-fluorobenzonitrile (500 g, 3.21 mol)
dropwise as a solution in toluene (1 L). The reaction is slowly
warmed to room temperature then heated to 90.degree. C. A cold
finger is used to condense tetramethylsilane as it boiled from the
reaction mixture. The reaction is heated at 90.degree. C. for 13
hours before cooling to room temperature. The reaction is cooed to
0.degree. C. with an ice bath then transferred slowly via cannula
to a pre-cooled (-5.degree. C.) solution of 6N aqueous HCl (3 L)
and ethyl acetate (3 L). The internal temperature during the quench
is kept at less than 5.degree. C. After addition, the flask is
allowed to warm to room temperature. The reaction is diluted with
ethyl acetate (2 L) to dissolve solids before transferring to a 22
L flask. The layers are separated and the aqueous layer was
extracted with ethyl acetate (1 L). The combined organic layers are
washed with brine (2 L), dried over anhydrous sodium sulfate, and
concentrated. 636.4 g. of the title compound is obtained (93%
yield). Analysis by HPLC and .sup.1H NMR analysis shows the purity
as greater than 98%.
Preparation 12
##STR00081##
[0462] To a thick slurry of the material from Preparation 11,
above, (101.8 g, 0.513 mol) and 4,4'-dimethoxybezhydrol (125 g,
0.513 mol) in 510 mL glacial acetic acid is added concentrated
sulfuric acid (5.5 mL). Upon addition, the reaction immediately
becomes red and homogeneous. The red color rapidly lightens to
orange over several minutes. An endotherm of 3-4.degree. C. is also
observed as the reaction becomes homogeneous. After approximately
15 minutes, the product begins to crystallize from the reaction
mixture resulting in a mild exotherm (<10.degree. C.). After 1
hour, the solid is isolated by filtration and washed with water (1
L) then isopropyl alcohol (0.5 L). The resulting white solid is
dried in vacuo at 50.degree. C. to afford 199.8 g of the title
compound (91% yield).
Example 37
2-Ethyl-butyl(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1-
,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
para-toluenesulfonate
##STR00082##
[0463] A. Preparation of
##STR00083##
[0465] To a slurry of sodium hydride (60% dispersion in mineral
oil, 2.94 g, 73.5 mmol) in dry dimethyl sulfoxide (25 mL) is added
the material from Preparation 10 (9.44 g, 36.7 mmol) dropwise as a
solution in dimethyl sulfoxide (21 mL). During the course of the
addition (40 min.), a cooling bath is used to maintain the
temperature at or below 25.degree. C. After stirring 15 minutes at
ambient temperature, the material from Preparation 12 (10.4 g, 24.5
mmol) is added in one portion as a solid. The slurry is stirred at
room temperature for 20 minutes before heating to 40.degree. C. for
2.75 hours. Analysis of the reaction mixture by HPLC shows no
additional progress after this point and the reaction is cooled to
room temperature. The reaction is quenched by addition of 1N
aqueous hydrogen chloride solution (50 mL), water (200 mL) and
ethyl acetate (200 mL). The layers are separated and the aqueous
layer is extracted with ethyl acetate (1.times.50 mL). The combined
organic layers are washed with water (2.times.100 mL) and 10%
aqueous sodium chloride solution (1.times.100 mL). The organic
layer is then dried over anhydrous sodium sulfate and concentrated
in vacuo to afford a crude oil. The crude product is purified on
silica gel eluting 1% methanol in methylene chloride followed by 5%
methanol in methylene chloride to afford 11.84 g. of the title
compound (73% yield) as a white foam.
B. Preparation of
##STR00084##
[0467] To a solution material from Step A, of the above (16.87 g,
25.4 mmol), in N,N-dimethylformamide (170 mL) is added powder
potassium carbonate (4.55 g, 33 mmol) and 3-(bromomethyl)pentane
(4.62 mL, 33 mmol). The reaction mixture is heated to 80.degree. C.
under nitrogen. After 1 h, analysis by thin layer chromatography
and HPLC indicates that the reaction was complete. The reaction is
cooled and diluted with water (500 mL) and methylene chloride (170
mL). The organic layer is washed with brine, dried over anhydrous
magnesium sulfate, and concentrated in vacuo to afford 17.8 g. of
the title compound (94% yield) as a foam.
C.
