Note: Descriptions are shown in the official language in which they were submitted.
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PHENOXYBENZYLAMINE DERIVATIVES AS SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS
This invention relates to novel diphenyl ether compounds which inhibit
monoamine re-
uptake. In particular compounds of the present invention exhibit activity as
selective
serotonin re-uptake inhibitors (SSRIs) and have utility therefore in a variety
of
therapeutic areas. Notably the compounds of the present invention are useful
in the
treatment or prevention of a variety of disorders, including those in which
the regulation
of monoamine transporter function is implicated, such as depression, attention
deficit
hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress
disorder,
substance abuse disorders and sexual dysfunction including premature
ejaculation, and
to pharmaceutical formulations containing such compounds.
According to a first aspect, the invention provides a compound of general
formula (I),
pharmaceutically acceptable salts, solvates or polymorphs thereof;
NR~ R2
R5
~O
R
Y
Z
(I)
wherein;
R' and Ra, which may be the same or different, are H, C,-Csalkyl or
(CHz)d(C3-Cscycloalkyl) wherein d = 0, 1, 2 or 3; or R'and R~ together with
the
nitrogen to which they are attached form an azetidine ring;
Z or Y is -SR3 and the other Z or Y is halogen or -R3; wherein R3 is
independently C,-C4
alkyl optionally substituted with fluorine; except that R3 is not CF3;
or Z and Y are linked so that, together with the interconnecting atoms, Z and
Y form a
fused 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated,
unsaturated or aromatic, and wherein when Z and Y form a heterocyclic ring, in
addition to carbon atoms, the linkage contains one or two heteroatoms
independently selected from oxygen, sulfur and nitrogen; with the proviso that
when R5 is fluorine and R2 is methyl then the fused ring is not 1,3-dioxolane
and
Z and Y together do not form a fused phenyl ring;
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R4 and R5, which may be the same or different, are:
A-X, wherein A = -CH=CH- or -(CHZ)P where p is 0, 1 or 2; X is hydrogen, F,
CI,
Br, I, CONR6R', SOZNR6R', SOzNHC(=O)R6, OH, C,_4alkoxy, NR$SOzR9,
N02, NR6R", CN, C02R'°, CHO, SR'°, S(O)R9 or S02R'°;
R6, R', R$ and
R'° which may be the same or different, are hydrogen or C,_salkyl
optionally substituted independently by one or more R'2; R9 is C,_6 alkyl
optionally substituted independently by one or more R'Z; R" is hydrogen,
C,_6 alkyl optionally substituted independently by one or more R'~, C(O)R6,
C02R9, C(O)NHRs or SOZNR6R'; R'~ is F (preferably up to 3), OH, COZH,
C3_6cycloalkyl, NHz, CONHZ, C,_6alkoxy, C,_salkoxycarbonyf or a 5- or 6-
membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected
from N, S and O optionally substituted independently by one or more R'3;
or R6 and R', together with the nitrogen to which they are attached, form a
4-, 5- or 6-membered heterocyclic ring optionally substituted
independently by one or more R'3; or
a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected
from N, S and O, optionally substituted independently by one or more R'3;
wherein R'3 is hydroxy, C,-C4alkoxy, F, C,-C6alkyl, haloalkyl, haloalkoxy,
-NH2, -NH(C,-Csalkyl) or -N(C,-Csalkyl)2.
Unless otherwise indicated, any alkyl group may be straight or branched and is
of 1 to 6
carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.
Unless otherwise indicated, any carbocyclyl group contains 3 to 8 ring-atoms,
and may
be saturated, unsaturated or aromatic. Preferred saturated carbocyclyl groups
are
cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclyl
groups contain
up to 3 double bonds. A preferred aromatic carbocyclyl group is phenyl. The
term
carbocylic should be similarly construed. In addition, the term carbocyclyl
includes any
fused combination of carbocyclyl groups, for example naphthyl, phenanthryl,
indanyl and
indenyl.
Unless otherwise indicated, any heterocyclyl group contains 5 to 7 ring-atoms
up to 4 of
which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be
saturated,
unsaturated or aromatic. Examples of heterocyclyl groups are furyl, thienyl,
pyrrolyl,
pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl,
imidazolyl, imidazolinyl,
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imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl,
isothiazolyl, oxadiazolyl,
triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino,
dithianyl,
thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl,
tetrazolyl,
triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl. In
addition, the term
heterocyclyl includes fused heterocyclyl groups, for example benzimidazolyl,
benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl,
oxazolopyridinyl,
benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl,
benzothiazolyl,
phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl. The term
heterocyclic
should be similarly construed.
Halo means fluoro, chloro, bromo or iodo.
Preferably R' and R2, which may be the same or different, are hydrogen or C,-
C6alkyl.
More preferably hydrogen or methyl.
When Z or Y is -SR3, R3 is preferably methyl or ethyl.
When ~ and Y form a fused ring, the ring is preferably a heterocyclic ring.
More
preferably, the linkage contains one or two sulfur atoms.
Preferably R4 and R5 are not both hydrogen.
Preferably R4 and R5, which may be the same or different, are
-(CH2)P X, where p is 0, 1 or 2 (preferably 0 or 1); X is hydrogen, hydroxy,
CONR6R',
SO~NR6R', NR$S02R9, SR'°, SOR9 or SO2R'° wherein R6, R', R8,
R9 and R'° are
as defined in the first aspect, or
a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected
from N,
S and O (preferably oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl,
pyridinyl
or pyrimidinyl).
More preferably R4 and R5, which may be the same or different, are:
-(CH2)P X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R', SOZNR6R' or
NR$S02R9;
wherein R6 and R', which may be the same or different, are hydrogen or
C,-C3alkyl optionally substituted by hydroxy, -CONH~ or C,-C3alkoxy
(preferably
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methoxy); R8 is hydrogen, hydroxyethyl or methyl; or R9 is methyl, ethyl,
isopropyl, trifluoromethyl or methoxyethyl; or
triazolyl, imidazolyl or pyrazolyl.
More preferably still R4 is hydrogen.
Preferably R6 and R', which may be the same or different, are hydrogen, C,-
C3alkyl
optionally substituted by hydroxy, -CONHZ or C,-C3alkoxy (preferably methoxy).
More
preferably R6 and R', which may be the same or different, are hydrogen or
methyl, more
preferably still hydrogen.
When present, R'2 is preferably oxadiazolyl, triazolyl, imidazolyl, oxazolyl,
pyrazolyl,
pyridinyl or pyrimidinyl. More preferably triazolyl, imidazolyl or pyrazolyl.
In the case where R6 and R', together with the nitrogen to which they are
attached, form
a heterocyclic ring, preferred rings are pyrrolidine or piperidine rings each
of which may
be substituted by OH or CONH~ or a morpholine ring which may be substituted by
CONH~.
Preferably R" is hydrogen or C,_s alkyl.
Preferably R$ is hydrogen, hydroxyethyl or methyl. More preferably hydrogen.
Preferably R9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyi.
More preferably
methyl or ethyl (preferably methyl).
Preferably R'° is methyl or ethyl.
Preferably p is 1 or 0, more preferably 0.
Preferably
R' and R~, which may be the same or different, are hydrogen or methyl;
when present, R3 is methyl or ethyl; or Z and Y are linked so that, together
with the
interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic or
heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein
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when Z and Y form a heterocyclic ring, in addition to carbon atoms, the
linkage
contains one or two heteroatoms independently selected from oxygen, sulfur and
nitrogen; and
R4 and R5, which may be the same or different, are
5 (CH~)p X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R', S02NR6R',
NR$S02R9,
SR'°, SOR9 or SOZR'° and wherein R6 and R', which may be
the same or
different, are hydrogen, C,-C3alkyl optionally substituted by hydroxy, -CONH~
or
C,-C3alkoxy (preferably methoxy); or R6 and R', together with the nitrogen to
which they are attached, may form a morpholine, pyrrolidine or piperidine ring
each of which may be substituted by OH or CONH2; R$ is hydrogen, hydroxyethyl
or methyl (preferably hydrogen); R9 is methyl, ethyl, isopropyl,
trifluoromethyl or
methoxyethyl; and R'° is methyl or ethyl; or
an oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or
pyrimidinyl group.
More preferably
R' and R2, which may be the same or different, are hydrogen or methyl;
when present, R3 is methyl or ethyl; or Z and Y are linked so that, together
with the
interconnecting atoms, Z and Y form a fused 5 to 7-membered heterocyclic ring
containing 1 or 2 sulfur atoms; and
R4 and R5 , which may be the same or different, are
-(CHOP X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R', SO~NRsR' or
NRBSO~R9;
wherein R6 and R', which may be the same or different, are hydrogen, C,-
C3alkyl
optionally substituted by hydroxy, -CONH~ or C,-C3alkoxy (preferably methoxy);
RS is hydrogen, hydroxyethyl or methyl; R9 is methyl, ethyl, isopropyl,
trifluoromethyl or methoxyethyl; or
triazolyl, imidazolyl or pyrazolyl.
