Note: Descriptions are shown in the official language in which they were submitted.
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SULFONAMIDE DERIVATIVES
The present invention relates to the potentiation of glutamate receptor
function using certain sulfonamide derivatives. It also relates to novel
s sulfonamide derivatives, to processes for their preparation and to
pharmaceutical
compositions containing them.
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,
so which causes excitation of this receiving neuron. L-Glutamate, which is the
most
abundant neurotransmitter in fihe CNS, mediates the major excitatory pathway
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
15 (1931 ); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29,
365 (1939); 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
2 o 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
25 depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA),
alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic
acid (KA). The second general type of receptor is the G-protein or second
messenger-linked "metabotropic" excitatory amino acid receptor. This second
type is coupled to multiple second messenger systems that lead to enhanced
3 o phosphoinositide hydrolysis, activation of phospholipase D, increases or
decreases in c-AMP formation, and changes in ion channel function. Schoepp
and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors
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appear not only to mediate normal synaptic transmission along excitatory
pathways, but also 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).
AMPA receptors are assembled from four protein sub-units known as
GIuR1 to GIuR4, while kainic acid receptors are assembled from the sub-units
GIuR5 to GIuR7, and KA-1 and KA-2. Wong and Mayer, Molecular
Pharmacology 44: 505-510, 1993. It is not yet known how these sub-units are
1 o combined in the natural state. However, the structures of certain human
variants
of each sub-unit have been elucidated, and cell lines expressing individual
sub-
unit variants have been cloned and incorporated into test systems designed to
identify compounds which bind to or interact with them, and hence which may
modulate their function. Thus, European patent application, publication number
EP-A2-0574257 discloses the human sub-unit variants GIuR1 B, GIuR2B,
GIuR3A and GIuR3B. European patent application, publication number EP-A1-
0583917 discloses the human sub-unit variant GIuR4B.
One distinctive property of AMPA and kainic acid receptors is their rapid
deactivation and desensitization to glutamate. Yamada and Tang, The Journal of
2 o Neuroscience, September 1993, 13(9): 3904-3915 and Kathryn M. Partin, J.
Neuroscience, November 1, 1996, 16(21 ): 6634-6647. The physiological
implications of rapid desensitization, and deactivation if any, are not fully
understood.
It is known that the rapid desensitization and deactivation of AMPA and/or
2 s kainic acid receptors to glutamate may be inhibited using certain
compounds.
This action of these compounds is often referred to in the alternative as
"potentiation" of the receptors. One such compound, which selectively
potentiates AMPA receptor function, is cyclothiazide. Partin et al., Neuron.
Vol.
11, 1069-1082, 1993.
3o AMPA receptor potentiators have been shown to improve memory in a
variety of animal tests. Staubli ef al., Proc. Natl. Acad. Sci., Vol. 91, pp
777-781,
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1994, Neurobiology, and Arai et al., The Journal of Pharmacology and
Experimental Therapeutics, 278: 627-638, 1996.
In addition, certain sulfonamide derivatives which potentiate glutamate
receptor function in a mammal have been disclosed in the following
International
Patent Application Publications: WO 98/33496 published August 6, 1998; WO
99/43285 published September 2, 1999; WO 00/06539; WO 00/06537, WO
00/06176, W O 00/06159, W O 00/06158, W O 00/06157, W O 00/06156, W O
00/06149, WO 00/06148, and WO 00/06083, all published February 10, 2000;
and WO 00/66546 published November 9, 2000.
to The present invention provides compounds of formula I:
R R O
W N CH CH -X-B-A-N-IS-R~ formula I
( ) ( ) H
O
wherein
A represents
R2
; (CH2) ; ; ; or
P.
Rsa ' ' Rsb H ' : R3b H
B represents
or
R4b~4b
R4a R4a
X represents O, NR, or S:
W represents R$S02-, R~3C(=O)-, R~3R15NC(=O)-, H~NC(=O)-, R~6, or
R~4OC(=O)-
2o R represents hydrogen, (1-6C)aikyl, or-(1-4C)alkylaromatic;
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R~ represents (1-6C)alkyl, (2-6C)alkenyl, halo(1-4C)alkyl, or NR9R~o;
RZ and R3a each independently represent hydrogen, (1-4C)alkyl, F, or
_O R~ ~
R3b represents hydrogen, (1-4C)alkyl, or-OR~2;
R4a and R4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy,
I,
Br, CI, or F;
R5 and R6 each independently represent hydrogen, (1-4C)alkyl, F, or
-OR11;
R' represents hydrogen, (1-4C)alkyl or -(1-4C)alkylaromatic;
Zo R8 represents (1-6C)alkyl,-(1-4C)alkylphenyl, halo(1-4C)alkyl,
unsubstituted or
substituted aromatic group, unsubstituted or substituted heteroaromatic group,
cycloalkyl, alkylcycloalkyl or NR9R'o;
n is zero or an integer 1, 2, 3, 4, or 5;
m is zero or an integer 1, 2, 3, 4, or 5;
p is an integer 1 or 2;
R9 and R~° each independently represent hydrogen or (1-4C)alkyl;
R~~ represents hydrogen or (1-4C)alkyl;
R'2 represents (1-4C)alkyl;
R~3 represents phenyl or (1-6C)alkyl;
2o R'4 represents (1-6C)alkyl;
R~5 represents (1-4C)alkyl; and
R'6 represents (1-4C)alkyl or-(1-4C)alkylphenyl;
or a pharmaceutically acceptable salt thereof, with the proviso that when W is
R~6, then B is other than
R4a
i ;
,,
R4b
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The present invention further provides a method of potentiating glutamate
receptor function in a patient, which comprises administering to said patient
an
effective amount of a compound of formula I.
The present invention provides a method of treating cognitive disorders in
s a patient, which comprises administering to said patient an effective amount
of a
compound of formula I.
The present invention provides a method of treating depression in a
patient, which comprises administering to said patient an effective amount of
a
compound of formula I.
The present invention provides a method of treating Alzheimer's disease
in a patient, which comprises administering to said patient an effective
amount of
a compound of formula I.
In addition, the present invention further provides a method of treating
psychosis or cognitive deficits associated with psychosis in a patient, which
15 comprises administering to said patient an effective amount of a compound
of
formula I.
According to another aspect, the present invention provides the use of a
compound of formula l, or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for potentiating glutamate receptor function.
2 o In addition, the present invention provides the use of a compound of
formula I or a pharmaceutically acceptable salt thereof for potentiating
glutamate
receptor function.
The invention further provides pharmaceutical compositions comprising, a
compound of formula I and a pharmaceutically acceptable diluent or carrier.
z 5 This invention also encompasses novel intermediates and processes for the
synthesis of the compounds of formula I.
In addition, the present invention includes compounds of the formula:
R6 R5
R$ S- N ~
IOI (CH2)~ (CH2)rt X-B-A-H-S-R
I I
O
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wherein
A represents
R2
1 ~ , i
-'- or ' '
(CHz) ~ . . ,
p: '
R3a Rsb H
Rsb H
B represents
R4a R4a '.
,,
~, ~ . , or
~' Rq.b R4b ,4b
.
X represents O, NR, or S:
R represents hydrogen, (1-6C)alkyl, or -(1-4C)alkylaromatic;
R~ represents (1-6C)alkyl, (2-6C)alkenyl, halo(1-4C)alkyl, or
NR9R'°;
R2 and R3a each independently represent hydrogen, (1-4C)alkyl, F, or
z0 -OR~1;
R3b represents hydrogen, (1-4C)alkyl, or-OR'2;
R4a and R4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy,
I,
Br, CI, or F;
R5 and R6 each independently represent hydrogen, (1-4C)alkyl, F, or
-OR";
R~ represents hydrogen;
R$ represents (1-6C)alkyl;
n is zero or an integer 1, 2, 3, 4, or 5;
m is zero or an integer 1, ~, 3, 4, or 5;
2 o p is an integer 1 or 2;
R9 and R~° each independently represent hydrogen or (1-4C)alkyl;
and
R~' represents hydrogen or (1-4C)alkyl;
R~2 rearesents (1-4C)alkyl;
or a pharmaceutically acceptable salt thereof.
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Included within the scope of the present invention are compounds of the
formula X:
R6 R5
2
W-N\ R II
(CH2)m (CH2)n X-B (CH2)p H--' I---R formula X
R3a O
wherein
B represents
''
v
or',
Rqb ~ R4b R4a R4b
,,
R4a R4a
..
X represents O, NR, or S:
W represents R$S02-, R~3C(=O)-, R~3R15NC(=O)-, H2NC(=O)-, R~6, or
R~4OC(=O)-;
R represents hydrogen, (1=6C)alkyl, or-(1-4C)alkylaromatic;
R~ represents (1-6C)alkyl, (2-6C)alkenyl, halo(1-4C)alkyl, or NR9R~o;
R2 and R3a each independently represent hydrogen, (1-4C)alkyl, F, or
_OR~~~
R3b represents hydrogen, (1-4C)alkyl, or-OR~2;
R4a and R4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy,
I,
Br, CI, or F;
R5 and R~ each independently represent hydrogen, (1-4C)alkyl, F, or
-OR11;
2o R'represents hydrogen, (1-4C)alkyl or-(1-4C)alkylaromatic;
R$ represents (1-6C)alkyl,-(1-4C)alkylphenyl, halo(1-4C)alkyl, unsubstituted
or
substituted aromatic group, unsubstituted or substituted heteroaromatic group,
cycloalkyl, alkylcycloalkyl, or NRgR~o;
n is zero or an integer 1, 2, 3, 4, or 5;
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m is zero or an integer 1, 2, 3, 4, or 5;
p is an integer 1 or 2;
R9 and R~° each independently represent hydrogen or (1-4C)alkyl;
R'~ represents hydrogen or (1-4C)alkyl;
R'2 represents (1-4C)alkyl;
R~3 represents phenyl or (1-6C)alkyl;
R~4 represents (1-6C)alkyl;
R~5 represents (1-4C)alkyl; and
R~6 represents (1-4C)alkyl or -(1-4C)alkylphenyl;
s o or a pharmaceutically acceptable salt thereof, with the proviso that when
W is
R~6, then B is other than
R4a
''
' ~
'' R4b
Further included within the scope of the present invention are compounds
of the formula XX:
17 R6 R5
_ O
W N OH2)m (CH )-X-B N-IS-R~ formula XX
2n
Rsb H
O
wherein
B represents
R4a R4a ' '
''
- .
or
'''
R4b ,4b
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X represents O, NR, or S:
W represents R$S02-, R~3C(=O)-, R~3R~5NC(=O)-, H2NC(=O)-, R~6, or
R~40C(=O)-;
R represents hydrogen, (1-6C)alkyl, or -(1-4C)alkylaromatic;
R~ represents (1-6C)alkyl, (2-6C)alkenyl, halo(1-4C)alkyl, or NR9R~o;
R2 and R3a each independently represent hydrogen, (1-4C)alkyl, F, or
_OR~T~
R3b represents hydrogen, (1-4C)alkyl, or-OR~2;
R4a and R4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy,
I,
s o Br, CI, or F;
R~ and R6 each independently represent hydrogen, (1-4C)alkyl, F, or
-OR11;
R7 represents hydrogen, (1-4C)alkyl or -(1-4C)alkylaromatic;
R$ represents (1-6C)alkyl,-(1-4C)alkylphenyl, halo(1-4G)alkyl, unsubstituted
or
substituted aromatic group, unsubstituted or substituted heteroaromatic group,
cycloalkyl, alkylcycloalkyl, or NR9R'o;
n is zero or an integer 1, 2, 3, 4, or 5;
m is zero or an integer 1, 2, 3, 4, or 5;
p is an integer 1 or 2;
2 o R9 and R'° each independently represent hydrogen or (1-4C)alkyl;
R~~ represents hydrogen or (1-4C)alkyl;
R'2 represents (1-4C)alkyl;
R13 represents phenyl or (1-6C)alkyl;
R~~ represents (1-6C)alkyl;
R~5 represents (1-4C)alkyl; and
R~6 represents (1-4C)alkyl or -(1-4C)alkylphenyl;
or a pharmaceutically acceptable salt thereof, with the proviso that when W is
R~6, then B is other than
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R4a
'', ;
Further included within the scope of the present invention are compounds
of the formula ?~;XX:
R6 R5
O
N ( H2) (CH )-X-B N-SI-R' formula ~;XX
m 2 " Rsb H H
wherein
B represents
R4a R4a '.
,,
,
' or
~' Rq.b ~~ R4b i4b
X represents O, NR, or S:
so W represents R$SO~-, R~3C(=O)-, R'3R15NC(=O)-, H2NC(=O)-, R'6, or
R~40C(-O)-
R represents hydrogen, (1-6C)alkyl, or -(1-4C)alkylaromatic;
R' represents (1-6C)alkyl, (2-6C)alkenyl, halo(1-4C)alkyl, or
NR9R~°;
R2 and R3a each independently represent hydrogen, (1-4C)alkyl, F, or
1~ -OR~1;
R3b represents hydrogen, (1-4C)alkyl, or-OR~2;
R4a and R4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy,
I,
Br, CI, or F;
R5 and R6 each independently represent hydrogen, (1-4C)alkyl, F, or
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_OR11 a
R' represents hydrogen, (1-4C)alkyl or -(1-4C)alkylaromatic;
R$ represents (1-6C)alkyl,-(1-4C)alkylphenyl, halo(1-4C)alkyl, unsubstituted
or
substituted aromatic group, unsubstituted or substituted heteroaromatic group,
s cycloalkyl, alkylcycloalkyl, or NR9R~°;
n is zero or an integer 1, 2, 3, 4, or 5;
m is zero or an integer 1, 2, 3, 4, or 5;
p is an integer 1 or 2;
R9 and R'° each independently represent hydrogen or (1-4C)alkyl;
Zo R~~ represents hydrogen or (1-4C)alkyl;
R'2 represents (1-4C)alkyl;
R~3 represents phenyl or (1-6C)alkyl;
R'4 represents (1-6C)alkyl;
R'S represents (1-4C)alkyl; and
15 R~6 represents (1-4C)alkyl or-(1-4C)alkylphenyl;
or a pharmaceutically acceptable salt thereof, with the proviso that when W is
R~6, then B is other than
R4a
In this specification, the term "potentiating glutamate receptor function"
2 o refers to any increased responsiveness of glutamate receptors, for example
AMPA receptors, to glutamate or an agonist, and includes but is not limited to
inhibition of rapid desensitization or deactivation of AMPA receptors to
glutamate.
A wide variety of conditions may be treated or prevented by compounds of
formula I and their pharmaceutically acceptable salts through their action as
2 s potentiators of glutamate receptor function. Such conditions include those
associated with glutamate hypofunction, such as psychiatric and neurological
disorders, for example cognitive disorders and neuro-degenerative disorders
such as Alzheimer's disease; age-related dementias; age-induced memory
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impairment; cognitive deficits due to autism, Down's syndrome and other
central
nervous system disorders with childhood onset, cognitive deficits post
electroconvulsive therapy, movement disorders such as tardive dyskinesia,
Hungtington's chorea, myoclonus, dystonia, spasticity, and Parkinson's
disease;
reversal of drug-induced states (such as cocaine, amphetamines, alcohol-
induced states); depression; attention deficit disorder; attention deficit
hyperactivity disorder; psychosis; cognitive deficits associated with
psychosis,
drug-induced psychosis, obesity, stroke, and sexual dysfunction. Compounds of
formula I may also be useful for improving memory (both short term and long
Zo term) and learning ability. The present invention provides the use of
compounds
of formula I for the treatment of each of these conditions.
The present invention includes the pharmaceutically acceptable salts of
the compounds defined by formula I. A compound of this invention can possess
a sufficiently acidic group, a sufficiently basic group, or both functional
groups,
15 and accordingly react with .any of a number of organic and inorganic bases,
and
inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term "pharmaceutically acceptable salt" as used herein, refers to salts of
the
compounds of the above formula which are substantially non-toxic to living
organisms. Typical pharmaceutically acceptable salts include those salts
2 o 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. Such
salts
include the pharmaceutically acceptable salts listed in Journal of
Pharmaceutical
Science, 66, 2-19 (1977), which are known to the skilled artisan.
25 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, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic
acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Examples
3 0 of such pharmaceutically acceptable salts are the sulfate, pyrosulfate,
bisulfate,
sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate,
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decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride,
dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, propionate,
phenylpropionate, salicylate, oxalate, malonate, succinate, suberate,
sebacate,
fumarate, malate, maleate, hydroxymaleate, mandelate, nicotinate,
isonicotinate,
cinnamate, hippurate, nitrate, phthalate, teraphthalate, butyne-1,4-dioate,
butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, hexyne-1,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate,
dinitrobenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, phthalate, p-
toluenesulfonate, p-bromobenzenesulfonate, p-chlorobenzenesulfonate,
1 o xylenesulfonate, phenylacetate, trifluoroacetate, phenylpropionate,
phenylbutyrate, citrate, lactate, a-hydroxybutyrate, glycolate, tartrate,
benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,
hydroxyethanesulfonate, 1-naphthalenesulfonate, 2-napththalenesulfonate, 1,5-
naphthalenedisulfonate, mandelate, tartarate, and the tike. 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 malefic acid, oxalic 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,
2 o 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.
2s 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
the above salts may form hydrates or exist in a substantially anhydrous form.
3 o 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
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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
1 o 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:
ee = E~ - E2 X 100
E
wherein E~ 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
2 o 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 specific stereoisomers and enantiomers of compounds of
3 o formula I can be prepared by one of ordinary skill in the art utilizing
well known
techniques and processes, such as those disclosed by J. Jacques, et al.,
"Enantiomers. Racemates, and Resolutions", John Wiley and Sons, Inc., 1981,
and E.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds", (Wiley
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Interscience 1994), and European Patent Application No. EP-A-838448,
published April 29, 1998. Examples of resolutions include recrystallization
techniques or chiral chromatography.
Some of the compounds of the present invention have one or more chirai
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.
~.o 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.
As used herein, the term "aromatic group" means the same as aryl, and
includes phenyl and a polycyclic aromatic carbocyclic ring such as 1- or 2-
naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like.
The term "heteroaromatic group" includes an aromatic 5-6 membered ring
2s containing from one to four heteroatoms selected from oxygen, sulfur and
nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing
from
one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a
benzene ring or another 5-6 membered ring containing one to four atoms
selected from oxygen, sulfur and nitrogen. Examples of heteroaromatic groups
are thienyl, furyl, oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl,
thiadiazolyl,
isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,
pyrimidyl,
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benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,
indolyl,
and quinolyl.
The term "substituted" as used in the term "substituted aromatic or
heteroaromatic group" herein signifies that one or more (for example one or
two)
s substituents may be present, said substituents being selected from atoms and
groups which, when present in the compound of formula I, do not prevent the
compound of formula I from functioning as a potentiator of glutamate receptor
function.
Examples of substituents which may be present in a substituted aromatic
or heteroaromatic group include halogen; vitro; cyano; (1-10C) alkyl; (2-
10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; halo(1-10C)alkyl; and (1-
6C)alkoxy.
The term (1-10C)alkyl includes (1-8C)alkyl, (1-6C)alkyl and (1-4C)alkyl.
Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-
butyl,
pentyl, hexyl, heptyl, octyl, nonyl and decyl.
The term (2-10C)alkenyl includes (3-10C)alkenyl, (2-8C)alkenyl, (2-
6C)alkenyl and (2-4C)alkenyl. Particular values are vinyl and prop-2-enyl.
The term (2-10C)alkynyl includes (3-10C)alkynyl, (2-8C)alkynyl, (2-
6C)alkynyl and (3-4C)alkynyl. A particular value is prop-2-ynyl.
2 o The term (3-8C)cycloalkyl, as such or in the term (3-8C)cycloalkyloxy,
includes monocyclic and polycyclic groups. Particular values are cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[2.2.2~octane. The term
includes
(3-6C)cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term (5-8C)cycloalkyl includes cyclopentyl, cyclohexyl, cycloheptyl
2 s and cyclooctyl.
The term hydroxy(3-8C)cycloalkyl includes hydroxy-cyclopentyl, such as 3-
hydroxycyclopentyl.
The term oxo(3-8C)cycloalkyl includes oxocyclopentyl, such as 3-
oxocyclopentyl.
3 o The terms "halogen", "Hal", "halo", or "halide" include fluorine,
chlorine,
bromine and iodine unless otherwise specified.
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The term halo(1-10C)alkyl includes halo(1-6C)alkyl, halo(1-4C)alkyl,
fluoro(1-10C)alky(, fluoro(1-6C)alkyl, fluoro(1-4C)alkyl, chloro(1-6C)alkyl
and
chloro(1-4C)alkyl, such as trifluoromethyl, 2,2,2-trifluoroethyl, and
chloromethyl.
The term (1-10C)alkoxy includes (1-6C)alkoxy and (1-4C)alkoxy, such as
methoxy, ethoxy, propoxy, isopropoxy and isobutoxy;
The term cyano(2-10C)alkenyl includes 2-cyanoethenyl.
The term (2-4C)alkylene includes ethylene, propylene and butylene. A
preferred value is ethylene.
The term thienyl includes thien-2-yl and thien-3-yl.
2o The term furyl includes fur-2-yl and fur-3-yl.
The term oxazolyl includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.
The term isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl.
The term oxadiazolyl includes [1,2,4]oxadiazol-3-yl and [1,2,4]oxadiazol-5-
y1.
The term pyrazolyl includes pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.
The term thiazolyl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl.
The term thiadiazolyl includes [1,2,4]thiadiazol-3-yl, and [1,2,4]thiadiazol-
5-yl.
The term isothiazolyl includes isothiazol-3-yl, isothiazol-4-yl and isothiazol-
2 0 5-yl.
The term imidazolyl includes imidazol-2-yl, imidazolyl-4-yl and imidazolyl-
5-yl.
The term triazolyl includes [1,2,4]firiazol-3-yl and [1,2,4]triazol-5-yl.
The term tetrazolyl includes tetrazol-5-yl.
The term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.
The term pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl
and pyridazin-6-yl.
The term pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl
and pyrimidin-6-yl.
3 o The term benzofuryl includes benzofur-2-yl and benzofur-3-yl.
The term benzothieny) includes benzothien-2-yl and benzothien-3-yl.
The.term benzimidazolyl includes benzimidazol-2-yl.
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The term benzoxazolyl includes benzoxazol-2-yl.
The term benzothiazolyl includes benzothiazol-2-yl.
The term indolyl includes indol-2-yl and indol-3-yl.
The term quinolyl includes quinol-2-yl.
The term dihydrothiazolyl includes 4,5-dihydrothiazol-2-yl, and the term (1-
4C)alkoxycarbonyldihydrothiazolyl includes 4-methoxycarbonyl-4,5-
dihydrothiazol-2-yl.
The term -(1-4C)alkyl(3-~C)cycloalkyl includes the following:
,,
' ' '. ;
and
Zo The term -(1-4C)alkylaromatic includes the following:
w ,~
~, ~ ~ a ~ w
/ ~ .~ ~ I /
a
/ ~ , , / , an
s ,
It is preferred that -(1-4C)alkylaromatic is -(1-4C)alkylphenyl.
R1 is preferably (1-6C)alkyl, with methyl, ethyl, propyl, 2-propyl, and butyl
1s being most preferred, and 2-propyl being most especially preferred.
Examples of particular values for y are 0 and 1.