2-Ethyl-butyl(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy-
]-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxyl-
ate
[0468] To a solution of the material from Step B, above (216 g, 289
mmol), is added anisole (94.4 mL, 868.3 mmol) and trifluoroacetic
acid (564 mL). The dark red solution is stirred at RT until
complete conversion is observed by HPLC (6.5 h). The reaction is
concentrated to a dark red oil. The residual trifluoroacetic acid
is removed by azeotropic distillation with chloroform. The
resulting oil is dissolved in methylene chloride (800 mL) and
washed with pH 4 buffer (4.times.1 L). The organic layer is dried
over anhydrous magnesium sulfate, filtered, and concentrated to a
crude oil. The product is purified on silica gel (2 Kg) eluting
methylene chloride, 10% ethyl acetate in methylene chloride, then
ethyl acetate. The appropriate fractions are concentrated in vacuo
to provide 132 g. of the title compound as a white foam (88%
yield).
D.
2-Ethyl-butyl(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy-
]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
[0469] The material from Step C, above (390 g, 750 mmol) and 187 mL
of trimethylsilyliodide are combined in 1.65 L of dichloromethane
and the mixture stirred at ambient temperature for 24 hours. At
this time the mixture is quenched with 10 mL of saturated aqueous
sodium hydrogencarbonate and combined with 325 mL of
tetrahydrofuran. The reaction is further quenched with a total of
2.0 L of saturated aqueous sodium hydrogencarbonate. The mixture is
stirred for 1 hour and the product is isolated by filtration. The
solids are washed with water and dichloromethane then dried in
vacuo to provide 230 g of the title compound.
[0470] The isolated solids are further purified by
recrystallization. A mixture of 245 g of the title compound is
combined with 2.0 L of water and 200 mL of acetonitrile. The
mixture is adjusted to pH 6.8 by the addition of 1.0 M hydrochloric
acid. An additional 1.0 L of acetonitrile is added and the mixture
is heated to effect a solution. The solution is allowed to cool to
ambient temperature producing a precipitate. After the mixture
cools to approximately 25.degree. C. for 20 minutes the solids are
collected by filtration. The solids are washed with water and dried
in vacuo to provide 211 g of the title compound.
E.
2-Ethyl-butyl(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy-
]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
para-toluenesulfonate
[0471] To a suspension of the material from Step D, above (211 g,
457 mmol) in 1100 mL of 2-propanol, is added p-toluenesulfonic acid
monohydrate (91.7 g, 480 mmol). The mixture is heated to 55.degree.
C. to effect a solution then allowed to cool to ambient temperature
for 2 hours and then further cooled to approximately 3.degree. C.
for 90 minutes. The solids are collected by filtration and washed
with 500 mL of cold 2-propanol. The solids are dried in vacuo to
provide 270 g (93% yield) of the final title compound as a white
powder.
[0472] .sup.1H NMR, 500 MHz dmso-d6, 9.23 (bs, 1H), 8.94 (bs, 1H),
7.56 (t, 1H), 7.45 (d, 2H), 7.30 (d, 1H), 7.24 (d, 1H), 7.09 (d,
2H), 4.37 (m, 1H), 4.17 (m, 1H), 4.13 (dd, 1H), 4.03 (dd, 1H), 3.04
(m, 1H), 2.94 (m, 1H), 2.26 (s, 3H), 2.07 (m, 1H), 1.96 (m, 1),
1.84 (m, 2H), 1.75 (m, 2H), 1.60 (m, 3H), 1.48 (m, 1H), 1.29 (m,
4H), 1.09 (m, 1H), 0.83 (t, 6H)
[0473] Mp=204.degree. C.
Example 38
2-Ethyl-butyl(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1-
,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
para-toluenesulfonate
##STR00085##
[0474] A.
(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-me-
thoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid
[0475] The material from Preparation 10 (20.0 g, 77.7 mmol) is
added to 311 mL of 1 M potassium tert-butoxide in tetrahydrofuran
followed by the addition of 6-Chloro-2-fluoro-benzotetrazole
(Preparation 11) (17.0 g, 85.7 mmol). The mixture is heated to
63.degree. C. and monitored for consumption of the aryl tetrazole
by HPLC. After 4 hours the reaction is cooled to 20.degree. C. and
quenched by the addition of trimethylsilyl chloride (16.9 g, 155.5
mmol). followed by heating to reflux for 30 minutes. The reaction
mixture is again cooled to ambient temperature and further quenched
by the addition of 224 mL of 1.5 M hydrochloric acid. The organic
phase is washed with two 50 mL portions of saturated aqueous sodium
chloride. The organic phase is then exchanged for ethyl acetate by
atmospheric distillation of the tetrahydrofuran with concurrent
addition of ethyl acetate until the distillation temperature
reaches 75.degree. C. The exchange of solvents effects the
precipitation of the desired product. The mixture is cooled to
10.degree. C. and the solids are collected by filtration, washed
with ethyl acetate, and dried to provide 43.4 g of product as a
white solid.
