EXCITATORY AMINO ACID RECEPTOR ANTAGONISTS
BACKGROUND OF THE INVENTION
In the mammalian central nervous system (CNS), the transmission of nerve
impulses is controlled by the interaction between a neurotransmitter, that is released by a
sending neuron, and a surface receptor on a receiving neuron, which causes excitation of
this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the
CNS, mediates the major excitatory pathwavs 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, Ami. 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.
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), a-amino-3-hydroxy-5-rnethylisoxazole-4-propionic acid
(AMPA), and kainic acid (KA). Molecular biological studies have established that AMPA
receptors are composed of subunits (GluR1 - GIUR4), 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 GIUR5, GluR6,
and/or GIUR7 subunits). Bleakman et a]., Molecular Phamiacology, 49, No.4, 581,(1996).
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).
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 United States Patent No.
5,446,051.and 5,670,516). Excitatory amino acid receptor antagonists may also be useful
as analgesic agents and for treating or preventing various forms of headache, including
cluster headache, tension-type headache, and chronic daily headache. In addition,
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.
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 (CepJialalgia, 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 propeities.(see
Maclntyre, 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 GluR5 and
KA2 have been observed. (Sahara et al., The Journal of Neuroscience, 17(17), 6611
(1997)). As such, migraine presents yet another neurological disorder which may be
implicated with glutamate receptor excitotoxicity.
The use of a neuroprotective agent, such as an excitatory amino acid receptor
antagonist, is believed to be useful in treating or preventing all of the aforementioned
disorders and/or reducing the amount of neurological damage associated with these
disorders. For example, studies have shown that AMPA receptor antagonists are
neuroprotective in focal and global ischemia models. The competitive AMPA receptor
antagonist NBQX (23-dmydroxy-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 GKY1
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 United States Patents Na.5,446,051 and 5,670,516
disclose that certain decahydroisoquinokne 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
decahydroisoquinpline derivative compounds are selective antagonists of the iGluR5
receptor and are useful for the treatment of various types of pain, including; severe,
chronic, intractable, and neuropathic pain.
In accordance with the present invention. Applicants have discovered novel
compounds that are antagonists of the iGluR5 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
The present invention provides a compound of Formula I

wherein
Z represents a sulfur or oxygen atom;
R1 represents hydrogen, CN, (C1-C4)alkyl-CO2H, CO2H, or tetrazole;
R2 represents hydrogen, halo, aryl, substituted aryl, CO2H, tetrazole, (C1-C4)alkyl,
(C1-C4)alkylaryl, heterocycle, substituted heterocycle, CF3 , NHR3, or O-R4;
R3 represents hydrogen, (C1-C4)alkyl, (C1-C4)alkylaryl, or aryl,;
R4 represents (C1-C6)alkyl, (C1-C4)alkylaryl, (C1-C4)alkyl-heterocycle, (C1
C6)alkyl)(C3-C10)cycloalkyl, (C3-C10)cycloalkyl, (C1-C4)alkyl)substituted)aryl, aryl, or
heterocycle; and
W, X, and Y each independently represent hydrogen, halo, (C1-C6)alkyl, (C1
C4)alkoxy, aryl, substituted aryl, CO2H, CO(NH2), CF3 NH-aryl, NH2, or NO2, or
optionally, X and R2 together, or W and X together, or Y and R2 together, along with the
carbon atoms to which they are attached, form a benzo-fused group;
with the proviso that where Z is sulfur, then R1 is hydrogen, CO2H, or tetrazole,
R2 is hydrogen, Halo, (C1-C4)alkyl, or CO2H, and W, X, and Y are each hydrogen, Halo,
(C1-C6)alkyl, CO2H, or COCNH2);
or a pharmaceutically acceptable salt or prodrug thereof.
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 1
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; ATDS-
induced dementia; amyotrophic lateral sclerosis; idiopathic and drug-induced Parkin son'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, ten sion-
type headache, and chronic daily headache; migraine; and acute and chronic pain states
including severe pain, intractable pain, neuropathic pain, and post-traumatic pain.
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-
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 earner, diluent or excipient This invention also
encompasses novel intermediates, and processes for the synthesis of the compounds of
Formula I.
Specifically, The present invention also provides a process for making compounds
of Formula 1(a):
wherein,
Z represents oxygen
R5 , R8 , and R10 each independently represents hydrogen, (C1-C20)alkyl, (C2-
C6)alkenyl, (Cr C6)alkylaryl, (C1-C6)alkyl(C3-C10)cycloalkyl, (C1-C6)alkyl-N,N-
C1-C6 dialkylamine, (C1-C6)alkyl-pyrrolidine, (C1-C6)alkyl-piperidine, or (C1-
C6)alkyl-morpholine; with the proviso that where R7 is CO2R10; or W\ X', or Y'
is CO2 R8, then at least one, but no more than two of R5, R8, and R10 is other
than hydrogen;
R6 represents tetrazole;
R7 represents hydrogen, halo, aryl, substituted aryl, CO2R10, tetrazole, (C1-
C4)alkyl, (C1-C4)alkylaryl, heterocycle, substituted heterocycle, CF3 , NHR3, ox
OR4;
R3 represents hydrogen, (C1-C4)alkyl, (C1-C4)alkylaryl, or aryl,;
R4 represents (C3-C6)alkyl, (C1-C4)alkylaryl, (C1-C4)alkyl-heterocycle, (C1-
C6)alkyl(C3-C10)cycloalkyl, (C3-C10)cycloalkyl, (C1-C4)alkyl)subsututed)aryl, aryl,
or heterocycle; and
W, X' and Y' each independently represent hydrogen, halo, (C1-C6)alkyl, CO2R8,
or COCNH2); or optionally, X' and R7 together, or W and X' together, or Y and
R7 together; along with the carbon atoms to which they are attached, form a
benzo-fused group;
comprising combining a compound of structure (10):

wherein Pg is a suitable nitrogen protecting group,
w,ith a suitable base in a suitable solvent, followed by addition of a compound of
structure^! lb):

wherein Pg is a suitable nitrogen protecting group;
R2 represents hydrogen, halo, aryl, substituted aryl, CO2H, tetrazole, (C1-C4)alkyl,
(C1-C4)alkylaryl, heterocycle, substituted heterocycle, CF3 , NHR3, or OR4;
R3 and R4 are as defined above, and
W, X, and Y each independently represent hydrogen, halo, (C1-C6)alkyl, (C1-
C4)aIkoxy, aryl, substituted aryl, CO2H, CO(NH2), CF3, NH-aryl, NH2, or NO2) or
optionally, X and R2 together, or W and X together, or Y and R2 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)

wherein Pg, R5, R7, W\X\ and Y are as defined above;
followed by removal of the nitrogen protecting groups, and precipitation with a suitable
acid.
In a further embodiment, the present invention provides yet another process for
synthesizing a compound of Formula 1(a):
wherein,
Z represents oxygen;
R5 , R8 , and R10 each independently represents hydrogen, (C1-C20)alkyl, (C2-
C6)alkenyl, (C1- C6)alkylaryl, (C1-C6)alkyl(C3-C10)cycloalkyl, (C1-C6)alkyl-N,N-
C1-C6 dialkylamine, (C1-C6)alkyl-pyrrolidine, (C1-C6)alkyl-piperidine, or (C1-
C6)alkyl-morpholine; with the proviso that where R7 is CO2R30; or W, X', or Y'
is CO2 R8, then at least one, but no more than two of R5, R8, and R10 is other
than hydrogen;
R6 represents tetrazole;
R7 represents hydrogen, halo, aryl, substituted aryl, CO2R10, tetrazole, (C1-
C4)alkyl, (C1-C4)alkylaryl, heterocycle, substituted heterocycle, CF3 , NHR3, or
OR4;
R3 represents hydrogen, (C1-C4)alkyl, (C1-C4)alkylaryl, or aryl,;
R4 represents (C1-C6)alkyl, (C1-C4)alkylaryl, (C1-C4)alkyl-heterocycle, (C1-
C6)alkyl(C3-C10)cycloalkyl, (C3-C10)cycloalkyl, (C1-C4)alkyl(substiruted)aryl, aryl,
or heterocycle; and
W, X' and Y' each independently represent hydrogen, halo, (C1-C6)alkyl, CO2R8,
or CO(NH2); or optionally, X' and R7 together, or W and X' together, or Y' and
R7 together, along with the carbon atoms to which they are attached, form a
benzo-tused group;
comprising combining a compound of structure (10).

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):

wherein,
R2 represents hydrogen, halo, aryl, substituted aryl, CO2H, tetrazole, (C1-C4)alkyl,
(C1-C4)alkylaryl, heterocycle, substituted heterocycle, CF3 , NHR3, or OR4;
R3 and R4 are as defined above, and
W, X, and Y each independently represent hydrogen, halo, (C1-C6)alkyl, (C1-
C4)alkoxy, aryl, substituted aryl, CO2H, CO(NH2), CF3, NH-aryl, NH2, or NO2, or
optionally, X and R2 together, or W and X together, or Y and R2 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):

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 1(a).
The present invention also provides the use of a compound of Formula I of
Formula 1(a) for the manufacture of a medicament for treating or preventing a
neurological disorder, or neurodegenerative condition.
More specifically, the present invention provides the use of a compound of
Formula I or Formula 1(a) for the manufacture of a medicament for treating or preventing
pain or migraine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds functional as iGluR5 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.
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.
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 la below:

wherein
Z is as defined hereinabove;
R represents hydrogen, (C1-C20)alkyl, (C2-C6)alkenyl, (C1-C6)alkylaryl, (C1-
C6)alkyl(C3-C10)cycloalkyl, (C1-C6)alkyl-N,N-C1-C6 dialkylamine, (C1-C6)alkyl-
pyrrolidine, (C1-C6)alkyl-piperidine, or (C1-C6)alkyl-morpholine;
R6 represents hydrogen, CN, (C1-C4)alkyl-CO2R , CO2R , or tetrazole;
R7 represents hydrogen, halo, aryl, substituted aryl, CO2R , tetrazole, (C1-
C4)alkyl, (C1-C4)alkylaryl, heterocycle, substituted heterocycle, CF3 , NHR3, or O-R4;
R and R are as defined hereinabove;