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The compounds of the present invention can be prepared by one of
ordinary skill in the art following art recognized techniques and procedures
such
as those that can be found, for example, in International Patent Application
Publications: WO 98/33496 published August 6, 1998; WO 99/43285 published
September 2, 1999; WO 00/06539; WO 00/06537, WO 00/06176, WO 00/06159,
W O 00/06158, W O 00/06157, W O 00106156, W O 00/06149, W O 00/06148, and
WO 00/06083, all published February 10, 2000; and WO 00/66546 published
November 9, 2000. More specifically, compounds of formula la and Ib can be
prepared as set forth in Scheme I. The reagents and starting materials are
so readily available to one of ordinary ski(I in the art. All substituents,
unless
otherwise specified are as previously defined.
Scheme I
R5 2
Step A R
NC CH2)~ x-B--RCN ~ NC~CH~)n X-B~(CH~)~~CN
Rs R~
(1) (2) ~ Step B
Step B'
Rs Ra
H~N~ H2N-(CH~)~CHZ)~ X-B~(CH~)P NHZ
(CHz)~ X-B-~NH2 s
R R
(3a) (3b)
Step C'
O
a, Il H O Step C
R O'N~H~)n X-B~H-S-R~,
O ~ Rs Z
formula la RB-S-H_(CHZ)~CH~)~ X-B R (CHZ)P H-O-R~,
O I's ~ O
R R
formula Ib
In Scheme I, step A the compound of structure (1 ) is alkylated under
standard conditions to provide the compound of structure (2). For example,
compound (1 ) is dissolved in a suitable organic solvent, such as THF, cooled
to
about-78°C and treated with about 1.1 to 2.1 equivalents of a suitable
base, such
as hexamethylsilylazide. The mixture is stirred for about 30 minutes and then
2 o treated with about 1 to 2 equivalents of a suitable alkylating agent, such
as
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iodomethane. The mixture is allowed to warm to room temperature and stirred
for
about 4 to 12 hours. The reaction is then quenched with water and extracted
with
a suitable organic solvent, such as ethyl acetate. The organic extracts are
washed
with water, brine, dried over anhydrous sodium sulfate, filtered, and
concentrated
under vacuum to provide the crude compound (2). This crude material can then
be purified by chromatography on silica gel to with a suitable eluent, such as
hexanes/ethyl acetate to provide the purified compound (2).
In Scheme I, step B compound (2) is reduced under standard conditions
well known in the art to provide the compound (3b). For example, compound (2)
is
Zo dissolved in a suitable organic solvent, such as THF and treated with about
2.1
equivalents of a suitable reducing agent, such as boron dimethylsulfide. The
reaction is heated at reflux for about 4 to 14 hours, then cooled to room
temperature, and quenched with a saturated solution of HCI in methanol. The
quenched reaction mixture is then treated with a suitable organic solvent,
such as
15 diethyl ether, cooled to about 0°C, and the precipitated product
(3b) collected by
filtration as the dihydrochloride salt.
In Scheme I, step C, compound (3b) is sulfonylated under conditions well
known in the art to provide the compound of formula Ib. For example, compound
(3b) dissolved in a suitable organic solvent. Examples of suitable organic
solvents
2 o include methylene chloride, tetrahydrofuran, and the like. The solution is
treated
with about 2.0 to about 5 equivalents of a suitable base, and then cooled to
about -
5°C to about 0°C. Examples of suitable bases include
triethylamine, pyridine, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), and the like. To the stirring solution
is
added about 2.1 to about 2.3 equivalents of LgS02R~~ wherein R~~ and R8~ are
2s equivalent The term "Lg" as used herein refers to a suitable leaving group.
Examples of suitable leaving groups include, CI, Br, and the like. CI is the
preferred leaving group. The reaction mixture is stirred at about 0°C
to about 25°C
for about 0.5 hours to about 16 hours. The compound of formula Ib is then
isolated and purified by techniques well known in the art, such as extraction
3 o techniques and chromatography. For example, the mixture is washed with 10%
sodium bisulfate, the layers separated and the aqueous extracted with several
times with a suitable organic solvent, such as methylene chloride. The organic
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extracts are combined, dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. The residue is then purified by flash
chromatography
on silica gel with a suitable eluent such as ethyl acetatelhexane to provide
the
purified compound of formula Ib.
s In Scheme I, step B', the compound (1 ) is reduced to the compound (3a) in
a manner analogous to the procedure set forth in Scheme I, step B.
In Scheme I, step C' the compound (3a) is sulfonylated to provide the
compound of formula la in a manner analogous to the procedure set forth in
Scheme I, step C.
1o Compounds of formula I' can be prepared as set forth in Scheme II. The
reagents and starting materials are readily available to one of ordinary skill
in the
art. All substituents, unless otherwise specified are as previously defined.
Scheme II
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R5
HZN-(CH~)~CH~)~ X-B-A-NHZ
Rs (4)
Step A
R5
PgNH-(CH2)~CHZ)~ X-B-A-NH2
Rs (5)
Step B
Rs O
PgNH-(CH2)~CHZ)~ X-B-A-H-S-R~
Rs (6) O
Step C
R5 O
HZN-(CH2)~CHZ)~ X-B-A-H-S-R~
Rs (7) O
Step D
O R5 O
R$ S-H-(CH~)~CH2)~ X-B-A-H-S-R~
O Rs O
formula I'
In Scheme II, step A, diamino compound (4) is protected with a suitable
protecting group "Pg" under standard conditions to provide the mono-protected
compound of structure (5). As used herein the term "Pg" refers to suitable
s protecting groups on the amine which are commonly employed to block or
protect the amine while reacting other functional groups on the compound.
Examples of suitable protecting groups used to protect the amino group and
their
preparation are disclosed by T. W. Greene, "Protective Groups in Organic
Synthesis," John Wiley & Sons, 1981, pages 218-287. Choice of the suitable
Zo 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. Preferred protecting groups are
t-
butoxycarbonyl also known as a BOC protecting group, and benzyloxycarbonyl,
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also known as CBz. For example, the diamino compound (4) is dissolved in a
suitable organic solvent, such as methylene chloride and treated with about
1.2
equivalents of triethylamine. The solution is then cooled to about -5
°C and
treated with one equivalent of as suitable protecting group, such as
benzylchloroformate. The reaction mixture was warmed up to room temperature
while stirring overnight. The reaction is then diluted with a suitable organic
solvent, such as ethyl acetate, rinsed with water, brine, dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum to provide the crude
mono-protected compound (5) wherein Pg represents a CBz protecting group.
1o The crude material can then be purified by techniques well known in the
art, such
as flash chromatography on silica gel with a suitable eluent, such as
methanol/methylene chloride.
In Scheme II, step B, the protected compound (5) is sulfonylated with a
compound of formula LgSO~R~ to provide sulfonamide (6) in a manner
1~ analogous to the procedure described in Scheme I, step C.
In Scheme i1, step C, sulfonamide (6) is deprotected under conditions well
known in the art as disclosed by T. W. Greene, "Protective Groups in Organic
Synthesis," John Wiley & Sons, 1981, pages 218-287 to provide the amino
derivative of structure (7). The conditions employed for deprotection will
depend
2 o upon the protecting group that needs to be removed and the substituents
present on the compound itself which must remain unaffected by the
deprotection reaction conditions, the conditions of which are well within the
knowledge of one of ordinary skill in the art. For example, sulfonamide (6)
wherein Pg represents a CBz protecting group is dissolved in a suitable
organic
25 solvent, such as ethanol and treated with a catalytic amount of 10%
palladium on
carbon. The reaction mixture is placed under an atmosphere of hydrogen for 2
to 12 hours and then filtered through Celite~. The filtrate is concentrated
under
vacuum and the crude amino derivative (7) is purified using standard
techniques
well known in the art, such as chromatography on silica gel with a suitable
3 o eluent, such as methanol/methylene chloride.
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In Scheme II, step D, the amino compound (7) is sulfonylated with a
compound of formula LgSOzR$ to provide sulfonamide of formula I' in a manner
analogous to the procedure described in Scheme I, step C.
The compounds of structures (12) and (13) can be prepared following the
procedures set forth in Scheme III below. The reagents and starting materials
are readily available to one of ordinary skill in the art. All substituents,
unless
otherwise specified are as previously defined.
Scheme III
Step A ~ Step B
-~ -,~ -~- ~ s
B i B i
/ C~ / \ ~ / CH3
($)
(9) (10)
Step D I Step C
Step E
_ \
/ NOz NHS ,'~NHZ
(11)
(12) (13)
In Scheme III, step A, the cyclopentene of structure (8) is converted to the
borane of structure (9) under standard conditions. For example, cyclopentene
(8) is dissolved in a suitable organic solvent, such as dry methylene chloride
under an atmosphere of nitrogen and cooled to about 0°C. The solution
is
1s treated with about 0.5 equivalents of monochloroborane-methyl sulfide. The
reaction mixture is allowed to warm to room temperature and stirred for about
8
to 16 hours. The solvent is removed under vacuum under a nitrogen atmosphere
to provide borane (9).
In Scheme III, step B, borane (9) is methylated to provide the
2 o methylborane of structure (10). For example borane (9) is dissolved in a
suitable
organic solvent, such as dry hexanes under an atmosphere of nitrogen. The
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solution is cooled to about 0°C and treated with about 0.3 equivalents
of
trimethylaluminum in hexanes. The reaction mixture is allowed to warm to room
temperature and stirred for about 1.5 hours. A precipitate results and the
supernatant is transferred via cannula to a nitrogen flushed separatory funnel
containing saturated aqueous ammonium chloride. The organic phase is then
transferred via cannula to a flask containing anhydrous sodium sulfate. The
organic solution is then transferred via cannula to a dry, nitrogen flushed
flask
and the solvent is removed under vacuum in the presence of a nitrogen
atmosphere to provide the methylated borane (10).
1o In Scheme III, step C, the methylated borane (10) is hydrolyzed to the
trans-cyclopentylamine of structure (13). For example, methylated borane (10)
is
dissolved in a suitable organic solvent, such as dry tetrahydrofuran and
cautiously treated in small portions with a slight excess of hydroxylamine-O-
sulfonic acid (referred to herein as "HAS") dissolved in tetrahydrofuran. The
15 reaction is exothermic. After addition is complete, the reaction mixture is
stirred
for about 24 hours and then filtered. The filtrate is concentrated under
vacuum
and the residue is treated with concentrated HCl:methanol:water:diethyl ether
'
(30:15:20:60, by volume). The mixture is stirred at room temperature for about
30 minutes. The layers are separated, the organic phase is washed with water
2 o and the water wash is combined with the aqueous phase. The aqueous phase
is
cooled to about 0°C, diethyl ether is added and the aqueous is made
basic with
sodium hydroxide. The organic phase is separated and the aqueous phase is
extracted with diethyl ether and ethyl acetate. The organic phase and organic
extracts are combined, dried over anhydrous sodium sulfate, filtered and
25 concentrated under vacuum to provide the cyclopentylamine (13).
)n Scheme III, step D, the cyclopentene of structure (8) is nitrated under
standard conditions to provide the compound of structure (11 ). For example,
see
the procedure disclosed by F.G. Bordwell, et al., J. Org. Chem., 1765-1769
(1963).
3 o In Scheme III, step E, the nitrated compound of structure (11 ) is reduced
under standard conditions to provide the amine of structure (12). For example,
compound (11 ) is dissolved in a suitable organic solvent, such as ethanol,
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treated with a suitable hydrogenation catalyst, such as palladium on carbon,
the
solution is placed under hydrogen at about 413.69 kPa (60 psi). After about 8
to
16 hours, the reaction mixture is filtered and the filtrate is concentrated
under
vacuum to provide the compound (12).
The compound of structure (12) can be prepared by the alternative
procedures set forth in Schemes (11A and (11B below. The reagents and starting
materials are readily available to one of ordinary skill in the art. All
substituents,
unless otherwise specified are as previously defined.
s o Scheme I I IA
Step A Step B
\v \ ~.
~N-OH - NH2
05~ (1~)
In Scheme IIIA, step A, the cyclopentanone of structure (14) is converted
to the corresponding oxime of structure (15) under conditions well known in
the
art. For example, cycfopentanone (14) is dissolved in a suitable organic
solvent,
15 such as ethanol, treated with about 2 equivalents of aqueous sodium
hydroxide
and about 1.5 equivalents-of hydroxylamine hydrochloride. The reaction mixture
is stirred for about 8 to 16 hours at room temperature. It is then diluted
with
water and the precipitated oxime (15) is collected by filtration and dried
under
vacuum at about 35°C.
2o In Scheme I(IA, step B, oxime (15) is hydrogenated under standard
conditions to provide the amine of structure (12). For example, oxime (15) is
dissolved in a suitable organic solvent, such as ethanol, treated with a
suitable
catalyst, such as palladium on carbon, and placed under hydrogen at about
413.69 kPa (60 psi). The hydrogenation is carried out at about 40°C for
about 8
2s to 16 hours. The reaction mixture is then filtered and the filtrate
concentrated
under vacuum to provide the amine (12).
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Scheme IIIB
o
(14)
Step A Step B
+ -~ :OH
MgBr
(16)
(15) Steps E-H Ste D
P Step C
_ _ ~ _
~NH2 ~ / O ~ / NH2
(13) (14)
(12)
In Scheme IIIB, step A, the epoxide (14) is coupled wifih the Grignard
reagent (15) to provide the alcohol (16). For example, Grignard (15) is
dissolved
in a suitable organic solvent, such as tetrahydrofuran and treated with a
catalytic
amount of copper iodide. To this solution is slowly added the epoxide (14)
dissolved in tetrahydrofuran. The reaction is exothermic. The reaction is
stirred
until the temperature reaches room temperature and it is quenched with aqueous
ammonium chloride. The quenched reaction is extracted with a suitable organic
to solvent, such as diethyl ether. The organic extracts are combined, washed
with
aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered,
and concentrated under vacuum to provide alcohol (16).
In Scheme IIIB, step B, alcohol (16) is converted to the compound of
structure (17) under standard conditions well known in the art. For example,
about one equivalent of triphenylphosphine is dissolved in a suitable organic
solvent, such as tetrahydrofuran. The solution is cooled to about 0°C
and a
solution of about one equivalent of diisopropyl azodicarboxylate in
tetrahydrofuran is added dropwise to the solution with stirring. To this
reaction
mixture is added about one equivalent of phthalimide followed by addition of
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_28_
about one equivalent of alcohol (16) dissolved in tetrahydrofuran maintaining
the
temperature between about 5°C and 0°C. The reaction is then
stirred at about
0°C for about 4 hours, warmed to room temperature, and stirred for 4 to
12
hours. The reaction is then quenched with water and extracted with a suitable
organic solvent, such as chloroform. The organic extracts are combined, washed
with water, dried over anhydrous magnesium sulfate, filtered, and concentrated
under vacuum to provide compound (17).
In Scheme IIIB, step C, compound (17) is converted to compound (12) in
an exchange reaction well known in the art. For example, compound (17) is
to dissolved in a suitable organic solvent, such as toluene, and an excess of
anhydrous hydrazine is added dropwise over about 15 minutes with stirring. The
reaction mixture is stirred for about one hour at room temperature and then
heated at about 90-95°C for about 6 hours. The reaction mixture is then
cooled
to room temperature, filtered, the precipitate rinsed with toluene, the
filtrates
15 combined, concentrated under vacuum to provide compound (12).
Alternatively, compound (17) is dissolved in 2-aminoethanol and heated at
about 80-90°C for about 1 to 2 hours. The reaction is then diluted with
diethyl
ether, washed with dilute sodium hydroxide, brine, dried over anhydrous sodium
sulfate, filtered, and concentrated to provide compound (12).
2o In Scheme IIIB, step D, compound (16) oxidized to the ketone of
structure (14) under standard conditions well known in the art. For example,
compound (16) is added dropwise to a suspension of an excess of pyridinium
chlorochromate in a suitable organic solvent, such as methylene chloride. The
reaction is stirred for about 8 to 48 hours at room temperature. It is then
diluted
25 with a diethyl ether, filtered through a pad of silica gel and the filtrate
concentrated under vacuum to provide crude compound (14). This material can
be purified by standard techniques, such as flash chromatography on silica gel
with a suitable eluent, such as ethyl acetate/hexane.
In Scheme IIIB, steps E through H, compound (16) is converted to
3 o the amine (13) using standard techniques and reactions well known in the
art.
For example, in step E, compound (16) is subjected to Mitsunobu conditions to
provide the cis-benzoate derivative. More specifically, compound (16) is
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dissolved in a suitable organic solvent, such as THF and combined with about
1.05 equivalents of diethyl azodicarboxylate (referred to herein as "DEAD"),
about 1.2 equivalents of benzoic acid and about 1.2 equivalents of
triphenylphosphine at about 0°C. The reaction is stirred for about 2
hours,
allowed to warm to room temperature and then concentrated under vacuum.
The crude residue can be purified by chromatography on silica gel with a
suitable
eluent, such as hexanes/methylene chloride to provide the cis-benzoate
derivative.
In Scheme lIIB, step F, the cis-benzoate is hydrolyzed under standard
conditions to provide the cis-alcohol. For example, the cis-benzoate is
combined
with 5% NaOHlmethanol and stirred at room temperature for about 3 hours. The
reaction mixture is then concentrated under vacuum, the residue dissolved in a
suitable organic solvent, such as diethyl ether, which is washed with water.
The
organic phase is then dried over potassium carbonate; filtered, and
concentrated
under vacuum. The residue can be purified by chromatography on silica gel with
a suifiable eluent, such as hexanes/methylene chloride to provide the cis-
alcohol.
In Scheme IIIB, step G, the cis-alcohol is converted to the phthalimide
derivative in a manner analogous to the procedure described above in Scheme
IVB, step B.
2 o In Scheme IIIB, step H, the phthalimide derivative is converted to the
trans-amine (13) in a manner analogous to the procedure described above in
Scheme IIIB, step C.
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Srhama IIIC'.
~OH
(16)
'~OH + O-~O
/ ~ / CH3
(16a) (16b)
In Scheme I11C,'the compound (16} is subjected to an enzymatic
resolution to provide the unreacted optically active alcohol (16a) and the
optically
active acetate (16b). For example, see the procedure described by Seemayer
and Schneider, Recl. Trav. Chim. Pays-Bas, 110, 171-174 (1991 ), "Enzymatic
Hydrolysis and Esterification. Routes to Optically Pure Cyclopentanols". More
specifically, the alcohol (16) is dissolved in a suitable organic solvent,
such as
tart-butyl methyl ether and combined with a suitable enzyme, such as Candida
1o antartctica B lipase. With stirring, about 0.5 to about 0.6 equivalents of
vinyl
acetate is added and the reaction is stirred at room temperature for about 2
to 4
hours. The reaction mixture is then filtered and the filtrated is concentrated
under vacuum to provide a mixture of the optically active alcohol (16a) and
optically active acetate (16b). .These compounds are then readily separated
from
z5 each other using standard techniques well known in the art, such as flash
chromatography on silica gel with a suitable eluent, such as ethyl
acetate/hexane.
It is understood by one of ordinary skill in the art that the corresponding
cyclohexyl derivatives of structures (12') and (13')
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NHZ ~ ~ ~NNZ
(12') (13')
can be prepared in a manner analogous to the procedures set forth above.
Compounds of formula Ic can be prepared by the procedures set forth in
Scheme IV. The reagents and starting materials are readily available to one of
ordinary skill in the art. All substituents, unless otherwise specified are as
previously defined.
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Scheme IV
B-A-NH Sty g-A-N-Ig-R' St-~ 02N-B-A-N-IS-R~
H II H II
(18) (1 g) O (20) O
Step C
O O
R-N-B-A-N-SI-R1 E tep D H N-B-A-N-SI-R'
H H II 2 H II
(22) O (21) O
Step E
O O
I I Step F
R N B A H II-R~ -~- R-N B A H SI R~
( ~ HZ)n-~ O (' Hz)~ IO
CN (23) (~4) NHS
Step G
O
Step H O
I
HCHB-A-H-i I-R E R-N-g-A-H-IS-R~
( I 2)n O (CHZ)n OI
NH NH
O-I-O O-I-O
R$ formula IC RS (25)
In Scheme IV, step A the compound of structure (18) is sulfonylated to
provide the compound of structure (19) in a manner analogous to the procedure
set forth in Scheme I, step C.
In Scheme IV, step B the compound (19) is nitrated under standard
conditions well known in the art to provide the nitro derivative of structure
(20).
For example, compound (19) is dissolved in trifluoroacetic acid and treated
with
excess sodium nitrate. The reaction mixture is stirred for about 3 to 8 hours
and
1 o then diluted with water. The quenched reaction mixture is extracted with a
suitable organic solvent, such as methylene chloride, the organic extracts are
combined, washed with saturated sodium carbonate, dried over anhydrous
magnesium sulfate, filtered, and concentrated under vacuum to provide crude
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nitro derivative (20). This crude material can then be purified by
chromatography
on silica gel with a suitable eluent, such as hexanes/ethyl acetate.
In Scheme IV, step C, the nitro derivative (20) is reduced to the amine of
structure (21 ) under standard conditions. For example, the nitro derivative
(20) is
dissolved in a suitable organic solvent, such as ethanol and treated with a
suitable hydrogenation catalyst, such as 5% palladium on carbon. The mixture
is
placed under about 40 psi of hydrogen and agitated for 8 to 14 hours. The
reaction mixture is then filtered through Celite~ to remove the catalyst and
the
filtrate is concentrated under vacuum to provide the crude amine (21 ). The
crude
so material can then be purified by chromatography on silica gel with a
suitable
eluent, such as hexanes/ethyl acetate.
In Scheme IV, step D, the amine (21 ) is alkylated under conditions well
known in the art to provide the compound of structure (22). For example, amine
(21 ) is dissolved in a suitable organic solvent, such as methanol, and
treated with
i5 an equivalent of an aldehyde, such as benzaldehyde and treated with a
catalytic
amount of acetic acid. The reaction mixture is stirred for about 4 hours and
then
treated with about 2 equivalents of a suitable reducing agent, such as sodium
borohydride. The reaction mixture is then stirred for about 8 to 14 hours at
room
temperature. The reaction is then diluted with water, extracted with a
suitable
2 0 organic solvent, the organic extracts are combined, dried over potassium
carbonate, filtered, and concentrated under vacuum to provide the crude
compound (22). This crude material can then be purified by chromafiography on
silica gel with a suitable eluent, such as hexanes/ethyl acetate.
In Scheme IV, step E, compound (22) is again alkylated under standard
2s conditions well known in the art to provide the nitrite of structure (23).
For
example, compound (22) dissolved in a suitable organic solvent, such as
methanol, is added to a solution of about 1.1 equivalents of sodium cyanide in
water. The reaction mixture is cooled to about 0°C and treated with
hydrochloric
acid and about 1.1 equivalents of formaldehyde is added. The reaction mixture
3 o is stirred for about 3 hours at 0°C, warmed to room temperature and
stirred for
about 14 hours. The reaction is then quenched with water and extracted with as
suitable organic solvent, such as methylene chloride. The organic extracts are
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combined, washed with brine, dried over anhydrous magnesium sulfate, filtered,
and concentrated under vacuum to provide the crude nitrite (23). The crude
material can be purified by chromatography on silica gel with a suitable
eluent,
such as hexanes/ethyl acetate.
In Scheme IV, step F, the nitrite (23) is reduced to the amine of structure
(24) in a manner analogous to the procedure described in Scheme I, step B.