B.
(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,-
5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid.hydrochloride
[0476] To a solution prepared from 85% potassium hydroxide (21.2 g
321 mmol) and 100 mL of water is added the material from Step A,
above (20.0 g, 45.9 mmol). The solution is heated to 103.degree. C.
for 26 hours at which time the HPLC analysis shows less than 4%
starting material remains. The reaction is cooled to 30.degree. C.
and is added over 20 minutes to 62 mL of 6 M hydrochloric acid
effecting the precipitation of the desired product. The mixture is
cooled to 10.degree. C. and the product is collected by filtration,
washed with 1 M hydrochloric acid, followed by a wash with
acetonitrile. The product is dried in vacuo to provide 17 g of the
title compound (89% yield) as a white solid.
[0477] The title compound (20.0 g) is then combined with 200 mL of
water and heated to 90.degree. C. to effect a solution. The
solution is cooled to 60.degree. C. and 40 mL of 6 M hydrochloric
acid is added effecting the precipitation of the title compound.
The mixture is stirred at 60.degree. C. for 45 minutes then cooled
to ambient temperature. The recrystallized hydrate product is
collected by filtration and washed with 100 mL of acetonitrile. The
product was dried in vacuo to 17 g of 2049266 as a white solid and
used in the next step
C.
2-Ethyl-butyl(3S,4aS,6S,8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy-
]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
para-toluenesulfonate
[0478] A mixture of the hydrate from Step B, above (30.0 g, 69.4
mmol), para-toluenesulfonic acid monohydrate (15.84 g, 83.3 mmol),
75.0 mL of 2-ethyl-1-butanol, and 6.0 mL of water is heated to
140.degree. C. over a two hour period. During the heating process,
a distillate is collected which contains 11 mL of aqueous and 14 mL
of organic phases. The mixture is cooled 70.degree. C. and 75 mL of
2-propanol is added. The mixture is further cooled to 50.degree. C.
and 150 mL of tert-butyl methyl ether is added over 20 minutes
effecting the precipitation of the product. The mixture is then
cooled to ambient temperature. The solids are collected by
filtration, washed with 50 mL of tert-butyl methyl ether, and dried
in-vacuo to provide 39.0 g (88.6% yield) of the final title
compound as a white solid.
[0479] A suspension of 10.0 g of the product, in a mixture of 49.0
mL of 2-propanol and 1.0 mL of water, was heated to solution. The
solution is allowed to cool to ambient temperature effecting
crystallization. The mixture is stirred for 1 hour at less than
29.degree. C. and then the solids are collected by filtration. The
solids are washed with 7 mL of 2-propanol and dried in-vacuo to
provide 8.73 g of the recrystallized title compound.
[0480] .sup.1H NMR, 500 MHz dmso-d6, 9.23 (bs, 1H), 8.94 (bs, 1H),
7.56 (t, 1H), 7.45 (d, 2H), 7.30 (d, 1H), 7.24 (d, 1H), 7.09 (d,
2H), 4.37 (m, 1H), 4.17 (m, 1H), 4.13 (dd, 1H), 4.03 (dd, 1H), 3.04
(m, 1H), 2.94 (m, 1H), 2.26 (s, 3H), 2.07 (m, 1H), 1.96 (m, 1H),
1.84 (m, 2H), 1.75 (m, 2H), 1.60 (m, 3H), 1.48 (m, 1H), 1.29 (m,
4H), 1.09 (m, 1H), 0.83 (t, 6H).
[0481] Mp=204.degree. C.