W', X' and Y' each independently represent hydrogen, halo, (C1-C6)alkyl, CO2R8 ,
or CO(NH2); or optionally, X' and R7 together, or W and X' together, or Y and R7
together, along with the carbon atoms to which they are attached, form a benzo-fused
group;
with the proviso that where Z is sulfur, then R6 is hydrogen, CO2R or tetrazole,
R7 is hydrogen, Halo, (C1-C4)alkyl, or CO2R10, and W', X', and Y' are each
independently hydrogen, Halo, (C1-C6)alkyl, CO2R9or CO(NH2);
R8 , R9 , and R10 each independently represent hydrogen, (C1-C20)alkyl, (C2-
C6)alkenyl, (C1-C6)alkylaryl, (C1-C6)alkyl(C3-C10)cycloalkyl, (C1-C6)alkyl-N,N-C1-C6
dialkylamine, (C1-C6)alkyl-pyrrolidine, (C1-C6)alkyl-piperidine, or (C1-C6)alkyl-
morpholine;
with the further proviso that where R6 is (C1-C4)alkyl-CO2R9 or CO:2R9; or R7 is
CO2R10; or W', X', or Y' is CO2 R8, then at least one, but no more than two of R5, R8,
R9, and R10 is other than hydrogen;
or a pharmaceutically acceptable salt thereof.
It is understood that the iGluR5 receptor antagonists of the present invention may
exist as pharmaceutically acceptable salts and, as such, salts are therefore included within
the scope of the present invention. The term "pharmaceutically acceptable salt" as used
herein, refers to salts of the compounds provided by, or employed in the present invention
which are substantially non-toxic to living organisms. Typical pharmaceutically
acceptable salts include those salts prepared by reaction of the compounds of the present
invention with a pharmaceutically acceptable mineral or organic acid or an organic or
inorganic base. Such salts are known as acid addition and base addition salts.
It will be understood by the skilled reader that most or all of the compounds used
in the present invention are capable of forming salts, and that the salt forms of
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.
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, bisulfite, 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-l,4-dioate, hexyne-l,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate,
phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate,
lactate, a-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.
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.
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.
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:

wherein E1 is the amount of the first enantiomer and E2 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, el
al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981.
The compounds of the present invention have one or more chiral centers and may
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.
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.
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.
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, l-(p-biphenylyl)-! -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).
As used herein the term "(C1-C4)alkyl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not
limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term "(C1-C6)alkyl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not
limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl,
and the like.
As used herein the term "(C1-C10)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-mefhyl-2-hexyl,
octyl, 4-methyl-3-heptyl and the like.
As used herein the term "(C1-C20)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 "(C1-C4)alkyl", "(C1-C6)alkyl", and
"(C1-C10)alkyl" are included within the definition of "(C1-C20)alkyl".
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.
As used herein, the term "(C1-C4)alkoxy" refers to an oxygen atom bearing a
straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and
includes, but is not limited to methyoxy, ethyoxy, n-propoxy, isopropoxy, n-butoxy, and
the like.
As used herein the term i'(C1-C6)alkoxy" refers to an oxygen atom bearing a
straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and
includes, but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-
pentoxy, n-hexoxy, and the like.
As used herein, the term "(C1-C6)alkyl(C1-C6)alkoxy" refers to a straight or
branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a (C1-
C6)alkoxy group attached to the aliphatic chain.
As used herein, the terms "Halo", "Halide" or "Hal" refer to a chlorine, bromine,
iodine or fluorine atom, unless otherwise specified herein.
As used herein the term "(C2-C6)alkenyr' refers to a straight or branched,
monovalent, unsaturated aliphatic chain having from two to six carbon atoms. Typical
C2-C6 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-
propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propeny], 1-propenyl, 2-propenyl, 2-butenyl,
2-pentenyl, and the like.
As used herein, the term "aryl" refers to a monovalent carbocyclic group
containing one or more fused or non-fused phenyl rings and includes, for example,
phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2.3,4-tetrahydronaphthyl, and the like.
The term "substituted aryl" refers to an aryl group substituted with one or two moieties
chosen from the group consisting of halogen, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-
C6)alkoxy, (C1-C6)alkyl(C3-C10)cycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkoxycarbonyl,
protected carboxy, carboxymethyl, hydroxymethyl. amino, aminomethyl, trifluoromethyl,
or trifluoromethoxy.
As used herein, the term "(C1-C6)alkylaryr refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an aryl group
attached to the aliphatic chain. Included within the term "C1-C6 alkylaryl" are the
following:

and the like.
As used herein, the term i'(C1-C4)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
As used herein, the term "aryl(C1-C6 )alkyl" refers to an aryl group which has a
straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms
attached to the aryl group. Included within the term "aryl(C1-C6 )alkyl" are the following:

As used herein the term "(C3-C10)cycloalkyl" refers to a saturated hydrocarbon
ring structure composed of one or more fused or unfused rings containing from three to
ten carbon atoms. Typical C3-C10 cycloalkyl groups include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantanyl, and the like.
As used herein, the term "C1-C6 alkyl(C3-C10)cycloalkyl" refers to a straight or
branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a (C3-
C10)cycloalkyl attached to the aliphatic chain. Included within the term "C1-C6 alkyl(C3-
C10)cycloalkyl" are the following:

As used herein, the term "(C1-C6) alkoxycarbonyl" refers to a carbonyl group
having a (C1-C6)alkyl group attached to the carbonyl carbon through an oxygen atom.
Examples of this group include t-butoxycarbonyl, methoxycarbonyl, and the like.
As used herein the term "heterocycle" refers to a five- or six-membered ring,
which contains one to four heteroatoms selected from the group consisting of oxygen,
sulfur, and 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, (CV
C6)alkyl, (C1-C4)alkoxy, C1-C6 alkyl(C3-C10)cycloalkyl, (C1-C6)lkylaryl, (C1-
C6)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.
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:
and the like, wherein all substituents are as previously defined hereinabove.
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:

and the like, wherein all substituents are as previously defined.
As used herein the term "N,N-C1-C6 dialkylamine" refers to a nitrogen atom
substituted with two straight or branched, monovalent, saturated aliphatic chains of 1 to 6
carbon atoms. Included within the term "N,N-C1-C6 dialkylamine" are -N(CH3)2, -
N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH2CH2CH2CH3)2, and the like.
As used herein the term "C1-C6alkyl-KN-C1-C6 dialkylamine" refers to straight or
branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an N.N-
C1-C6 dialkylamine attached to the aliphatic chain. Included within the term "C1-C6
alkyl-N,N-C1-C6 dialkylamine" are the following:

and the like.
As used herein the term "(C1-C6)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 "(C1-C6)alkyl-
pyrrolidine" are the following:

and the like.
As used herein the term "(C1-C6)alkyl-piperidine" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a piperidine
attached to the aliphatic chain. Included within the scope of the term "(C1-C6)alkyl-
piperidine" are the following:

and the like.
As used herein the term "(C1-C6)alkyl-morpholine" refers to a straight or
branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a
morpholine attached to the aliphatic chain. Included within the scope of the term "C1-C6
alkyl-morpholine" are the following:

and the like.
The designation refers to a bond that protrudes forward out of the plane
of the page.
The designation refers to a bond that protrudes backward out of the
plane of the page.
As used herein the term "iGluR.5" refers to the kainate ionotropic glutamate
receptor, subtype 5, of the larger class of excitatory amino acid receptors.
As used herein the term "migraine" refers a disorder of the nervous system
characterized by recurrent attacks of head pain (which are not caused by a structural brain
abnormalitiy such as those resulting from tumor or stroke), gasrointestinal disturbances,
and possibly neurological symptoms such as visual distortion. Characteristic headaches
of migraine usually last one day and are commonly accompanied by nausea, emesis, and
photophobia.
Migraine may represent a "chronic" condition, or an "acute" episode. The term
"chronic", as used herein, means a condition of slow progress and long continuance. As
such, a chronic condition is treated when it is diagnosed and treatment continued
throughout the course of the disease. Conversely, the term "acute"means an exacerbated
event or attack, of short course, followed by a period of remission. Thus, the treatment of
migraine contemplates both acute events and chronic conditions. In an acute event,
compound is administered at the onset of symptoms and discontinued when the symptoms
disappear. As described above, a chronic condition is treated throughout the course of the
disease.
As used herein the term "patient" refers to a mammal, such a mouse, gerbil, guinea
pig, rat, dog or human. It is understood, however, that the preferred patient is a human.
The term "iGluR5 receptor antagonist" or "iGluR5 antagonist", as used herein,
refers to those excitatory amino acid receptor antagonists which bind to, and antagonize
the activity of, the iGluR5 kainate receptor subtype. As a preferred embodiment, the
present invention further provides selective iGluR.5 receptor antagonists. "Selective
iGluR.5 receptor antagonist" or "selective iGluR.5 antagonist" as used herein, includes
those excitatory amino acid receptor antagonists which selectively bind to, and
antagonize, the iGluR.5 kainate receptor subtype, relative to the iGluR2 AMPA receptor
subtype. Preferably, the "selective iGluR5 antagonists" for use according to the methods
of the present invention have a binding affinity at least 10 fold greater for iGluR5 than for
iGluR2, more preferably at least 100 fold greater. WO 98/45270 provides examples of
selective iGluR5 receptor antagonists and discloses methods for synthesis.
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.
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.
A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of
each compound used in the present method of treatment. Preferably, daily doses will be
about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25
mg/kg.
Oral administration is a preferred route of administering the compounds employed
in the present invention whether administered alone, or as a combination of compounds
capable of acting as an iGluR5 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 iGluR5 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.
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.
Compositions are preferably formulated in a unit dosage form, each dosage
containing from about 1 to about 500 mg of each compound individually or in a single
unit dosage form, more preferably about 5 to about 300 mg (for example 25 mg). The
term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for
a patient, each unit containing a predetermined quantity of active material calculated to
produce the desired therapeutic effect, in association with a suitable pharmaceutical
carrier, diluent, or excipient.
The inert ingredients and manner of formulation of the pharmaceutical
compositions are conventional. The usual methods of formulation used in pharmaceutical
science may be used here. All of the usual types of compositions may be used, including
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.
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.
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.
Tablets are often coated with sugar as a flavor and sealant. The compounds may
also be formulated as chewable tablets, by using large amounts of pleasant-tasting
substances such as mannitol in the formulation, as is now well-established practice.
Instantly dissolving tablet-like formulations are also now frequently used to assure that
the patient consumes the dosage form, and to avoid the difficulty in swallowing solid
objects that bothers some patients.
A lubricant is often necessary in a tablet formulation to prevent the tablet and
punches from sticking in the die. The lubricant is chosen from such slippery solids as
talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
Tablet disintegrators are substances which swell when wetted to break up the
tablet and release the compound. They include starches, clays, celluloses, algins and
gums. More particularly, com 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.
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.
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.
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.
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.

Active Ingredient 250
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S.
sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the
resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules
so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60
mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a
tablet machine to yield tablets each weighing 150 mg.
Formulation 5
Capsules each containing 80 mg medicament are made as follows:
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
Suspensions each containing 50 mg of medicament per 5 ml dose are made as follows:

The medicament is passed through a No. 4:5 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.