More preferably still
R' and R2, which may be the same or different, are hydrogen or methyl;
when present R3 is methyl or ethyl; or Z and Y are linked so that, together
with the
interconnecting atoms, Z and Y form a fused saturated 5 to 7-membered
heterocyclic ring containing 1 or 2 sulfur atoms;
R4 is hydrogen, and
RS is
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-(CH2)P X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R', SO~NRsR' or
NR8S02R9;
wherein R6 and R', which may be the same or different, are hydrogen, C,-
C3alkyl
optionally substituted by hydroxy, -CONHz or C,-C3alkoxy (preferably methoxy);
R$ is hydrogen, hydroxyethyl or methyl; R9 is methyl, ethyl, isopropyl,
trifluoromethyl or methoxyethyl; or
triazolyl, imidazolyl or pyrazolyl.
More preferably still R4 and R5 are not both hydrogen.
Preferred compounds are:
4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]-
benzenesulfonamide
(Example 2);
3-[(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-
benzenesulfonamide
(Example 12);
4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(dimethylamino)methyl]-
benzenesulfonamide
(Example 16);
4-[3-chloro-4-(methylsulfanyl)phenoxy]-3-[(dimethylamino)methyl]-
benzenesulfonamide
(Example 17);
3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]-
benzenesulfonamide
(Example 18);
N,N-dimethyl-N-[2-(6-quinolinyloxy)benzyl]amine (Example 29);
3-[(methylamino)methyl]-4-(6-quinolinyloxy)benzenesulfonamide (Example 35);
4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]benzamide (Example
60);
4-(2,3-dihydro-1-benzothien-5-yloxy)-N-methyl-3-[(methylamino)methyl]-
benzamide
(Example 62);
N-{3-[(methylamino)methyl]-4-[3-methyl-4-
(methylsulfanyl)phenoxy]benzyl~methanesulfonamide (Example 75);
3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzamide
(Example
79);
4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]benzamide
(Example
88);
~3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]phenyl-
methanol
(Example 90);
3-[(dimethylamino)methyl]-4-(6-quinolinyloxy)benzamide (Example 100);
3-[(methylamino)methyl]-4-(6-quinolinyloxy)benzamide (Example 102);
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N-methyl-N-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-
phenyl~methanesulfonamide (Example 116) and
N-{4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]phenyl~-
methanesulfonamide (Example 124).
According to a second aspect the invention provides compound of formula (I) or
(XIX)
NR~ R2
R5
~O
R
Y
(I) Z
and pharmaceutically acceptable salts or solvates thereof wherein (in this
aspect): R'
and R2 independently represent H, C~-Cg alkyl or (CH~)d(C3-Cscycloalkyl)
wherein d = 0,
1, 2 or 3, or wherein NR'R2 when taken together represent a 4-membered ring
wherein
R' and RZ together represent C3 alkyl; Z and Y both independently represent -
SR3
wherein, when Z = -SR3 then Y = halogen, -ORa, -Ra or -SRa; or when Y = -SR3
then Z =
halogen, -ORa, Ra or -SRa; and R3 and Ra independently represent: C,-C4 alkyl
(optionally
substituted with fluorine atoms e.g. -CF3); or Z and Y when taken together can
represent a fused 5 to 7 membered ring as illustrated by general formula XIX,
wherein
said 5 to 7 membered ring may be saturated, unsaturated or aromatic, and
wherein said
5 to 7 membered ring may optionally contain one or more heteroatoms P and Q,
wherein P and Q = may be independently O, S or N, and wherein E, F, or G
independently represent CH or CHI and wherein k and p may independently be =
0, 1, 2
or 3, and m = 1,2 or 3; and
NR~R2
R5
Rq O
(E)l \ F)p
P
(xlx) \
(G)m
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R4 and RS independently represent A-X wherein A = -(CHZ)n , wherein n
represents 0, 1
or 2 and wherein X represents: H, F, CI, Br, I, CONRsR' or SO~NRsR', OH,
NR$SO~R9,
NO~, NR6R", CN, COzR'°, CHO, S(O)mR'° wherein m = 0, 1 or 2 and
wherein R6, R', R$
and R'° independently represent H or C,_6 alkyl, wherein R9 represents
C,_6 alkyl, R"
represents H, C,_s alkyl, C(O)RE, C02R9, C(O)NHR6 or S02NR6R6 and wherein said
C,_6
alkyl group is optionally substituted by one or more groups selected from OH,
COzH, Cg_6
cycloalkyl, NHZ, CONHZ, C,.6 alkoxy, C,_s alkoxycarbonyl and a 5- or 6-
membered
heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O;
or with the
proviso that when P=Q= oxygen then both k and p are not zero; with the proviso
that Z
and Y together do not form a fused phenyl ring; R4 or R5 may be representative
of a 5- or
6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N,
S and
O; and in addition, R6 and R' may, together with the N atom to which they are
attached,
represent a 5- or 6- membered heterocyclic ring which may be optionally
substituted;
and pharmaceutically acceptable salts or solvates thereof with the proviso
that both R4
Z 5 and R5 are not H.
For the avoidance of doubt, unless otherwise indicated, the term substituted
means
substituted by one or more defined groups. In the case where groups may be
selected
from a number of alternatives groups, the selected groups may be the same or
different.
For the avoidance of doubt, the term independently means that where more than
one
substituent is selected from a number of possible substituents, those
substituents may
be the same or different.
According to a third aspect, the invention provides a compound of general
formula I and
pharmaceutically acceptable salts thereof, wherein R', Rz , R3, Z and Y are as
defined in
the first aspect; and R4 and R5, which may be the same or different, are -
(CHz)P A',
wherein p is 0, 1 or 2 and A' is a polar group. In this aspect, polar groups
may be defined
as those having a negative ~-value (see C Hansch and A Leo, 'Substituent
Constants for
Correlation Analysis in Chemistry and Biology', Wiley, New York, 1979). In
this system,
H has a ~-value of 0.00, -OCH3 has a ~-value of -0.02, and -SO~NH~ has a ~-
value of -
1.82, for example [see Table VI-I, 'Well-Characterized Aromatic Substituents',
p 49, ibid].
More preferred polar groups have a more negative ~-value: thus, preferred
groups have
~-values of a greater negative value than -0.1, more preferably a greater
negative value
than -0.5, and most preferably a greater negative value than -1Ø Even when p
is other
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than zero in the above definition, the definition of A' is based on the above
reference as
if p was zero.
Unless otherwise specified, the compounds of the first, second and third
aspects are
hereinafter defined as compounds of the invention.
The compounds of the invention have the advantage that they are selective
inhibitors of
the re-uptake of serotonin (SRIs) (and so are likely to have reduced side
effects), they
have a rapid onset of action (making them suitable for administration shortly
before an
effect is required), they have desirable potency and associated properties.
Compounds
that selectively inhibit the re-uptake of serotonin, but not noradrenaline or
dopamine, are
preferred.
We have found that compounds of formula I which possess these properties have
a
relatively polar group at R41R5.
The pharmaceutically or veterinarily acceptable salts of the compounds of
formula I
which contain a basic centre are, for example, non-toxic acid addition salts
formed with
inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and
phosphoric
acid, with carboxylic acids or with organo-sulfonic acids. Examples include
the HCI, HBr,
HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate,
benzoate,
succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate,
gluconate, camsylate,
methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and
pamoate
salts. Compounds of the invention can also provide pharmaceutically or
veterinarily
acceptable metal salts, in particular non-toxic alkali and alkaline earth
metal salts, with
bases. Examples include the sodium, potassium, aluminium, calcium, magnesium,
zinc,
diolamine, olamine, ethylenediamine, tromethamine, chloine, megulamine and
diethanolamine salts. For reviews on suitable pharmaceutical salts see Berge
et al, J.
Pharm, Sci., 66, 1-19, 1977; P L Gould, International Journal of
Pharmaceutics, 33
(1986), 201-217; and Bighley et al, Encyclopedia of Pharmaceutical Technology,
Marcel
Dekker Inc, New York 1996, Volume 13, page 453-497.
Hereinafter, the compounds, their pharmaceutically acceptable salts, their
solvates and
polymorphs, defined in any aspect of the invention (except intermediate
compounds in
chemical processes) are referred to as "compounds of the invention".
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The pharmaceutically acceptable solvates of the compounds of the invention
include the
hydrates thereof.