Example 39
[0482] To establish that the iGluR.sub.5 receptor subtype is
mediating a pharmacological response in a neurological disease or
disorder, the binding affinity of the panel compounds to the
iGluR.sub.5 receptor is first measured using standard methods. For
example, the activity of compounds acting at the iGluR.sub.5
receptor can be determined by radiolabelled ligand binding studies
at the cloned and expressed human iGluR5 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
iGluR.sub.5 receptor subtype can then be determined by comparing
antagonist activity at the iGluR.sub.5 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 GluR.sub.1, GluR.sub.2, GluR.sub.3 and
GluR.sub.4 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 GluR.sub.6 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. Ther. 70; 65-89).
iGluR5 Antagonist Binding Affinity Profiles
[0483] Cell lines (HEK293 cells) stably transfected with human
iGluR receptors are employed. Displacement of .sup.3[H] AMPA by
increasing concentrations of antagonist is measured on iGluR.sub.1,
iGluR.sub.2, iGluR.sub.3, and iGluR.sub.4 expressing cells, while
displacement of .sup.3[H] kainate (KA) is measured on iGluR.sub.5,
iGluR.sub.6, iGluR.sub.7, and KA2-expressing cells. Estimated
antagonist binding activity (K.sub.i) in .mu.M, for example, is
determined for Compounds of Formula I. As an indicia of
selectivity, the ratio of binding affinity to the iGluR.sub.2 AMPA
receptor subtype, versus the binding affinity to iGluR.sub.5
kainate receptor subtype (K.sub.i at iGluR.sub.2/K.sub.i at iGluR5)
is also determined The iGluR5 receptor antagonist compounds, as
provided by the present invention, provide a K.sub.i at the iGluR5
receptor subtype of less than 5000 .mu.M, preferably less than 500
.mu.M , even more preferably less than 50 .mu.M, and most
preferably less than 5 .mu.M. The preferred selective iGluR5
receptor antagonists compounds, as provided by the present
invention, display a greater binding affinity (lower K.sub.i) for
iGluR.sub.5 than that for iGluR.sub.2, preferably at least 10 fold
greater for iGluR.sub.5 than that for iGluR.sub.2, and even more
preferably at least 100 fold, and most preferably at least 1000
fold. than that for iGluR.sub.2.
Example 40
[0484] The following animal model may be employed to determine the
ability of each of the compounds of Formula I to inhibit protein
extravasation, an exemplary functional assay of the neuronal
mechanism of migraine.
Animal Model of Dural Protein Extravasation
[0485] 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 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.
[0486] The femoral vein is exposed and a dose of the test compound
is injected intravenously (i.v.) at a dosing volume of 1 ml/Kg or,
in the alternative, test compound is administered orally (p.o) via
gavage at a volume of 2.0 ml/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
intensity of 1.0 mA (5 Hz, 4 msec duration) with a Model 273
potentiostat/galvanostat (EG&G Princeton Applied Research).
[0487] 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 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.
[0488] A fluorescence microscope (Zeiss) equipped with a grating
monochromatic and a 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
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.
[0489] 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 was
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 approximately
1.8 in guinea pigs. In contrast, a compound which completely
prevents the extravasation in the dura from the stimulated side
would yield a ratio of approximately 1.0.
[0490] Dose-response curves are generated for each of the compounds
of Formula I and the dose that inhibits the extravasation by 50%
(ID.sub.50) or 100% (ID.sub.100) is approximated.
Example 41
[0491] To demonstrate the utility of compounds of the present
invention to treat pain or provide analgesic effects, several well
known animal models may be employed. For example, international
application WO 98/45270 describes the well known Formalin Test,
which is described below:
Formalin Test
[0492] For example, male Sprague-Dawley rats (200-250 g; Charles
River, Portage, Mich.) are housed in group cages and maintained in
a constant temperature and a 12 hour light/12 hour dark cycle 4-7
days before studies are performed Animals have free access to food
and water at all times prior to the day of the experiment.
[0493] Drugs or vehicles are administered intraperitoneally (i.p.)
or orally (p.o.) by gavage in a volume of about 1 ml/kg. The test
is performed in custom made Plexiglas.RTM. boxes about
25.times.25.times.20 cm in size (according to Shibata et al., Pain
38; 347-352, 1989, Wheeler-Aceto et al., Pain, 40; 229-238,1990). A
mirror placed at the back of the cage allows the unhindered
observation of the formalin injected paw. Rats are acclimated
individually in the cubicles at least 1 hour prior to the
experiment. All testing is conducted between, for example, 08:00
and 14:00 h and the testing room temperature is maintained at about
21-23.degree. C.
[0494] Test compounds are administered about 30 minutes prior to
the formalin injection. Formalin (50 micoliters of a 5% solution in
saline) is injected subcutaneously into the dorsal lateral surface
of the right hind paw with a 27 gauge needle. Observation is
started immediately after the formalin injection. Formalin-induced
pain is quantified by recording, for example, in 5 minute
intervals, the number of formalin injected pawlicking events and
the number of seconds each licking event lasts. These recordings
are made for about 50 minutes after the formalin injection.