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.
Compounds of Formula I and Formula 1(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 1(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 United States Patents Nos.
5,356,902 (issued October 18, 1994) and 5,446,051 (issued August 29, 1995) and
5,670,516 (issued September 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.
Compounds of Formula I, wherein Z represents an oxygen atom, may be
synthesized according to Scheme I.
In Scheme I, step A, the compound of structure (1) is treated with a trialkylsilyl
iodide (Alk3Sil) 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-decahydroisoquinolie-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 Alk3Sil 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.
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 °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 °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.
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, (C1-C4)alkyl-CO2R9, or CO2R9) 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 °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.
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 HC1 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.
In Scheme I, Step D, the compound of structure (6) is hydrolyzed under standard
conditions to give the compound of structure (7) wherein R1 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% HC1 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 R1
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.
In Scheme I, where it is desired that the compound of structure (7) contain a
tetrazole at R1, compound (6) (wherein U for the purposes of this step is nitrile) is treated
with a compound of Alk3SnN3 in Step E to give the compound of structure (6a). This is
followed by hydroysis in Step F, to provide the compound of structure (7) (wherein R1 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°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 R1 is tetrazole)
may then be purified, all of which occur under standard conditions well known in the art
as described in Step D above.
As an alternative to Steps D and F above, the compounds of structure (6) and (6a)
may be selectivley hydrolyzed under standard conditions known in the art to provide a
compound of structure (7a):

For example, compound (6) may be hydrolyzed to provide compounds of (7a)
wherein R6 is as defined hereinabove, other than tetrazole, whereas compound (6a) may
be hydrolyzed to provide compounds of (7a) wherein R6 is tetrazole. Compound (7a) can
then be deprotected under standard conditions to provide the compound of structure (9):

Methods for the selective hydrolysis of compounds of structure (6) and (6a) are
well known in the art.
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.
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.

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-l, a solution of compound (6), dissolved in 6N HC1, is heated to reflux
(90-95 °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 R1
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 R1 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 R1 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 R1 is tetrazole.
In Scheme I, Step H, the compound of Formula I may be nonselectively or
selectively esterified to provide the compounds of Formula la. 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°C for about 1 to 2 hours.
The reaction mixture is then concentrated under vacuum to provide the crude compound
of Formula la. 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 °C) for
about 15-25 hours. The reaction mixture is then concentrated under vacuum to provide the
crude compound of Formula la. 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.
Compounds of Formula I, wherein Z represents an oxygen atom and R1 represents
tetrazole may alternatively be synthesized according to the procedures set forth in
Scheme III.
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% HC1 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).
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 °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 IN 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.
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 °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 °C
and treated with about 1-1.5 equivalents of compound (11) (where R2, 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% HO 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
In Scheme III, Step D, compound (12) is treated with a compound of formula
Alk3SnN3, 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 R1 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 °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' 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.
In Scheme HI, Step E, the compound of Formula I is nonselectively, or selectively,
esterified to provide the compound of Formula la, wherein R6 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 °C for about 1-2 hours. The reaction
mixture is then concentrated under vacuum to provide the crude compound of Formula la,
wherein R7 is tetrazole. This material is precipitated with diethyl ether and filtered to
provide the purified compound of Formula la. 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 °C) for about 15-25 hours. The reaction mixture is then concentrated under vacuum to
provide the crude compound of Formula la. 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.
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 R1 is tetrazole. This alternate route is
provided in Scheme IV(a) and IV(b) below:

hi Scheme IV(a), Step A, the compound of structure (11) is treated under standard
conditions to provide the compound of structure (1 la). 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 wanned 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 HC1 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)
In Scheme IV(a), Step B, the compound of structure (1 la) is protected with a
suitable nitrogen protecting group under standard conditions to provide the compound of
structure (1 lb). 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 (llb) 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 alchohol. The product of compound (1 lb) is dried and
concentrated under vaccum to provide the concentrated compound of structure (llb).

In Scheme IV(b), Step A, the compound of structure (10) (from Scheme III above)
is treated with the compound of structure (1 lb) 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 (1 lb) 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 IN aqueous HC1 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 vaccum 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)
As one of ordinary skill in the art will recognize, the compound of structure (12a)
may then be deprotected using, for example TM SI (iodotrimethylsilane) in methylene
chloride, to provide the compound of Formula I. wherein R1 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 la, wherein R6
is tetrazole.
Scheme IV(a) and IV(b), above, provide procedures for the synthesis of Formula I
and 1(a) compounds where R1 or R6 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 1(a) or Formula 1. Scheme
IV(c) provides a general synthetic route for these procedures.

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 R6 is tetrazole.
For example, compound 12(a), dissolved in a suitable solvent such as DMF, is treated
with a compound of the formula R5-LG where LG represents a suitable leaving group
such as a halide. For example R5 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°C under nitrogen for about lhour. The reaction is
then cooled to ambient temperature and submitted to standard extractive worhup
techniques know to the skilled artisan to provide purified compound 12(b), wherein R6 is
tetrazole.
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 1(a) wherein R1 or
R6 is tetrazole. For example, to a solution of compound 12(a) or 12(b) is added anisole
and trifluoroacetic acid (TFA). The solution is stired 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.
Compounds 12(c) and 12(d) are further deprotected in Step C to provide the final
products of Formula I or 1(a) (wherein Rl or R6 is tetrazole). For example, compound
12(c) or 12(d) is combined with TMSI in CH2CI2 and the reaction is stirred until
complete. The Final compounds of Formula 1 or 1(a) wherein R1 or R6 is tetrazole may
be isolated after standard workup conditions.
Surprisingly, and as a further embodiment of the present invention, Applicants
have discovered alternative nucleophilic aromatic substitution procedures for the
synthesis of Formula 1 or Formula 1(a) (wherein R1 or R6 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.

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 reactionis heated until complete. For example, the reaction is heated
to about 65°C for about 4 hours. The compound 12(c) is isolated by standard workup
techniques.
In Scheme IV(d), Step B, compound 12(c) is deprotected to provide the compound
of Formula I wherein R1 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°C until the reaction is complete. The mixture is cooled then added to a suitable acid,
such as HC1, to provide the precipitated acid salt of Formula I, wherein R1 is tetrazole.
The acid salt of Formula I (R1 is tetrazole) can purified by standard recrystallization
techniques and isolated as the salt or a solvate thereof such as the hydrate.
In Scheme IV(d), Step C, Formula I is esterifed with a compound of the formula
R5-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 R5-OH, and water is heated to about 140°C until complete. The ester salt of
Formula 1(a) where R6 is tetrazole is isolated by standard techniques and may be purified
by standard recrystallization techniques.
Compounds of Formula I, wherein Z represents a sulfur atom, may be synthesized
according to Scheme V.
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°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).
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-carboxylate is mixed with about 1-2.5
equivalents of substituted aryl thiol (wherein U represents hydrogen, CN, (C1-C4)alkyl-
CO2R9, or CO2R9 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.
In Scheme V, Step C, compound (15) is concomitantly deprotected and
hydrolyzed under standard conditions to provide the compound of Formula I wherein R1
is other than tetrazole, but otherwise as defined hereinabove. For example, a solution of
compound (15) dissolved in 6M HC1 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 R1 is other than tetrazole, but otherwise as
defined hereinabove. The compound of Formula 1 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.
In Scheme V, Step D, where it is desired that the compound of Formula I contain a
tetrazole at R1, compound (15), wherein U is nitrile, is treated under standard conditions
with a compound of formula Alk3SnN3, 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 °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.
In Scheme V, Step E, compound (16) is concomitantly deprotected and hydrolyzed
under standard conditions to provide the compound of Formula I, wherein R1 is tetrazole.
For example, a solution of compound (16), dissolved in 6M HC1, 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 R1 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 1 wherein Rl is
tetrazole.
In Scheme V, Step F, the compound of Formula 1 is esterified under standard
conditions well known in the art to provide the compound of Formula la. 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 °C) for about 15-24 hours. The reaction mixture is concentrated under vacuum to
provide the crude compound of Formula la. 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 la.
The Formula 1 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 United States Patents 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 VT
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 United
States Patents No. 4,902,695, No. 5,446,051, and No. 5,356,902.
Scheme VI

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 R5-Br
(where R5 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°C for about 3 hours, cooled
and partitioned between 50:50 ethyl acetate/heptane and IN 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).
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; "µL"' refers to microliters; "mol" refers to moles; "minor refers
to millimoles; "psi" refers to pounds per square inch: "mm Hg" refers to millimeters of
mercury; "min" refers to minutes; "h" or "hr" refers to hours; "°C" refers to degrees
Celsius; "TLC" refers to thin layer chromatography; "HPLC" refers to high performance
liquid chromatography; "Rf" refers to retention factor; "R," refers to retention time: ""d"
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;
"PPh3" refers to triphenylphosphine; "DEAD" refers to diethyl azodicarboxylate; "RT"
refers to room temperature; "Kj" refers to the dissociation constant of an enzyme-
antagonist complex and serves as an index of ligand binding; and "ID50" and "ID100"
refer to doses of an administered therapeutic agent which produce, respectively, a 50 %
and 100% reduction in a physiological response.

To a -78 °C solution of (3S, 4aR4aS, 8aR) 6-oxo-2-tert-butoxycarbonyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-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 (1.24g, 32.73 mmol) was added in portions. The resulting
mixture was slowly wanned up to room temperature over 5 hours. The reaction mixture
was cooled down to 0 °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 (3X). The combined organic
phases were dried, filtered and concentrated in vacuo. Flash chromatography (silicagel,
70% ethyl acetate/hexane) gave ethyl (35,4aR4a5, 65, 8ai?) 6-hydroxy-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (2.4 g, 35%)
and the title compound (4.15 g, 60%)
Ion Electrospray Mass Spectrum M+Na: 350.2

A. Preparation of ethyl (35, 4aR4aS, 6S, 8aR) 6-(3-ethoxycarbonyl-naphthalen-2-yloxy)-2-
tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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 (35, 4aR4aS, 65, 8aR) 6-(3-Carboxy-naphthalen-2-yloxy)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
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
°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 aminoacid (57 mg, 70%),
Mass Spectrum (Fast Atom Bombardement) M-HC1+1: 370.2
'H NMR (CD3OD, 200.13 MHz): 8.35 (s, 1 H); 7.83 (t, J = 7.9 Hz, 2 H); 7.48 (m, 3 H);
4.63 (m, 1 H); 4.10 (m, 1 H); 3.40 (m, 1H); 3.15 (m, 1 H); 2.26-1.55 (m, 10 H).