5 The compounds of the invention may possess one or more chiral centres and so
exist in
a number of stereoisomeric forms. All stereoisomers and mixtures thereof are
included
in the scope of the present invention. Racemic compounds may either be
separated
using preparative HPLC and a column with a chiral stationary phase or resolved
to yield
individual enantiomers utilising methods known to those skilled in the art. In
addition,
10 chiral intermediate compounds may be resolved and used to prepare chiral
compounds
of the invention.
In cases where the compounds of the invention exist as the E and Z isomers,
the
invention includes individual isomers as well as mixtures thereof.
In cases where compounds of the invention exist as tautomeric isomers, the
invention
includes individual tautomers as well as mixtures thereof.
In cases where the compounds of the invention exist as optical isomers, the
invention
includes individual isomers as well as mixtures thereof.
In cases where the compounds of the invention exist as diastereoisomers, the
invention
includes individual diastereoisomers as well as mixtures thereof.
Separation of diastereoisomers or E and Z isomers may be achieved by
conventional
techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. An
individual
enantiomer of a compound of the invention may be prepared from a corresponding
optically pure intermediate or by resolution, such as by H.P.L.C. of the
corresponding
racemate using a suitable chiral support or by fractional crystallisation of
the
diastereoisomeric salts formed by reaction of the corresponding racemate with
a suitable
optically active acid or base, as appropriate.
The compounds of the invention may exist in one or more tautomeric forms. All
tautomers and mixtures thereof are included in the scope of the present
invention. For
example, a claim to 2-hydroxypyridinyl would also cover its tautomeric form, a-
pyridonyl.
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It will be appreciated by those skilled in the art that certain protected
derivatives of
compounds of the invention, which may be made prior to a final deprotection
stage, may
not possess pharmacological activity as such, but may, in certain instances,
be
administered orally or parenterally and thereafter metabolised in the body to
form
compounds of the invention which are pharmacologically active. Such
derivatives may
therefore be described as "prodrugs". Further, certain compounds of the
invention may act
as prodrugs of other compounds of the invention.
All protected derivatives and prodrugs of compounds of the invention are
included within
the scope of the invention. Examples of suitable pro-drugs for the compounds
of the
present invention are described in Drugs of Today, Volume 19, Number 9, 1983,
pp 499 -
538 and in Topics in Chemistry, Chapter 31, pp 306 - 316 and in "Design of
Prodrugs" by
H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents
are
incorporated herein by reference).
It will further be appreciated by those skilled in the art, that certain
moieties, known to
those skilled in the art as "pro-moieties", for example as described by H.
Bundgaard in
"Design of Prodrugs" (the disclosure in which document is incorporated herein
by
reference) may be placed on appropriate functionalities when such
functionalities are
present within the compounds of the invention.
Preferred prodrugs for compounds of the invention include: esters, carbonate
esters, hemi-
esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides,
carbamates, azo-
compounds, phosphamides, glycosides, ethers, acetals and ketals.
The invention also includes all suitable isotopic variations of the compounds
of the
invention. An isotopic variation is defined as one in which at least one atom
is replaced
by an atom having the same atomic number but an atomic mass different from the
atomic mass usually found in nature. Examples of isotopes that can be
incorporated into
compounds of the invention include isotopes of hydrogen, carbon, nitrogen,
oxygen,
phosphorus, sulphur, fluorine and chlorine such as ZH, 3H, '3C, '4C, '5N, "O,
'$O, 31P, szP,
35S' ~aF and 36C1, respectively. Certain isotopic variations of the invention,
for example,
those in which a radioactive isotope such as 3H or'4C is incorporated, are
useful in drug
and/or substrate tissue distribution studies. Tritiated, i.e. 3H, and carbon-
14, i.e. '4C
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isotopes are particularly preferred for their ease of preparation and
detectability.
Further, substitution with isotopes such as deuterium, i.e. 2H, may afford
certain
therapeutic advantages resulting from greater metabolic stability, for
example, increased
in vivo half-life or reduced dosage requirements and hence may be preferred in
some
circumstances. Isotopic variations of the compounds of the invention can
generally be
prepared by conventional procedures such as by the methods or preparations
described
in the Examples and Preparations hereafter using appropriate isotopic
variations of
suitable reagents.
Compounds of the invention may be prepared, in known manner in a variety of
ways. In
the following reaction schemes and hereafter, unless otherwise stated, R' to
R'3, Z and Y
are as defined in the first aspect. These processes form further aspects of
the invention.
Throughout the specification, general formulae are designated by Roman
numerals I, II,
III, IV etc. Subsets of these general formulae are defined as la, Ib, Ic etc,
.... IVa, IVb,
IVc etc.
Compounds of general formula (I) may be prepared from compounds of formula
(II) by
reaction with an amine of general formula HNR'Rz, or with a suitable salt form
thereof,
together with a hydride reducing agent in a suitable solvent (see Scheme 1 ).
When
either R' or R~ is hydrogen, suitable solvents include protic solvents such as
ethanol,
and sodium borohydride is an appropriate reducing agent as exemplified by
Example 36
herein. When neither R' or R~ are hydrogen, tetrahydrofuranl dichloromethane
is a
suitable solvent system and sodium triacetoxyborohydride is a suitable
reducing agent.
In such reactions the use of a salt form of HNR'R2, such as the hydrochloride
is
preferable, and an auxiliary base, to aid solubility of the HNR'R2 salt, such
as
triethylamine may optionally be added along with acetic acid, as exemplified
by Example
25 herein.
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SCHEME1
O OH 0 NR~ R2
Rs ~ Rs ~ Rs
~ ~ ---~. ~ ~ --,-
Ra \ L \ Y Ra \ O Ra \ 0
(III)
,Y _Y
Z Z
(II) (I)
Compounds of formula (II) may be prepared in turn from the coupling of
compounds of
general formula (IV) with aldehyde compounds of general formula (Ill), wherein
L is a
suitable leaving group such as halogen (F, CI, Br or I) or a sulfonate ester
such as
trifluoromethanesulfonate or methanesulfonate, preferably L is F or CI. Such
coupling
reaction may be accomplished by techniques known in the art, such as via
reaction with
potassium carbonate in a suitable solvent such as dimethylformamide under
appropriate
reaction conditions such as elevated temperature and in an inert atmosphere.
Thus according to a further aspect, the invention provides a process for
preparing
compounds of general formula (I) from compounds of the general formula (II).
Alternatively, R4 and/or RS may be introduced after ether coupling (see Scheme
2).
Compounds of genera( formula (I) may be prepared from compounds of general
formula
(la), i.e. compounds of general formula (I) where R4 and RS are hydrogen.
Compounds of
general formula (la) may be prepared from (11a) in an analogous fashion to the
preparation of (I) from (II) (see Scheme 1 ), while compounds of general
formula (11a)
may be prepared from (IV) and (Illa) in an analogous fashion to the
preparation of (II)
(see Scheme 1 ).
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14
SCHEME2
OH O O NR~R2
\ ~ ~ ~
'Y L ~O O
Z
(IV) (Illa)
\ ~ \
~Y _Y
Z Z
(11a) (la) (I)
Thus according to a fiurther aspect, the invention provides a process for
preparing
compounds of general formula (I) from compounds of the general formula (la).
Methodologies for introducing R4 and/or R5 into compounds of formula (la)
include:
i) Where Ra/R~ are halogen, by reaction of (la) with a suitable halogenating
agent in
an inert solvent which does not adversely afFect the reaction. Suitable
halogenating agents include trifluoromethanesulfonic acid and N-
iodosuccinimide
and suitable inert solvents include dichloromethane.
ii) Where R4/R5 are -NO2, by reaction of (la) with a suitable nitrating agent,
such as
an alkali metal nitrate, in a solvent which does not adversely affect the
reaction
at, or below, room temperature. Suitable nitrating agents include
trifluoromethanesulfonic acid/ potassium nitrate and suitable solvents include
trifluoroacetic acid.
iii) Where R4/R5 is -S02NR6R' by reaction of an intermediate sulfonyl chloride
with
the requisite amine of formula HNR6R' in a suitable solvent. Suitable solvents
include a mixture of water and dichloromethane and the reactions are generally
perfiormed at or below room temperature. The intermediate sulfonyl chlorides
may be prepared from compounds of formula (la) by reaction with chlorosulfonic
acid under low temperature conditions in the presence of a solvent which does
not adversely afifect the reaction, either with or without subsequent
treatment with
a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride,
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oxalyl chloride or thionyl chloride in a solvent which does not adversely
affect the
reaction. Suitable solvents for the reaction with chlorosulfonic acid include
trifluoroacetic acid and a typical reaction temperature is 0 °C.