In Scheme iV, step G, the amine (24) is sulfonylated to provide the
compound of structure (25) in a manner analogous to the procedure described in
Scheme I, step C.
1o In Scheme IV, step H, the compound (25) is dealkylated under standard
conditions to provide the compound of formula Ic. For example, compound (25)
is dissolved in a suitable organic solvent, such as THF, treated with a slight
excess of ammonium formate and a catalytic amount of palladium on carbon.
The reaction mixture is stirred at room temperature for about 14 hours and
then
s5 heated at reflux for about 8~hours. After cooling, the reaction mixture is
filtered
through Celite~ which is washed is water. The filtrate is extracted with a
suitable
organic solvent, such as ethyl acetate. The organic extracts are combined,
washed with brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated under vacuum to provide the crude compound of formula Ic. This
2 o crude material can then be purified by chromatography on silica gel with a
suitable eluent, such as hexanes/ethyl acetate.
Compounds of formulas Id and 1e can be prepared by the procedures set
forth in Scheme V. The reagents.and starting materials are readily available
to
one of ordinary skill in the art. All substituents, unless otherwise specified
are as
25 previously defined.
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Scheme V
O~N-B O p OZN-B OH St~ 02N-B OH O
Ste A
I I
(26) NH2 HCI N-i I-R~
(27) (28) H O
Step C
OH OH
Step D
R-N-B O ~' HEN-B 0
H (30) N SI ~ R1 (29) H I I Ra
O O
Step E
OH Step F OH
R-N-B
II' ~ R-N-B p
(CHZ)~_1 N-S_R~ (CH~)~ H-SI_R~
H
fCN O I HZ IO
(31) (32)
Step G
OH Step H OH
HN-B Ii E R-N-g O
( ~ Hz)n H I I R1 ( i HZ)n H I I R~
NH O NH O
O=S=O O=S=O
Ra formula 1e Ra formula Id
In Scheme V, step A, the compound of structure (26) is converted to the
alcohol of structure (27) under standard conditions. For example, compound
(26)
s is treated with excess trimethylsily)cyanate and zinc iodide under a
nitrogen
atmosphere at room temperature, The mixture is stirred for about 14 hours and
treated with methylene chloride and saturated sodium carbonate. The layers are
separated and the organic layer is washed with water, dried over anhydrous
magnesium sulfate, filtered, and concentrated under vacuum. The residue is
to dissolved in a suitable organic solvent and treated with a suitable
reducing agent,
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such as borane-dimethylsulfide. The reaction mixture is stirred at room
temperature for about 14 hours and then treated with concentrated hydrochloric
acid until a pH of about 2 is achieved. A suitable organic solvent, such as
diethyl
ether is then added and the resulting precipitate is collected by filtration,
rinsed
s with diethyl ether and dried under vacuum to provide compound (27) as the
hydrochloride salt.
In Scheme V, step B, the compound (27) is sulfonylated to provide the
compound of structure (28) in a manner analogous to the procedure described in
Scheme I, step C.
so In Scheme V, step C, the compound (28) is reduced to provide the amine
of structure (29) in a manner analogous to the procedure described in Scheme
IV, step C.
In Scheme V, step D, the amine (29) is alkylated to provide the compound
of structure (30) in a manner analogous to the procedure described in Scheme
15 IV, step D.
In Scheme V, step E, the compound (30) is again alkylated to provide the
nitrite of structure (31 ) in a manner analogous to the procedure described in
Scheme IV, step E.
In Scheme V, step F, the nitrite (31 ) is reduced to the amine of structure
20 (32) in a manner analogous to the procedure described in Scheme IV, step F.
In Scheme V, step G, the amine (32) is sulfonylated to provide the
compound of formula Id in a manner analogous to the procedure described in
Scheme IV, step G.
In Scheme V, step H, the compound of formula Id is dealkylated to provide
2s the compound of formula 1e in a manner analogous to the procedure described
in
Scheme IV, step H.
Compounds of formula Ig can be prepared by the procedures set forth in
Scheme VI. The reagents and starting materials are readily available to one of
ordinary skill in the art. All substituents, unless otherwise specified are as
3 o previously defined.
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Scheme VI
R5 OH O
W-H-(CHz)~-(CHZ)~ X-B--r(CH2)P H-IS-R~
R ~Rsa IO
formula If
DAST
R5 F O
W-H-(CHZ)~--(CHZ)~ X-B--I-(CH2)p H-S-R~
R ~Rsa IO
formula Ig
In Scheme VI the compound of formulas If is converted under
conditions well known in the art to provide the corresponding fluorinated
compound
of formulas Ig. For example, For example, the compound of formula If is
dissolved
in a suitable organic solvent, such as methylene chloride and the solution is
cooled
to about -78°C under an inert atmosphere, such as nitrogen. To this
solution is
added slowly, about one equivalent of diethylaminosulfur trifluoride (DAST)
dissolved in a suitable organic solvent, such as methylene chloride with
stirring.
z o The reaction is then allowed to warm to room temperature and the compound
of
formula If or Ig is then isolated and purified using techniques and procedures
well
known in the art, such as extraction techniques and chromatography. For
example, the reaction is diluted with water and methylene chloride. The layers
are
separated and the organic layer is washed with water, dried over anhydrous
sodium sulfate, filtered and concentrated under vacuum to provide the crude
compound of formula Ig. This crude material can then be purified by standard
techniques, such as recrystallization from a suitable eluent, or flash
chromatography or radial chromatography on silica gel, with a suitable eluent,
such
as hexane/ethyl acetate or methylene chloride to provide purified compound of
2 o formula Ig.
Compounds of formula I wherein W represents R~3C(=O)-, R~3R~5NC(=O)-
H2NC(=O)-, R~6, or R~40C(=O)- can further be prepared following the
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procedures set forth in Scheme VI I. The reagents and starting materials are
readily available to one of ordinary skill in the art. All substituents,
unless
otherwise specified are as previously defined.
Scheme VII
O R5 O O R5 O
R~3--~-H-(CH2)~CHZ)~ X-B'A-H-S-R~ HZN-LL--H-(CHZ)~CHZ)~ X-B-A-H-S-R~
Rs O Rs O
formula Ih formula Ii
Step A Step
Rs O
H2N-(CH~)~CH2)~ X-B-A-H-S-R~
Rs O
(7)
Step C Step D
7 5
O R5 O
R~6 N-(CHZ)m R CHa)~ X-B-A-N-O-R~ R~40-~-N- CH CH -X-B-A-N-S-R~
H II I-I ( ~)"' 2)n H II
R O Rs O
6
formula Ij ' ' formula Ik
Step E
O R5 ~ O
R~3 i -~.L-H-(CH2)~CH~)~ X-B-A-N-S-R~
R~5 Rs O
formula Im
In Scheme I, step A the compound of structure (7) is acylated under
standard conditions to provide the compound of formula Ih. For example, the
compound (7) is dissolved in a suitable organic solvent, such as methylene
to chloride, the solution is cooled to about 0°C, and about 2 to 3
equivalents of a
suitable base, such as triethylamine is added. The reaction is then treated
with
about 1.5 equivalents of a compound of formula R~3C(=O)Lg wherein Lg is a
leaving group, such as CI or Br. Examples of compounds of formula R~3C(=O)Lg
are acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride,
and the
like. The reaction mixture is then stirred for about 4 to 14 hours, quenched
with
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water and the layers separated. The organic phase is rinsed with water, dried
over anhydrous sodium sulfate, filtered, and concentrated under vacuum to
provide the crude compound of formula Ih. This crude material can be purified
by chromatography on silica gel with a suitable eluent, such as hexanes/ethyl
acetate to provide the purified compound of formula Ih.
In Scheme VII, step B the compound (7) is converted to the compound of
formula Ii under conditions well known in the art. For example, compound (7)
is
combined with about 2 equivalents of sodium cyanate in a suitable organic
solvent, such as toluene and heated to about 50°C. The mixture is then
treated
so with about 1.4 equivalents of trifluoroacetic acid and the mixture is
heated to
about 70°C for about one hour. The reaction is then concentrated under
vacuum
and the residue is treated with aqueous sodium hydroxide and methylene
chloride. The layers are separated and the organic phase is rinsed with brine,
filtered through potassium carbonate, and the filtrate is concentrated under
s5 vacuum to provide the crude compound of formula Ii. This crude material can
be
purified by chromatography on silica gel with a suitable eluent, such as
hexanes/ethyl acetate to provide the purified compound of formula Ii.
In Scheme VII, step C the compound (7) is converted to the secondary or
tertiary amine of formula Ij under standard conditions well known in the art.
The
2 o secondary amine can be prepared via reductive alkylation as described by
Jerry
March, "Advanced Organic Chemistry: Reactions, MechanismsL and Structure,"
Fourth Edition, John Wiley & Sons, (1992), pages 898-900, reaction No. 6-15.
For example, compound (7) is dissolved in a suitable organic solvent, such as
methanol and treated with about one equivalent of an aldehyde or ketone, such
2 s as benzaldehyde and treated with about 0.05 equivalents of acetic acid
(catalytic
amount). The reaction mixture is stirred for about 2 to 8 hours and then
treated
with a suitable reducing agent, such as about 2 equivalents of sodium
borohydride. The reaction mixture is then stirred for about 8 to 14 hours at
room
temperature and then diluted with water. The quenched reaction is extracted
3 o with a suitable organic solvent, such as methylene chloride, the organic
extracts
are combined, filtered through potassium carbonate, and concentrated under
vacuum to provide the crude secondary amine of formula Ij. This crude material
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can be purified by chromatography on silica gel with a suitable eluent, such
as
ethyl acetate to provide the purified compound of formula Ij.
In addition, the tertiary amine can be prepared via dialkylation conditions
as described by Jerry March, "Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure," Fourth Edition, John Wiley & Sons, (1992), pages
411-413, 476 and 899-900. For example, compound (7) is dissolved in a suitable
organic solvent, such as methanol and treated with an excess of formaldehyde.
The reaction mixture is stirred at room temperature for about 1 to 3 hours.
About
2 to 8 equivalents of a suitable reducing agent, such as sodium borohydride is
1o then added and the reaction mixture is stirred for about 6 to 14 hours at
room
temperature. The reaction is then concentrated under vacuum and the residue is
dissolved in water and a suitable organic solvent, such as methylene chloride.
The layers are separated and the aqueous is extracted with methylene chloride.
The organic layer and organic extracts are combined, washed with water and
15 brine, dried over anhydrous magnesium sulfate, filtered and concentrated
under
vacuum to provide the crude tertiary amine of formula Ij. This crude material
can
be purified by chromatography on silica gel with a suitable eluent, such as
methylene chloride:methanol to provide the purified compound of formula Ij.
In Scheme VII, step D compound (7) is converted to the carbamate of
2 o formula Ik under conditions well known in the art such as those described
by
Theodora W. Greene, "Protective Groups in Organic Synthesis," John Wiley &
Sons, (1981 ), Chapter 7. For example, compound (7) is dissolved in a suitable
organic solvent such as methylene chloride, the solution is cooled to about
0°C
and about 2.5 equivalents of a suitable base, such as triethylamine is added.
To
25 this stirring solution is then added about 1.5 equivalents of a suitable
chloroformate, such as methyl chloroformate, and the reaction is stirred for
about
8 to 14 hours. The reaction is then quenched with wafer and the product is
isolated and purified using standard techniques and procedures, such as
extraction and chromatography. For example, the quenched reaction is
3 o extracted with a suitable organic solvent, such as methylene chloride, the
combined organic extracts are dried over anhydrous sodium sulfate, filtered,
and
concentrated under vacuum to provide crude compound of formula Ik. This
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crude material can be purified by chromatography on silica gel with a suitable
eluent, such as ethyl acetate to provide the purified compound of formula ik.
In Scheme VII, step E compound (7) is converted to the substituted urea
of formula Im under conditions well known in the art. For example, compound
(7)
is dissolved in a suitable organic solvent, such as methylene chloride, the
solution is cooled to about 0°C and treated with about 2.5 equivalents
of a
suitable base, such as triethylamine. To this stirring solution is then added
about
1.5 equivalents of a carbamoyl chloride, such as N-methyl-N-phenylcarbamoyl
chloride and the reaction is stirred for about 8 to 14 hours. The reaction is
then
so quenched with water and the product is isolated and purified using standard
techniques and procedures, such as extraction and chromatography. For
example, the quenched reaction is extracted with a suitable organic solvent,
such
as methyiene chloride, the combined organic extracts are dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum to provide crude
compound of formula Im. This~crude material can be purified by chromatography
on silica gel with a suitable eluent, such as ethyl acetate to provide the
purified
compound of formula im.
The following examples further illustrate the invention and represent
2 o typical syntheses of the compounds of formula ! as described generally
above.
The reagents and starting materials are readily available to one of ordinary
skill in
the art. As used herein the term "Chromatotron°" (Harrison Research
Inc., 840
Moana Court, Palo Alto California 94306) is recognized by one of ordinary
skill
in the art as an instrument which is used to perform centrifugal thin-layer
25 chromatography. As used herein, the following terms have the meanings
indicated: "eq" refers to equivalents; "g" refers to grams; "mg" refers to
milligrams; "L" refers to liters; "mL" refers to milliliters; "p,L" refers to
microliters;
"mol" refers to moles; "mmol" refers to millimoles; "psi" refers to pounds per
square inch; "min" refers to minutes; "h" or "hr" refers to hours; "°C"
refers to
3 o degrees Celsius; "TLC" refers to thin layer chromatography; "HPLC" refers
to
high performance liquid chromatography; "Rf' refers to retention factor; "Rt'
refers to retention time; "8"refers to part per million down-field from
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tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N,N-
dimethylformamide; "DMSO" refers to methyl sulfoxide; "LDA" refers to lithium
diisopropylamide; "EtOAc" refers to ethyl acetate; "aq" refers to aqueous;
"iPrOAc" refers to isopropyl acetate; "MTBE" refers to tert-butyl methyl
ether;
"methyl DAST" refers to dimethylaminosulfur trifluoride, "DAST" refers to
diethylaminosulfur trifluoride, "DBU" refers to 1,3-diazabicyclo[5.4.0]undec-7-
ene;
as used herein "Pd(dppf)2CI2 catalyst" refers to ([1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2CI2; as
used herein the terms "Me", "Et", "Pr", "iPr", and "Bu" refer to methyl,
ethyl,
so propyl, isopropyl, and butyl respectively, and "RT" refers to room
temperature.
Preparation 1
Chloro-bis-(2-phenyl-cyclopentyl)-borane.
/ \
. \ / ci
Scheme 11l, step A: Modification of H. C. Brown et. al., Tetrahedron
Asymmetry, 7, 3527-3534 (1996). 1-Phenylcyclopentene (commercial 96%)(10.0
g, 69.4 mmol) was placed in an oven-dried flask under nitrogen and diluted
with
60 mL of dry methylene chloride. The solution was cooled to 0°C and
monochloroborane-methyl sulfide complex (3.6 mL, 34.7 mmoL) was added
2 o dropwise via syringe. The solution was allowed to warm to room temperature
and stirred overnight. The solvent is removed by aspirator vacuum under a
nitrogen atmosphere to provide a crude colorless oil. This oil is used
directly in
the next step without further characterization.
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Preparation 2
Methyl-bis-(2-phenyl-cyclopentyl)-borane
'.
/ \
\ / CH3
Scheme III, step B: Chloro-bis-(2-phenyl-cyclopentyl)-borane from
s preparation 1 was diluted with 60 mL of dry hexanes under nitrogen. The
solution was cooled to 0°C and a 2M solution of trimethyialuminum in
hexanes
(5.8 mL) was added dropwise causing the reaction to turn orange. The reaction
was allowed to warm to room temperature and stirred for 1.5 hours. During this
time a red-brown mass precipitated out of solution, leaving a yellow
supernatant.
to The hexane supernatant was transferred via cannula to a nitrogen flushed
separatory funnel containing 50 mL of saturated aqueous ammonium chloride.
The organic phase becomes colorless and was transferred via cannula to a dry
flask containing sodium sulfate for drying. The solution was then transferred
via
cannula to a dry, nitrogen-flushed flask and the solvent removed under
aspirator
1 s vacuum and nitrogen. The clear oil was used directly without further
characterization.
Preparation 3
(+,-) Trans-2-phenyl-cyclopent lay mine
/ \
HZN
Scheme III, step C: Methyl-bis-(2-phenyl-cyclopentyl)-borane (theoretical
34.7 mmoL) from preparation 2 was diluted with 40 mL of dry tetrahydrofuran.
8.3 g (72.9 mmol) of hydroxylamine-O-sulphonic acid (HSA) was slurried in a
separate dry flask in 60 mL of THF and small portions are transferred via
cannula
to control the exothermic reaction. The cloudy white solution was stirred at
room
temperature for 24 hours. The reaction mixture was filtered and the THF
removed in vacuo. The residue was treated with 30 mL of concentrated HCI, 15
mL of methanol, 20 mL of water and 60 mL of diethyl ether and stirred at room
temperature for 30 minutes. The aqueous phase was collected and the organic
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phase washed with water and combined with the aqueous phase. The aqueous
phase was cooled to 0°C, layered with diethyl ether, and made strongly
basic
with sodium hydroxide pellets. The organic phase was separated and the
aqueous phase extracted with diethyl ether (2X) and ethyl acetate (1X). The
organic phases were combined and dried over sodium sulfate. The filtrate was
concentrated to 5.96 (53%) of the title compound as a yellow oil.
Mass Spectrum (ES MS): M +1 = 162.
Preparation 4
zo ~5-Nitro-cyclopent-1-enyl~benzene
/ \ f
r
O~N
Scheme III, step D: (5-Nitro-cyclopent-1-enyl)-benzene was prepared
according to the procedure of F. G. BordweN et. al., J. Org. Chem., 1765-1769,
1963. The title compound was prepared by nitration of 1-phenylcyclopentene
(3.0
g, 20.8 mmol) and purified by radial chromatography eluting with 85:15
hexanes:ethyl acetate to yield 0.63 g (12%) as a yellow oil.
Preparation 5
(+,-) Cis -2-phenyl-cyclopent lad
/ \
HZN
Scheme III, step E: (5-Nitro-cyclopent-1-enyl)-benzene (0.63 g, 3.3 mmol}
from preparation 4 above, was hydrogenated in 25 mL of ethanol using 0.16 g of
5% Pd/C at room temperature overnight at 413.69 kPa (60 psi). The solution
was filtered over celite and concentrated in vacuo to 230 mg (43%) of the
title
compound as a colorless oil.
Mass Spectrum (ES MS): M +1 = 162.
Preparation 6
+,-) 2-Phenyl-cyclopentanone oxime
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/ \
r
N
OH
Scheme IlIA, step A: 2-Phenyl-cyclopentanone (prepared according to R.
Sudha et. al. J. Org. Chem., 61, 1877-1879, 1996) (1.0 g, 6.2 mmol) was
dissolved in 20 mL of absolute ethanol. To this solution was added sodium
hydroxide (0.5 g, 12.5 mmol) dissolved in 10 mL water followed by
hydroxylamine
hydrochloride (0.65 g, 9.36 mmol) and stirred overnight at room temperature.
The reaction was diluted with water and the precipitate collected by
filtration.
The white solid was vacuum oven-dried at 35°C for 30 minutes to give
0.75 g
(69%) of the title compound.
s o Analysis calculated for C11 H13N0: %C, 75.40; %H, 7.48; %N, 7.99. Found:
%C, 75.32; %H, 7.22; %N, 7.92.
Mass Spectrum (ES MS): M +1 = 176.
Preparation 7
Alternative synthesis of (+,-) Cis -2-Phenyl-c cl~nt lamina
/ \
HaN
Scheme IIIA, step B: (+,-) 2-Phenyl-cyclopentanone oxime from
preparation 6 above was dissolved in 35 mL of ethanol and hydrogenated using
2 0 90 mg of 5% Pd/C at 40°C overnight at 413.69 kPa (60 psi). The
solution was
filtered and concentrated in vacuo to give 0.43 g (62%) of a colorless oil.
Some
dimeric material resulted by this procedure according to the mass spec. The
cisarans ratio was estimated to be 4:1. The amine was used directly without
further purification. Mass Spectrum (ES MS): M +1 = 306, 162.
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Preparation 8
Alternative synthesis of (+.-) Cis -2-Phen r~ I-cyclopentylamine.
/ \
r
HzN
s Scheme IIIB, step A: A one liter three necked round bottom flask
equipped with a mechanical stirrer, addition funnel, thermometer is charged
with
1 M THF solution of phenylmagnesium bromide (300 mL, 300.0 mmol) and
copper iodide (3.8 g, 20.0 mmol). To this reaction mixture was then added
cyclopentene oxide (25.23 g, 300.0 mmol) dissolved in THF (50.0 mL) dropwise
so over a period of 60 minutes (reaction was quite exothermic, reaching THF
reflux
by the end of addition). The reaction mixture was then stirred to room
temperature and quenched .with 25% solution of ammonium chloride (200.0 mL).
Added ether (80.0 mL) and separated upper organic layer. Washed organic
layer with 25% ammonium chloride solution, dried with anhydrous magnesium
15 sulfate, filtered and concentrated filtrate to provide (+,-) trans-2-phenyl-
cyclopentanol as a brown oil ( mass = 47.7 g);
~H nmr (CDCI3) 8 1.6-1.8 (m, 4H), 2.0-2.2 (m, 2H), 2.8-2.88 (m, 1 H), 4.13-
4.16
(m, 1 H), 7.2-7.4 (aromatic, 5H); '3C (CDCI3) 8 22.46, 32.57, 34.64, 55.13,
81.11,
127.10, 128.11, 129.25, 144.05).
Scheme IIIB, step B: A 500 mL three necked round bottom flask equipped
with a mechanical stirrer, thermometer, reflux condenser, addition funnel and
a
nitrogen blanket is charged with triphenylphosphine (16.19 g, 61.73 mmol) and
THF (200 mL). To the solution at 0°C was added dropwise, a
solution of
diisopropyl azodicarboxylate (12.15 mL, 61.73 mmol) dissolved in THF (30 mL)
over a period of 10 minutes. A massive precipitate formed immediately after
addition. To the slurry was then added solid phthalimide (9.08 g, 61.73 mmol),
followed by a solution of 5-phenylcyclopentane-1-of (10.0 g, 61.73 mmol)
dissolved in THF (30 mL) over a period of 20 minutes maintaining temperature
at
3 0 0°C to 5°C (reaction mixture went into solufiion by the end
of alcoholic substrate
addition). Reaction was then stirred at 0°C for 4.0 hours and brought
to room
temperature overnight for convenience. Quenched reaction with water (200 mL)
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and extracted organics with chloroform (200 mL). Washed the organic with water
(100 mL) and dried with anhydrous magnesium sulfate. Subsequent filtration
and concentration under reduced pressure afforded an oil which solidified on
equilibrating to room temperature. To the precipitate was then added hexane
(250.0 mL) with vigorous stirring. Filtered off triphenylphosphine oxide
precipitate
and concentrated filtrate to an oil. Silica gel plug filtration of the oil
with 1:1 ethyl
acetate:hexanes and subsequent concentration of product fractions afforded an
off white precipitate of (+,-) Cis-2-(2-phenyl-cyclopentyl)-isoindole-1,3-
dione
(mass = 12.58, 69.6%);
~ H nmr (CDCI3) b 1.6-1.8 (m, 1 H), 2.0-2.1 (m, 1 H), 2.2-2.35 (m, 2H), 2.4-
2.68 (m,
2H), 3.39-3.5 (m, 1 H), 5.0-5.1 (m, 1 H), 6.9-7.15 (aromatic, 5H), 7.52-7.64
(aromatic, 4H); ~3C (CDCI3) 8 25.4, 28.89, 30.56, 50.34, 54.60, 122.89,
126.44,
128.01, 128.41, 131.67, 139.68, 168.86).
z5 Scheme IIIB, step C: A 1000 mL three necked flask equipped with a
mechanical stirrer, thermometer, addition funnel and a reflux condenser is
charged with (+,-) cis-2-(2-phenyl-cyclopentyl)-isoindole-1,3-dione (27.34 g,
93.91 mmol) and toluene (400.0 mL). To this solution was added anhydrous
hydrazine (29.48 mL, 939.09 mmol) dropwise over a period of 15 minutes.