A. Preparation of ethyl (35, 4aR4aS, 65, 8aR) 6-(4-ethoxycarbonyl-biphenyl-3-yloxy)-2-
tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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%).
Mass Spectrum (Fast Atom Bombardement) M+Na: 574.2
B. Preparation of (35", 4aR4aS, 6S, 8aR) 6-(4-carboxy-biphenyl-3-yloxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
To a solution of the material from step A (400mg) 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 (2X). The aqueous phase was made acidic by addition of
hydrochloric acid (10 %, pH= 3-4) and extracted with ethyl acetate (3X). 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 (350mg, 95%)
Mass Spectrum (Fast Atom Bombardement) M+l: 496.2
C. Preparation of (35, 4aR4aS, 6S, 8aR) 6-(4-carboxy-biphenyl-3-yloxy)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
The material from step B (350mg, 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 aminoacid (250 mg, 82%).
Ion Electrospray Mass Spectrum M-HC1+1: 396.2
1H NMR (CD3OD, 200.13 MHz): 7.90 (d, J = 8.1 Hz, 1 H); 7.78 (m, 2 H); 7.53-7.27 (m,
5 H); 4.60 (m, 1 H); 4.08 (dd, J = 12.0, 3.3 Hz. 1 H); 3.37 (m, 1 H); 3.12 (dd, J = 12.7, 4.3
Hz, 1 H); 2.18-1.59 (m, 10 H).

A. Preparation of ethyl (35, 4aR4aS, 65, 8aR) 6-(4-eThoxycarbonyl-biphenyl-3-yloxy)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate hydrochloride
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%).
Ion Electrospray Mass Spectrum M-HC1+1: 452.2
Analysis calcd. for: C27H33NO5.1 HC1. 0.8 H20: C 64.55, H 7.14, N 2.79; Found: C
64.64, H 7.34, N 3.00.

A. Preparation of ethyl (35, 4aR4aS, 65, 8aR) 6-(5-chloro-2-ethoxycarbonyl-phenoxy)-2-
tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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 °C for 24 h.
Flash chromatography (silicagel, 40% diethyl ether/hexane) gave 132 mg of the title
intermediate (71%).
Mass Spectrum (Fast Atom Bombardement) M+l: 510.3
B. Preparation of (35, 4aR4aS, 65, 8aR) 6-(2-carboxy-5-chloro-2-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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%).
Mass Spectrum (Fast Atom Bombardement) M+Na: 476.2
C. Preparation of (35, 4aR4aS, 65, 8aR) 6-(2-carboxy-5-chloro-2-phenoxy)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
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 aminoacid (98 mg, 97%).
Mass Spectrum (Fast Atom Bombardement) M-HCl+1: 354.1
Analysis calcd. for: C17H202NO5.1 HC1. 0.5 H20: C 51.14, H 5.55, N 3.51; Found: C
51.37, H 5.90, N 3.82.

A. Preparation of ethyl (35, 4aR4aS, 65, 8aR) 6-(5-chloro-2-ethoxycarbonyl-phenoxy)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate hydrochloride
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%).
Ion Electrospray Mass Spectrum M-HCl+1: 410.2
'H NMR (CDC13, 200.13 MHz): 9.85 (br s, 2 H); 7.64 (d, J = 8.2 Hz, 1 H); 6.90 (m, 2 H);
5.28 (br s, 1 H); 4.24 (m, 5 H); 3.91 (br s, 1H); 3.42, 3.26 (2 br s, 2 H); 2.65-1.78 (m, 10
H); 1.32-1.18 (m, 6 H).
Example 6
Preparation of (35, 4aR4aS, 65, 8aR) 6-(2-carboxy-4,5-difluoro-phenoxy)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of ethyl (35*, 4aR4aS, 6S, 8aR) 6-(2-ethoxycarbonyl-4,5-difluoro-phenoxy)-
2-tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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%).
Ion Electrospray Mass Spectrum M+Na: 534.2
B. Preparation of (35, 4aR4aS. 65, 8aR) 6-(2-carboxy-4,5-difluoro-2-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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%).
Mass Spectrum (Fast Atom Bombardement) M+Na: 478.2
C. Preparation of (35, 4aR4aS, 65, 8aR) 6-(2-carboxy-4,5-difluoro-2-phenoxy)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
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 aminoacid (98
mg, 97%).
Mass Spectrum (Fast Atom Bombardement) M-HC1+1: 356.1
'H NMR(CD3OD, 200.13 MHz): 7.70 (t, J = 9.9 Hz, 1 H); 7.21 (dd, J = 6.6, 5.8 Hz, I H);
4.44 (m, 1 H); 4.07 (br d, J = 14.4 Hz, 1 H); 3.35 (m. 1 H); 3.16 (dd, J = 12.5, 3.7 Hz, 1
H); 2.23-1.49 (m, 10 H).

A. Preparation of ethyl (3S, 4aR4aS 6S, 8aR) 6-(2-ethoxycarbonyl-4-chloro-phenoxy)-2-
tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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.
Mass Spectrum (Fast Atom Bombardement) M+l :511.1
B. Preparation of (35, 4aR4aS, 6S, 8aR) 6-(2-carboxy-4-chloro-phenoxy)-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride.
A solution of the material from step A (106 mg, 0.20 mmol) in tetrahydrofuran (1
mL) was treated with 3N HC1 (3 mL) and heated at 80°C overnight. The crude was
concentrate in vacuo and washed with ethyl acetate (2x) to afford 25 mg (31% yield) of
the title compound.
Mass Spectrum (Fast Atom Bombardement) M-HC1+1: 354.1
Analysis calculated for C17H21C12NO5: %C, 52.32; %H, 5.42; %N, 3.59. Found: %C,
52.39; %H, 5.61; %N, 3.60.
Example 8
Preparation of (35, 4aR4aS, 6S, 8aR) 6-(2-carboxy-4-nitro-phenoxy)-l,2,3,4.4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of ethyl (3S, 4aR4aS, 6S, 8aR) 6-(2-ethoxycarbonyl-4-nitro-phenoxy)-2-
tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
Following the procedures as described in Example 1 A, 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.
Mass Spectrum (Fast Atom Bombardemenf) M+l: 521.3
B. Preparation of (35, 4aR4aS, 6S, 8aR) 6-(2-carboxy-4-nitro-phenoxy)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride.
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.
Mass Spectrum (Fast Atom Bombardement) M-HC1+]: 365.1
Analysis calculated for C17H21C1N207: %C, 50.94; %H, 5.28; %N, 6.99. Found: %C,
50.88; %H, 5.35; %N, 6.80.

A. Ethyl (3S, 4aR4aS, 8aR) 6-oxo-2-tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylate.
60
To a solution of ethyl (35, 4aR, 6R4aS, 8aR) 6-oxo-2-methoxycarbonyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (3.54 g, 12.5 mmol) in
methylene chloride (l00mL) under nitrogen, iodotrimethylsilane (l0.0g, 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 (7mL, 50 mmol) was added. After stirring for 15 minutes a
solution of di-tert-butyl-dicarbonate (2.73g, 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 IN 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. (35, 4aR4aS, 8aR) 6-oxo-2-tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid.
To a solution of ester from preparation 2 A (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 (x2). The aqueous phase was made
acidic by addition of 10 % hydrochloric acid (pH= 3-4) and extracted with ethyl acetate
(x3). The resulting organic phases were combined, dried and concentrated in vacuo to
afford the title compound (8.85 g, 100%)
C. (35, 4aR4aS, 65, SaR) 6-hydroxy-2-tert-butoxycarbonyl-t,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid.
To an ice-cooled solution of ketone from preparation 2B (11.34g, 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 IN 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%)

A. Preparation of (35", 4aR4aS, 65, 8aR) 6-(3-chloro-2-cyano-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
To an ice-cooled solution of the material from preparation 2 (400 mg, 1.34 mmol)
in dry tetrahydrofliran (5.6 mL) under nitrogen a solution of potassium tert-butoxide (1M
in tetrahydrofliran, 3.0 mL) was slowly added. The resulting suspension was stirred at
room temperature for 25 min and again cooled to 0-5 °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 (x2). The
aqueous phase was made acidic (pH= 3-4) with 10 % hydrochloric acid and extracted with
ethyl acetate (x2). 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%).
Ion Electrospray Mass Spectrum M+1-t-butylOCO: 335.2
B. Preparation of (35, 4aR4aS. 65, 8aR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-2-
tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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 °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 (2X) 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%).
Ion Electrospray Mass Spectrum M+l: 478.1
C. Preparation of (35. 4aR4aS, 65, 8aR) 6-[3-chIoro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
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 (IX). The aqueous layer was
washed with ethyl acetate (2X) and concentrated in vacuo to afford a white solid (320 mg,
92%).
Ion Electrospray Mass Spectrum M-HC1+1: 378.1
1HNMR (CD3OD, 200.13 MHz): 7.54 (t, J = 8.3 Hz, 1 H); 7.22 (t, J = 8.1 Hz, 2H); 4.47
(m, 1 H); 4.00 (dd, J = 12.6, 3.5 Hz, 1 H); 3.21 (t J - 12.6 Hz, 1 H); 3.06 (dd, J = 12.7.
4.7 Hz, 1 H); 2.21-1.59 (m, 10 H).
Example 10
Preparation of 2-Ethyl-butyl (35, 4aR4aS, 65, 8aR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-
phenoxy]-l, 2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate hydrochloride