Suitable solvents
for the reaction with chlorinating agents include acetonitrile and suitable
5 conditions include at reflux, as illustrated in Example 12 herein.
For example, compounds of formula (1q), where R5 is -SOzNR6R', may be
prepared via the intermediate sulfonyl chlorides (XVIII) from compounds of
formula (la) by reaction of (la) with chlorosulfonic acid, either with or
without
10 subsequent treatment with a chlorinating agent such as phosphorus
oxychloride,
phosphorus pentachloride, oxalyl chloride or thionyl chloride, followed by
reaction
with HNR6R' (see scheme 2a). Reaction conditions typically comprise low
temperature. The reaction can talee place either neat, i.e. in the absence of
solvent, or in the presence of an inert solvent which does not adversely
affect the
15 reaction. The intermediate sulfonyl chloride (XVII) may be isolated,
purified and
then reacted with HNR6R', alternatively it may be generated in situ, without
isolation, and then reacted with HNR6R'.
SCHEME 2a
NR~R2 " ~ NR~R2
R6R7NS0
O , O
_Y wY
Z Z Z
(la) (XVIII) (1q)
Thus according to a further aspect, the invention provides a process for
preparing
compounds of general formula (I) from compounds of the general formula (II).
In a
preferred embodiment, there is provided a process for preparing compounds of
formula
(1q) by reacting compounds of formula (la) in a suitable solvent, with
chlorosulfonic acid,
either with or without subsequent treatmenfi with a chlorinating agent such as
phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl
chloride, to
give compounds of formula (XVIII) followed by reaction with HNR6R'to give
compounds
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16
of formula (1q). Preferably compounds of formula (XVIII) are generated in situ
and
reacted with HNR6R' without isolation.
Alternatively, compounds of general formula (I) having a particular R4/R5
substituent may
be converted into other compounds of formula (I) using known techniques. For
example:
i) When R4/R5 is halogen such as chloro, bromo or iodo, it may be converted to
cyano via reaction with a cyanide salt in the presence of a Pd(0) or
(II)catalyst in
a high boiling solvent at elevated temperatures. Suitable Pd catalysts include
palladium tetrakis(triphenylphosphine), suitable cyanide salts include Zn(CN)2
and suitable high boiling solvents which do not adversely affect the reaction
include dimethylformamide as exemplified by Example 78 herein;
ii) When R4/RS is halogen such as chloro, bromo or iodo, it may be converted
to the
corresponding ester -C02R by treatment with carbon monoxide at high pressure
with a Pd(0) or (II) catalyst, in an alcohol solvent (ROH wherein R is C, - C4
alkyl), in the presence of a base at elevated temperatures. For example the
reaction may be carried out at pressures in the region of about 100 p.s.i,
whilst
suitable Pd catalysts include dichlorobis(triphenylphosphine) palladium (II),
suitable bases include triethylamine and suitable alcohol solvents include
methanol as exemplified by Preparation 50 herein;
iii) When R4/R5 is nitro, it may be reduced to the corresponding -NH2 group
via
treatment with a reducing agent in a erotic solvent at, or above, room
temperature. Suitable reducing agents include iron powder / calcium chloride,
suitable erotic solvents include aqueous ethanol and a typical reaction
temperature is from about 70°C to about 100°C, preferably about
90°C, as
exemplified by Example 103 herein;
iv) When R4/RS is -NHS, it may be converted to the corresponding -NHS02R9
group
by reaction with a sulfonylating agent in the presence of a base in an inert
solvent
which does not adversely affect the reaction at, or below, room temperature.
Suitable sulfonylating agents include methanesulfonyl chloride, suitable bases
include triethylamine and suitable inert solvents include dichloromethane as
exemplified by Example 128 herein;
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v) When R4/R5 is a -NHSOZR9 group, it may be converted to the corresponding -
NR$SOZR9 group via treatment with an alkylating agent and a base in a suitable
inert solvent. Examples of suitable alkylating agents include methyl iodide,
suitable bases include potassium carbonate and suitable inert solvents include
acetonitrile, as exemplified by Preparation 88 herein;
vi) When R4/R5 is a nitrite -CN, it may be converted to the corresponding -
C(O)NHz
group by hydrolysis under basic, oxidative or acid conditions. Basic
hydrolysis is
preferably conducted with a hydroxide salt such as potassium hydroxide in a
protic solvent such as t-butanol at elevated temperatures, as exemplified in
Example 79 herein.
vii) When R4/R5 is an ester -CO~R, it may be reduced to the corresponding
alcohol
group -CH~OH via treatment with a hydride reducing agent, such as lithium
aluminium hydride, as exemplified by Preparation 69 herein;
viii) When R4/R5 is an ester-C02R, it may be converted to the corresponding
acid -
COzH by treatment with a suitable hydroxide salt in the presence of water and
a
suitable co-solvent. Suitable hydroxide salts include lithium hydroxide and
suitable co-solvents include tetrahydrofuran, as exemplified by Preparation 55
herein;
ix) When R4/R5 is an acid -CO2H, it may be converted to the corresponding
amide -
CONR6R' by treatment with a coupling agent, a base and an amine HNR6R' in a
suitable inert solvent which does not adversely affect the reaction. Suitable
coupling agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride in the presence of 1-hydroxybenzotriazole, suitable bases
include
triethylamine and suitable solvents include dichloromethane, as exemplified by
Preparation 59 herein;
x) When R4/RS is halogen such as chloro, bromo or iodo, it may be converted to
an
a,~i-unsaturated amide, by treatment with acrylamide, a Pd(0) or (II) catalyst
and
a suitable base, in an inert solvent which does not adversely affect the
reaction,
at elevated temperatures. Suitable Pd catalysts include palladium (II) acetate
in
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18
the presence of trio-tolyl)phosphine, suitable bases include triethylamine and
suitable inert solvents include acetonitrile as exemplified by Example 50
herein;
xi) When R4/RS is an a,,~-unsaturated amide, it may be converted to -
CH2CHZC02NH2, by treatment with a suitable reducing agent at an appropriate
temperature, in a suitable solvent which does not adversely affect the
reaction.
Suitable reducing agents include samarium diiodide at room temperature and
suitable solvents include tetrahydrofuran containing a small amount of water,
as
exemplified by Example 51 herein;
xii) When R4/R5 is -CH~OH, it may be converted to -CHZNR$SOZR9 by means of a
Mitsunobu reaction at an appropriate temperature, in a suitable solvent which
does not adversely affect the reaction. Suitable reagents include diethyl
azodicarboxylate, triphenylphosphine and tent-butyl methylsulfonylcarbamate,
0°C is a suitable reaction temperature and tetrahydrofuran is a
suitable solvent
as exemplified by Preparation 72 herein;
Alternatively, compounds of general formula (I) having a particular NR'R~
group may be
converted into other compounds of general formula (I) having a different NR'RZ
group.
For example:
Compounds of formula (1b) wherein either R' or Rz is hydrogen, can be
converted
into a compound of formula (lc) wherein neither R' nor RZ are hydrogen, by
reaction of the compound of formula (1b) with an aldehyde and a hydride
reducing agent. Suitable aldehydes include formaldehyde, suitable reducing
agents include sodium tri(acetoxy)borohydride and the reaction is preferably
conducted in a solvent which does not interfere with the reaction, such as
dichloromethane at or below room temperature, as exemplified by Example 12
herein.
ii) Compounds of formula (1b) wherein R' or R2 is hydrogen, can be converted
into a
compound of formula (lc) wherein R' or R~ is methyl, by reaction of the
compound of formula (1b) with a formylating agent in a suitable solvent,
followed
by subsequent reduction of the intermediate N-formyl compound with a hydride
reducing agent in an inert solvent, preferably at elevated temperature.
Suitable
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19
formylating agents include pentafluorophenyl formats (formed from formic acid,
pentafluorophenol and dicyclohexylcarbodiimide) and suitable solvents for the
formylation include dichloromethane. Suitable reducing agents include borane-
tetrahydrofuran complex and suitable inert solvents for the reduction include
tetrahydrofuran as exemplified by Example 110 herein.
Alternatively, compounds of general formula (I) may be prepared from compounds
of
formula V (see Scheme 3) wherein L is as defined for Scheme 1 and T is a group
which
can be converted into CH~NR'R2. Examples of suitable T substitutents include: -
CO~R'°,
-CN and -C(O)NR'R2.
SCHEME3
NR'Rz
Rs
OH
5
R / T / one or more steps R~ \ O
Ra \ L \ Y
Z \
Y
Z
(vi) (i~ M
O)
Methodologies for converting compounds of formula (V) to (I), include:
i) Where T is -C02R'° and R'° = methyl or ethyl, by reaction
with an amine of
general formula NHR'R~ to form an amide, followed by reduction to provide an
amine.
ii) Where T = -CN, by reduction to its corresponding amine of formula -CH2NH2.
iii) Where T = -C(O)NR'R~, by reduction to provide an amine.