2 o Stirred reaction at room temperature for 60 minutes then heated it at
90°C-95°C
for 6.0 hours. Cooled. reaction to room temperature, filtered precipitates,
washed
cake with toluene (50.0 mL) and concentrated filtrate to provide the title
compound as an oil (mass = 15.13 g);
~ H nmr (CDCI3) 8 0.6-0.8 (b, 1 H), 1.5-1.6 (m, 1 H), 1.63-1.69 (m, 1 H), 1.9-
2.0 (m,
25 2H, 2.0-2.1 (m, 2H), 3.05-3.1 (m, 1 H), 3.4-3.7 (m, 1 H), 7.19-7.35
(aromatic, 5H);
~3C (CDCI3) 8 23.05, 27.96, 34.98, 51.75, 56.68, 126.86, 128.96, 129.20,
142.00).
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Example 1
Preparation of1(meth lethyl sulfon 11~~2-f4-
~~j(meth I~yl)sulfon llamino)methyl phenoxylpropyl}amine.
H O
N-S
II
O O 1 ~ O
II
S-N
II H
O
Preparation of 4-(cyanoethoxy)benzenecarbonitrile.
O ~ ~ CN
NC~
In a 250 mL round-bottomed flask fitted with a stir bar, at room
temperature, and under a nitrogen atmosphere, a solution of 4-cyanophenol (2
g,
Zo 16.8 mmol) in acetone (75 mL) is treated with potassium carbonate (2.8 g,
20.2
mmol) and 2-bromopropionitrile (2.48 g, 18.5 mmol). The reaction mixture is
heated at reflux (60°C) overnight. The mixture is then allowed to cool
to room
temperature, acetone is removed in vacuum, 1 N HCI (50 mL) is added and the
organic is extracted with EtOAc (3x50 mL). The combined organic layer is
washed with H20 (2X50 mL), brine (50 mL), dried over anhydrous Na2SOq.,
filtered, and concentrated under reduced vacuum to yield crude product which
is
purified by recrystallization from CH2CI2 / Et3N to yield the intermediate
title
compound (1.1 g, 38%). Electrospray MS 190 (M*+18).
Preparation of 2-f4-(aminomethLrl pheno~laropylamine dihydrochloride.
H2 2HCI
O
H2N
Scheme l, step B: )nto a 100 mL single neck flask a solution of 4-
(cyanoethoxy)benzenecarbonitrile (1 g, 5.8 mmol) in THF (20 mL) is treated
with
boron dimethylsulfide 10 M in THF (1.3 mL, 12.8 mmol) and the mixture is
heated to reflux overnight. The reaction mixture is cooled down to room
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temperature and quenched with saturated solution of HCI in methanol (10 mL).
Diethyl ether (20 mL) is added to the mixture and it is cooled down to 0
°C. The
product is precipitated out of the solution as dihydrochloride salt. The salt
is
filtered and dried in vacuum to provide the intermediate title compound (1.35
g,
, 88%) as a white solid crystal. Electron spray M.S. 181 (M*+1 ).
Preparation of final title compound.
Scheme I, step C: Into a 25 mL single neck flask is placed 2-[4-
(aminomethyl)phenoxy]propylamine dihydrochloride (0.5 g, 1.97 mmol) in
Zo methylene chloride (10 mL) and the solution is cooled down to 0 °C.
DBU, (1.75
mL, 11.8 mmol) is added to the mixture and after 30 minutes isopropylsulfonyl
chloride (0.62 mL, 4.33 mmol) is added to the reaction mixture. The mixture is
warmed up to RT while stirring for 12 hour. The reaction mixture is quenched
with a 1 N HCI until pH is below 4-5. The product is extracted with CH2CI2
(3x30
mL) and the combined organic layers are washed with H20 (30 mL), dried over
anhydrous Na2S04, filtered, and concentrated under reduced vacuum. The
resulting semi-solid is purified via flash chromatography (silica gel,
gradient) and
eluting with a solvent of Hexanes/EtOAc 40-45% to provide the final title
compound (307 mg, 40%) as a white crystalline solid. Electron spray M.S. 391.1
2 0 (M*-1 ).
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Example 2
Preparation of f(meth~h~ sulfon~~11~2-f4- 2-
]',[ methylethLrl~sulfonyl]amino ethLrl~ahenoxylpropyl amine.
O
I I
N-S
H II
O ~ ~ ~ O
I I
S-N
II H
O
Preparation of 214 ~cyanomethyl)phenoxylpropanenitrile.
CN
O
NC~
4-Hydroxybenzylcyanide (2 g, 15 mmol), Potassium carbonate (2.5 g, 18
mmol), and 2-bromopropionitrile ('1.43 mL, 16.5 mmol), in acetone (65 mL) are
Zo combined in a manner analogous to the procedure described in example 1 to
provide the intermediate title compound (2.1 g, 75%) as a white crystalline
solid.
Electron spray M.S. 203.9 (M*+18).
Preparation of 2-f4-(2-aminoethyl)phenoxy,]'propylamine dihydrochloride.
NH2 2HCI
O
H2N
Scheme I, step B: 2-[4-(Cyanomethyl)phenoxy]propanenitrile (2 g, 10.7
mmol) in THF (50 mL) is treated with boron dimethylsulfide 2 M in THF (11.8
mL,
23.6 mmol) in a manner analogous to the procedure described in example 1 to
provide the intermediate title compound (2.7 g, 95%) as a white crystalline
solid.
2 o Electron spray M.S. 195 (M+1 ).
Preparation of final title compound.
Scheme l, step C: 2-[4-(2-Aminoethyl)phenoxy]propylamine
dihydrochloride (1 g, 3.74 mmol), DBU (3.4 mL, 22.4 mmol), and
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isopropylsulfonyl chloride (0.92 mL, 8.2 mmol) in methylene chloride (20 mL)
at
OoC are combined in a manner analogous to the procedure described in example
1 to provide the final title compound (280 mg, 18%) as a white crystalline
solid.
Electron spray M.S. 407 (M*+H).
Analysis for C~7H3pN2O5S2:
Theory: C, 50.22 H, 7.44 N, 6.89
Found: C, 50.26 H, 7.36 N, 6.85
Example 3
so Preparation ofl(methylethyl)sulfonyll~2-[4-(3-
ff(methylethyl)sulfonyllamino)~ropyl phenoxylprop r~l amine.
O
I I
O
H O
-S
I I
O
O
N
H
s5 Preparation of 2-f4-(2-cyanoethyl phenoxylpropanenitrile.
CN
O
NC~
3-(4-Hydroxyphenyl)propionitrile (2 g, 13.6 mmol), potassium carbonate
(2.25 g, 16.31 mmol), and 2-bromopropionitrile (1.3 mL, 14.95 mmol), in
acetone
(60 mL) are combined in a manner analogous to the procedure described in
2 o example 1 to provide the intermediate title compound (1.8 g, 67%) as a
white
crystalline solid. Electron spray M.S. 218 (M*+18).
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Preparation of 2-f4-(3-aminoprop,Lrllphenoxy].propylamine dihydrochloride.
H2 2HCI
Scheme I, step B: 2-[4-(2-Cyanoethyl)phenoxy]propanenitrile (1 g, 5
mmol) in THF (20 mL) is treated with boron dimethylsulfide 2 M in THF (5.5 mL,
11 mmol) in a manner analogous to the procedure described in example 1 to
provide the intermediate title compound (1.3 g, 93%) as a white crystalline
solid.
Electron spray M.S. 209 (M+1 ).
Preparation of the final compound.
Z o Scheme I, step C: 2-[4-(3-Aminopropyl)phenoxy]propylamine
dihydrochloride (850 mg, 3 mmol), DBU (2.7 mL, 18 mmol), and isopropylsulfonyl
chloride (0.74 mL, 6.6 mmol), in methylene chloride (15 mL) at 0 oC are
combined in a manner analogous to the procedure described in example 1 to
provide the final title compound (515 mg, 41 %) as a white crystalline solid.
Electron spray M,S. 421.1 (M*+H).
Analysis for CqgH32N2O5S2:
Theory: C, 51.40 H, 7.67 N, 6.66
Found: C, 51.43 H, 7.62 N, 6.63
2 o Example 4
Preiparation of f (methylethyl)sulfonyll~~[~2-
f[~meth 1y ethyl)sulfonyllamino)ethoxy)phenyllmethyl amine.
s-
I I
O
H ICI
-S
I I
0
N
H
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Pre~~aration of 4-(cyanomethoxy)benzenecarbonitrile.
O ~ ~ CN
NC-~
4-Cyanophenol (2 g, 16.8 mmol), potassium carbonate (2.8 g, 20 mmol),
and bromoacetonitrile (1.3 mL, 18.45 mmol) in acetone (70 mL) are combined in
a manner analogous to the procedure described in example 1 to provide the
intermediate title compound (2.6 g, 98%) as a white crystalline solid.
Electron
spray M.S. 175.9 (M*+18).
Preparation of 2-[4~aminomethyl)phenoxylethylamine dihydrochloride.
H2 2HCI
H2N
Scheme I, step B': 4-(Cyanomethoxy)benzenecarbonitrile (1 g, 6.3 mmol)
in THF (25 mL) is treated with boron dimethylsuifide 2 M in THF (7 mL, 13.9
mmol) in a manner analogous to the procedure described in example 1 to
provide the intermediate title compound (1.4 g, 93%) as a white crystalline
solid.
Electron spray M.S. 257 (M+18).
Preparation of the final compound.
Scheme I, step C': 2-[4-(Aminomethyl)phenoxy]ethylamine
dihydrochloride (500 mg, 2.1 mmol), DBU (1.9 mL, 12.5 mmol), and
2 o isopropylsulfonyl chloride (0.52 mL, 4.6 mmol), in methylene chloride (10
mL) at
0 oC are combined in a manner analogous to the procedure described in
example 1 to provide the final title compound (126 mg, 16%) as a white
crystalline solid. Electron spray M.S. 396 (M*+18).
Analysis for C~5H~gN~O5S2:
Theory: C, 47.60 H, 6.92 N, 7.40
Found: C, 47.43 H, 6.77 N, 7.27
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Example 5
Preparation of f methylethlrl sulfonyll 2-f4-(2-
~f(meth I~~ sulfon~]amino eth~l)phenox l~yl amine.
O
II
N-S
O H O
O
S-N
II H
O
Preparation of 2-[~cyanomethyl~phenoxylethanenitrile.
CN
O
NC--~
4-Hydroxybenzylcyanide (2 g, 15 mmol), potassium carbonate (2.5 g, 18
mmol), and bromoacetonitrile (1.15 mL, 16.5 mmol), in acetone (65 mL) are
1 o combined in a manner analogous to the procedure described in example 1 to
provide the intermediate title compound (2.55 g, 98%) as a white crystalline
solid.
Electron spray M.S. 172.1 (M*),
Preparation of 2-f4-(2-aminoethoxY~phenyllethylamine dihydrochloride.
NH2 2HCI
,O
H2 ~N
Scheme t, step B': 2-[4-(Cyanomethyl)phenoxy]ethanenitrile (1 g, 5.8
mmol) in THF (25 mL) is treated with boron dimethylsulfide 2 M in THF (6.4 mL,
12.8 mmol) in a manner analogous to the procedure described in example 1 to
provide the intermediate title compound (1.25 g, 85%) as a white crystalline
solid.
2 o Electron spray M.S. 181 (M+1 ).
Preparation of the final compound.
Scheme I, step C': 2-[4-(2-Aminoethoxy)phenyl]ethylamine dihydrochloride
(300 mg, 1.18 mmol), DBU (1.05 mL, 7.08 mmol), and isopropylsulfonyl chloride
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(0.29 mL, 2.6 mmol), in methylene chloride (6 mL) at OoC are combined in a
manner analogous to the procedure described in example 1 to provide the final
title compound (158 mg, 34%) as a white crystalline solid. Electron spray M.S.
393 (M*+H).
Analysis for C~6H2gN2O5S2:
Theory: C, 48.96 H, 7.19 N, 7.14
Found: C, 49.25 H, 7.27 N, 7.18
Example 6
s o Preparation of j(methylethyl sulfonyll~2 j4-(3-
~f(methylethyl sulfonyamino~pro~~yl~phenox 1Y ethLrl~amine.
O
I I
S-
I I
O
PrJoaration of 3-[~c,,ranomethoxy)phen~]propanenitrile.
CN
O
NC--~
3-(4-Hydroxyphenyl)propionitrile (2 g, 13.6 mmol), potassium carbonate
(2.25 g, 16.31 mmol), and bromoacetonitrile (1.04 mL, 14.95 mmol), in acetone
(60 mL) are combined in a manner analogous to the procedure described in
example 1 to provide the intermediate title compound (1.8 g, 72%) as a white
2 o crystalline solid. Electron spray M.S.186.1 (M*+1 ).
Preparation of 3-[4-(2-aminoethoxy)phenyllproaylamine dihydrochloride.
2HCI
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Scheme I, step B': 3-[4-(Cyanomethoxy)phenyl]propanenitrile (1 g, 5.37
mmol) in THF (25 mL) is treated with boron dimethylsulfide 2 M in THF (6 mL,
11.8 mmol) in a manner analogous to the procedure described in example 1 to
provide the intermediate title compound (1.33 g, 93%) as a white crystalline
solid.
s Electron spray M.S. 195 (M+1 ).
Preparation of the final compound.
Scheme I, step C': 3-[4-(2-Aminoethoxy)phenyl]propylamine
dihydrochloride (300 mg, 1.12 mmol), DBU (1 mL, 6.72 mmol), and
o isopropylsulfonyl chloride (0.28 mL, 2.47 mmol), in methylene chloride (6
mL) at
0 oC are combined in a manner analogous to the procedure described in
example 1 to provide the final title compound (155 mg, 34%) as a white
crystalline solid. Electron spray M.S. 407.1 (M*+1 ).
Analysis fOr Cq7H30N2~5s2~
15 Theory: C, 50.22 H, 7.44 N, 6.89
Found: C, 49.94 H,7.30 N, 6.84
Example 7
Preparation of~(methyleth rLl sulfonyllf2-f4-(1-methyl-2-
2 0 ~ methylethyl)sulfonyllamino~ethyl~phenoxylethLrl)amine.
O
I I
N-S
H II
O ~ ~ O
O
S-N
II H
O
Preparation of 2-[~cyanomethyl,~phenoxy]ethanenitrile.
CN
O
NC-~
25 4-Hydroxybenzylcyanide (2 g, 15 mmol), potassium carbonate (2.5 g, 18
mmol), and 2-bromopropionitrile (1.15 mL, 16.5 mmol), in acetone (65 mL) are
combined in a manner analogous to the procedure described in example 1 to
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provide the intermediate title compound (2.55 g, 98%) as a white crystalline
solid.
Electron spray M.S. 172.1 (M*).
Preparation of 2-f4- cyanomethoxy)phen rLJlpropanenitrile.
CN
O
NC-/
Scheme I, step A: In a 50 mL round-bottomed fiasle fitted with a stir bar, at
room temperature, and under a nitrogen atmosphere, a solution of 2-j4-
(cyanomethy!)phenoxy]ethanenitrile (1.4 g, 8.13 mmol) in THF (25 mL) is cooled
down to -78 °C and is then treated with 1 M solution of
hexamethylsilylazide (8.9
so mL, 8.9 mmol) in THF. The mixture is stirred at -78 °C for 30
minutes prior to the
addition of iodomethane (0.51 mL, 8.13 mmol). The reaction mixture is allowed
to warm up to RT overnight while stirring. Water (50 mL) is then added to the
mixture and the organic is extracted with EtOAc (3x50 mL). The combined
organic layers are washed with H2O (2X50 mL), brine (50 mL), dried over
15 anhydrous Na2S04, filtered, and concentrated under reduced vacuum to yield
crude product which is purified by flash chromatography (silica gel,
isocratic)
and eluting with a solvent of Hexanes/EtOAc 30% to provide the final title
compound (690 mg, 46%) as a white crystalline solid. Electron pray M.S. 204.1
(M*+18).
Preparation of 2-C4-(2-aminoethoxy)phenyllaropylamine dihydrochloride.
NHZ 2HCl
H2N
Scheme I, step B: 2-[4-(Cyanomethoxy)phenyl]propanenitrile (690 mg, 3.7
mmol) in THF (15 mL) is treated with boron dimethylsulfide 10 M in THF (0.815
mL, 8.15 mmol) in a manner analogous to the procedure described in example 1
to provide the intermediate title compound (800 mg, 81 %) as a white
crystalline
solid. Electron spray M.S. 195 (M+1 ).
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Preparation of the final compound.
Scheme I, step C: 2-[4-(2-Aminoethoxy)phenyl]propylamine
dihydrochloride (500 mg, 1.87 mmol), DBU (1.67 mL, 11.2 mmol), and
isopropylsulfonyl chloride (0.4 mL, 4.11 mmol), in methylene chloride (10 mL)
at
0 oC are combined in a manner analogous to the procedure described in
example 1 to provide the final title compound (415 mg, 54%) as a white
crystalline solid. Electron spray M.S. 407.2 (M*+H).
Analysis for C~7H3pN2O5S2:
z o Theory: C, 50.22 H, 7.44 N, 6.89
Found: C, 50.42 H, 7.23 N, 6.99
Example 8
Preparation of f(methylethtrl sulfonyll ~2-f4- 2-
~[(methylethyl)sulfonyl]amino~ethylthio~phen rLllethyl~amine.
O
n
N-S
H n
S ~ ~ O
O
S-N
II H
O
Preparation of 2 L4-(ethoxythioxomethylthio~ahenyl]ethanenitrile.
CN
S ~
S
2 o In a 100 mL round-bottomed flask fitted with a stir bar, at room
temperature, and under a nitrogen atmosphere, a solution of 4-
aminobenzylcyanide (5 g, 37.8 mmol) in HCI:H2O (10:50 mL) is gradually treated
with an aqueous solution of sodium nitrite (2.9 g, 41.6 mmol). The reaction
mixture is stirred at 0 °C for 2 hours. This mixture is then added to a
solution of
potassium ethylxanthate (7.3 g, 46.4 mmol) in H20. The reaction mixture is
then
stirred overnight. Water is added to the mixture and the organic is extracted
with
EtOAc (3x50 mL). The combined organic layer is washed with H20 (2X50 mL),
brine (50 mL), dried over anhydrous Na2S04, and filtered. The filtrate is
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concentrated under reduced vacuum to yield the crude product which is purified
by flash chromatography (Silica gel, isocratic) and eluting with a solvent of
Hexanes/EtOAc 15% to provide the intermediate title compound (2.6 g, 29%).
s Preparation of 2~4-sulfanlrlphenyl ethanenitrile.
CN
HS
Into a 100 mL single neck flask a solution of 2-[4-
so (ethoxythioxomethylthio)phenyl]ethanenitrile (2.6 g, 11 mmol) in
THF:MeOH:H20
(25:15:10 mL) is treated with potassium hydroxide (1.85 g, 33 mmol) and the
mixture is heated to 60 °C for 4 hours. The reaction mixture is then
quenched
with a 6N H2S04. The product is extracted with EtOAc (3x20 mL) and the
combined organic layer is washed with H20 (30 mL), dried over anhydrous
15 Na2S04, filtered, and concentrated under reduced vacuum. The resulting
crude
product is purified via flash chromatography (Silica gel, gradient) and
eluting with
a solvent of Hexanes/EtOAc 15-25% to provide the intermediate title compound
(576 mg, 36%) as a white solid crystal.
2 o Preparation of 2-f4-(cyanomethylthio)phenyl]ethanenitrile.
CN
S
NC-~
2-(4-Sulfanylphenyl)ethanenitrile (550 mg, 3.7 mmol), potassium
carbonate (622 mg, 4.5 mmol), and bromoacetonitrile (280 ~L, 4 mmol), in
25 acetone (15 mL) are combined in a manner analogous to the procedure
described in example 1 to provide the intermediate title compound (371 mg,
54%) as a white crystalline solid. Electron spray M.S. 187.0 (M*-1 ).
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Preparation of 2-f4-(2-aminoeth 1y thio)phenylleth rLlamine dihydrochloride.
NH2 2HCI
H2N
Scheme I, step B': 2-[4-(Cyanomethylthio)phenyl]ethanenitrile (360 mg,
s 1.9 mmol) in THF (10 mL) is treated with boron dimethylsulfide 2 M in THF
(2.1
mL, 4.2 mmol) in a manner analogous to the procedure described in example 1
to provide the intermediate title compound (500 mg, 98°l°) as a
white crystalline
solid. Electron spray M.S. 197.1 (M+1 ).
to Preparation of the final compound.
Scheme I, step C': 2-[4-(2-Aminoethylthio)phenyl]ethylamine
dihydrochloride (500 mg, 1.85 mmol), DBU (1.7 mL, 11.1 mmol), and
isopropylsulfonyl chloride (0.46 mL, 4.1 mmol) in methylene chloride (10 mL)
at 0
oC are combined in a manner analogous to the procedure described in example
15 1 to provide the final title compound (392 mg, 52%) as a white crystalline
solid.
Electron spray M.S. 409.2 (M*+H).
Analysis for C~gH2gN2O4S3~
Theory: C, 47.03 H, 6.91 N, 6.86
Found: C, 47.29 H, 6.97 N, 6.88
Example 9
Preparation of f(methylethLrl)sulfonyl~(~4-fmethyl(2-
~[ meth~rlethyl)sulfonyllamino ethyl aminol~phenyl~ethyl)amine.
O
N-S
H O
2 s Pre~~aration of 2-f4 j~cyanomethyl)aminol~henyl~ethanenitrile.
H CN
NC~
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In a 100 mL round-bottomed flask fitted with a stir bar, at room
temperature, and under a nitrogen atmosphere, a solution of 4-
aminobenzylcyanide (2 g, 15.1 mmol) in methanol (30 mL) is treated with a
solution of sodium cyanide (0.74 g, 15.1 mmol) in water (20 mL). The reaction
mixture is cooled to 0 °C. The mixture is treated first with 5N HCI (3
mL) and
then with formaldehyde (1.25 mL, 15.1 mmol), The reaction mixture is stirred
at
0°C for 3 hours and at room temperature overnight. The reaction is
poured into
H20 and the organic is extracted with CH2CL2 (3x25 mL). The combined organic
layer is washed with H20 (2X50 mL), brine (50 mL), dried over anhydrous
Na2S04, filtered, and concentrated under reduced vacuum to provide the
intermediate title compound (2.5 g, 97%). Electrospray MS 189.0 (M*+18).
Preparation of 2-f4-f(cyanomethYl)methylaminolphenyl)ethanenitrile.