[0495] Several different scoring parameters have been reported for
the formalin test. The total time spent licking and biting the
injected paw is demonstrated to be most relevant (Coderre et al.,
Eur. J. Neurosci. 6; 1328-1334, 1993; Abbott et al., Pain, 60;
91-102, 1995) and may be chosen for the testing score. The early
phase score is the sum of time spent licking, in seconds, from time
0 to 5 minutes. The late phase is scored in 5 minute blocks from 15
minutes to 40 minutes and is expressed accordingly or also by
adding the total number of seconds spent licking from minute 15 to
minute 40 of the observation period.
[0496] Data may be presented as means with standard errors of means
(.+-.SEM). Data may also be evaluated by one-way analysis of
variance (ANOVA) and the appropriate contrasts analyzed by Dunnett
"t" test for two sided comparisons. Differences are considered to
be significant if, for example, the P-value is less than 0.05.
Statistics may be determined at the 5 minute time point and at 5
minute intervals between 15 and 40 minutes. Where data are
expressed as total amount of time spent licking in the late phase,
statistics may be performed on the total time spent licking as well
and may be indicated accordingly.
[0497] In addition to the Formalin Test, the well known Mouse
Writhing Test, essentially as described in published International
Application WO 00/028980, may also be employed to demonstrate the
analgesic properties of compounds of the present invention.
Mouse Writhing Test
[0498] An accepted procedure for detecting and comparing the
analgesic activity of different classes of analgesic drugs, for
which there is a good correlation with human analgesic activity, is
the prevention of acetic acid-induced writhing in mice. Mice are
orally administered various doses of a test compound or placebo
prior to testing. The mice are then injected intraperitoneally with
acetic acid (0.55% solution, 10 mL/kg) five minutes prior to a
designated observation period Inhibition of writhing behavior is
demonstrative of analgesic activity. Haubrich et al., "Pharmacology
of pravadoline: a new analgesic agent", The Journal of Pharmacology
and Experimental Therapeutics, 255 (1990) 511-522. For scoring
purposes "writhe" is indicated by whole body stretching or
contracting of the abdomen during an observation period beginning
about five minutes after receiving the acetic acid.
[0499] ED.sub.50 values, and their standard error of means (SEM),
are determined using accepted numerical methods for all test
compounds administered. For example, see R. E. Kirk (1982)
"Experimental Design: Procedures for the behavioral sciences," 2nd
ed. One method to establish the significance of the analgesic
activity of a given test compound compared to that of another is to
calculate the SEM values for each ED.sub.50 value. If the SEM
values do not overlap the line of addition, then the ED50 values
are significantly different from the line of addition.
[0500] Yet another accepted animal model to demonstrate the ability
of a particular compound to treat pain, or provide analgesic
effects, is the well known Rat Model of Carrageenan-induced Thermal
Hyperalgesia, also described in published International Application
WO 00/028980.
Carrageenan-Induced Thermal Hyperalgesia in Rats
[0501] Another accepted method for detecting and comparing the
analgesic activity of different classes of analgesic compounds for
which there is good correlation with human analgesic activity is
the reversal of carrageenan-induced thermal hyperalgesia in rats
(Hargreaves et al. Pain 32:77-88, 1988).
[0502] Rats are administered a dose test compound or vehicle and
then injected subcutaneously into one hindpaw, with carrageenan
(1.5% w/v, 100 .mu.l). The response to noxious thermal stimulus is
determined two hours later using a commercially available thermal
plantar device (Ugo Basil, Italy) according to established methods
(Hargreaves et al. Pain 32:77-88, 1988). Briefly, animals are
habituated to a plastic behavioral enclosure for 5 min. A heat
source is positioned directly beneath a hindpaw and the time taken
for hindpaw withdrawal monitored automatically. If the animal does
not respond within 20 sec, the stimulus is automatically terminated
to prevent tissue damage. Measurements for both the injured and
contralateral (control) hindpaw are recorded. Thermal hyperalgesia
is evidenced by a shorter response latency by the injured as
compared to the control paw.
[0503] ED.sub.50 values and their standard error of means (SEM) are
determined using accepted numerical methods. For example, see R. E.
Kirk (1982) "Experimental Design: Procedures for the behavioral
sciences," 2nd ed.
* * * * *