Compounds of general formula (V) may be prepared in turn by the coupling of
compounds of general formula (VI) and compounds of the general formula (IV).
Reagents and conditions for such coupling reactions are as previously defined
for the
coupling of compounds of general formulae (IV) and (III) in Scheme 1.
Compounds of general formula (VI) may be prepared in turn from compounds of
general
formula (VII) (see Scheme 4).
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SCHEME 4
T R$ T
L R L
(VII) (VI)
Compounds of formula (VI) may be prepared by aromatic electrophilic
substitution of
5 compounds of formula (VII) to give compounds of formula (Vi) directly.
Alternatively
compounds of formula (VI) may be prepared in two or more steps; aromatic
electrophilic
substitution of compounds of formula (VII) to give intermediate compounds
which then
undergo further reaction to give compounds of formula (VI). The intermediate
compounds may be isolated or generated in situ without isolation. A preferred
route is
10 shown in Scheme 5.
SCHEME 5
CISO T R6R~NS02 T
T /
L
L L
(VII) (VIII) (Vla)
Compounds of formula (VII) are reacted with sulfonyl chloride to give
compounds of
15 formula (VIII) followed by reaction with NHR6R'to give compounds of formula
(Vla).
According to further aspects, the invention provides compounds of formulae
(II), (11a)
and (V) as defined above.
20 Compounds of formulae (III), (Illa), (IV), (VI) or (VII) are either known
and available from
commercial sources or are available from commercially available materials
using known
techniques (see Examples hereinafter).
It will be apparent to those skilled in the art that sensitive functional
groups may need to be
protected and deprotected during synthesis of a compound of formula I. This
may be
achieved by conventional techniques, for example as described in 'Protective
Groups in
Organic Synthesis', 3rd edition, by T W Greene and P G M Wuts, John Wiley and
Sons
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21
Inc, 1999. Example 35 provides one example of a protecting group strategy
employed in
the synthesis of a compound of the present invention.
The skilled chemist will appreciate that diaryl ethers may be prepared using a
number of
synthetic methodologies. For a review of methodologies see J S Sawyer,
Tetrahedron,
56 (2000) 5045-5065, incorporated herein by reference.
The compounds of the invention are useful because they have pharmacological
activity
in mammals, including humans. More particularly, they are useful in the
treatment or
prevention of a disorder in which the regulation of monoamine transporter
function is
implicated. Disease states that may be mentioned include hypertension,
depression
(e.g. depression in cancer patients, depression in Parkinson's patients,
postmyocardial
infarction depression, subsyndromal symptomatic depression, depression in
infertile
women, paediatric depression, major depression, single episode depression,
recurrent
depression, child abuse induced depression, post partum depression and grumpy
old
man syndrome), generalized anxiety disorder, phobias (e.g. agoraphobia, social
phobia
and simple phobias), posttraumatic stress syndrome, avoidant personality
disorder,
premature ejaculation, eating disorders (e.g. anorexia nervosa and bulimia
nervosa),
obesity, chemical dependencies (e.g. addictions to alcohol, cocaine, heroin,
phenobarbital, nicotine and benzodiazepines), cluster headache, migraine,
pain,
Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory
disorders
(e.g. dementia, amnestic disorders, and age-related cognitive decline (ARCD)),
Parkinson's diseases (e.g. dementia in Parkinson's disease, neuroleptic-
induced
parkinsonism and tardive dyskinesias), endocrine disorders (e.g.
hyperprolactinaemia),
vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,
gastrointestinal
tract disorders (involving changes in motility and secretion), negative
symptoms of
schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress
incontinence,
Tourette's syndrome, trichotillomania, kleptomania, male impotence, attention
deficit
hyperactivity disorder (ADHD), chronic paroxysmal hemicrania, headache
(associated
with vascular disorders), emotional lability, pathological crying, sleeping
disorder
(cataplexy) and shock.
Disorders of particular interest include depression, attention deficit
hyperactivity disorder,
obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse
disorders and sexual dysfunction including (in particular) premature
ejaculation.
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22
Premature ejaculation may be defined as persistent or recurrent ejaculation
before, upon
or shortly after penile penetration of a sexual partner. It may also be
defined as
ejaculation occurring before the individual wishes [see 'The Merck Manual',
16t" edition,
p 1576, published by Merck Research Laboratories, 1992].
Thus, according to further aspects, the invention provides:
i) a compound of the invention for use as a pharmaceutical;
ii) the use of a compound of the invention in the manufacture of a medicament
for
the treatment or prevention of a disorder in which the regulation of monoamine
transporter function is implicated, for example depression, attention deficit
hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress
disorder, substance abuse disorders or sexual dysfunction including premature
ejaculation;
iii) the use of a compound of the invention in the manufacture of a medicament
for
the treatment or prevention of premature ejaculation;
iv) a method of treatment or prevention of depression, attention deficit
hyperactivity
disorder, obsessive-compulsive disorder, post-traumatic stress disorder,
substance abuse disorders or sexual dysfunction including premature
ejaculation,
which comprises administering a therapeutically effective amount of a compound
of the invention to a patient in need of such treatment or prevention;
v) a method of increasing ejaculatory latency which comprises the
administration of
an effective amount of a compound of the invention to a male desiring
increased
ejaculatory latency; and
vi) a compound of the invention for the treatment or prevention of a disorder
in
which the regulation of monoamine transporter function is implicated, for
example
depression, attention deficit hyperactivity disorder, obsessive-compulsive
disorder, post-traumatic stress disorder, substance abuse disorders or sexual
dysfunction including premature ejaculation.
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23
vii) a compound of the invention for treating premature ejaculation.
It is to be appreciated that all references herein to treatment include
curative, palliative
and prophylactic treatment.
The compounds of the invention may be administered alone or as part of a
combination
therapy. If a combination of active agents are administered, then they may be
administered simultaneously, separately or sequentially. In particular, the
compounds of
the invention may be combined with the following preferably for the treatment
of PE:
i) Alpha-Mockers (e.g. phentolamine, doxazasim, tamsulosin, terazasin,
prazasin
and Example 19 of W09830560. A possible rationale for alpha-blockers treating
premature ejaculation is as follows. Muscular activity of the ejaculatory
smooth
muscles (vas deferens, seminal vesicles and urethra) are controlled by the
sympathetic nervous system through the release of noradrenalin. Noradrenalin
acts on the alpha 1 adrenoreceptors, stimulating muscle contractions, leading
to
seminal emission and subsequently ejaculation. Blocking these receptors will
therefore inhibit ejaculation.
ii) Apomorphine - teachings on the use of apomorphine as a pharmaceutical may
be found in US-A-5945117.
iii) Dopamine D2 agonists (e.g. Premiprixal, Pharmacia Upjohn compound number
PNU95666).
iv) Melanocortin receptor agonists (e.g. Melanotan II).
v) PGE1 receptor agonists (e.g. alprostadil).
vi) Mono amine transport inhibitors, particularly Noradrenaline Re-uptake
Inhibitors
(NRIs) (e.g. Reboxetine), other Serotonin Re-uptake Inhibitors (SRIs) (e.g.
paroxetine) or Dopamine Re-uptake Inhibitors (DRIs).
vii) 5-HT3 antagonists (e.g. ondansetron and granisetron). A possible
rationale for 5-
HT3 antagonists treating premature ejaculation is as follows. 5-HT3 receptors,
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24
present in the lumen of the posterior portion of the urethra, are stimulated
by 5-
HT in the semen during seminal emission, leading to a sensitisation of the
spinal
relex pathway which leads to ejaculation. Therefore, an antagonist would
prevent
this sensitisation and thus delay ejaculation.
viii) PDE inhibitors such as PDEZ (e.g. erythro-9-(2-hydroxyl-3-nonyl)-
adenine) and
Example 100 of EP 0771799-incorporated herein by reference) and in particular
a
PDE5 inhibitor (e.g. sildenafil, 1-{[3-(3,4-dihydro-5-methyl-4-oXO-7-
propylimidazo[5,1-f]-as-trazin-2-yl)-4-ethoxyphenyljsulfonyl}-4-
ethylpiperazine i.e.
vardenafil / Bayer BA 38-9456 or IC351 (see structure below, Icos Lilly)). A
possible rationale for PDE inhibitors treating premature ejaculation is as
follows. c
AMP and CGMP levels in the ejaculatory smooth muscles regulate muscle tone
of these ejaculatory muscles and so delay ejaculation.