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 °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%).
Ion Electrospray Mass Spectrum M-HCl+1: 462.3
'H NMR (CD3OD, 200.13 MHz): 7.53 (t, J = 8.0 Hz, 1 H); 7.24 (d, J = 8.2 Hz, 1 H); 7.19
(d, J = 8.0 Hz, 1 H); 4.45 (br s, 1 H); 4.22 (dd, J = 10.8, 5.7 Hz. 1 H); 4.14 (m, 2 H); 3.23
(t, J = 12.6 Hz, 1 H); 3.11 (d, J = 9.6 Hz, 1 H); 2.19-1.36 (m, 15 H); 0.91 (t, J = 7.5 Hz, 6
H).
Example 11
Preparation of (35, 4aR4aS, 65, 8aR) 6-[3-methoxy-2-(l(2)H-tetrazoI-5-yl)-phenoxy]-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of (35, 4aR4aS, 65, 8aR) 6-(3-methoxy-2-cyano-phenoxy)-2-tert-
butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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
aeetate/hexane/2.5 % acetic acid), 429 mg of the title compound (74%).
Ion Electrospray Mass Spectrum M+l-/-butylOCO: 331.3
B. Preparation of (35, 4aR4aS. 65, 8aR) 6-[3-methoxy-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
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 °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 aminoacid (17 mg, 5%, two steps).
Ion Electrospray Mass Spectrum M-HC1+1: 374.2
1HNMR (CD3OD, 200.13 MHz): 7.50 (t, J = 8.5 Hz, 1 H); 6.82 (dd, J = 12.0, 8.5 Hz, 2
H); 4.43 (m, 1 H); 4.02 (dd, J = 12.3, 3.6 Hz, 1 H); 3.81 (s, 3 H); 3.22 (d, J = 12.8 Hz, 1
H); 3.07 (dd, J = 12.8, 4.3 Hz, 1 H); 2.14-1.29 (m, 10 H).
Example 12
Preparation of (35, 4aR4aS, 65, 8aR) 6-[3-fluoro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of (35, 4aR4aS, 65, 8aR) 6-(3-fluoro-2-cyano-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
Following the procedures as described in Example 9,step A, material from
preparation 2 (300 mg, 1 mmol) in tetrahydrofitran (4.2 mL) was treated with a solution of
potassium terr-butoxide (1 M in tetrahydrofiiran, 2.2 mL) and 2,6-difluorobenzonitrile
(209 mg, 1.5 mmol) to give 377 mg of the title compound (90%),
Ion Electrospray Mass Spectrum M+Na: 441.2
B. Preparation of (35", 4aR4aS, 65, 8aR) 6-[3-fluoro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-2-
tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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 °C for 31 h to give the desired compound (120 mg, 29%).
Ion Electrospray Mass Spectrum M+l: 462.3
C. Preparation of (35, 4aR4aS, 65, 8aR) 6-[3-fluoro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride.
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 aminoacid (60 mg, 64%).
Ion Electrospray Mass Spectrum M-HC1+1: 362.2
'HNMR (CD3OD, 200.13 MHz): 7.57 (dt, J = 8.3, 6.7 Hz, 1 H); 7.13 (d, .1 = 8.9 Hz, 1 H);
6.97-6.88 (m, 1 H); 4.59-4.49 (m, 1 H); 4.05 (dd, J = 12.1, 4.3 Hz, 1 H); 3.38-3.25 (m, 1
H); 3.11 (dd, J = 12.9, 4.6 Hz, 1 H); 2.27-1.39 (m, 10 H).
Example 13
Preparation of (35, 4aR4aS, 6S, 8aR) 6-[4-fluoro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of (35, 4aR4aS, 65, 8aR) 6-(4-fluoro-2-cyano-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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%).
Ion Electrospray Mass Spectrum M+Na: 441.2
B. Preparation of (35*, 4aR4aS. 65, 8aR) 6-[4-fluoro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-2-
tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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 °C for 24 h to give the desired compound (249 mg, 66%).
Ion Electrospray Mass Spectrum M+l: 462.3
C. Preparation of (35,4aR4aS. 65. 8aR) 6-[4-fiuoro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride.
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%)
Ion Electrospray Mass Spectrum M-HC1+1: 362.2
1H NMR (CD3OD, 200.13 MHz): 7.70 (dt, J = 8.4, 1.9 Hz, 1 H); 7.33 (dd, J = 5.9, 1.5 Hz,
2 H); 4.54 (m, 1 H); 4.02 (dd, J = 12.2, 4.2 Hz. I H); 3.42-3.30 (m, 1 H); 3.14 (dd, J =
12.8, 4.4 Hz, 1 H); 2.17-1.52 (m, 10 H).
Example 14
Preparation of (35, 4aR4aS, 65, SaR) 6-[4-methyl-2-(l(2)flr-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of (35, 4aR4aS, 65, 8aR) 6-(4-methyl-2-cyano-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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%).
Ion Electrospray Mass Spectrum M+l: 415.2
B. Preparation of (35, 4aR4aS, 65, SaR) 6-[4-methyl-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride.
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 °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 aminoacid (37 mg, 29%, two steps)
Ion Electrospray Mass Spectrum M-HC1+1: 358.3
1HNMR (CD3OD, 500 MHz): 7.79 (s, 1 H); 7.35 (d, J = 7.1 Hz, 1 H); 7.18 (d, J = 8.6 Hz.
lH);4.54(m, 1 H); 4.07 (d, J= 11.1 Hz, 1 H); 3.40 (t. J = 12.9 Hz, 1 H); 3.14 (d, J - 9.5
Hz, 1 H); 2.34 (s, 3 H); 2.32-1.57 (m, 10 H).
Example 15
Preparation of (35, 4aR4aS, 65, 8aR) 6-[5-bromo-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of (35, 4aR4aS, 65, 8aR) 6-(5-bromo-2-cyano-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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%).
Ion Electrospray Mass Spectrum M+Na: 501.0
B. Preparation of (35, 4aR4aS, 65, SaR) 6-[5-bromo-2-(l(2)H-tetrazol-5-yl)-phenoxy]-2-
tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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 °C for 30 h to give the desired compound (380 mg, 74%).
Ion Electrospray Mass Spectrum M+l: 522.1
C. Preparation of (35, 4aR4aS, 65, 8aR) 6-[5-bromo-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride.
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 aminoacid (290 mg, 95%)
Ion Electrospray Mass Spectrum M-HC1+1: 422.0
Analysis calcd. for: C17H20BrN5O3.1 HC1. 1.5 H20: C 42.03, H 4.98, N 14.42; Found:
C 41.75, H 4.59, N 14.02.
Preparation of (35, 4aR4aS. 65, 8aR) 6-[3,5-difluoro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of (35, 4aR4aS, 65, 8aR) 6-(3,5-difluoro-2-cyano-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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%).
Ion Electrospray Mass Spectrum M+Na: 459.2
B. Preparation of (35, 4aR4aS, 65, 8aR) 6-[3,5-ditluoro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride.
To the compound from step A (75 mg, 0.17 mmol), toluene (0.2 mL) and azidotri-
n-butylstannane (140 µL, 0.51 mmol) were added at room temperature. The reaction
mixture was allowed to stir at 100°C for four days. Then, it was cooled at room
temperature and treated with a IN 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, 2x5 cm, (A) watert0.05% trifluoroacetic acid, (B) acetonitrile/ 0.05%
trifluoroacetic acid; 10 mL/min, 5-40% B in 15 min] the desired aminoacid (6 mg, 9%,
two steps).
Ion Electrospray Mass Spectrum M-HCl+l: 380,2
1H-NMR (MeOH-d4. 200.15 MHz): 7.02 (dd, J = 11.0, 1.6 Hz, 1 H); 6.87-6.76 (m, 1 H);
4.59-4.39 (m, 1 H); 4.02 (dd, J = 12.6, 3.8 Hz, 1 H); 3.21-3.05 (m, 2 H); 2.20-1.78 (m. 8
H); 1.49-1.29 (m, 2 H).
Example 17
Preparation of (35, 4aR4aS, 65, 8aR) 6-[4-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of ethyl (35, 4aR4aS, 65, 8aR) 6-(4-chloro-2-cyano-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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%).
Ion Electrospray Mass Spectrum M+l: 463.2
B. Preparation of (35, 4aR4aS, 65, 8aR) 6-(4-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy)-2-
tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
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 °C for 76 h and at 70
°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 (2X). The aqueous
layer was made acidic by addition of hydrochloric acid (10%, till pH=5-6) and extracted
with ethyl acetate (3X). The combined organic phases were dried and concentrated in
vacuo to afford the title compound as a foam (98 mg, 79%, two steps).
Ion Electrospray Mass Spectrum M+l: 478.2
C. Preparation of (35, 4aR4aS, 65, 8aR) 6-[4-chloro-2-(l(2)H-tetrazol-5-yI)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride.
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 aminoacid (37 mg, 49%)
Ion Electrospray Mass Spectrum M-HC1+1: 378.1
1H NMR (CD3OD, 200.13 MHz): 7.95 (d, J = 2.6 Hz, 1 H); 7.54 (dd, J = 9.0, 2.6 Hz, 1
H); 7.32 (d, J = 9.0 Hz, 1 H); 4.59 (m, 1 H); 4.14 (dd, J = 13.4, 2.7 Hz, 1 H); 3.22 (dd, J =
13.0, 4.4 Hz, 1 H); 2.21-1.65 (m, 10 H).
Example 18
Preparation of (35, 4aR4aS, 65, 8aR) 6-[5-methyl-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of ethyl (35, 4aR4aS, 65, SaR) 6-(5-methyl-2-cyano-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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
°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, x2), dried and evaporated in vacuo. Flash
chromatography (silicagel, 25% ethyl acetate/hexane) gave 86 mg of the desired
compound (32%).
Ion Electrospray Mass Spectrum M+l-t-butyl OCO: 343.3
B. Preparation of (35, 4aR4aS. 65, 8aR) 6-[5-methyl-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
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 °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)
Ion Electrospray Mass Spectrum M+l: 358.3
1HNMR (CD3OD, 200.13 MHz): 7.86 (d, J = 7.9 Hz, 1 H); 7.14 (s, 1 H); 6.96 (d, J = 7.9
Hz, 1 H); 4.89 (m, 1 H); 4.09 (dd, J = 12.3, 3.7 Hz, 1 H); 3.42 (t, J = 13.0 Hz, 1H); 3.15
(dd, J - 12.9, 4.1 Hz, 1 H); 2.43 (s, 3H); 2.21-1.51 (m, 10 H).
Example 19
Preparation of (35, 4aR4aS, 65, 8aR) 6-[5-methoxy-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Preparation of ethyl (35, AaR4aS, 65, 8aR) 6-(5-methoxy-2-cyano-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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%).
Ion Electrospray Mass Spectrum M+Na: 481.1
B. Preparation of (35, 4aR4aS, 65, 8aR) 6-[5-methoxy-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride.
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 °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)
Ion Electrospray Mass Spectrum M+l: 374.2
Analysis calcd. for: C18H23N504.1.7 HC1.0.2 CH3CH2OH: C 49.71, H 5.87, N 15.75;
Found: C 50.05, H 5.52, N 15.51.
Example 20
Preparation of (35, 4aR4aS. 6S, 8aR) 6-[2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid

A. Preparation of ethyl (35", 4aR4aS, 65, SaR) 6-(2-cyano-phenoxy)-2-tert-
butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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%).
Mass Spectrum (Fast Atom Bombardement) M+l: 429.3
B. (35, 4aR4aS. 65, 8aR) 6-[2-(l(2)H-tetrazol-5-yl)-phenoxy]-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid.
The intermediate from step A (45 mg, 0.105 mmol), was treated with
azidotributyltin (0.17 mL, 0.626 mmol) and heated at 80°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°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.
Mass Spectrum (Fast Atom Bombardement) M+l: 344.2
1HNMR(CD3OD, 200.13 MHz): 7.54 (m, 1 H),7.33 (m, 1H); 7.13 (m, 2 H); 4.12 (m, 1
H); 3.22 (m, 1 H); 2.95 (m, 1 H); 2.59 (m, 1H); 2.10-1.39 (m, 10 H).
Example 21
Preparation of (35, 4aR4aS 65, 8aR) 6-[5-Benzyloxy-3-fluoro-2-(l(2)H-tetrazol-5-yl)-
phenoxy]-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. 4-Benzyloxy-2,6-difluorobenzonitrile
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 °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°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 (3X) and the combined organic phases were back-extractted with ethyl
acetate (3X). 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).
Ion Electrospray Mass Spectrum M+18: 263.
B. Preparation of ethyl (35", 4aR4aS, 6S, 8aR) 6-(5-benzyloxy-3-fluoro-2-cyano-phenoxy)-
2-tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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.
Ion Electrospray Mass Spectrum M+Na: 547
C. Preparation of (35, 4aR4aS, 65, 8aR) 6-[5-Benzyloxy-3-fluoro-2-(l(2)H-tetrazol-5-yl)-
phenoxy]-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
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°C for 5 d gave the desired
tetrazol. The crude product was disolved 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 aminoacid as
a pale yellow solid (25 mg , 45%) and small amount (7 mg, 13%) slightly impure.
Ion Electrospray Mass Spectrum M+l: 568.
Preparation 3
Preparation of ethyl (35, 4aR4aS, 6R, 8aR) 6-methanesulfonyloxy-2-methoxycarbonyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.