CN
NC-'
In a 25 mL round-bottomed flask fitted with a stir bar, at room
temperature, and under a nitrogen atmosphere, a solution of 2-{4-
2 0 [(cyanomethyl)amino]phenyl}ethanenitrile (1 g, 5.8 mmol) in formaldehyde
(4 mL)
and formic acid (4 mL) is prepared. The reaction mixture is refluxed for 2
hours.
The mixture was cooled to room temperature. The mixture is basified and
poured into H20 and the organic was extracted with EtOAc (3x20 mL). The
combined organic layer is washed with H20 (2X20 mL), brine (20 mL), dried over
anhydrous Na2S04, filtered, and concentrated under reduced vacuum, The
resulting semi-solid is purified via flash chromatography (Silica gel,
gradient) and
eluting with a solvent of Hexanes/EtOAc 25-35% to provide the intermediate
title
compound (610 mg, 57%). Electrospray MS 186.0(M*+1 ).
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Preparation of (2-aminoethyl~j4-(2-aminoethyl)phenyllmeth lamine.
NH2 2HCI
H2N
Scheme i, step B': 2-{4-[(Cyanomethyl)methylamino]phenyl}ethanenitrile
(600 mg, 3.24 mmol) in THF (15 mL) is treated with boron dimethylsulfide 2 M
in
THF (3.6 mL, 7.13 mmol) in a manner analogous to the procedure described in
example 1 to provide the intermediate title compound as a white crystalline
solid.
Preparation of the final compound.
to Scheme I, step C': (2-Aminoethyl)[4-(2-aminoethyl)phenyl]methylamine (1
g, 8.3 mmol), DBU (3.4 mL, 22.5 mmol), and isopropylsulfonyl chloride (0.932
mL, 4.1 mmol), in methylene chloride (15 mL) at 0 oC are combined in a manner
analogous to the procedure described in example 1 to provide the final title
compound (72 mg, 5%) as a white crystalline solid. Electron spray M.S. 409.2
(M*+H).
Analysis for C~7H31N3~4S2-
Theory: C, 50.35 H, 7.70 N, 10.36
Found: C, 50.42 H, 7.59 N, 10.18
Examlale 10
Preparation of fCmethylethyl)sulfonyl~(2~4-[(2-
~f(methylethyl)sulfonyllamino)eth r~l benzylaminolphenyl~ethyl)amine.
O
I I
N-S
H O
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Preparation of 2-(4-jbenzylaminolphenyl)ethanenitrile.
H CN
V
In a 250 mL round-bottomed flask fitted with a stir bar, at room
. temperature, and under a nitrogen atmosphere, a solution of 4-
aminobenzylcyanide (2.3 mL, 22.7 mmol) is treated with benzaldehyde (0.74 g,
22.7 mmol) and a few drops of acetic acid. The reaction mixture is stirred at
room temperature for 5 hours. The mixture is treated with sodium borohydride
(1.6 g, 44 mmol) and the reaction mixture is stirred at room temperature
so overnight. The reaction is poured info H20 and the organic is extracted
with
CH2CL2 (3x50 mL). The combined organic extracts are washed with H20 (2X50
mL), brine (50 mL), dried over anhydrous Na2S04, filtered, and concentrated
under reduced vacuum to yield crude product (5 g, 100%). Electrospray MS 223
(M*+1 ).
Preparation of 2-f4-f(cyanomethyl benzylaminolahenyl)efihanenitrile.
CN
NC
2-f4-[Benzylamino]phenyl)ethanenitrile (2 g, 9 mmol), formaldehyde (0.75
mL, 9 mmol), sodium cyanide (440 mg, 9 mmol), and 5N HCI (1.8 mL) in
z o , MeOH:H2O (15:15 mL) at 0 oC are combined in a manner analogous to the
procedure described in example 9 to provide the intermediate title
compound(2.25 g, 96%). Electron spray M.S. 262.1 (M*~-H).
Preparation of (2-aminoethyl)~4-(2-aminoeth rLl phen~rllbenzylamine
dihydrochloride.
NHS 2HCi
N
H2N
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Scheme I, step B': 2-{4-[(Cyanomethyl)benzylamino]phenyl}ethanenitrile
(1 g, 3.8 mmol) in THF (20 mL) is treated with boron dimethylsulfide 2 M in
THF
(4.2 mL, 8.4 mmol) in a manner analogous to the procedure described in
example 1 to provide the intermediate title compound (1.3g, 100%) as a white
crystalline solid. Electron spray M.S. 270.1 (M*+H).
Preparation of the final compound.
Scheme I, step C': (2-Aminoethyl)[4-(2-aminoethyl)phenyl]benzylamine
dihydrochloride (1.3 g, 3.8 mmol), DBU (3.4 mL, 22.8 mmol), and
Zo isopropylsulfonyl chloride (0.95 mL, 8.4 mmol), in methylene chloride (20
mL) at
0 oC are combined in a manner analogous to the procedure described in
example 1 to provide the final title compound (588 mg, 33%) as a white
crystalline solid. Electron spray M.S. 482.3 (M*+H).
Analysis fOr C23H35N3~4S2~
Theory: C, 57.35 H, 7.32 N, 8.72
Found: C, 57.35 H, 7.40 N, 8.71
Example 11
Preparation of f(methylethLrl sulfonyll(2-(~2-
2 0 ~~methylethyl sulfonyl]'amino~ethyl)amino]phenyl)eth rLI)amine.
O
I I
H H O
O
S-N
II H
O
Scheme I, step C': Into a 25 mL single neck flask is placed
[(methylethyl)sulfonyl](2-(4-[(2-
2s {[(methylethyl)sulfonyl]amino]ethyl)benzylamino]phenyl}ethyl)amine (0.465
g,
0.97 mmol) in THF (5 mL) and the solution is treated with aqueous solution of
5M
ammonium formate (2 mL, 4.8 mmol) and catalytic amount of the palladium on
carbon. The mixture is stirred at room temperature under atmospheric hydrogen
for 12 hours. The reaction mixture is filtered over a layer of Celite~, water
is
3 o added to the filtrate and the organic is extracted with EtOAc (3x20 mL).
The
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combined organic extracts are washed with H20 (30 mL), dried over anhydrous
Na2S04, filtered, and concentrated under reduced vacuum. The resulting semi-
solid is purified via flash chromatography (Silica gel, gradient) and eluting
with a
solvent of Hexanes/EtOAc 35-45% to provide the final title compound (257 mg,
68%) as a white crystalline solid. Electron spray M.S. 392.1 (M*+1 ).
Analysis for C~gH2gN3O4S2:
Theory: C, 49.08 H, 7.47 N, 10.73
Found: C, 48.83 H, 7.40 N, 10.72
Example 12
Preparation of cis-f(methylethyl)sulfonyll 2-f![4-(2-
f f(methylethyl)sulfonyllaminolcyclopentyl)phenLrl]amino)e hyl)amine.
H
O
S-N HN
H O=S=O
Preparation of trans-2-phenylcyclopentan-1-of.
\ /
HO
Scheme IIIB, step A: In a 3-neck round bottomed flask fitted with a
condenser, a thermometer, a mechanical stirrer, a solution of 1,2-epoxy
cyclopentane (25.0 g, 297.2 mmol) in tetrahydrofuran (60 mL) is added dropwise
2 o to a mixture of phenylmagnesium bromide (99.1 mL) and copper (II) iodide
(4.0
g, 20.8 mmol). After an hour of addition, the temperature inside the vessel
exceeds the reflux temperature of 60° C, and the reaction mixture
ceases
foaming. The reaction mixture is cooled down to room temperature overnight
and is then treated dropwise with a 25% solution of ammonium chloride (45 mL)
2 s until 'blue' copper chloride precipitates out. The organic layer is washed
with
H2O, filtered it through magnesium sulfate (MgS04), and concentrated under
vacuum to yield 26.61 g of the crude product. This crude material is further
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purified by Prep HPLC 2000 (Hexanes:EtOAc, 3:1, isocratic) to provide the
intermediate title compound (22.4 g, 46.5 %) as an orange oil.
Preparation of cis-2-(2-phenylc~pentyl)isoindoline-1 3-dione.
Scheme IIIB, step B: in a 2-Liter 3-neck round bottomed flask fitted with a
condenser, a thermometer, and a mechanical stirrer a solution of diisopropyl
azodicarboxylate (95 mL, 481.4 mmol) in THF (100 mL) is added to a solution of
triphenylphosphine (126.3 g, 481.4 mmol) in THF (1400 mL). This mixture is
z o treated with a phthalimide (70.8 g, 481.4 mmol) and a solution of trans-2-
phenylcyclopentan-1-of (78.1 g, 481.4 mmol) in THF (100 mL). The reaction
temperature is kept between 0°C and 5°C during the addition and
the mixture is
warmed up to room temperature gradually. The reaction mixture is then
quenched with H20 (460 mL), and extracted with CH~CI2 (3 x 300 mL). The
s5 combined organic extracts are washed with H20, filtered through magnesium
sulfate, and concentrated under vacuum, yielding 330 g of brown oil. This
crude
material is washed with hexanes to yield 60 g of yellow oil. This material is
further purified by flash chromatography (CH~CI2:Hexanes, 3:1 ) to provide the
intermediate title compound (30.8 g, 22 %) as a white solid.
Preparation of cis-2-phenylcyclopentylamine.
H2N
Scheme IIIB, step C: In a 2-Liter 3-neck round bottomed flask fitted with a
mechanical stirrer, condenser, thermometer, a solution of cis-2-(2-
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phenylcyclopentyl)isoindoline-1,3-dione (30.8 g, 105.72 mmol) in toluene (423
mL, Aldrich) is treated with hydrazine (33.2 mL, 105.72 mmol). The mixture is
heated at reflux (90°C) for 6 hours and then cooled to room
temperature. The
resulting precipitate is filtered and rinsed with an additional 200 mL
toluene. The
combined filtrate is concentrated under vacuum yielding 18.6 g of yellow oil.
The
crude material is purified by flash chromatography (CH2CI2: methanol, 9:1 ) to
provide the intermediate title compound (11.52 g, 68 %) as a yellow oil.
Preparation of cis-f(methylethyl)sulfonyll(2-phenylcyclopent r1 amine.
\ /
HN
O=S=O
Scheme IV, step A: In a 2-Liter, 3-neck, round bottomed flask fitted with a
thermometer, a solution of cis-2-phenylcyclopentylamine (11.52 g, 71.42 mmol,)
in CH2CI2 (476 mL) is treated with DBU (10.7 mL, 71.42 mmol) via additional
funnel. The reaction is cooled down to 0 °C and isopropylsulfonyl
chloride (8.0
mL, 71.42 mmol) is added. The mixture is gradually warmed to room
temperature while stirring over night. The reaction mixture is then quenched
with
H20 (476 mL), and the mixture is extracted with CH2CI2 (2 x 300 mL). The
combined organic extracts are washed with brine (500 mL), filtered through
magnesium sulfate, and concentrated under vacuum to yield 11.0 g of a yellow
2 0 oil. This crude material is further purified by flash chromatography
(Hexanes:
EtOAc, 3:1 ) to provide the intermediate title compound (9.30 g, 49 %) as
white
solid.
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Preparation of cis-~(methylethLrl sulfonyllf2-(4-nitrophen~cyclopentylLamine.
02N
HN
i
O=S=O
Scheme IV, step B: In a 2-Liter round bottomed flask fitted with a stirrer, a
solution of cis-[(methylethyl)sulfonyl](2-phenylcyclopentyl)amine (10.37 g,
38.78
mmol) in trifluoroacetic acid (260 mL) is treated with sodium nitrate (9.9 g,
116.35
mmol) and the mixture is stirred at room temperature for five hours. The
reaction
mixture then quenched with H20 (200 mL) and the mixture is extracted with
CH2CI2 (2x200 mL). The combined organic extracts are washed with saturated
sodium bicarbonate (200 mL), dried over magnesium sulfate, filtered, and
Zo concentrated under vacuum to yield 14.3 g of crude product as a brown oil.
This
material is further purified by Prep HPLC 2000 (Hexane: EtOAc, 3:1 ) to
provide
the intermediate title compound (7.8 g, 64 %) as a yellow solid.
Preparation of cis-[2-(4-aminophenLrl)cyclopentyl~methylethyl)sulfonyllamine.
H2N
HN
O=S=O
Scheme IV, step C: A solution of cis-[(methylethyl)sulfonyl][2-(4-
nitrophenyl)cyclopentyl]amine (7.8 g, 24.97 mmol) and palladium on carbon (390
mg, 5 mole%) in absolute ethanol (200 mL) is combined in a Parr bottle. The
mixture is shaken on a Parr shaker at room temperature under 40 psi of
2 o hydrogen for 12 hours. The reaction mixture is filtered through the
Celite° and
the filtrate is concentrated under vacuum to yield 5.9 g of brown crystals.
This
material is further purified by Prep HPLC 2000 (Hexanes: EtOAc, 1:1 ) to
provide
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the intermediate title compound (3.4 g, 48 %) as white crystals. EMS 284.0
(M*+1 ).
Preparation of cis-[(meth I~~ sulfonyll 2-(4-
Jlbenzylaminolphenyl~cyclopentLrl)amine.
H ~
HN
O=S=O
Scheme IV, step D: A solution of benzaldehyde (1.22 mL, 12.0 mmol) in
acetic acid (36 mg, 0.6 mmol) is added to a solution of cis-[2-(4-
aminophenyl)cyclopentyl][(methylethyl)sulfonyl]amine (3.4 g, 12.0 mmol) in
to methanol (48 mL). The reaction is stirred for four hours, then sodium
borohydride (910 mg, 24 mmol) is added, and the mixture is stirred overnight
at
room temperature. The reaction mixture is then diluted with Hz0 (150 mL), and
the mixture is extracted with CH2CI2 (3 x 100 mL). The combined organic.layers
are dried over K~C03, filtered, and concentrated under vacuum to yield 4.36 g
as
a brown oil. This material is further purified by Prep HPLC 2000 (Hexanes:
EtOAc, 3:1 ) to provide the intermediate title compound (2.9 g, 65 %) as a
yellow
oil. EMS 373.0 (M*+1 ).
Preparation of cis-2~~4~2-
2 o fL(meth le~thy_I)sulfonyllamino~cyclopent I)y ,
phenyl]benzylamino~ethanenitrile.
N
NC
HN
i
O=S=O
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Scheme IV, step E: In a 250 mL 3-neck round bottom flask fitted with a
thermometer and stirbar, a solution of sodium cyanide (401 mg, 8.17 mmol) in
H20 (20 mL) is treated with a solution of cis-[(methylethyl)sulfonyl](2-{4-
[benzylamino]phenyl]~cyclopentyl)amine (2.9 g, 7.79 mmol) in methanol (20 mL).
The reaction mixture is cooled to 0 °C in an ice bath, and hydrochloric
acid (2.32
mL) is added by syringe followed by formaldehyde, 37 %, (0.23 mL, 8.17 mmol).
The mixture is stirred for an additional three hours at 0 °C and
gradually warmed
to room temperature overnight. The reaction mixture is then quenched with H20
(100 mL) and the mixture is extracted with CH2CI2 (3 x 100 mL). The combined
s o organic extracts are washed with brine (1 x 100 mL), dried over magnesium
sulfate, filtered, and concentrated under vacuum to yield 1.95 g as a brown
foam.
This material is further purified by Prep HPLC 2000 (Hexanes: EtOAc, 3:1 ) to
provide the intermediate title compound (850 mg, 27 %) as a colorless foam.
Pre~~aration of cis-(2~4 j(2-
aminoethyl)benzylaminolphenyl, cycloaentLr( ~(methylethyl)su(fonyflamine.
N ~
H2N
HN
O=S=O
Scheme IV, step F: A solution of cis-2-{(4-(2-
{[(methylethyl)sulfonyl]amino}cyclopentyl)phenyl]benzylamino)ethanenitrile
(760
2 o mg, 1.85 mmol) in THF (6.2 mL) is treated with a solution of borane-
tetrahydrofuran 1 M (1.85 mL, 1.85 mmol) and the mixture is heated at reflux
(65°C) overnight. The reaction mixture is cooled to room temperature
and
treated with a 1:1 mixture THF: MeOH (5.6 mL). When foaming ceases sodium
hydroxide 5N (16.7 mL) is added to the reaction and the reaction mixture is
heated at reflux (55°C) for 5 hours. The mixture is then cooled to room
temperature and the mixture is extracted with CH2CI2 (2 x 50 mL). The combined
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organic layers are further washed by saturated sodium bicarbonate (50 mL),
dried over magnesium sulfate, filtered, and concentrated under vacuum to yield
740 mg of a brown oil. This material is further purified on a Chromatotron~
(CH2Cl2: MeOH, 9:1 with concentrated ammonium hydroxide (1 mL per 500 mL)
to provide the intermediate title compound (370 mg, 48 %) as a brown foam.
EMS 416.0 (M*+1 )
Elemental Analysis:
Theory: C; 66.47 H; 8.00 N;10.11
Found: C; 65.22 H; 8.07 N; 9.72
Preparation of cis-[(methylethyl)sulfonyll(2-~[4-(2-
~methylethyl)sulfonyl]'amino cyclopentyl)phenyl]benzylamino ethyl amine.
.. \
~N
S-N
p H HIV
O=S=O
Scheme iV, step G: A solution of cis-(2-{4-[(2-
aminoethyl)benzylamino]phenyl}cyclopentyl)[(methylethyl)sulfonyl]amine (175
mg, 0.4211 mmol) in CHZCI2 (2.8 mL) and DBU (0.23 mL, 1.053 mmol) is treated
with isopropylsulfonyl chloride (0.07 mL, 0.6317 mmol) at 0 °C. The
reaction
mixture is warmed to room temperature while stirring overnight. The mixture is
then quenched with H20 (5 mL) and the mixture is extracted with CH2CIz (2 x 10
2 o mL). The combined organic layers are washed with brine (10 mL), dried over
magnesium sulfate, filtered, and concentrated under vacuum to yield 271 mg of
a
brown oil. This crude material is further purified on a Chromatotron~.
(Hexanes:
EtOAc, 2:1 ) to provide the intermediate title compound (195 mg, 89 %) as a
brown foam. EMS 523.0 (M*+1 ).
2 5 Elemental Analysis:
Theory: C; 59.85 H; 7.53 N; 8.05
Found: C; 57.62 H; 7.12 N; 7.84
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Preparation of final title compound.
Scheme IV, step H: In a round bottom flask, a solution of cis-
[(methylethyl)sulfonyl](2-([4-(2-
([(methylethyi)sulfonyl]amino)cyclopentyl)phenyl]benzylamino]ethyi)amine (80
mg, 0.1533 mmol) in THF (10 mL) is treated with ammonium formate (48 mg,
0.7667 mmol) and palladium on carbon (10 mg). The reaction mixture is stirred
at room temperature overnight and then heated at reflux (65 °C) for 8
hours. The
mixture is then filtered through Celite~, and the Celite~ cake is washed with
H20
(10 mL). Ethyl acetate is added to the filtrate and the mixture is extracted
with
1 o ethyl acetate (3 x 10 mL). The combined organic layers are washed with
brine
(40 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum
to yield 104 mg as a purple foam. This crude material is further purified on a
Chromatotron~ (Hexanes: EtOAc;1:1) to provide the final title compound (6 mg,
9
%) as a yellow oil. EMS 433.0 (M*+1 ). FI-EMS 432 (M*+1 )
Example 13
Preparation of cis-(2-~~[4-(2-
~f(methylethyl)sulfonyllamino)cyclopent~)phenyllamino eth~(methylsulfonyl)ami
ne.
H
O
-S-N HN
O H O=S=O
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_Preparation of cis-(2-f f4-(2-
~f(methyleth rLl)sulfonyllamino)c~pent~~l)phenyllbenz lay mino
ethyl~(methylsulfon
I amine.
O N
-..S_N~
p H HN
O=S=O
Scheme IV, step G: In a round bottom flask, a solution of cis-(2-~4-[(2-
aminoethyl)benzylamino]phenyl}cyclopentyl)[(methylethyl)sulfonyl]amine (175
mg, 0.4211 mmol, prepared in example 12) in CH2CI2 (3 mL) is combined with
DBU (0.23 mL, 1.053 mmol) at 0 °C and treated with isopropylsulfonyl
chloride
(0.07 mL, 0.6317 mmol). The mixture is then gradually warmed to room
o temperature overnight. The reaction is then quenched with HBO (5 mL), and
mixture is extracted with CH2CI2 (2 x 10 mL). The combined organic extracts
are
washed with brine (10 mL), dried over magnesium sulfate, filtered, and
concentrated under vacuum to yield 292 mg of a brown oil. This crude material
is
further purified on a Chromatotron° (Hexanes: EtOAc, 1:1 ) to provide
the
s5 intermediate title compound (149 mg, 72 %) as a yellow foam. EMS 495.0
(M*~-1 ).
Elemental Analysis:
Theory: C; 58.39 H; 7.,15 N; 8.51
Found: C; 56.50 H; 6.75 N; 8.20
Preparation of final tifile compound.
Scheme IV, step H: In a round bottom flask, a solution of cis-(2-{[4-(2-
~[(methylethyl)sulfonyl]amino)cyclopentyl)phenyl]benzylamino]ethyl)(methylsulfo
n
yl)amine (65 mg, 0.132 mmol) in THF (10 mL) is treated with ammonium formate
2s (42 mg, 0.66 mmol) and palladium on carbon (10 mg). The reaction mixture is
stirred at room temperature overnight and then heated at reflux (65°C)
for 8
hours. The mixture is then filtered through Celite~, and the Celite~ cake is
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washed with H20 (10 mL). Ethyl acetate is added to the filtrate and mixture is
extracted with ethyl acetate (3 x 10 mL). The combined organic layers are
washed with brine (40 mL), dried over magnesium sulfate, filtered, and
concentrated under vacuum to yield 59 mg of a purple foam. This crude material
is further purified on a Chromatotron~ (Hexanes: EtOAc;1:1 ) to provide the
final
title compound (6 mg, 11 %) as a yellow oi(.
EMS 405.0 (M*+1 )
FI-EMS 404 (M*+1 )
s o Example 14
Preparation of ~2-hydroxy-2-f4-~2-
~(methylsulfonyl)aminolethyl benzylamino~phenylpropyl~'[(meth
ler~thyl)sulfonyllam
ine.
N-
H O
O ~--~ ~ ~ OH
-S-N
II H
O
Preparation of 1-amino-2~(4-nitrophenyl)propan-2-of hydrochloride.
NH2 HCI
02N
OH
Scheme V, step A: Trimethylsylilcyanate (100 mL, 703.05 mmol, Aldrich)
is added to 4-nitroacetophenone (38.75 g, 234.35 mmol) and zinc iodide (7.5 g,
23.44 mmol) in a 1 L round bottomed flask, neat, fitted with a stirbar, and
under a
2 o nitrogen atmosphere, at room temperature. The mixture is stirred overnight
and
diluted with 100 mL dichloromethane, followed by slow addition of 100 mL
saturated sodium carbonate. The layers are separated, and the organic layer is
washed once with deionized water, filtered through magnesium sulfate (MgS04),
and concentrated under vacuum, yielding 25.9 g orange oil. This product is
dissolved in tefirahydrofuran (327 mL, anhydrous) in a 1 L 3-neck round
bottomed
flask, fitted with a thermometer, reflux condenser, stirbar, and addition
funnel.