Met
N
IC351 (Icos Lilly)
ix) Potassium channel openers.
x) P2X purinergic receptor antagonists.
xi) Endothelin receptor antagonists
For human use the compounds of the invention can be administered alone but in
human
therapy will generally be administered in admixture with a suitable
pharmaceutical
excipient, diluent or carrier selected with regard to the intended route of
administration
and standard pharmaceutical practice.
For example, the compounds of the invention, can be administered orally,
buccally or
sublingually in the form of tablets, capsules (including soft gel capsules),
ovules, elixirs,
solutions or suspensions, which may contain flavouring or colouring agents,
for
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immediate-, delayed-, modified-, sustained-, dual-, controlled-release or
pulsatile delivery
applications. The compounds of the invention may also be administered via
intracavernosal injection. The compounds of the invention may also be
administered via
fast dispersing or fast dissolving dosage forms.
5
Such tablets may contain excipients such as microcrystalline cellulose,
lactose, sodium
citrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch
(preferably
corn, potato or tapioca starch), disintegrants such as sodium starch
glycollate,
croscarmellose sodium and certain complex silicates, and granulation binders
such as
10 polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMG),
hydroxypropylcellulose
(HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as
magnesium
stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in
gelatin capsules.
15 Preferred excipients in this regard include lactose, starch, a cellulose,
milk sugar or high
molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs,
the
compounds of the invention, and their pharmaceutically acceptable salts, may
be
combined with various sweetening or flavouring agents, colouring matter or
dyes, with
emulsifying and/or suspending agents and with diluents such as water, ethanol,
20 propylene glycol and glycerin, and combinations thereof.
Modified release and pulsatile release dosage forms may contain excipients
such as
those detailed for immediate release dosage forms together with additional
excipients
that act as release rate modifiers, these being coated on and/or included in
the body of
25 the device. Release rate modifiers include, but are not exclusively limited
to,
hydroxypropylmethyl cellulose, methyl cellulose, sodium
carboxymethylcellulose, ethyl
cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer,
ammonio
methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax,
cellulose
acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid
copolymer
and mixtures thereof. Modified release and pulsatile release dosage forms may
contain
one or a combination of release rate modifying excipients. Release rate
modifying
excipients may be present both within the dosage form i.e. within the matrix,
and/or on
the dosage form, i.e. upon the surface or coating.
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Fast dispersing or dissolving dosage formulations (FDDFs) may contain the
following
ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose
sodium,
crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin,
hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl
methacrylate, mint
flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch
glycolate,
sodium stearyl fumarate, sorbitol, xylitol. The terms dispersing or dissolving
as used
herein to describe FDDFs are dependent upon the solubility of the drug
substance used
i.e. where the drug substance is insoluble a fast dispersing dosage form can
be
prepared and where the drug substance is soluble a fast dissolving dosage form
can be
prepared.
The compounds of the invention can also be administered parenterally, for
example,
intravenously, intra-arterially, intraperitoneally, intrathecally,
intraventricularly,
intraurethrally, intrasternally, intracranially, intramuscularly or
subcutaneously, or they
may be administered by infusion techniques. For such parenteral administration
they
are best used in the form of a sterile aqueous solution which may contain
other
substances, for example, enough salts or glucose to make the solution isotonic
with
blood. The aqueous solutions should be suitably buffered (preferably to a pH
of from 3
to 9), if necessary. The preparation of suitable parenteral formulations under
sterile
conditions is readily accomplished by standard pharmaceutical techniques well
known to
those skilled in the art.
The following dosage levels and other dosage levels herein are for the average
human
subject having a weight range of about 65 to 70 kg. The skilled person will
readily be
able to determine the dosage levels required for a subject whose weight falls
outside this
range, such as children and the elderly.
For oral and parenteral administration to human patients, the daily dosage
level of the
compounds of the invention or salts or solvates thereof will usually be from
10 to 500 mg
(in single or divided doses).
Thus, for example, tablets or capsules of the compounds of the invention may
contain
from 5 mg to 250 mg of active compound for administration singly or two or
more at a
time, as appropriate. The physician in any event will determine the actual
dosage which
will be most suitable for any individual patient and it will vary with the
age, weight and
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27
response of the particular patient. The above dosages are exemplary of the
average
case. There can, of course, be individual instances where higher or lower
dosage
ranges are merited and such are within the scope of this invention. The
skilled person
will also appreciate that, in the treatment of certain conditions (including
PE),
compounds of the invention may be taken as a single dose on an "as required"
basis
(i.e. as needed or desired).
Example Tablet Formulation
In general a tablet formulation could typically contain between about 0.01 mg
and 500mg
of a compound of the invention whilst tablet fill weights may range from 50mg
to
1000mg. An example formulation for a 10mg tablet is illustrated:
In rg edient %w/w
Compound of the invention 10.000*
Lactose 64.125
Starch 21.375
Croscarmellose Sodium 3.000
Magnesium Stearate 1.500
* This quantity is typically adjusted in accordance with drug activity.
The compounds of the invention can also be administered intranasally or by
inhalation
and are conveniently delivered in the form of a dry powder inhaler or an
aerosol spray
presentation from a pressurised container, pump, spray or nebulizer with the
use of a
suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetra-
fluoro-ethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A
[trade
mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon
dioxide or
other suitable gas. In the case of a pressurised aerosol, the dosage unit may
be
determined by providing a valve to deliver a metered amount. The pressurised
container, pump, spray or nebulizer may contain a solution or suspension of
the active
compound, e.g. using a mixture of ethanol and the propellant as the solvent,
which may
additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and
cartridges (made,
for example, from gelatin) for use in an inhaler or insufflator may be
formulated to
contain a powder mix of a compound of the invention and a suitable powder base
such
as lactose or starch.
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Aerosol or dry powder formulations are preferably arranged so that each
metered dose
or "puff' contains from 1 to 50 mg of a compound of the invention for delivery
to the
patient. The overall daily dose with an aerosol will be in the range of from 1
to 50 mg
which may be administered in a single dose or, more usually, in divided doses
throughout the day.
The compounds of the invention may also be formulated for delivery via an
atomiser.
Formulations for atomiser devices may contain the following ingredients as
soiubilisers,
emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol,
low
molecular weight polyethylene glycols, sodium chloride, fluorocarbons,
polyethylene
glycol ethers, sorbitan trioleate, oleic acid.
Alternatively, the compounds of the invention can be administered in the form
of a
suppository or pessary, or they may be applied topically in the form of a gel,
hydrogel,
lotion, solution, cream, ointment or dusting powder. The compounds of the
invention
may also be dermally or transdermally administered, for example, by the use of
a skin
patch. They may also be administered by the ocular, pulmonary or rectal
routes.
For ophthalmic use, the compounds can be formulated as micronized suspensions
in
isotonic, pH adjusted, sterile saline, or, preferably, as solutions in
isotonic, pH adjusted,
sterile saline, optionally in combination with a preservative such as a
benzylalkonium
chloride. Alternatively, they may be formulated in an ointment such as
petrolatum.
For application topically to the skin, the compounds of the invention can be
formulated
as a suitable ointment containing the active compound suspended or dissolved
in, for
example, a mixture with one or more of the following: mineral oil, liquid
petrolatum, white
petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound,
emulsifying
wax and water. Alternatively, they can be formulated as a suitable lotion or
cream,
suspended or dissolved in, for example, a mixture of one or more of the
following:
mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin,
polysorbate 60,
cetyl esters, wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
The compounds of the invention may also be used in combination with a
cyclodextrin.
Cyclodextrins are known to form inclusion and non-inclusion complexes with
drug
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29
molecules. Formation of a drug-cyclodextrin complex may modify the solubility,
dissolution rate, bioavailability and/or stability property of a drug
molecule. Drug-
cyclodextrin complexes are generally useful for most dosage forms and
administration
routes. As an alternative to direct complexation with the drug the
cyclodextrin may be
used as an auxiliary additive, e.g. as a carrier; diluent or solubiliser.
Alpha-, beta- and
gamma-cyclodextrins are most commonly used and suitable examples are described
in
WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
F,or oral or parenteral administration to human patients the daily dosage
levels of
compounds of the invention will be from 0.01 to 30 mg/kg (in single or divided
doses)
and preferably will be in the range 0.01 to 5 mg/kg. Thus tablets will contain
1 mg to 0.4g
of compound for administration singly or two or more at a time, as
appropriate. The
physician will in any event determine the actual dosage which will be most
suitable for
any particular patient and it will vary with the age, weight and response of
the particular
patient. The above dosages are, of course only exemplary of the average case
and
there may be instances where higher or lower doses are merited, and such are
within
the scope of the invention.