To an ice-cooled solution of ethyl (35, 4aRaS, 6R, 8aR) 6-hydroxy-2-
methoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-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 x 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%).
Ion Electrospray Mass Spectrum M+l: 364
Example 22
Preparation of (35, 4aR4aS 6S, 8aR) 6-((3-carboxy-2-naphthalenyl)thio)-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Methyl 3-(((trifiuoromethane)sulfonyl)oxy)-2-naphthoate.
To a solution of methyl 3-hydroxy-2-naphtoate (500 mg, 2.47 mmol) and 4-(N,N-
dimethylamino)pyridine (603 mg, 4.94 mmol) in dichloromethane (25 mL) at 0 °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 °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 trazes 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.
Electronic Impact Mass Spectrum M+: 334.
Analysis Calculated for C13H9F3O5S: C, 46.71; H, 2.71
Found: C, 46.54; H, 2.66
B. Methyl 3-mercapto-2-naphthoate
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 °C 5-10 min, then 5-10 min at room temperature]
was added and the reaction mixture was warmed to reflux (bath temp 90 °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 °C and stirred for 45 min.
Glacial acetic acid (0.5 mL) was added and the reaction mixture stirred at 0 °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%).
Electronic Impact Mass Spectrum M+: 218.
C. Ethyl (35, 4aRaS. 65, 8aR) 6-((3-methoxycarbonyl-2-naphthalenyl)thio)-2-
methoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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).
1H NMR (CDC13, 200.15 MHz): 8.39 (s, 1H); 7.83 d, J = 7.8 Hz, 1H); 7.74 (d,
overlapping, 1H); 7.72 (s, IH); 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, IH): 2.45 (m,
IH); 2.2-1.7 (m, 8H); 1.45 (m, IH); 1.24 (t, J = 7.1 Hz. 3H).
D. (35, 4aR4aS, 65, 8aR) 6-((3-Carboxy-2-naphthalenyl)thio)-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid hydrochloride.
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 (3x), followed by
addition of acetone and concentration in vacuo (3x), to give an off-white solid (30 mg,
96% yield).
M.p.>183°C with dec.
Fast Atom Bombardment Mass Spectrum M-Cl+1: 386.
Analysis Calculated for C21NO4S.2HoO: C, 55.08; H, 6.16; N, 3.06
Found: C, 55.08; H, 6.34; N, 3.19
Example 23
Preparation of (35, 4aR4aS, 65, 8aR) 6-(2-(l(2)H-tetrazolylphenyl)thio)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Ethyl (3S, 4aR4aS, 6S, 8aR) 6-((2-cyanophenyl)thio)-2-methoxycarbonyl-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3 -carboxylate.
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.
Electronic Impact Mass Spectrum M+: 402.
B. (3S, 4aR4aS 6S, 8aR) 6-(2-(l(2)H-Tetrazolylphenyl)thio)-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid hydrochloride
The alkylated decahydroisoquinoline from step A (122 mg, 0.30 mmol) and
azidotributyltin (199 mg, 0.60 mmol) were stirred at 80 °C for 2 days. More
azidotributyltin (242 mg, 0.73 mmol) was added and the reaction stirred at 80 °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 HC1 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.
Fast Atom Bombardment Mass Spectrum M+1: 360
Analysis Calculated for C17H22ClN5O2S.3H2O: C, 45.38; H, 6.27; N, 15.56
Found: C, 45.18; H, 5.82; N, 15.35
Example 24
Preparation of (3S, 4aR4aS, 65, 8aR) 6-((2-carboxy-5-methylphenyl)thio)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Ethyl 4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate
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.
Electronic Impact Mass Spectrum M+: 312.
Analysis Calculated for C11H11F3O5S: C, 42.31; H, 3.55
Found: C, 42.89; H, 3.84
B. Ethyl 2-mercapto-4-methylbenzoate
To a solution of the triflate from step A (500 mg, 1.60 mmol) and
tetrakistriphenylphosphine palladium(O) (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 wanned to reflux (bath
temp 90 °C) for 3.5 h. The reaction mixture was cooled down to 0 °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 °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 °C.
Electronic Impact Mass Spectrum M+: 196.
C. Ethyl (3S, 4aR4aS, 6S, 8aR) 6-((2-ethoxycarbonyl-5-methylphenyl)thio)-2-
methoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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)
Electronic Impact Mass Spectrum M+: 463.
D. (3S, 4aR4aS. 6S, SaR) 6-((2-Carboxy-5-methylphenyl)thio)-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid hydrochloride
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).
M.p.>177°C(dec).
Fast Atom Bombardment Mass Spectrum M-HC1+1: 350.
1H NMR (CD3OD, 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 (35', 4aR4aS, 6S, 8aR) 6-((2-carboxy-5-chlorophenyl)thio)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Ethyl 2-mercapto-4-Chlorobenzoate.
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 °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 (2X100 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%).
Electronic Impact Mass Spectrum M+: 216.
B. Ethyl (35, 4aR4aS, 65, 8aR) 6-((2-ethoxycarbonyl-5-chlorophenyl)thio)-2-
methoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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.
Electronic Impact Mass Spectrum M+l: 485
C. (35, 4aR4aS, 65, 8aR) 6-((2-Carboxy-5-chlorophenyl)thio)-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid hydrochloride
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 (3x5 mL), to give an off-
white solid (17 mg, 68%)
Fast Atom Bombardment Mass Spectrum M+l: 370
Analysis calculated for C17H21C12NO4S.I.5 H2O: C, 47.12; H, 5.58; N, 3.23. Found: C,
47.12; H, 5.51; N, 3.39.
Example 26
Preparation of (35, 4aR4aS, 6S, 8aR) 6-((2-carboxy-4-chlorophenyl)thio)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. Ethyl 5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)benzoate
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° 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).
Electronic Impact Mass Spectrum M+: 332.
B. Ethyl 2-mercapto-5-chlorobenzoate
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, 1.0 mmol) and
sodium hydride (95%, 24 mg, 1.0 mmol) in tetrahydrofuran (2 mL) as in Example 22,
Step B) was added and the reaction mixture was warmed at 90 °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.
Electronic Impact Mass Spectrum M+-triisopropylsilyl: 216
C, Ethyl (35, 4aR4aS, 65, 8aR) 6-((2-ethoxycarbonyl-4-chlorophenyl)thio)-2-
methoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
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 lh at room temperature. A solution of
material from preparation 3 (50 mg, 0.13 mmol) in N.N-dimefhylformamide (0.5 mL) was
then added and the resulting mixture was stirred at 60 °C overnight. Ethyl acetate and
water were added and the phases were separated. The organic phase was washed
sucessively 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.
Electronic Impact Mass Spectrum M+-3 carboxylates: 279
D. (35, 4aR4aS, 6S, 8aR) 6-((2-Carboxy-4-chlorophenyl)thio)-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid hydrochloride
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).
1H NMR (CD3OD, 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).
Fast Atom Bombardment Mass Spectrum M-HC1+1: 370
Example 27
Preparation of Ethyl(35, 4aR4aS, 6S, 8aR) 6-((2-ethoxycarbonyl-5-chlorophenyl)thio)-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate hydrochloride

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.
Ion Electrospray Mass Spectrum M-HCT+1: 425
Preparation 4
4-Benzyl-2-fluoro-benzonitrile
Replacement Section

A. Trifluoro-methanesulfonic acid 4-cyano-3-fluoro-phenyl ester
To a solution of 16.0 g (116.6 mmol) of 2-tluoro-4-hydroxybenzonitrile and 50.0 g
(140.0 mmol) of N-phenyltrifluoromethanesulfonimide in 250 raL of dichlorormethane 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
dichlorormethane. The combined organic portions are dried (Na2SO4), filtered and
concentrated in vacuo. Chromatography (silica gel, 50% chloroform/hexane) of the
residue affords 26.7 g (85%) of the title compound.
Field Desorption Mass Spectrum: M=269.
B. 4-Benzyl-2-fluoro-benzonitrile
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°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 (MgSO4), filtered, and concentrated in vacuo.
Chromatography (Biotage, 100% toluene) of the residue affords 0.76 g (65%) of the title
compound.
Field Desorption Mass Spectrum: M=211.
Example 28
(3S, 4aR4aS, 6S, 8aR) 6-[5-Benzyl-2-(l(2)H-tetrazol-5-yl)-phenoxy]-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid hydrochloride

Following the procedures as described in Example 9 using 0.45 g (1.51 mmol) of
material from Preparation 2 and 0.32g (1.51 mmol) of material from Preparation 4 affords
0.13 g (21% overall yield) of the title compound.
Electrospray Mass Spectrum: M+l=434.