Borane-dimethylsulfide, 2M, (98 mL, 195.96 mmol) is added dropwise, and the
reaction is stirred overnight at room temperature. Concentrated hydrochloric
acid
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(HCI) is added to pH = 2, and the acidic mixture is poured into 1 L of diethyl
ether
(Et20), and the precipitate is vacuum filtered off. The precipitate is washed
with
Et20 (2 x 100 mL). The precipitate is dried by heated vacuum for 2 hours at
45°C, to provide the intermediate title compound (11.6 g, 25 %).
Mass Spec-Electrospray (MS-ES) 197.0 (M*+1 )
Preparation of [2-hydroxy-~4-nitrophenrl)prowllf(methylethyl)sulfonyl]lamine.
O
ii
N-S
H n
02N ~ ~ OH O
Scheme V, step B: 1-Amino-2-(4-nitrophenyl)propan-2-of hydrochloride
so (11.6 g, 59.12 mmol), is added to THF (394 mL) in a 2-Liter, 3-neck, round
bottomed flask fitted with a thermometer, addition funnel, and under a
nitrogen
atmosphere. Triethylamine (20.6 mL, 147.8 mmol) is added, and the reaction
temperature is reduced to 0°C in an ice bath. Isopropylsulfonyl
chloride (10.0
mL, 88.68 mmol) is added by addition funnel at 0°C, and gradually
warmed to
room temperature overnight in the ice bath. The reaction is quenched with
water
(400 mL), and the layers are separated. The aqueous layer is extracted with
CH2CI2 (2 x 300 mL), and the organic extracts are combined. The combined
organic extracts are washed with brine (1 x 500 mL), filtered through MgS04,
and
concentrated under vacuum, yielding 15.4 g brown oil. This crude material is
2 o further purified by running through two Waters Prep-pak's~, on a Waters
Prep
HPLC 2000, in a 1:1 hexanes: ethyl acetate solvent system to provide the
intermediate title compound (1.41 g, 8 %) as a yellow oil.
Mass Spec-Electrospray (MS-ES) 303.0 (M*+1 ).
2 s Preparation of f2-(4-aminoQhenyl)-2-hydrox p~~j(methyleth~)sulfo~llamine.
O
ii
N-S
n
H2N ~ ~ OH O
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Scheme V, step C: [2-Hydroxy-2-(4-
nitrophenyl)propyl][(methylethyl)sulfonyl]amine (2.41 ~ g, 7.97 mmol) is
dissolved
into absolute ethanol (200 mL) and added to 5 % paNadium on carbon, wetted
with ethanol (2 mL) in a nitrogen flushed Parr bottle. The reaction vessel is
stopped off and shaken on a Parr shaker at room temperature under 40 psi of
hydrogen, overnight. The reaction mixture is then filtered through Celite~ to
remove the catalyst, and the filtrate is concentrated under vacuum, yielding
1.82
g colorless oil. This material was further purified by running through one
Waters
Prep-pak's~, on a Waters Prep HPLC 2000, in a 1:1 hexanes: ethyl acetate
~o solvent system to provide the intermediate title compound (1.1 g, 64 %)
white
crystals. Electrospray-MS 274.0 (M*+1 )
Preparation of (2-hydrox~{4-
benzylaminolphenLrl)prop rL(methylethyl)sulfonyllamine.
H
H ~ ~ OH
Scheme V, step D: A mixture of benzaldehyde (0.52 mL, 5.14 mmol) and
acetic acid (15 mg, 0.257 mmol), is added to a solution of [2-(4-aminophenyl)-
2-
hydroxypropyl][(methylethyl)sulfonyl]amine (1.4 g, 5.14 mmol) in MeOH (23 mL),
in a 250 mL round bottomed flask fitted with a stirbar, and under a nitrogen
2 o atmosphere. The reaction is stirred for four hours, then sodium
borohydride is
added, and stirred overnight, at room temperature. The reaction is then
diluted
with water (150 mL), and extracted with CH2CI2 (3 x 100 mL). The organic
extracts are combined and filtered through potassium carbonate (KZC03), and
concentrated under vacuum, yielding 2.132 g of a brown oil. This material is
further purified by running it through one Waters Prep-pak~, on a Waters Prep
HPLC 2000, in 3:2 hexanes: ethyl acetate solvent system, to provide the
intermediate title compound (1.62 g, 87 %) as a yellow oil.
Electrospray-MS 373.0 (M*+1 ).
3o Preparation of 2-ff4-(1-hydroxy-1-methyl-2-
~('(methylethyl)sulfonyl)amino~eth~rl phenyllbenzylamino~ethanenitrile
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/ \ _ N_
/ Ho
NC OH
Scheme V, step E: A solution of (2-hydroxy-2-(4-
[benzylamino]phenyl}propyl)[(methylethyl)sulfonyl]amine (1.0 g, 2.76 mmol) in
MeOH (7 mL) is added to sodium cyanide (142 mg, 2.90 mmol) dissolved in H20
(7 mL) in a 100 mL 3-neck round bottomed flask fitted with a thermometer,
stirbar, and under a nitrogen atmosphere. The reaction vessel is cooled to
0°C in
an ice bath, and hydrochloric acid (0.8 mL) is added by syringe, followed by
addition of formaldehyde, 37 %, (0.2 mL, 2.90 mmol) by syringe, and the
reaction
mixture is stirred for an additional three hours at 0°C. The ice bath
is removed
Zo and the reaction mixture is gradually warmed to room temperature overnight.
The reaction is then poured into H20 (50 mL) and extracted with CH~CI2 (3 x 25
mL). The organic extracts are combined, washed with brine (1 x 100 mL),
filtered
through MgS04, and concentrated under vacuum, yielding 939 g of a brown
foam. This material is further purified by running it over a 6000 ~,m rotor on
a
i5 Chromatotron~, in 1:1 hexanes : ethyl acetate solvent system to provide the
intermediate title compound (690 mg, 62 %) as a colorless foam.
Electrospray-MS 402.0 (M*f1
)
Elemental Analysis:
C (Theory) 62.82 C (Found)
62.42
2 o H (Theory) 6.78 H (Found)
6.74
N (Theory) 10.47 N (Found)
10.14
Preparation of (2-~4-f(2-aminoeth~ Benz I~lphenyl
hydroxyprop r1 ~(methylethyl sulfonLrl]lamine.
N_
H
OH
2 5 H2N
Scheme V, step F: A solution of 2-{[4-(1-hydroxy-1-methyl-2-
{[(methylethyl)sulfonyl]amino)ethyl)phenyl]benzylamino)ethanenitrile (600 mg,
1.5
mmol) in warm THF (3 mL) is added to lithium aluminum hydride (57 mg, 1.5
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mmol) in THF (7mL) in a 100 mL 3 neck round bottomed flask, fitted with a
thermometer, addition funnel, stirbar, under a nitrogen atmosphere, in an ice
bath (0°C). The reaction mixture is stirred overnight at room
temperature. The
reaction is then cooled in an ice bath (0°C), and 1 mL H20, 1 mL 5N
sodium
hydroxide (NaOH), and 3 mL H20 are added in consecutive increments. After
foaming ceases, the mixture is filtered, and the precipitate is washed with 10
mL
hot THF. The organic filtrate is concentrated under vacuum yielding 456 mg as
a
yellow oil. This material is further purified by running it over a 4000 ~,m
rotor on a
Chromatotron~, in 9:1 CH2CI2: methanol solvent system, to provide the
so intermediate title compound (80 mg, 13 %) as a yellow foam.
Electrospray-MS 406.0 (M*+1 )
Preparation of final title compound.
Scheme V, step G: A solution of (2-~4-[(2-
is aminoethyl)benzylamino]phenyl)-2-hydroXypropyl)[(methylethyl)sulfonyl]amine
(80 mg, 0.1973 mmol) in THF (1.3 mL) is treated with DBU (0.08 mL, 0.4933
mmol), and the reaction temperature is reduced to 0°C with an ice bath.
Methanesulfonyl chloride (0.02 mL, 0.1973 mmol) is added by syringe at
0°C,
and gradually warmed to room temperature overnight in the ice bath. The
2 o reaction is then quenched with H20 (2 mL), and the layers are separated.
The
aqueous layer is then extracted with CH2CI2 (2 x 5 mL), the organic extracts
are
combined, washed with brine (1 x 10 mL), filtered through MgS04, and
concentrated under vacuum, yielding 100 mg of a yellow oil. This material was
further purified by running it over a 1000 ~,m rotor on a
Chromatotron°, in a 3:1
25 CH2CI2: ethyl acetate solvent system to provide the final title compound (7
mg, 7
%) as a yellow oil.
Electrospray-MS 485.0 (M*+1 )
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Example 15
Preparation of (meth Is~yl~[2-L~2-[(methylsulfonyl)aminolethoxy)j2-
naphthyl~)ethyllamine.
H O
O H I ~ ~ N_O
-S-N~o
O
Preparation of (6-methoxy-2-naphthyl)methan-1-ol.
( ~ ~ ~OH
~O
A solution of 6-methoxy-2-naphthoic acid (15.0 g, 74.2 mmol) in warm
THF (75 mL) is added to lithium aluminum hydride (2.83 g, 74.2 mmol) in THF
(150 mL), in a 1 L 3-neck round bottomed flask, fitted with a thermometer,
stir bar,
Zo and addition funnel, in an ice bath (0°C), under a nitrogen
atmosphere. The
reaction is stirred overnight at room temperature: It is then cooled in ice
bath
(0°C), with consecutive addition of 1 mL increments of deionized water
and 5N
sodium hydroxide (NaOH). 3 mL deionized water is then added (as per Feiser
work up). The precipitate is filtered off and washed with hot THF (75 mL). The
~.s filtrate is concentrated under vacuum yielding the intermediate title
compound
(9.23 g, 66%) as a white solid.
Preparation of 6-(bromomethyl)-2-methoxynaphthalene.
I ~ ~ 'Br
0
2 o Bromine (2.82 mL, 55.04 mmol) is added dropwise to triphenylphosphine
(9.4 g, 35.78 mmol) dissolved in methylene chloride (12 mL) in a 250 mL 3-neck
round bottomed flask, fitted with a thermometer, stirbar, addition funnel,
under a
nitrogen atmosphere, and in an ice bath (0°C). The solution turns a
yellow color
and is retitrated with triphenylphosphine until a white color emerges. (6-
Methoxy-
25 2-naphthyl)methan-1-of (5.18 g, 27.52 mmol) dissolved in 1:1 THF:methylene
chloride (32 mL) is then added, the ice bath is removed, and the reaction
mixture
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is stirred to room temperature. The reaction mixture is then concentrated
under
vacuum and extracted with diethyl ether (3 x 20 mL), and the combined extracts
are concentrated under vacuum to yield 16.60 g of a yellow oil. This material
is
purified by silica gel chromatography, using a Waters HPLC Prep 2000, over two
Prep-Pak, in a 3:1 hexanes: ethyl acetate solvent system to yield the
intermediate title compound (3.923 g, 57%). Electrospray-MS M*+/-1
(252.1, 250.1 )
Preparation of 2-(6-methoxy-2-naphthy()ethanenitrile.
~CN
~O
A solution of 6-(bromomethyl)-2-methoxynaphthalene (3.923 g, 15.62
mmol) in dimethylsulfoxide (10 mL) is added to a solution of sodium cyanide
(1.15 g, 23.43 mmol) in DMSO (15 mL), heated to 50°C, in a 250 mL 3-
neck
round bottomed flask, fitted with a stirbar, thermometer, condenser, and
addition
funnel, under a nitrogen atmosphere. The reaction mixture is stirred at
50°C for
0.5 hr, then the temperature is increased to 70°C, and stirred an
additional 1.0 hr.
The reaction is then cooled to room temperature and poured over ice. The
mixture is then extracted with methylene chloride (3 x 20 mL), and the organic
extracts are washed with deionized wafer ( 3 x 50 mL). The organic extracts
are
2 o then filtered through magnesium sulfate, and concentrated under vacuum,
yielding 2.10 g of a brown oil. This material is purified by silica gel
chromatography, using a Waters HPLC Prep 2000, over two Prep-Pak ~, in a 3:1
hexanes: ethyl acetate solvent system to provide the intermediate title
compound
(990 mg, 32%) as yellow powder. Electrospray-MS 198.1 (M*+1 )
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Preparation of 2-(6-methox~2-naphth~rl ethylamine.
NH2
i~
0
2-(6-Methoxy-2-naphthyl)ethanenitrile (5.0 g, 25.35 mmol) is dissolved into
absolute ethanol (200 mL), saturated with ammonia, and added to Rainey nickel
(2.5 g) wetted with ethanol (2 mL), in a nitrogen flushed Parr bottle. The
reaction
vessel is stopped off and shaken on a Parr shaker at 50°C and 60 psi
hydrogen
overnight. The catalyst is then filtered off with Celite~, and the organic
layer is
concentrated under vacuum yielding 6.1 g greenish oil. This material is
further
purified by running through one Waters Prep-pak's~, on a Waters Prep HPLC
2000, in a 1:1 methylene chloride: ethyl acetate solvent system to provide the
intermediate title compound (5.70 g) as white crystals. Electrospray-MS 202.0
(M*t1 )
Preparation of [2-(6-methoxy(2-naphth~l))ethyl]~methylsulfonyl)amine.
O
H
N_
W
O
~
O
A solution of 2-(6-methoxy-2-naphthyl)ethylamine (2.85 g, 14.16 mmol) in
THF (95 mL) in a 250 mL 3-neck round bottomed flask fitted with a thermometer,
addition funnel, and under a nitrogen atmosphere is treated with triethylamine
(3.94 mL, 28.32 mmol), and the reaction temperature is reduced to 0°C
in an ice
2 o bath. Methanesulfonyl chloride (2.4 mL, 21.24 mmol) is added by addition
funnel
at 0°C, and the mixture is gradually warmed to room temperature
overnight. The
reaction is then quenched with deionized water (H20, 100 mL), and the layers
are separated. The aqueous layer is extracted with methylene chloride (2 x 75
mL), and the organic layers are combined. The combined organic layers are
washed with brine (1 x 100 mL), filtered through MgS04, and concentrated under
vacuum, yielding 3.10 g orange oil. This crude material is further purified by
running through one Waters Prep-Pak ~, on a Waters Prep HPLC 2000, in a 3:1
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hexanes: ethyl acetate solvent system, to provide the intermediate title
compound (600 mg, 14 %) as a yellow solid. Mass Spec-Electrospray (MS-ES)
308.0 (M*+1 )
Preparation of f2-(6-hydroxy 2-na~hthyl~ethLrll(methylsulfonyl amine.
H O
N-S-
O
HO
A solution of boron tribromide (3.6 mL, 3.0 eq) in methylene chloride (15
mL) is added dropwise to [2-(6-methoxy(2-naphthyl))ethyl](methylsulfonyl)amine
(12.76 mmo() in methylene chloride (70 mL) in a 250 mL round bottomed flask
to fitted with a stirbar, and under a nitrogen atmosphere, at room
temperature. The
reaction mixture is stirred for two hours, or until. starting material is
consumed as
indicated by Thin Layer Chromatography. Water (60 mL) is added slowly, and
the layers are separated. The organic layer is filtered through potassium
carbonate, and concentrated under vacuum to provide the intermediate title
s5 compound which is used without further purification.
Preparation of 2-(~2-f(methylsulfonyl)aminoleth~rl)-2-
naphthyloxy)ethanenitrile
H O
N-S-
O
NC~O
A solution of [2-(6-hydroxyl2-naphthyl))ethyl](methylsulfonyl)amine (12.36
2 o mmol) in acetone (82 mL) is treated with cyanomethylbromide (Q.95 mL, 1.1
eq)
and potassium carbonate (4.27 g, 2.5 eq) in a 250 mL round bottomed flask
fitted
with a stirbar and under a nitrogen atmosphere. The reaction mixture is
stirred at
room temperature, overnight. The reaction mixture is then washed with water
(80
mL) and extracted with methylene chloride (3 x 50 mL). The organic layers are
25 combined and filtered through MgS04, and concentrated under vacuum. This
material is further purified by silica gel chromatography, employing the
Water's
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Prep 2000 while eluting with a solvent of hexanes/ethyl acetate 3:1 to provide
the
title compound.
Preparation of f2-f6-(2-aminoethoxv)(2-naphthvl)lethvl'~(methvlsulfonvl)amine.
H O
N_O
H2N~0
2-(6-{2-[(Methylsulfonyl)amino]ethyl}-2-naphthyloxy)ethanenitrile (191.91
mmol), borane dimethylsulfide, reagent (192 mL, 10 M, 10.0 equivalents), and
THF (2300 mL) are combined in a 3000 mL 3-neck round bottomed flask, affixed
with a thermometer, condenser, and rubber stopper. Under a nitrogen
Z o atmosphere, with stirring, reaction is refluxed at 70°C overnight.
The reaction
mixture is cooled to room temperature. 1:1 THF: MeOH (581 mL) is added by
syringe, and when foaming ceases, 5N NaOH (1745 mL) is added by syringe.
Then the mixture is refluxed at 55°C for an additional five hours. The
reaction
mixture is cooled to room temperature, and extracted three times with
methylene
chloride (3 x 1000 mL). The organic layer is dried with sodium sulfate,
filtered,
and concentrated in vacuum. This material is washed with a saturated sodium
bicarbonate solution (200 mL) for two hours, and extracted three times with
methylene chloride (3 x 200 mL). The organic layer is dried with sodium
sulfate,
filtered, and concentrated in vacuum to provide the intermediate title
compound
2 o which is used without further purification.
Preparation of final title compound.
Scheme II, step D: {2-[6-(2-Aminoethoxy}(2-
naphthyl)]ethyl}(methylsulfonyl)amine (0.571 mmol) is dissolved in methylene
chloride in a 15 mL round bottomed flask, under a nitrogen system. The
reaction
mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 equivalents)
is added by
syringe, followed by methanesulfonyl chloride (0.07 mL, 1.5 Eq.), also by
syringe,
and mixed overnight. The reaction is quenched with 20 mL water, and layers are
separated. The organic layer is washed with water (20 mL), dried with sodium
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sulfate, filtered, and concentrated in vacuum. The crude residue is further
purified by silica ge! chromatography on a Chromatotron~ employing a 2000uM
rotor in a 1:1 hexanes: ethyl acetate solvent system to provide the final
title
compound.
Example 16
Preparation of f(methvlethvl)sulfonvllf2-(6-1'2-
f(methvlsulfonvl)aminolethoxv)(2-
naahthvlllethvllamine.
H O
O H I ~ ~ N_O
-S-NCO /
O
so Preparation of f2-(6-methoxy(2-
naphthyl))ethLrllf(methylethyl)sulfonyl]amine.
H O
I \ \. N S
O
O / /
2-(6-Methoxy-2-naphthyl)ethylamine (2.85 g, 14.16 mmol) is added to THF
(95 mL) in a 250 mL 3-neck round bottomed flask fitted with a thermometer,
addition funnel, and under a .nitrogen atmosphere. Triethylamine (3.94 mL,
28.32 mmol) is added, and the reaction temperature is reduced to 0°C in
an ice
bath. Isopropylsulfonyl chloride (1.64 mL, 21.24 mmol) is added by addition
funnel at 0°C, and gradually warmed to room temperature overnight. The
reaction is quenched with deionized water (100 mL), and the layers are
separated. The aqueous layer is extracted with methylene chloride (2 x 75 mL),
2 o and the organic layers are combined, washed with brine (1 x 100 mL),
filtered
through MgS04, and concentrated under vacuum, yielding 1.58 g orange oil.
This crude material is further purified by running through one Waters Prep-
Pak~,
on a Waters Prep HPLC 2000, in a 3:1 hexanes: ethyl acetate solvent system, to
provide the intermediate title compound (560 mg, 14 %) as a yellow solid. Mass
2 5 Spec-Electrospray (MS-ES) 280.0 (M*+1 )
Preparation of f2-(6-hydroxY(2-napht~)ethyll![(methylethyl)sulfonLrl]amine.
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H
N-S
O
HO / /
A solution of boron tribromide (13 mL, 3.0 eq) in methylene chloride (15
mL) is added dropwise to [2-(6-methoxy(2-
naphthyl))ethyl][(methylethyl)sulfonylJamine (45.73 mmol) in methylene
chloride
(260 mL) in a 1 L round bottomed flask fitted with a stirbar, and under a
nitrogen
atmosphere, at room temperature. The reaction mixture is stirred for two
hours,
or until starting material is consumed as indicated by Thin Layer
Chromatography
(TLC). Water (60 mL) is added slowly, and then the layers are separated. The
organic layer is filtered through potassium carbonate, and concentrated under
1o vacuum to provide the intermediate title compound which is used without
further
purification.
Preaaration of 2-f6-l2-ff(methvlethvl)sulfonvllamino)ethvl)-2-
naphthyloxy~ethanenitrile.
H O
N-S
O
NC O
[2-(6-Hydroxyl2-naphthyl))ethyl][(methylethyl)sulfonyl]amine (13.07 mmol),
cyanomethylbromide (1.00 mL, 1.1 eq), potassium carbonate (4.52 g, 2.5 eq),
and acetone (87 mL) are combined in a 250 mL round bottomed flask fitted with
a stirbar and under a nitrogen atmosphere. The reaction mixture is stirred at
2 o room temperature, overnight. The reaction mixture is then washed with
water (80
mL) and extracted with methylene chloride (3 x 50 mL). The organic layers are
combined and filtered through MgS04, and concentrated under vacuum. This
material is further purified by silica gel chromatography, employing the
Water's
Prep 2000 while eluting with a solvent of hexanes/.ethyl acetate 3:1 to yield
the
2 5 intermediate title compound.
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Preparation of f2-[~2-aminoethoxY~2-
naphthyl)]ethyl}meth Iy ethyl)sulfonyllamine.
H O
N-S
O
H2N~0 ~~ ~
2-[6-(2-([(Methylethyl)sulfonyl]amino}ethyl)-2-naphthyloxy]ethanenitrile
(5.66 mmol), borane dimethylsulfide reagent (2.27 mL, 10 M, 10.0 equivalents),
and THF (68 mL) are combined in a 250 mL 3-neck round bottomed flask, affixed
with a thermometer, condenser, and rubber stopper. Under a nitrogen
atmosphere, with stirring, reaction is refluxed at 70°C overnight. The
reaction
mixture is cooled to room temperature. 1:1 THF: MeOH (17 mL) is added by
so syringe, and when foaming ceases, 5N NaOH (51 mL) is added by syringe. Then
the mixture is refluxed at 55°C for an additional five hours. The
reaction mixture
is cooled to room temperature, and extracted three times with methylene
chloride
(3 x 50 mL). The organic layer is dried with sodium sulfate, filtered, and
concentrated in vacuum. This material is washed with a saturated sodium
bicarbonate solution (50 mL) for two hours, and extracted three times with
methylene chloride (3 x 50 mL). The organic layer is dried with sodium
sulfate,
filtered, and concentrated in vacuum to provide the intermediate title
compound
which is used without further purification.
2 o Preparation of final title compound.
Scheme II, step D: f2-[6-(2-Aminoethoxy)(2-
naphthyl)]ethyl[(methylethyl)sulfonyl]amine (0.571 mmol) is dissolved in
methylene chloride in a 15 mL round bottomed flask, under a nitrogen system.
The reaction mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5
eq) is added
by syringe, followed by methanesulfonyl chloride (0.07 mL, 1.5 Eq.), also by
syringe, and mixed overnight. The reaction is quenched with 20 mL water, and
the layers are separated. The organic layer is washed with water (20 mL),
dried
with sodium sulfate, filtered, and concentrated in vacuum. This material is
further
purified by silica gel chromatography on a Chromatotron~ employing a 2000uM
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rotor in a 1:1 hexanes: ethyl acetate solvent system to provide the final
title
compound.