Oral administration is preferred. Preferably, administration takes place
shortly before an
effect is required.
For veterinary use, a compound of the invention is administered as a suitably
acceptable
formulation in accordance with normal veterinary practice and the veterinary
surgeon will
determine the dosing regimen and route of administration which will be most
appropriate
for a particular animal.
Thus according to a further aspect, the invention provides a pharmaceutical
formulation
containing a compound of the invention and a pharmaceutically acceptable
adjuvant,
diluent or carrier.
The invention is illustrated by the following non-limiting examples in which
the following
abbreviations and definitions are used:
Arbocel~ filter agent
br broad
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Boc tert-butoxycarbonyl
CDI carbonyldiimidazole
chemical shift
d doublet
0 heat
DCCI dicyclohexylcarbodiimide
DCM dichloromethane
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
ES+ electrospray ionisation positive scan
ES- electrospray ionisation negative scan
Ex Example
h hours
HOBt 1-hydroxybenzotriazole
HPLC high pressure liquid chromatography
m/z mass spectrum peak
min minutes
MS mass spectrum
NMR nuclear magnetic resonance
Prec precursor
Prep preparation
q quartet
s singlet
t triplet
Tf trifluoromethanesulfonyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TS+ thermospray ionisation positive scan
WSCDI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
'H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with
the
proposed structures. Characteristic chemical shifts (b) are given in parts-per-
million
downfield from tetramethylsilane using conventional abbreviations for
designation of
5 major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad.
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The following abbreviations have been used for common solvents: CDC13,
deuterochloroform; DMSO, dimethylsulfoxide. The abbreviation psi means pounds
per
square inch and LRMS means low resolution mass spectrometry. Where thin layer
chromatography (TLC) has been used it refers to silica gel TLC using silica
gel 60 Fzsa
plates, Rf is the distance travelled by a compound divided by the distance
travelled by
the solvent front on a TLC plate. Melting points were determined using a
Perkin Elmer
DSC7 at a heating rate of 20°C/minute).
Where indicated, compounds were characterised as their hydrochloride salts. A
typical
procedure for formation of hydrochloride salts is given in Example 12. The
procedure
can be carried out with other solvents e.g. diethyl ether or DCM.
Commercial starting materials were obtained from Aldrich Chemical Co,
Lancaster
Synthesis Ltd or Acros Organics.
E)CAMPLE 1
3-f(Methylamino)methyll-4-f3-methyl-4-methylsulfanyl)phenoxyl-
benzenesulfonamide
0 0
H NHS \ N~Me
H
O
\ Me
SMe
The amide of Preparation 8 (760 mg, 2.07 mmol) was slurried in THF (10 mL) and
the
resulting suspension was treated with borane.tetrahydrofuran complex (1 M
solution in
THF, 6.22 mL, 6.22 mmol) at room temperature. The resulting solution was
heated at
reflux for 5 hours under an atmosphere of dry nitrogen. The reaction was
cooled to room
temperature and treated cautiously with 6M HCI solution (6 mL). The resulting
mixture
was heated at reflux for 30 min. After cooling to room temperature the mixture
was
diluted with water (10 mL) and basified by cautious addition of potassium
carbonate
solid. The aqueous layer was extracted with EtOAc (20 mL) which gave a
precipitate in
the organic layer, and the aqueous layer was further extracted with DCM (2 x
20 mL).
The EtOAc fraction was washed with 2M NaOH (20 mL) giving a clear two-phase
separation and the basic layer was extracted with DCM (4 x 25 mL). All the
organic
fractions were combined and washed with brine (20 mL), dried (MgS04) and
evaporated
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to a colourless oil. Purification by flash chromatography [SiOa; 95:5:0.5 to
90:10:1
(EtOAc/ MeOH/ 880 NH3)] afforded a white powder of the desired amine (646 mg,
89%).
8H (300 MHz, ds DMSO) 2.26 (3H, d), 2.32 (3H, d), 2.45 (3H, d), 3.75 (2H, d),
6.90 (3H,
m), 7.25 (3H, br), 7.67 (1 H, t) 7.98 (1 H, d); MS m/z (TS+) 353 (MH+).
Compounds of formula Id, i.e. compounds of general formula I where R' is
methyl, RZ is
hydrogen and RS is -SO~NH~ , shown in Table 1 were prepared in an analogous
fashion
to Example 1 from the precursors indicated.
H N'~S o ~ N~Me
a \\~\\/~H
s o
i
Y
Z
(Id)
Table 1
Example Precursor data
I
Y
z
2 Prep 9 HCI salt: 8H (CD30D, 400 MHz) 2.80 (3H, s),
3.42 (2H, m), 4.41 (2H, s), 6.86-7.00 (2H,
m), 7.09 (1 H, s), 7.23 (1 H, d), 7.90 (1 H, d),
s 8.05 (1 H, s); MS m/z (TS+) 351 (MH+)
3 Prep 12 HCI salt: 5H (CD30D, 300 MHz) 2.54 (3H, s),
2.82 (3H, s), 4.43 (2H, s), 7.00 (1 H, d), 7.20
(1 H, d), 7.34 (1 H, s), 7.42 (1 H, d), 7.95 (1 H,
sMe d), 8.11 (1H, s); MS m/z (TS+) 373 (MH+)
4 Prep 11 HCI salt: 8H (CD30D, 400 MHz) 2.45 (3H, s),
2.73 (3H, s), 5.44 (2H, s), 6.97 (3H, m), 7.42
(1 H, m), 7.89 (1 H, m), 8.03 (1 H, s); MS m/z
sme (ES+) 357 (MH+)
5 Prep 10 HCI salt: 8H (CD30D, 400 MHz) 2.79 (3H, s),
3.18 (2H, m), 4.38 (2H, s), 4.41 (2H, m),
s o 6.68 (2H, m), 6.97 (1 H, d), 7.13 (1 H, d),
SJ 7.91 (1 H, d), 8.03 (1 H, s); MS m/z (TS+) 367
(M H+)
6 Prep 13 HCI salt: 8,~ (CD30D, 400 MHz) 2.78 (3H, s),
3.15 (2H, m), 4.38 (4H, m), 6.79 (1 H, d),
6.85 (3H, m), 7.84 (1 H, d), 8.00 (1 H, s); MS
of m/z (ES+) 367 (MH+)
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33
Example Precursor data
I
/ Y
Z
7 Prep 14 HCI salt: 8,., (CD30D, 400 MHz) 2.81 (3H, s),
I ~ 4.43 (2H, s), 5.09 (4H, s), 6.93 (1 H, d), 7.12
/ (2H, s+d), 7.40 (1 H, d), 7.90 (1 H, d), 8.08
o (1 H, s); MS m/z (TS+) 335 (MH+)
8 Prep 15 HCI salt: sH (CD30D, 400 MHz) 2.16 (2H,
I ~ m), 2.80 (3H, s), 2.92 (4H, t), 4.40 (2H, s),
/ 6.86 (1 H, d), 6.94 (1 H, d), 7.03 (1 H, s), 7.30
(1 H, d), 7.88 (1 H, d), 8.03 (1 H, s); MS m/z
(TS+) 333 (MH+)
9 Prep 16 HCI salt: 8H (CD30D, 400 MHz) 2.32 (3H, s),
I ~ 2.43 (3H, s), 2.81 (3H, s), 4.41 (2H, s), 6.84
SMe (1 H, d), 6.91 (1 H, d), 7.06 (1 H, s), 7.24 (1 H,
Me d), 7.89 (1 H, d), 8.05 (1 H, s); MS m/z (ES+)
352 (MH+)
Prep 17 HCI salt: 8H (CD30D, 400 MHz) 2.78 (3H, s),
I ~ 4.21 (4H, s), 4.39 (2H, s), 6.89 (1 H, d), 7.01
/ (1 H, d), 7.08 (1 H, s), 7.38 (1 H, d), 7.85 (1 H,
s d), 8.02 (1 H, s); MS m/z (TSB) 351 (MH+)
11 Prep 18 ~H (CD30D, 400 MHz) 2.76 (3H, s), 3.30
I ~ (2H, m), 3.42 (2H, m), 4.33 (2H, s), 6.90
/ S (1 H, d), 6.94 (1 H, d), 7:00 (1 H, s), 7.29 (2H,
d), 7.89 (1 H, d), 8.04 (1 H, s); MS m/z (ES+)
351 (MH+), (ES-) 349 (M-H+)
EXAMPLES 12 and 13
3-f(Dimethylamino methyll-4-f3-methyl-4-(methylsulfanyl)phenoxyl-
benzenesulfonamide
(Example 12) and 3-j(dimefi~famino)methyfl-N methyl-4-f3-meth~rl-4-
5 (methylsulfanyl)phenoxy]benzenesulfonamide (Example 13)
o ~
lea Me~ lea
Me Me
Formaldehyde (37% aq. solution, 282 p.L, 3.76 mmol) was added to a suspension
of the
secondary amine from Example 1 (409 mg, 1.16 mmol) in DCM (20 mL) at room
temperature under nitrogen. The resulting mixture was stirred for 15 minutes
before the
10 addition of sodium triacetoxyborohydride (984 mg, 4.64 mmol). The resulting
reaction
mixture was stirred for 5 hours before being basified with saturated NaHC03
solution (10
mL) and extracted with DCM (3X20 mL). The organic Payers were washed with
brine (10
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34
mL), dried (MgS04) and evaporated to a yellow oil. This was purified by HPLC
(Phenomonex Luna C,8 75 x 4.6 mm column, CH3CN, H20, TFA). Fractions
containing
the major product were evaporated and the residue was treated with sat. NaHCO3
solution (5 mL), and extracted with DCM (3X30 mL). The combined organic
fractions
were washed with brine (30 mL), dried (MgS04) and evaporated to give a white
foam
(155 mg, 36%) of Example 12; 8H (300 MHz, CDCI3) 2.30 (6H, s), 2.35 (3H, s),
2.48 (3H,
s), 3.60 (2H, s), 6.83 (3H, m), 7.20 (1 H, m), 7.28 (2H, s), 7.74 (1 H, d),
8.08 (1 H, s); MS
m/z (TS+) 367 (MHO).