To a degassed solution of 2.5 g (9.3 mmol) of the triflate from Preparation 4, Step
A above, 1.3g (10.4 mmol) thiophene and 1.4 g (10.4 mmol) of potassium carbonate in
24mL of toluene is added to 0.4 g (0.37 mmol) of tetrakis (triphenylphosphine)
palladium(0). The mixture is heated to 90°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 MgSO4, filtered, and concentrated in vacuo.
Chromatography (silica gel, 10% ethyl acetate/hexane) of the residue affords 1.2 g (79%)
of the title compound.
Field Desorption Mass Spectrum: M=203.
Example 29
(35, 4aR4aS, 65, SaR) 6-[5-(2-thienyl)-2-( l(2)H-tetrazol-5-yl)-phenoxy]-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. (35, 4aR4aS, 65, 8aR) 6-[5-(2-thienyl)-2-cyano]-phenoxy-2-methoxycarbonyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxilic acid
Following the procedures as described in Step A of Example 9, using 1.0 g (3.9 mmol) of
(35, 4aR4aS, 65, 8aR) 6-hydroxy-2-methoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxilic acid (prepared as described in United States Patent
No. 4,902,695, 5,446,051, and No. 5,356,902) and 0.8g (3.9 mmol) of material from
Preparation 5, affords 0.84 g (49%) of the title compound.
Electrospray Mass Spectrum: M+NH4+=458.
B. (35, 4aR4aS, 65, 8aR) 6-[5-(2-thienyl)-2-(l(2)H-tetrazol-5-yl)-phenoxy]-2-
methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
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°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 (MgSO4), 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.
Electrospray Mass Spectrum: M+l=484.
C, (35,4aR4aS. 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
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.
Electrospray Mass Spectrum: M+l = 426.
Preparation 6
3,2' -Difluoro-biphenyl-4 -carbonitrile

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(tripbenylphosphine)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°C overnight. The reaction is diluted with ethyl acetate and washed with distilled
water (2x). The separated aqueous layer is back extracted with ethyl acetate (3x). 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,4aR4aS,6S,8aR)6-[2'-FIuoro-4-(2H-tetrazoi-5-yl)-biphenyl-3-yloxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride

A. (3S.-4aR4aS.6S.8aR) 6-(4-Cyano-2'-fluoro-biphenyl-3-yloxy)-
l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester.
The material from Preparation 6 (0.36 gm. 1.67 mmol) is added to a 0°C solution
of material from Preparation 2 (0.50 gm, 1.67 mmol) and potassium tert-butoxide (1.0 M
in tetrahydroftiran, 5.01 mL) in anhydrous tetrahydrofuran (6 mL), after the solution is
stirred at 0°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°C. The reaciton
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 (3X).
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,4aRaS,6S,8aR)6-[2'-Fluoro-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy1-
1,2,3.4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
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°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,4aR4aS,6S)8aR)6-[2'-Fluoro-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
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 (2X) and then with diethyl ether (2X). 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,-4aR4aS,6S,8aR)6-[4'-Methyi-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

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,4aR4aS;,6S,8aR)6-[5-Naphthalen-2-yl-2-(2H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

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,-4aR4aS;.6S,8aR)6-[2,-Methoxy-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

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 0.41gm (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.
MS (m/z, ES+): 450.2

A. Preparation of 2-Benzyloxy-4-fluoro-benzonitrile
To 2.5mL benzyl alcohol in 80mL THF is added 1.87g NaH. After one hour
stirring at room temperature, 5.0g 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 recrystallizde in carbon tetrachloride to
give 3.24g (39.7%) of the title compound.
1HNMR (400 MHz, CDC13) d 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-l-yl-benzonitrile
To 0.180g pyrazole in 5mL DMF is added 0.105g NaH. After stirring 50 minutes
at room temperature, 0.200 g of the material from Step A, above, is added all at once with
5mL 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 .181g (74.8%) of the title compound.
'H NMR (400 MHz, CDCI3) S 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-l-yl-benzonitrile
To 0.395g of the material from Step B, above, dissolved in lOmL THF, is added a
catalytic amount of 10% Pd/C and excess ammonium formate. The reaction is heated to
50°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 0.152g
of the final title compound (57.1%).
1H NMR (400 MHz, DMSO-d) d 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
(35, 4aR4aS. 65, 8aR) 6-[5-Pyrazol-l-yl-2-(2H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
hydrochloride

A. Preparation of (3.S", 4aR4aS, 65, 8aR) 6-(2-Cyano-5-pyrazol-l-yl-phenoxy)-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-
ethyl ester
To 0.145g of the material from Preparation 7. 0.256g of Ethyl (35, 4aR4aS, 6S,
8aR) 6-hydroxy-2-tert-butoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-
carboxylate (prepared essentially as described in Preparation 1), and 0.308g
triphenylphosphine are added to .18mL 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 0.226g of the
title compound (58.4% yield).
1H NMR (400 MHz, CDC13) d 7.9 (m, 1H), 7.8 (m. 1H), 7.7-7.6 (dd, lH),7.4(m, 1H),
7.25-7.18 (m, 1H), 7.18-7.1 (d, 1H), 6.5-6.4 (in, 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).
MS m/z: 395.3 (m+-99).
B. (35, 4aR4aS, 65, 8aR) 6-[5-Pyrazol-l-yl-2-(2H-l:etrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3
ethyl ester
To 0.220g of the material from Step A, above, is added. 5mL azidotributyltin and
.5mL toluene. The reaction is heated to 90°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/CHCl3 provides
0.142g of the title compound (59.4% yield).
1H NMR (400 MHz, d-MeOH) d 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), .92-.84 (t, 1H).
C. (35, 4aR4aS, 65, 8aR) 6-[5-Pyrazol-l-yl-2-(2F(-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester
To 0.129g of the material from Step B, above, dissolved in lOmL MeOH is added
0.72mL IN NaOH. The reaction is heated to 50°C overnight. 0 .72mL IN 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/CHCl3 provides 0.040g of the title compound
(32.8% yield), which is used directly in the following step.
D. (35,4aR4aS, 6S, 8aR) 6-[5-Pyrazol-l-yl-2-(2H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
To 0.040g of the material from Step C, above, dissolved in 5mL CH2CI2, is added
3mL 2M HC1 in diethyl ether. After stirring four hours at ambient temperature, the
reaction is concentrated in vacuo.
1H NMR (400 MHz, d-MeOH) d 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).
MS m/z: 410.2 (m++l).

A. Preparation of 2-Benzyloxy-4-indol-l-yl-benzonitrile
Using indole, the title compound is prepared according to the procedures
described in Preparation 7, step B and provides.39g (91.1% yield).
'H NMR (400 MHz, CDCI3) d 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-l-yl-benzonitrile
Using the material from Step A, above, the title compound is prepared according
to the procedures described in Preparation 7, step C and provides. 188g (66.7% yield).
1HNMR (400 MHz, CDC13) d 7.65-7.54 (m, 3H), 7.27-7.1 (m, 5H), 6.67 (d, 1H).
Example 35
(35, 4aR4aS, 65, 8aR) 6-[5-mdol-l-yl-2-(2H-tetrazol-5-yl)-phenoxy]-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid

A. (35, 4aR4aS, 65, 8aR) 6-(2-Cyano-5-indol-l-yl-phenoxy)-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester
Using the material from Preparation 8, above, the title compound is prepared
according to the procedures described in Example 34, step A and provides .233g (53.4%
yield).
MS m/z: 444.3 (m+ -99).
B. (3S, 4aR4aS. 65, 8aR) 6-[5-indol-l-yl-2-(2H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-
ethyl ester
Using the material from Step A, above, the title compound is prepared according
to the procedures described in Example 34, step B and provides .19g (76% yield).
MSm/z: 585.2 (M"-1).
C. (3S, 4aR4aS, 6S, 8aR) 6-[5-indol-l-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
Using the material from Step B, above, the title compound was prepared according
to the procedures described in Example 34, step C and provides . l00g (58.5% yield).
MSm/z: 557.3 (M"-l).
D. (3S, 4aR4aS, 6S, 8aR) 6-[5-indol-l-yl-2-(2H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
Using the material from Step C, above, ihe title compound is prepared according
to the procedures described in Example 34, step D and provides .078g (92.9% yield).
1HNMR(400 MHz,d-MeOH) 8 8.14-8.11 (d, IH), 7.64-7.6 (d, 2H), 7.55 (s, 1H), 7.43 (s,
1H), 7.37-7.35 (d, IH), 7.22-7.18 (t, IH), 7.15-7.1 (t, IH), 6.7 (s, IH), 4.74-4.64 (m,
IH), 4.03-4.0 (d, IH), 3.37-3.3 (t, IH), 3.15-3.1 (dd, IH), 2.18-1.93 (m, 5H), 1.85-1.68
(m, 3H), 1.68-1.55 (m,2H).
MSm/z: 459.2 (m++l).
Preparation 9
2-Hydroxy-4-pyrrol-1 -yl-benzonitrile

A. Preparation of 2-Benzyloxy-4-pyrrol-l-yl-benzonitrile
Using pyrrole, the title compound is prepared according to the procedures
described in Preparation 7, step B and provides .457g (94.6% yield).
1H NMR (400 MHz, CDC13) 8 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-l-yl-benzonitrile
Using the material from Step A, above, the title compound is prepared according
to the procedures described in Preparation 7, step C and provides.213g (70.5% yield).
1H NMR (400 MHz,d-MeOH) d 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
(3,9, 4aR4aS, 6S, 8aR) 6-[5-Pyrrol-l-y!-2-(2H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride

A. (35, 4aR4aS, 65, 8aR) 6-(2-Cyano-5-pyrrol-l-yl-phenoxy)-1.2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-2,3-clicarboxylic acid 2-tert-butyl ester 3-ethyl ester
Using the material from Preparation 9, above, the title compound is prepared
according to the procedures described in Example 34, step A and provides .216g (38%
yield).
MSm/z: 394.2 (M+-99).
B. (35, 4aR4aS, 65, 8aR) 6-[5-Pyrrol-l-yl-2-(2H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-
ethyl ester
Using the material from Step A, above, the title compound is prepared according
to the procedures described in Example 34, step B and provides .074g (35% yield) which
is used directly in the following step.
C. (35, 4aR4aS, 65, 8aR) 6-[5-Pyrrol-l-yl-2-(2H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester
Using the material from Step B, above, the title compound is prepared according
to the procedures described in Example 34, step C and provides.014g, (22.6% yield)
which is used directly in the following step.
D. (3S, 4aR4aS 6S, SaR) 6-[5-Pyrrol-l-yl-2-(2H-tetrazol-5-yl)-phenoxy]-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid hydrochloride
Using the material from Step C, above, the title compound is prepared according to
the procedures described in Example 34, step D. and provides .012g (97.5% yield).
1HNMR (400 MHz,d-MeOH) 5 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).
MS m/z: 409.3 (M++l), 407.3 (M" -1).
Preparation 10
(35, 4aR4aS, 6S, 8aR) 6-hydroxy-2-methoxycarbonyl-1.2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid.