Example 17
Preparation of f2-f6-~2-(~(methylethyl)sulfonylLamino)ethoxy)(2-
naphthyl)lethyl)(methylsulfonyl)amine.
H O
N-S-
O \ \ ~ y
-
0
Scheme II, step D: {2-[6-(2-Aminoethoxy)(2-
Zo naphthyl)]ethyl}(methylsulfonyl)amine (0.571 mmol) is dissolved in
methylene
chloride in a 15 mL round bottomed flask, under a nitrogen system. The
reaction
mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added
by syringe,
followed by isopropylsulfonyl chloride (0.095 mL, 1.5 eq.), also by syringe,
and
mixed overnight. The reaction is quenched with 20 mL water, and the layers are
separated. The organic layer is washed with water (20 mL), dried with sodium
sulfate, filtered, and concentrated in vacuum. This material is further
purified by
silica gel chromatography on a Chromatotron~ employing a 2000uM rotor in a 1:1
hexanes: ethyl acetate solvent system to provide the title compound.
2 0 Example 18
Preparation o~methylethyl)sulfonyl]{2-f6-(2-
f[Lmethylethyl)sulfonyllamino ethoxy~(2-naphthyl)lethyl~amine.
H_
\ \ N S
O
S-N\/\ ~ ~ ~ O
O
O
Scheme II, step D: ~2-[6-(2-Aminoethoxy)(2-
naphthyl)]ethyl}[(methylethyl)sulfonyl]amine (0.571 mmol) is dissolved in
methylene chloride in a 15 mL round bottomed flask, under a nitrogen system.
The reaction mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5
eq.) is
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added by syringe, followed by isopropylsulfonyl chloride (0.095 mL, 1.5 eq.),
also
by syringe, and mixed overnight. The reaction is quenched with 20 mL water,
and
layers are separated. The organic layer is washed with water (20 mL), dried
with
sodium sulfate, filtered, and concentrated in vacuum. The crude residue is
further purified by silica gel chromatography on a Chromatotron~ employing a
2000uM rotor in a 1:1 hexanes: ethyl acetate solvent system to provide the
title
compound.
Example 19
2 o Preparation of [(methylethy!)sulfonyllr2-(6-
{~methylsulfony!)aminolethoxy)(2-
naphthyl))propyllamine.
H O
O H I W ~ N
-S-NCO /
O
Preparation of 2-(6-methoxy-2-naphthyl~propanamide.
NH2
O
O
A solution of 2-(6-methoxy-2-naphthyl)propionic acid (50.0 g, 217.14
mmoi, LKT Laboratories, Inc., St. Paul Minnesota) in THF (217 mL) is added
dropwise to oxalyl chloride (76 mL, 868.56 mmol) in THF (217 mL), in a 2000 mL
round bottomed flask fitted with a stirbar and under a nitrogen atmosphere.
The
reaction is catalyzed with dimethylformamide (1 drop), and stirred at room
2 o temperature for two hours. The reaction mixture is then concentrated under
vacuum, and diluted with 1,4-dioxane (217 mL). This solution is added dropwise
to concentrated ammonium hydroxide (65 mL) and stirred overnight. The
reaction mixture is extracted with ethyl acetate (2 x 250 mL), the organic
extracts
are combined, filtered through potassium carbonate, and concentrated under
vacuum, yielding 91.2 g of an off-white solid. This material is purified by
vacuuming off excess solvent to provide the intermediate title compound (44.0
g,
88%) as a brown solid. Electrospray-MS 230.1 (M*+1 ).
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Preparation of 2-(6-methoxy-2-naphthyl)propylamine.
I \ \ NH2
\O
2-(6-Methoxy-2-naphthyl)propanamide (44.0 g, 191.91 mmol), borane
dimethylsulfide reagent (192 mL, 10 M), and THF (2312 mL) are combined in a
3000 mL 3-neck round bottomed flask, affixed with a thermometer, condenser,
and addition funnel. Under a nitrogen atmosphere, with stirring, the reaction
is
refluxed at 70°C overnight. The reaction mixture is cooled to room
temperature.
1:1 THF: MeOH (17 mL) is then added by syringe, and when foaming ceases, 5N
1o NaOH (51 mL) is added by syringe. Then the mixture is refluxed at
55°C for an
additional five hours. The reaction mixture is then cooled to room
temperature,
and extracted three times with methylene chloride (3 x 50 mL). The organic
layer
is dried with sodium sulfate, filtered, and concentrated in vacuum. This
material
is stirred with a saturated sodium bicarbonate solution (50 mL) for two hours,
and
1s extracted three times with methylene chloride (3 x 50 mL). The organic
layer is
dried with sodium sulfate, filtered, and concentrated in vacuum to provide the
intermediate title compound (35.32 g, 85%) as a white solid. Electrospray-MS
216.0 (M~+1 ).
2 o Preparation of f2-(6-methoxy(2-naJ-~hth rI )propyllj(meth ley
fhyl)sulfonyllamine.
H
I \ \ N'S
O
w0 /
2-(6-Methoxy-2-naphthyl)propylamine (35.32 g, 164.05 mmol) is dissolved
in methylene chloride in a 3000 mL round bottomed flask, under a nitrogen
system. The mixture is cooled to 0°C, and triethylamine (68.5 mL,
492.15 mmol)
25 is added by syringe, followed by isopropylsuifonyl chloride (36.85 mL,
328.1
mmol), also by syringe, and the reaction mixture is stirred overnight. The
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reaction is quenched with 1000 mL water, and the layers are separated. The
organic layer is washed with water (1000 mL), dried with sodium sulfate,
filtered,
and concentrated in vacuum, yielding 69.1 g of a viscous yellow oil. This
material
is further purified by silica gel chromatography on a Waters prep 2000
employing
s two Prep-Pak's~ in a 3:1 hexanes: ethyl acetate solvent system to yield the
intermediate title compound (33.5 g, 64%) as white powder. Electrospray-M
322.0 (M*+1 ).
Pre~aaration of L2~6-hydro~(2-naphth rLl))propyllj(meth
Ir~ethyl)sulfonyllamine.
H O
W W
HO
A solution of boron tribromide (3.6 mL, 38.28 mmol) in methylene chloride
(15 mL), is added dropwise to [2-(6-methoxy(2-
naphthyl))propyl][(methylethyl)sulfonyl]amine (12.76 mmol) in methylene
chloride
(70 mL) in a 250 mL round bottomed flask fitted with a stirbar, and under a
nitrogen atmosphere, at room temperature. The reaction mixture is stirred for
two hours, or until starting material is consumed as indicated by Thin Layer
Chromatography (TLC). Water (60 mL) is added slowly, and then the layers are
separated. The organic layer is filtered through potassium carbonate, and
concentrated under vacuum to provide the intermediate title compound (3.80 g,
2 0 97%) as an off-white solid. Electrospray-MS 308.0 (M*+1 ).
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_Preparation of 2-f6-(1-meth~~f(meth I~yl sulfon Ily amino~eth r~l)-2-
naphthyloxy]ethanenitriie.
H O
N_S
O
NCO
[2-(6-Hydroxyl2-naphthyl))propyl][(methylethyl)sulfonyl]amine (3.80 g,
12.36 mmol), cyanomethylbromide (0.95 mL, 13.60 mmol), and potassium
carbonate (4.27 g, 30.9 mmol) are combined in acetone (82.4 mL), in a 250 mL
round bottomed flask, at room temperature under a nitrogen atmosphere and
stirred overnight. The reaction is washed with water (85 mL), and extracted
with
methylene chloride (3 x 100 mL). The organic extracts are combined and
filtered
1 o through MgS04. The filtrate is concentrated under vacuum, yielding 3.97 g
of
brown oil. This material is purified by silica gel chromatography with a
Waters
Prep 2000, employing two Prep-Pak's~ in a 3:1 hexanes: ethyl acetate solvent
system, yielding the intermediate title compound (1.96 g, 46%) as a brown oil.
Electrospray-MS 347.0 (M*+1 ).
Preparation of~'2-_ f6-(2-aminoethox~r)(2-
naphthyl)lpropyl)[~-methylethyl)sulfony~amine.
H O
W . w N_O
H~N~O
2-[6-(1-Methyl-2-~j(methylethyl)sulfonyl]amino)ethyl)-2-
2 o naphthyloxy]ethanenitrile (1.96 g, 5.66 mmol), borane dimethylsuifide
reagent
(2.27 mL, 22.64 mmol, 10 M), and THF (68 mL) are combined in a 250 mL 3-
neck round bottomed flask, affixed with a thermometer, condenser, and rubber
stopper. Under a nitrogen atmosphere, with stirring, the reaction is refluxed
at
70°C overnight. The reaction mixture is then cooled to room
temperature. 1:1
THF: MeOH (17 mL) is added by syringe, and when foaming ceases, 5N NaOH
(51 mL) is added by syringe. Then the mixture is refluxed at 55°C for
an
additional five hours. The reaction mixture is cooled to room temperature, and
extracted three times with methyiene chloride (3 x 50 mL). The organic layer
is
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dried with sodium sulfate, filtered, and concentrated in vacuum. This material
is
washed with a saturated sodium bicarbonate solution (50 mL) for two hours, and
extracted three times with methylene chloride (3 x 50 mL). The organic layer
is
dried with sodium sulfate, filtered, and concentrated in vacuum, yielding 2.33
g of
a brown oil. This material is purified by silica gel chromatography, with a
Waters
Prep 2000, employing one Prep-Pak's~ in a 9:1 methylene chloride:methanol
solvent system, to provide the intermediate title compound (1.17 g, 59%) as a
brown foam. Electrospray-MS 351.0 (M*+1 ).
so Preparation of final title compound.
Scheme II, step D: ~2-[6-(2-Aminoethoxy)(2-
naphthyl)]propyl}[(methylethyl)sulfonyl]amine (0.571 mmol) is dissolved in
methylene chloride in a 15 mL round bottomed flask, under a nitrogen system.
The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq) is
added by
syringe, followed by methanesulfonyl chloride (0.07 mL, 1.5 eq.), also by
syringe,
and mixed overnight. The reaction is quenched with 20 mL water, and layers are
separated. The organic layer is washed with water (20 mL), dried with sodium
sulfate, filtered, and concentrated in vacuum, yielding 118 mg of a viscous
yellow
oil. This material is further purified by silica gel chromatography on a
2 o Chromatotron~ employing a 2000uM rotor in a 1:1 hexanes:ethyl acetate
solvent
system, to provide the final title compound (46 mg, 19 %) as a brown foam.
Electrospray-MS 429.0 (M*+1 ).
Elemental Analysis:
C(Theory):53.25 C(Found):52.95
H(Theory):6.59 H(Found):6.68
N(Theory):6.54 N(Found):6.16
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Example 20
_Preparation of [(meth I~~ sulfon~2-[~2-
(~meth I~~ sulfon~]amino~ethox~)(2-naphtha lprowl~amine.
H O
O H I \ \ N_O
S-NCO /
O
Scheme 11, step D: {2-[6-(2-Aminoethoxy)(2-
naphthyl)]propyl]~[(methylethyl)sulfonyl]amine (0.571 mmol) is dissolved in
methylene chloride in a 15 mL round bottomed flask, under a nitrogen system.
The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5
equivalents) is
added by syringe, followed by isopropylsulfonyl chloride (0.095 mL, 1.5 eq.),
also
Z o by syringe, and mixed overnight. The reaction is quenched with 20 mL
wafer,
and the layers are separated. The organic layer is washed with water (20 mL),
dried with sodium sulfate, filtered, and concentrated in vacuum, yielding 326
mg
of a viscous yellow oil. This material is further purified by silica gel
chromatography on a Chromatotron~ employing a 2000uM rotor in a 1:1
hexanes: ethyl acetate solvent system to provide the title compound (100 mg,
38
%) as a brown foam. Electrospray-MS 457.0 (M*+1 ).
Elemental Analysis:
C(Theory):55.24 C(Found): 54.89
H(Theory):7.06 H(Found):7.00
2 o N(Theory): 6.13 N(Found): 5.99
Example 21
Rreparation of (methylsulfonyl~{2-[~2~[(trifluoromethy~sulfonyllamino ethox )y
(2-
naphthyl~ethyl amine.
H O
p H \ \ N-~,
F3C-S-NCO I / /
25'
Scheme 1l, step D: {2-[6-(2-Aminoethoxy)(2-
naphthyl)]ethyl}(methylsulfonyl)amine (0.571 mmol, prepared in example 15) is
dissolved in methylene chloride in a 15 mL round bottomed flask, under a
nitrogen system. The mixture is cooled to 0°C, and triethylamine (0.2
mL, 2.5 eq)
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is added by syringe, followed by trifluoromethylsulfonyl chloride (0.09 mL,
1.5
eq.), also by syringe, and mixed overnight. The reaction is quenched with 20
mL
water, and layers are separated. The organic layer is washed with water (20
mL),
dried with sodium sulfate, ~Itered, and concentrated in vacuum. The residue is
further purified by silica gel chromatography on a Chromatotron~ employing a
2000uM rotor in a 1:1 hexanes: ethyl acetate solvent system to provide the
title
compound.
Example 22
1o Prelaaration of N-[2-(,6~'2-[~methylsulfonyl aminoleth~)-2-
naphthyloxy)ethy~acetamide.
H O
N_S-
O.
~O
Scheme VII, step A: (2-[6-(2-Aminoethoxy)(2-
naphthyl)]ethyl~(methylsulfonyl)amine (0.571 mmol) is dissolved in methylene
chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture
is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by
syringe, followed
by acetyl chloride (0.06 mL, 1.5 eq.), also by syringe, and mixed overnight.
The
reaction is quenched with 20 mL water, and layers are separated, The organic
layer is washed with water (20 mL), dried with sodium sulfate, filtered, and
2 o concentrated in vacuum. The residue is further purified by silica gel
chromatography on a Chromatotron~ employing a 2000uM rotor in a 1:1
hexanes: ethyl acefiate solvent system to provide the title compound.
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Example 23
Preparation of (methylsulfonyl f2-(6- 2-f(phenylsulfonyl)aminolethoxy~(2-
naphthyl~ eth 1y famine.
H O
O H I ~ ~ N_O
S_N~O /
O
Scheme II, step D: ~2-[6-(2-Aminoethoxy)(2-
naphthyl)]ethyl}(methylsulfonyl)amine (0.571 mmol) is dissolved in methylene
chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture
is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by
syringe, followed
by phenylsulfonyl chloride (0.11 mL, 1.5 eq.), also by syringe, and mixed
so overnight. The reaction is quenched with 20 mL water, and layers are
separated.
The organic layer is washed with water (20 mL), dried with sodium sulfate,
filtered, and concentrated in vacuum. The residue is further purified by
silica gel
chromatography on a Chromatotron~ employing a 2000uM rotor in a 1:1
hexanes: ethyl acetate solvent system to provide the title compound.
Example 24
Preparation of N-f2-(6-f2-f(meth Isy ulfonyl)aminolethyl~(2-
naphthyloxYl)ethyl)benzamide.
H O
O H I ~ W N
NCO / .i
2 o Scheme VI I, step A: {2-[6-(2-Aminoethoxy)(2-
naphthyl)]ethyl}(methylsulfonyl)amine (0.571 mmol) is dissolved in methylene
chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture
is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by
syringe, followed
by benzoyl chloride (0.04 mL, 1.5 eq.), also by syringe, and mixed overnight.
The reaction is quenched with 20 mL water, and layers are separated. The
organic layer is washed with water (20 mL), dried with sodium sulfate,
filtered,
and concentrated in vacuum. The residue is further purified by silica gel
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chromatography on a Chromatotron° employing a 2000uM rotor in a 1:1
hexanes: ethyl acetate solvent system to provide the final title compound.
Example 25
Preparation of N-f2-(6-f2-f(methylsulfonyl)amino]ethyl~-2-
naphthyloxy)ethyllbutanamide.
H O
H I \ \ N _O-
N~C / /
Scheme VII, step A: {2-[6-(2-Aminoethoxy)(2-
naphthyl)]ethyl~(methylsulfonyl)amine (0.571 mmol) is dissolved in methylene
1o chloride in a 15 mL round bottomed flask, under a nitrogen system. The
mixture
is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by
syringe, followed
by butyryl chloride (0.05 mL, 1.5 eq.), also by syringe, and mixed overnight.
The
reaction is quenched with 20 mL water, and layers are separated. The organic
layer is washed with water (20 mL), dried with sodium sulfate, filtered, and
concentrated in vacuum. The residue is further purified by silica gel
chromatography on a Chromatotron~ employing a 2000uM rotor in a 1:1
hexanes: ethyl acetate solvent system to provide the title compound.
Example 26
2 o Preparation of methoxy-N-f2-(6-f2-f(meth Is~r ulfonyl)amino]ethyl~(2-
naphthyloxy~)ethyl~Icarboxamide.
H O
O HP \ \ N_O
,O~--N~
O
Scheme VII, step D: ~2-[6-(2-Aminoethoxy)(2-
naphthyl)]ethyl}(methylsulfonyl)amine (0.571 mmol) is dissolved in methylene
chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture
is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by
syringe, followed
by methyl chloroformate (0.06 mL, 1.5 eq.), also by syringe, and mixed
overnight.
The reaction is quenched with 20 mL water, and layers are separated. The
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organic layer is washed with water (20 mL), dried with sodium sulfate,
filtered,
and concentrated in vacuum. The residue is further purified by silica gel
chromatography on a Chromatotron~ employing a 2000uM rotor in a 1:1
hexanes: ethyl acetate solvent system to provide the title compound.
~5
Example 27
Preaaration of lmethvlahenvlaminol-N-f2-(6-f2-f(methvlsulfonvl)aminolethvl~(2-
naphthyloxy~ ethyl]carboxamide.
H O
O I \ \ N-O,.
\ N-~--NCO
Zo Scheme VII, step E: {2-[6-(2-Aminoethoxy)(2-
naphthyl)]ethyl}(methylsulfonyl)amine (0.571 mmol) is dissolved in methylene
chloride in a 15 mL round bottomed flasle, under a nitrogen system. The
mixture
is cooled to 0°C, and triethylamine (0.2 mL, 2.5 equivalents) is added
by syringe,
followed by N-methyl-N-phenylcarbamoyl chloride (80 mg, 1.5 Eq.), also by
s5 syringe, and mixed overnight. The reaction is quenched with 20 mL water,
and
layers are separated. The organic layer is washed with water (20 mL), dried
with
sodium sulfate, filtered, and concentrated in vacuum. The residue is further
purified by silica gel chromatography on a Chromatotron~ employing a 2000uM
rotor in a 1:1 hexanes:ethyl acetate to provide the title compound.
Example 28
Preaaration of lmethvlsulfonvl)(2-f6-(2-
(~(trifluoromethvl)sulfonvllamino'~ethoxv)(2-
naahthvl)lethvl~amine.
H
O H I ~ W N_O
F3C-S-NCO
O
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Scheme II, step D: The title compound is prepared in a manner
analogous to the procedure set forth in example 21 from ~2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl}[(methylethyl)sulfonyl]amine (prepared in example 16).
Example 29
Preparation of N-f2-(6~2-f methylsulfonLrl)aminolethyl~-2-
naphthyloxy)ethyllacetamide.
H O
O H I ~ ~ ~ N O
-~-NCO
Scheme VII, step A: The title compound is prepared in a manner
Zo analogous to the procedure set forth in example 22 from ~2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl}[(methylethyl)sulfonyl]amine (prepared in example 16).
rreaarazton or tmemmsunonvmz-tt7-i~-itanenmsutronvnammoiemox
15 naphthyl)~ethyllamine.
H
O H I w w N_O
~ S_N~O
O
Scheme II, step D: The title compound is prepared in a manner
analogous to the procedure set forth in example 23 from {2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl[(methylethyl)sulfonyl]amine (prepared in example 16).
~o
Example 31
Preparation of N-[2-(~2-[(methylsulfonyl)aminolethLrl~(2-
naphthyloxy~)ethyllbenzamide.
H o
N-S
v
~ N I / i
~O
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Scheme Vll, step A: The title compound is prepared in a manner
analogous to the procedure set forth in example 24 from j2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl)[(methylethyl)sulfonyl]amine (prepared in example 16).
Example 32
Preparation of N-f2-(6-~2-f methylsulfon r~l)amino~ethLrl~-2-
naphthyloxy)ethyllbutanamide.
H O
O H I \ \ N_O
~N~O
Scheme VII, step A: The title compound is prepared in a manner
to analogous to the procedure set forth in example 25 from {2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl}[(methylethyl)sulfonyl]amine (prepared in example 16).
Example 33
Preparation of methoxy-N-[2-(6-~2-j(methylsulfonyl)aminolethyl~(2-
naiphth rLloxy~)ethyl]Icarboxamide.
H
O H I \ \ N_O
~ -~-NCO
Scheme V(I, step A: The title compound is prepared in a manner
analogous to the procedure set forth in example 26 from j2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl}[(methylethyl)sulfonyl]amine (prepared in example 16).
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Example 34
Preaaration of (methvlahenvlaminol-N-f2-(6-f2-f(methvlsulfonvllaminolethvl)(2-
naahthvloxv))ethvllcarboxamide.
H O
W W N
N-~--NCO
Scheme VII, step E: The title compound is prepared in a manner
analogous to the procedure set forth in example 27 from ~2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl)[(methylethyl)sulfonyl]amine (prepared in example 16).
Example 35
so Preparation of f(methylethyl)sulfony~2 j6~2-
~[~trifluoromethyl sulfonyllamino ethoxy~(2-na~~hthyl)iaropyl;amine.
O
O H I ~ w N 0
F3C-S-NCO /
O
Scheme II, step D: The title compound is prepared in a manner
analogous to the procedure set forth in example 21 from {2-[6-(2-
aminoethoxy)(2-
i5 naphthyl)]propyl)[(methylethyl)sulfonyl]amine (prepared in example 19).
Example 36
Preparation of N-~2-f6-~1-methyl-2~[(methylethyl)sulfonyllamino)ethyl
naphthyloxy]ethyl~acetamide.
H O
O H ~ w N O
~N~O I / /
Scheme VII, step A: The title compound is prepared in a manner
analogous to the procedure set forth in example 22 from {2-[6-(2-
aminoethoxy)(2-
naphthyl)]propyl}[(methylethyl)sulfonyl]amine (prepared in example 19).
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Example 37
Preparation of f methylethyl)sulfonYl]f2-(~2-f hhenylsulfonyl)aminolethoxy)(2-
n~~hth~lpropyllamine.
H O
O H I \ \ N_O
~ S_N~O / /
O
Scheme 1l, step D: The title compound is prepared in a manner
analogous to the procedure set forth in example 23 from ~2-(6-(2-
aminoethoxy)(2-
naphthyl)]propyl}[(methylethyl)sulfonyl]amine (prepared in example 19).
Example 38
to Preparation of N-f2-f6-(1-meth rll-2~[(methylethyl sulfonyllamino)ethyl)(2-
naphthylox~r)]ethyl)benzamide.
H O
O H \ W N 0
N~ I
O
Scheme VII, step A: The title compound is prepared in a manner
analogous to the procedure set forth in example 24 from {2-[6-(2-
aminoethoxy)(2-
i5 naphthyl)]propyl}[(methylethyl)sulfonyl]amine (prepared in example 19).
Example 39
Preparation of N-~2-f6-(1-methy~j(methylethyl)sulfonyllamino ethyl)-2-
naphthyloxy]ethyl~butanamide.
H
O H I \ \ N_O
~N~O
Scheme VII, step A: The title compound is prepared in a manner
analogous to the procedure set forth in example 25 from {2-[6-(2-
aminoethoxy)(2-
naphthyl)]propyl}[(methylethyl)sulfonyl]amine (prepared in example 19)
Example 40
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Preparation of methoxy-N~'21~1-methyl-2-
~[Lmethylethyl)sulfonvllamino~ethvl)(2-naphthvloxv)lethvl~carboxamide.
H O
p H I \ \ N 0
~ --~-Nip / /
Scheme VII, step D: The title compound is prepared in a manner
s analogous to the procedure set forth in example 26 from {2-[6-(2-
aminoethoxy)(2-
naphthyl)]propyl~[(methylethyl)sulfonyl]amine (prepared in example 19~
Example 41
Preparation of N-~2-f6-(1-methyl-2-f~meth Iy ethy I~sulfonyllamino~ethyl~2-
1o naphthyloxy)]eth~~l)~methylphen~rlamino)carboxamide.
H O
H, ' I \ w N
N-~L-Nip /
Scheme VII, step E: The title compound is prepared in a manner
analogous to the procedure set forth in example 27 from {2-[6-(2-
aminoethoxy)(2-
naphthyl)]propyl}[(methylethyl)sulfonyl]amine (prepared in example 19)
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Example 42
Preparation of (methylsulfonyl)[~6-f2-fbenzylamino]iethoxy~(2-
napht~l) ethyllamine.
H O
H I W w N
N~
.~ O
/
Scheme VII, step C: {2-[6-(2-Aminoethoxy)(2-
naphthyl)]ethyl}(methylsulfonyl)amine (0.343 mmol, prepared in example 15)
dissolved in methanol (2 mL) is added to a 15 mL round bottomed flask fitted
with a stirbar and under a nitrogen atmosphere. Benzaldehyde (0.06 mL, 1.0
eq.) is treated with a catalytic amount of acetic acid and stirred at room
Zo temperature for4 hours. Sodium borohydride (26 mg, 2.0 eq.) is added, and
the
reaction is stirred overnight at room temperature. The reaction mixture is
then
diluted with water (5 mL), and extracted with methylene chloride (3 x 25 mL).
The organic extracts are combined and filtered through potassium carbonate,
and concentrated under vacuum. The residue is further purified by silica gel
i5 chromatography, employing a Chromatotron~ and a 2000 uM rotor in 100% ethyl
acetate eluent to provide the title compound.
Example 43
Preparation of f(methylethyl)sulfonyll[~6-f2-[benzylamino]ethoxy~(2-
2 o na~hthyl~ ethyllamine. .
H O
H I W ~ N
N~
O
Scheme VII, step C: The title compound is prepared in a manner
analogous to the procedure set forth in example 42 from {2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl}[(methylethyl)sulfonyl]amine (prepared in example 16).
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Example 44
Preparation of ~(methylethyl sulfonyl~[~6-f2-fbenzylaminolethoxy)(2-
naphthyl))propyllamine.
H O
I \ \ No
NCO / /
r
Scheme VII, step C: ~2-[6-(2-Aminoethoxy)(2-
naphthyl)]propyl}[(methylethyl)sulfonyl]amine (0.343 mmol, prepared in example
19) dissolved in methanol (2 mL) is added to a 15 mL round bottomed
flask~fitted
with a stirbar and under a nitrogen atmosphere. Benzaldehyde (0.06 mL, 1.0
eq.) dissolved in acetic acid (1 mg, 0.05 eq.) is added by syringe and stirred
at
1 o room temperature for 4 hours. Sodium borohydride (26 mg, 2.0 eq.) is
added,
and the reaction is stirred overnight at room temperature. Reaction mixture is
diluted with water (5 mL), and extracted with methylene chloride (3 x 25 mL).
The organic extracts are combined and filtered through potassium carbonate,
and concentrated under vacuum, yielding 126 mg as a brown oil. This material
is was further purified by silica gel chromatography, employing a
Chromatotron~
and a 2000 uM rotor in 100% ethyl acetate eluent to provide the title compound
(81 mg, 54%) as a yellow foam. Electrospray-MS 441.0 (M*+1 ).
Exam~~le 45
2 o Preparation of amino-N-[2~6-~2-[(methylsulfonyl)aminolethLrl)(2-
naphthyloxy~ethyllamide.
H O
O H I \ ~ N_O
HZN-~-NCO / /
Scheme VII, step B: Trifluoroacetic acid (0.06 mL, 1.4 eq.) in toluene (1
mL) is added dropwise to a solution of {2-[6-(2-aminoethoxy)(2-
2s naphthyl)]ethyl}(methylsulfonyl)amine (0.571 mmol, prepared in example 15)
and
sodium cyanate (74 mg, 2.0 eq.) in toluene (3 mL) with stirring, at
50°C, and
under a nitrogen atmosphere in a 15 mL round bottomed flask. The solution is
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then heated to 70°C and stirred for one hour. The reaction mixture is
concentrated under vacuum. This material is washed with 1 N NaOH (15 mL),
and extracted with methylene chloride (3 x 15 mL). The organic extracts are
combined and washed with brine (1 x 50 mL), filtered through potassium
carbonate, and concentrated under vacuum. The residue is then purified by
silica gel chromatography, employing a Chromatotron~ with a 4000 uM rotor and
1:1 hexanes:ethyl acetate eluent to provide the title compound.
Examale 46
to Preparation of amino-N- 216~2~~methyleth I)sy_ ulfonyllamino)ethyl~(2-
naphthyloxy)lethtrl amide.
H O
O H I W ~ N_O
H~N~N~O
Scheme VII, step B: The title compound is prepared in a manner
analogous to the procedure set forth in example 45 from ~2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl}[(methylethyl)sulfonyl]amine (prepared in example 16).
Example 47
Preparation of amino-N-~2-f6-(1-methyl-2-~[(methylethyl)sulfonyl amino)eth
rLl)(2-
naahthyloxy)lethyl)amide.
H O
O H I ~ ~ N_O
H2N-~-NCO
Scheme VII, step B: Trifluoroacetic acid (0.06 mL, 1.4 eq.) in toluene (1
mL) is added dropwise to {2-[6-(2-aminoethoxy)(2-
naphthyl)]propyl}[(methylethyl)sulfonyl]amine (0.571 mmol, prepared in Example
19) and sodium cyanate (74 mg, 2.0 eq.) in toluene (3 mL) with stirring, at
50°C,
and under a nitrogen atmosphere in a 15 mL round bottomed flask. Solution was
heated to 70°C and stirred for one hour. The reaction mixture is
concentrated
under vacuum. This material is washed with 1 N NaOH (15 mL), and extracted
with methylene chloride (3 x 15 mL). The organic extracts are combined and
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washed with brine (1 x 50 mL), filtered through potassium carbonate, and
concentrated under vacuum to yield 400 mg orange foam. This material is
purified by silica gel chromatography, employing a Ghromatotron~ with a 4000
uM rotor and 1:1 hexanes:ethyl acetate eluent to provide the title compound
(165
mg, 73%) as a yellow liquid. Electrospray-MS 394.0 (M*+1 ).
Example 48
Preparation of (methylamino)-N-f2- 6-f2-[(methylsulfonyl aminoletf~l~2-
naphthyloxy))ethyllcarboxamide.
H O
H p H ( \ \ N-O-
~N-~-NCO
Scheme VII, step E: Methyl isocyanate (0.05 mL, 1.0 eq.) is added
dropwise to {2-[6-(2-aminoethoxy)(2-naphthyl)]ethyl)(methylsulfonyl)amine
(0.7133 mmol, prepared in example 15) in THF (5 mL) at 0°C, in a 15 mL
round
bottomed flask fitted with a stirbar. The reaction is stirred overnight in an
ice
bath, gradually warming to room temperature. The reaction mixture is then
quenched with water (5 mL) and is extracted with methylene chloride (3 x 15
mL).
The organic extracts are combined and washed with brine (1 x 50 mL), filtered
through MgS04, and concentrated under vacuum. This material is then purified
by silica gel chromatography, employing a Chromatotron~ with a 2000 uM rotor
2 o and 1:1 methylene chloride:ethyl acetate eluent to provide the title
compound.
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Example 49
Preparation of (methvlamino)-N-f2-f6-(2-~f(methvlethvl)sulfonvliamino~ethv11f2-
naahthvloxv)iethvl~carboxamide.
H O
p H I ~ W N
~N-~-Nip /
Scheme VII, step E: The title compound is prepared in a manner
analogous to the procedure set forth in example 48 from {2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl}[(methylethyl)sulfonyl]amine (prepared in example 16).
Example 50
to Preparation of (meth lad)-N-f2-f6-(1-meth-2-
~~(methylethylysulfon Il~)ethyll(2-na~hthYlox~]ethyl~carboxamide.
H O
p H I \ \ - N O
~N~-N~p % /
Scheme VII, step E: Methyl isocyanate (0.05 mL, 1.0 eq.) is added
dropwise to ~2-[6-(2-aminoethoxy)(2-
naphthyl)]propyl)[(methylethyl)sulfonyl]amine
(0.7133 mmol, prepared in Example 19) in THF (5 mL) at 0°C, in a 15 mL
round
bottomed flask fitted with a stirbar. The reaction is then stirred overnight
in ice
bath, gradually warming to room temperature. The reaction mixture is quenched
with water (5 mL) and is extracted with methylene chloride (3 x 15 mL). The
organic extracts are combined and washed with brine (1 x 50 mL), filtered
2 o through MgS04, and concentrated under vacuum, yielding 184 mg yellow foam.
This material is purified by silica gel chromatography, employing a
Chromatotron~ with a 2000 uM rotor and 1:1 methylene chloride:ethyl acetate
eluent to provide the title compound (130 mg, 45 %) as a colorless oil.
Electrospray-MS 408.0 (M*+1 ).
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Example 51
Preparation of~2-~6-f2-(dimethylamino)ethoxyl(2-
naphth~)~ethyl (methylsulfonLrl)amine.
H O
-NCO / /
Scheme VII, step C:. To a stirring solution of ~2-[6-(2-aminoethoxy)(2-
naphthyl)]ethyl}(methylsulfonyl)amine (0.713 mmol, prepared in example 15 in
methanol (5 mL) is added formaldehyde (0.85 mL, 16 eq.) over a 15 minute
period and let the mixture to stirr at room temperature for one hour. Sodium
borohydride (216 mg, 8 eq) is added to the reaction and the mixture is stirred
at
Zo room temperature over night. The reaction is concentrated under vacuum and
the crude product is dissolved in 2:1 methylene chloride:water (30 mL).
Organic
material is extracted with methylene chloride (2x 30 mL) and the combined
organic layer is washed with water (30 mL) and brine (30 mL), dried over
MgS04, and concentrated under vacuum. The residue is then purified by silica
gel chromatography, employing a Chrori~atotron~ with a 2000 uM rotor and 9:1
methylene chloride:methanol eluent to provide the title compound.
Example 52
Preparation of (2~6-f2-(dimeth lay mino~ethoxyl(2-
2 o naphthyl) ethyl)~methylethyl)sulfonyllamine.
H O
N O
-NCO
Scheme VII, step C: The title compound is prepared in a manner
analogous to the procedure set forth in example 51 from {2-[6-(2-
aminoethoxy)(2-
naphthyl)]ethyl][(methylethyl)sulfonyl]amine (prepared in example 16).
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Example 53
Preparation of (~'6-f2-~ imethylamino)ethoxy]~2-
naphthyl~~prop r~(meth Iy ethLrl)sulfonyllamine.
H O
\ N
-NCO
Scheme VII, step C: To a stirring solution of {2-[6-(2-aminoethoxy)(2-
naphthyl)]propyl}[(methylethyl)sulfonyl]amine (0.713 mmol, prepared in Example
19) in methanol (5 mL) is added formaldehyde (0.85 mL, 16 eq.) over a 15
minute period and let the mixture to stirr at room temperature for one hour.
Sodium borohydride (216 mg, 8 eq) is addedto the reaction and the mixture is
so stirred at room temperature over night. The reaction is concentrated under
vacuum and the crude product is dissolved in 2:1 methylene chloride:water (30
mL). Organic material is extracted with methylene chloride (2x 30 mL) and the
combined organic layer is washed with water (30 mL) and brine (30 mL), dried
over MgS04, and concentrated under vacuum. The residue is then purified by
silica gel chromatography, employing a Chromatotron~ with a 2000 uM rotor and
9:1 methylene chloride:methanol eluent to provide the title compound (42 mg,
16
%) as a yellow foam. Electrospray-MS 379.0 (M'~+1 ).
Elemental Analysis:
C(Theory):63.46 C(Found):62.15
2 o H(Theory): 7.99 H(Found): 7.49
N(Theory):7.40 N(Found):7.10
The ability of compounds of formula I to potentiate glutamate receptor-
2 s mediated response may be determined using fluorescent calcium indicator
dyes
(Molecular Probes, Eugene, Oregon, Fluo-3) and by measuring glutamate-
evoked efflux of calcium into GIuR4 transfected HEK293 cells, as described in
more detail below.
In one test, 96 well plates containing confluent monolayers of HEK 293
3 o cells stably expressing human GIuR4B (obtained as described in European
Patent Application Publication Number EP-A1-583917) are prepared. The tissue
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culture medium in the wells is then discarded, and the wells are each washed
once with 200 p1 of buffer (glucose, 10mM, sodium chloride, 138mM, magnesium
chloride, 1 mM, potassium chloride, 5mM, calcium chloride, 5mM, N-[2-
hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid], 10mM, to pH 7.1 to 7.3).
The
plates are then incubated for 60 minutes in the dark with 20 pM FIuo3-AM dye
(obtained from Molecular Probes Inc., Eugene, Oregon) in buffer in each well.
After the incubation, each well is washed once with 100 p1 buffer, 200 NI of
buffer
is added and the plates are incubated for 30 minutes.
Solutions for use in the test are also prepared as follows. 30 pM, 10 pM, 3
1 o pM and 1 pM dilutions of test compound are prepared using buffer from a 10
mM
solution of test compound in DMSO. 100 pM cyclothiazide solution is prepared
by adding 3 p1 of 100 mM cyclothiazide to 3 mL of buffer. Control buffer
solution
is prepared by adding 1.5 p1 DMSO to 498.5 p1 of buffer.
Each test is then performed as follows. 200 p1 of control buffer in each
well is discarded and replaced with 45 p1 of control buffer solution. A
baseline
fluorescent measurement is taken using a FLUOROSKAN II fluorimeter
(Obtained from Labsystems, Needham Heights, MA, USA, a Division of Life
Sciences International Plc). The buffer is then removed and replaced with 45
p1
of buffer and 45 p1 of test compound in buffer in appropriate wells. A second
2 o fluorescent reading is taken after 5 minutes incubation. 15 p1 of 400 pM
glutamate solution is then added to each well (final glutamate concentration
100
pM), and a third reading is taken. The activities of test compounds and
cyclothiazide solutions are determined by subtracting the second from the
third
reading (fluorescence due to addition of glutamate in the presence or absence
of
test compound or cyclothiazide) and are expressed relative to enhance
fluorescence produced by 100 pM cyclothiazide.
In another test, HEK293 cells stably expressing human GIuR4 (obtained
as described in European Patent Application Publication No. EP-A1-0583917)
are used in the electrophysiological characterization of AMPA receptor
3 o potentiators. The extracellular recording solution contains (in mM): 140
NaCI, 5
KCI, 10 HEPES, 1 MgCl2, 2 CaCl2, 10 glucose, pH = 7.4 with NaOH, 295 mOsm
kg-1. The intracellular recording solution contains (in mM): 140 CsCI, 1
MgCl2,
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HEPES, (N-[2-hydroxyethyl]piperazine-N1-[2-ethanesulfonic acid]) 10 EGTA
(ethylene-bis(oxyethylene-nitrilo)tetraacetic acid), pH = 7.2 with CsOH, 295
mOsm kg-1. With these solutions, recording pipettes have a resistance of 2-3
MSS. Using the whole-cell voltage clamp technique (Hamill et a1.(19$1
)Pflugers
5 Arch., 391: 85-100), cells are voltage-clamped at -60mV and control current
responses to 1 mM glutamate are evoked. Responses to 1 mM glutamate are
then determined in the presence of test compound. Compounds are deemed
active in this test if, at a test concentration of 10 pM or less, they produce
a
greater than 10% increase in the value of the current evoked by 1 mM
glutamate.
1o In order to determine the potency of test compounds, the concentration of
the test compound, both in the bathing solution and co-applied with glutamate,
is
increased in half log units until the maximum effect was seen. Data collected
in
this manner are fit to the Hill equation, yielding an EC5o value, indicative
of the
potency of the test compound. Reversibility of test compound activity is
determined by assessing control glutamate 1 mM responses. Once the control
responses to the glutamate challenge are re-established, the potentiation of
these responses by 100 pM cyclothiazide is determined by its inclusion in both
the bathing solution and the glutamate-containing solution. In this manner,
the
efficacy of the test compound relative to that of cyclothiazide can be
determined.
2 o According to another aspect, the present invention provides a
pharmaceutical composition, which comprises a compound of formula I or a
pharmaceutically acceptable salt thereof and a pharmaceutically acceptable
diluent or carrier.
The pharmaceutical compositions are prepared by known procedures
using well-known and readily available ingredients. In making the compositions
of the present invention, the active ingredient will usually be mixed with a
carrier,
or diluted by a carrier, or enclosed within a carrier, and may be in the form
of a
capsule, sachet, paper, or other container. When the carrier serves as a
diluent,
it may be a solid, semi-solid, or liquid material which acts as a vehicle,
excipient,
3 0 or medium for the active ingredient. The compositions can be in the form
of
tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions,
emulsions, solutions, syrups, aerosols, ointments containing, for example, up
to
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10% by weight of active compound, soft and hard gelatin capsules,
suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers, excipients, and diluents include
lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium
phosphate, alginates, tragcanth, gelatin, calcium silicate, micro-crystalline
cellulose, polyvinylpyrrolidone, cellulose, water syrup, mefihyl cellulose,
methyl
and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The
formulations can additionally include lubricating agents, wetting agents,
emulsifying and suspending agents, preserving agents, sweetening agents, or
1 o flavoring agents. Compositions of the invention may be formulated so as to
provide quick, sustained, or delayed release of the active ingredient after
administration to the patient by employing procedures well known in the art.
The compositions are preferably formulated in a unit dosage form, each
dosage containing from about 1 mg to about 500 mg, more preferably about 5
mg to about 300 mg (for example 25 mg) of the active ingredient. The term
"unit
dosage form" refers to a physically discrete unifi suitable as unitary dosages
for
human subjects and other mammals, 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.
2 o As used herein the term "patient" refers to a mammal, such as a mouse,
guinea pig, rat, dog or human. It is understood that the preferred patient is
a
human.
As used herein, the terms "treating" or "to treat" each mean to alleviate
symptoms, eliminate the causation either on a temporary or permanent basis, or
to prevent or slow the appearance of 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 of a
compound of formula I which is effective, upon single or multiple dose
3 o administration to a patient, in treating the patient suffering from the
named
disorder.
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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, a number of factors are considered by the attending
s diagnostician, including, but not limited to: the species of mammal; its
size, age,
and general health; the specific disease or disorder involved; the degree of
or
involvement or the severity of the disease or disorder; the response of the
individual patient; the particular compound administered; the mode of
administration; the bioavailability characteristics of the preparation
administered;
Zo the dose regimen selected; the use of concomitant medication; and other
relevant circumstances.
The compounds of formula I can be administered by a variety of routes
including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular,
bucal or intranasal routes. Alternatively, the compounds of formula I may be
s5 administered by continuous infusion. A typical daily dose will contain from
about
0.01 mg/kg to about 100 mg/kg of the compound of formula I. 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.
The compounds of the present invention as a class are particularly useful
2 o in the treatment methods of the present invention, but certain groups,
substituents, and configurations are preferred. The following paragraphs
describe such preferred groups, substituents, and configurations. It will be
understood that these preferences are applicable both to the treatment methods
and to the new compounds of the present invention.
2 s a) R is preferably hydrogen;
b) W is preferably R$S02- or R~3C(=O), and most preferably R$S02.
c) R~ is preferably (1-4C)alkyl, CF3, N(CH3)2, or NH(CH3), most
preferably methyl, ethyl, propyl, CF3, or 2-propyl, and it is most
especially preferred that R~ is 2-propyl;
3 o d) R2 is preferably hydrogen, F, methyl, ethyl, propyl, hydroxy, or
methoxy, most preferably hydrogen, F, hydroxy, or methyl, and it is
most especially preferred that R2 is F or methyl;
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e) R3a is preferably hydrogen, F, methyl, ethyl, propyl, hydroxy, or
methoxy, and most preferably hydrogen, F, hydroxy, or methyl;
f) R3b is preferably hydrogen, methyl, ethyl, propyl, or methoxy, most
preferably hydrogen, or methyl, and it is most especially preferred
that R3b is hydrogen;
g) R4a is preferably hydrogen, F, methyl, ethyl, methoxy, or ethoxy,
and most preferably hydrogen, F, methyl or methoxy, and it is most
especially preferred that R4a is hydrogen;
h) R4b iS preferably hydrogen, F, methyl, ethyl, methoxy, or ethoxy,
1 o and most preferably hydrogen, F, methyl or methoxy, and it is most
especially preferred that R4b is hydrogen;
i) R5 is preferably hydrogen, methyl, or ethyl, most preferably
hydrogen or methyl, and it is most especially preferred that R5 is
hydrogen;
j) R6 is preferably hydrogen, methyl, or ethyl, most preferably
hydrogen or methyl, and it is most especially preferred that R6 is
hydrogen;
k) R' is preferably hydrogen or methyl with hydrogen being most
preferred;
1) R$ is preferably (1-4C)alkyl, CF3, N(CH3)2, phenyl, or NH(CH3),
most preferably methyl, ethyl, propyl, 2-propyl, phenyl, or CF3, and
it is most especially preferred that R$ is 2-propyl;
m) R9 is preferably hydrogen or methyl;
n) R~° is preferably hydrogen or methyl;
0) R~~ is preferably hydrogen, methyl or ethyl, and most preferably
hydrogen;
p) n is preferably zero, 1, 2 or 3, most preferably zero or 1, and it is
most especially preferred that n is zero;
q) m is preferably 1, 2 or 3, and most preferably 1 or 2;
3 o r) p is preferably 1;
s) When R2 is hydrogen, R3a is preferably F or methyl;
t) When R3a is hydrogen, R2 is preferably F or methyl;
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u) R'2 is preferably methyl;
v) R~3 is preferably methyl, ethyl, propyl, or phenyl;
w) R~4 Is preferably methyl, ethyl, or propyl, with methyl being most
preferred;
x) R~5 is preferably methyl, ethyl, or propyl, with methyl being most
preferred;
y) R~6 is preferably methyl, ethyl, propyl, or benzyl, with methyl and
benzyl being most preferred;
z) B is preferably;
R4a
',
or
' R4b
R'"'
'
with
or
'
being most preferred.
aa) In addition, when W is R~3C(=O)- or R~6, it is especially preferred
that B is
R4a
'
'
' R4b
'
'
Wlth
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\ /
\ /
being most especially preferred.