To a slurry of 17.3 g of (3S, 4aR4aS, 8aR) 6-oxo-2-methoxycarbonyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-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

To a 12L 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 °C before
adding azidotrimethylsilane (512.5 mL, 3.86 mol) via canula such that the internal
temperature is maintained at less than 3 °C. To this flask is added 6-chloro-2-
fluorobenzonitrile (500 g, 3.21 mol) dropwise as a solution in toluene (lL). The reaction
is slowly warmed to room temperature then heated to 90 °C. A cold finger is used to
condense tetramethylsilane as it boiled from the reaction mixture. The reaction is heated
at 90 °C for 13 hours before cooling to room temperature. The reaction is cooed to 0 °C
with an ice bath then transferred slowly via cannula to a pre-cooled (-5 °C) solution of 6N
aqueous HC1 (3L) and ethyl acetate (3L). The internal temperature during the quench is
kept at less than 5 °C. After addition, the flask is allowed to warm to room temperature.
The reaction is diluted with ethyl acetate (2 L) to disolve solids before tranferring to a 22L
flask. The layers are separated and the aqueous layer was extracted with ethyl acetate
(1L). The combined organic layers are washed with brine (2L), dried over anhydrous
sodium sulfate, and concentrated. 636.4 g. of the title compound is obtained (93% yield).
Analysis by HPLC and 'H NMR analysis shows the purity as greater than 98%.
Preparation 12

To a thick slurry of the material from Preparation 11, above, (101.8 g, .513 mol)
and 4,4'-dirnethoxybezhydrol (125 g, .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
endothenn of 3-4 °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 °C). After 1 hour, the solid is isolated by filtration and
washed with water (1L) then isopropyl alcohol (.5 L). The resulting white solid is dried in
vacuo at 50 °C to afford 199.8 g of the title compound (91% yield).
Example 37
2-Ethyl-butyl (3S, 4aR4aS, 65', 8aR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate para-toluenesulfonate

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 °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 °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 IN aqueous hydrogen chloride
solution (50 mL), water (200 mL) and ethyl actetate (200 mL). The layers are separated
and the aqueous layer is extracted with ethyl acetate (1x50 mL). The combined organic
layers are washed with water (2x100 mL) and 10% aqueous sodium chloride solution
(1x100 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

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
°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 (35, 4aR4aS, 6S, SaR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-2-
methoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
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 (4x 1L). 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, 4aR4aS, 6S, 8aR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
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.
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 oC 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, 4aR4aS, 6S, 8aR) 6-[3-chloro-2-( 1 (2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate para-toluenesulfonate
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 °C to effect a solution then allowed to cool to ambient temperature
for 2 hours and then further cooled to approximately 3 °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.
1HNMR, 500 MHz dmso-d6, 9.23 (bs. 1H), 8.94 (bs, 1H), 7.56 (t, 1H), 7.45 (d.
2H), 7.30 (d, IH), 7.24 (d, IH), 7.09 (d, 2H), 4.37 (m, IH), 4.17 (m, IH), 4.13 (dd, 1H),
4.03 (dd, IH), 3.04 (m, 1H), 2.94 (m, IH), 2.26 (s. 3H), 2.07 (m, 1H), 1.96 (m, IH), 1.84
(m, 2H), 1.75 (m, 2H), 1.60 (m, 3H), 1.48 (m, IH), 1.29 (m, 4H), 1.09 (m. IH), 0.83 (t.
6H)
Mp = 204 oc
Example 38
2-Ethyl-butyl (35, 4aR4aS, 6S, 8aR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate para-toluenesulfonate

A. (35, 4aR4aS, 65, 8aR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-2-
methoxycarbonyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
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 °C and
monitored for consumption of the aryl tetrazole by HPLC. After 4 hours the reaction is
cooled to 20 °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 °C. The exchange of solvents effects the
precipitation of the desired product. The mixture is cooled to 10 °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. (35, 4aR4aS, 65, SaR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid • hydrochloride
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 °C for 26 hours at which time the HPLC analysis shows less than 4%
starting material remains. The reaction is cooled to 30 °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 °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.
The title compound (20.0 g) is then combined with 200 mL of water and heated to
90 °C to effect a solution. The solution is cooled to 60 °C. and 40 mL of 6 M
hydrochloric acid is added effecting the precipitation of the title compound. The mixture
is stirred at 60 °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, 4aR4aR 6S, 8aR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate para-toluenesulfonate
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-l-butanol,
and 6.0 mL of water is heated to 140 °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 °C and 75 mL of 2-propanol is added. The mixture is
further cooled to 50 °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.
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 °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.
1H NMR, 500 MHz dmso-d6, 9.23 (bs, IH), 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 (tn, 1H), 1.84
(m, 2H), 1.75 (m, 2H), 1.60 (m, 3H), 1.48 (m, IH), 1.29 (m, 4H), 1.09 (m, 1H), 0.83 (t,
6H).
Mp = 204 °C
Example 39
To establish that the iGluR5 receptor subtype is mediating a pharmacological
response in a neurological disease or disorder, the binding affinity of the panel
compounds to the iGluR5 receptor is first measured using standard methods. For
example, the activity of compounds acting at the iGluR5 receptor can be determined by
radiolabeled ligand binding studies at the cloned and expressed hµMan 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 iGluR5 receptor subtype can then be determined by comparing
antagonist activity at the iGluR5 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 hµMan GluR1, GluR2,GluR3 and GIUR4 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 hµMan GluR6 receptors
(Hoo et al, Recept. Channels 2;327-338); and whole-cell voltage clamp
electrophysiological recordings of functional activity at AMPA receptors in acutely
isolated cerebellar Purkinje neurons (Bleakman et al., 1996, Mol. Pharmacol. 49; 581-
585) and other tissues expressing AMPA receptors (Fletcher and Lodge, 1996, Pharmacol.
Ther. 70; 65-89).
iGluR5 antagonist binding affinity profiles
Cell lines (HEK293 cells) stably transfected with hµMan iGluR receptors are
employed. Displacement of 3[H] AMPA by increasing concentrations of antagonist is
measured on iGluR1, iGluR2, iGluR3, and iGluR4 expressing cells, while displacement
of 3[H] kainate (KA) is measured on iGluR5. iGluR6, iGluR7, and KA2-expressing
cells. Estimated antagonist binding activity (Kj) in µM, for example, is determined for
Compounds of Formula I. As an indicia of selectivity, the ratio of binding affinity to the
iGluR2 AMPA receptor subtype, versus the binding affinity to iGluR5 kainate receptor
subtype (Kj at iGluR2 / Kj at iGluR5) is also determined. The iGluR5 receptor antagonist
compounds, as provided by the present invention, provide a Kj at the iGluR5 receptor
subtype of less than 5000µM, preferably less than 500µM . even more preferably less
than 50µM, and most preferably less than 5µM. The preferred selective iGluR5 receptor
antagonists compounds, as provided by the present invention, display a greater binding
affinity (lower K1) for iGluR5 than that for iGluR2 , preferably at least 10 fold greater for
iGluR5 than that for iGluR2, and even more preferably at least 100 fold, and most
preferably at least 1000 fold, than that for iGluR2
Example 40
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
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.
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 2.0ml/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).
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.
A fluorescence microscope (Zeiss) equipped with a grating monchromator 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.
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 apprximately 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.
Dose-response curves are generated for each of the compounds of Formula I and
the dose that inhibits the extravasation by 50% (ID50) or 100% (ID 100) is approximated.
Example 41
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
For example, male Sprague-Dawley rats (200-250g; Charles River,Portage, MI)
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.
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®
boxes about 25 x 25 x 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 °C.
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.
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 o/.,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.
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.
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
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.
ED50 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 ED50 value. If the
SEM values do not overlap the line of addition, then the ED50 values are significantly
different from the line of addition.
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
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).
Rats are administered a dose test compound or vehicle and then injected
subcutaneously into one hindpaw, with carrageenan (1.5% w/v, 100 µ1). 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.
ED50 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.
We Claim:
1. A compound of the Formula:

wherein,
Z is oxygen;
R5 represents hydrogen or (Cl-C6)alkyl;
R6 represents hydrogen, CN, (Cl-C4)alkyl-CO2R9, CO2R9, or tetrazole;
R7 represents hydrogen, halo, phenyl, naphthalyl, phenyl substituted with one or
two moieties selected from the group consisting of halogen, (C1-C6)alkyl, and (C1-
C6)alkoxy; CO2R10, tetrazole, thiophenyl, pyrrolyl, pyrazolyl; (Cl-C4)alkyl, (Cl-
C4)alkyl phenyl, or O-R4;
R4 represents (Cl-C6)alkyl or (Cl-C4)alkyl phenyl:
W, X' and Y' each independently represent hydrogen, halo, or (Cl-C6)alkyl;
R9 and RIO each independently represent hydrogen or (Cl-C6)alkyl;
with the proviso that where R6 is (Cl-C4)alkyl-CO2R9 or CO2R9 ; or R7 is
CO2R10; then at least one, but no more than two of R5, R9, and R10 is other than
hydrogen;
or a pharmaceutically acceptable salt thereof.
2. The compound as claimed in claim 1, wherein R represents C1-C6alkyl.
3. The compound as claimed in claim 1, wherein R6 represents tetrazole.
4. The compound as claimed in claim 1, wherein X' and Y" represent hydrogen.
5. The compound as claimed in claim 1, wherein R7 represents hydrogen.
6. The compound as claimed in claim 1, wherein W represents Halo.
7. The compound as claimed in claim l wherein W represents C1.
8. The compound as claimed in claim 1, wherein the compound is 2-Ethyl-butyl (3S,
4aS, 6S, SaR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquirloline-3-carboxylate or a pharmaceutically acceptable salt thereof.
9. The compound as claimed in claim 1 wherein the pharmaceutically acceptable salt
is the hydrochloride salt.
10. The compound as claimed in claim 1, wherein the compound is 2-Ethyl-butyl
(3S, 4aS, 65, 8aR) 6-[3-chloro-2-(l(2)H-tetrazol-5-yl)-phenoxy]-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylate para-toluenesulfonate.
11. A pharmaceutical composition comprising an effective amount of the compound
as claimed in claim 1, in combination with a pharmaceutically acceptable earner, diluent,
or excipient.
12. A pharmaceutical composition according to Claim 11 comprising an effective
amount of the compound which is 2-Ethyl-butyl (35, 4aS', 65", SaR) 6-[3-Chloro-2-(l(2)H-
tetrazol-5-yl)-phenoxy]-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate para-
toluenesulfonate, in combination with a pharmaceutically acceptable carrier, diluent, or
excipient.

The present invention provides novel compounds of

or the pharmaceutically acceptable salts thereof, and compositions thereof.