A minor product was also obtained after HPLC purification. The relevant
fractions were
evaporated and the residue was treated with sat. NaHC03 solution (5 mL), and
extracted
with DCM (2X30 mL). The combined organic fractions were washed with brine (30
mL),
dried (MgS04) and evaporated to a gum. This was taken up in DCM (5 mL),
treated with
1 M ethereal HCI (2 mL) and evaporated to give a white powder (39 mg, 9%) of
Example
13; HCI salt: bH (CDCI3, 300 MHz) 2.30 (6H, s), 2.35 (3H, s), 2.48 (3H, s),
3.60 (2H, s),
6.83 (3H, m), 7.20 (1 H, m), 7.28 (2H, s), 7.74 (1 H, d), 8.08 (1 H, s); MS
m/z (TS+) 381
(M H+)
In a repeat reaction, using 1 equivalent of formaldehyde to the amine of
Example 1,
Example 12 was obtained in 78% yield after column chromatography [SiOa;
95:5:0.5 to
90:10:1 (EtOAc/ MeOH/ 880 NH3)~. This was taken up in EtOAc and converted to
the
HCI salt by the addition of 1 M ethereal HCI. The resulting precipitate was
filtered and
dried in vacuo to give Example 12 HCI salt; m.p. 188°C.
Alternatively, Example 12 can also be formed from the amine of Example 1 by
the
method of Example 110.
Example 12 was also prepared as follows.
A solution of the hydrochloride salt from Example 94 (20 g) in trifluoroacetic
acid (100
mL) was slowly added to a solution of chlorosulfonic acid (72 g) keeping the
temperature
between 0 and 5 °C. After 1 h the reaction mixture was quenched slowly
into water (200
mL), at 0-20 °C. The mixture was then extracted with dichloromethane
(200 mL) and
separated. The aqueous layer was then extracted with dichloromethane (60 mL)
and
separated. The combined organic layers were washed with water (200 mL). The
layers
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were separated and the dichloromethane removed in vacuo to give a solid.
Acetonitrile
(240 mL) was added and to this slurry was added phosphorus oxychloride (28.8
mL).
The solution was then heated at reflux overnight. The reaction mixture was
cooled to
room temperature and quenched into a stirred mixture of ammonia (90 mL),
5 dichloromethane (240 mL) and water (100 mL), keeping the temperature between
0 °C
and 10 °C. The mixture was adjusted with ammonia (if necessary) to
greater than pHB.
After 15 mins the reaction mixture was allowed to warm to room temperature and
the
layers separated. The organic layer was concentrated in vacuo to give a thick
brown oil.
This was dissolved in acetone (100 mL) and slurried with carbon (Norit SX
plus, 50%
10 wlw) filtered and treated with another charge of carbon (Norit SX plus,
50%w/w). This
mixture was again filtered and the solution concentrated, replacing with water
(200 mL).
The slurry was granulated, filtered and vacuum dried overnight to give the
title product
as a creamy white solid (yield 40%).
15 EXAMPLES 14 and 15
4-(2.3-Dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyll-
benzenesulfonamide
and 4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-~(dimethylamino methy]-N-
methylbenzenesulfonamide
20 These compounds were formed in an analogous fashion to Examples 12 and 13
starting
from the secondary amine of Example 5.
EXAMPLE 14. NCI salt: 8H (CD3OD, 400 MHz) 2.97 (6H, s), 3.18 (2H, m), 4.42
(2H, m),
4.52 (2H, s), 6.68 (2H, d), 6.99 (1 H, d), 7.14 (1 H, d), 7.94 (1 H, d), 8.07
(1 H, s); MS m/z
(ES~) 381 (MH+).
25 EXAMPLE 15. NCI salt: 8H (CD30D, 400 MHz) 2.56 (3H, s), 2.80 (6H, s), 3.17
(2H, m),
4.35 (2H, s), 4.41 (2H, m), 6.68 (2H, m), 6.98 (1 H, d), 7.13 (1 H, d), 7.81
(1 H, d), x.00
(1 H, s); MS m/z (ES+) 395 (MH+).
Compounds of formula 1e, i.e. compounds of general formula I where R' and RZ
are
30 methyl and RS is -SOzNHz, shown in Table 2 were prepared according to
Example 12
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from the precursors indicated. The N-methyl sulfonamides analogous to Example
13
were not isolated in these reactions and HPLC purification was not required.
o,,s o
I-~ZN' ~ ~ ~NMe2
O
Y
Z
(1e)
Table 2
ExamplePrecursor data
I
/ Y
Z
16 Example HCI salt: 8H (CD30D, 400 MHz) 2.98
2 (6H, s), 3.41
(2H, m), 4.58 (2H, s), 6.95 (2H, m),
7.08 (1 H, s),
I / 7.25 (1 H, d), 7.95 (1 H, d), 8.05
(1 H, s); MS m/z
(ES*) 365 (MH*)
17 Example HCI salt: sH (CD3OD, 300 MHz) 2.54
3 (3H, s), 2.98
(6H, s), 4.53 (2H, s), 7.01 (1 H,
d), 7.20 (1 H, dd),
I / ~, 7.33 (1 H, s), 7.42 (1 H, d), 7.99
(1 H, d), 8.04 (1 H, s);
SMe MS m/z (TS*) 387 (MH*)
18 Example HCI salt: 8H (CD30D, 400 MHz) 2.43
4 (3H, s), 2.88
(6H, s), 4.42 (2H, s), 6.99 (3H, m),
7.42 (1 H, t), 7.92
/ F (1H, d), 8.06 (1H, s); MS m/z (ES*)
371 (MH*)
SMe
19 Example HCI salt: 8,., (CD30D, 400 MHz) 2.89
6 (3H, s), 3.17
(2H, m), 4.39 (2H, m), 4.47 (2H, s),
6.78 (1 H, d),
/ S 6.87 (3H, m), 7.89 (1 H, d), 8.01
(1 H, s); MS m/z
of (TS*) 367 (MH*)
20 Example TFA salt: 8H (CDCI3, 400 MHz) 2.22
7 (6H, s), 3.60
(2H, t), 5.05 (4H, d), 6.75-6.90 (3H,
m), 7.20 (1 H, d),
/ 7.60 (1 H, m), 8.00 (1 H, m); MS m/z
349 (MH*)
0
21 Example HCI salt: 8H (CD30D, 400 MHz) 2.10
8 (2H, m), 2.85-
3.00 (1 OH, m), 4.30 (1 H, brs), 4.50
(2H, s), 6.80-
/ 6.95 (2H, m), 7.05 (1 H, s), 7.25
(1 H, d), 7.80 (1 H,
d), 8.10 (1 H, s); MS m/z (ES*) 347
(MH*)
22 Example HCI salt: 8H (CD30D, 400 MHz) 2.93
(6H, s), 4.21
10 I ~ (4H, s), 4.50 (2H, s), 6.91 (1 H,
d), 7.02 (1 H, d), 7.09
(1 H, s), 7.37 (1 H, d), 7.91 (1 H,
d), 8.05 (1 H, s); MS
s m/z (TS*) 365 (MH*)
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ExamplePrecursor data
Y
Z
23 Example HCI salt: 8H (DMSO-d6, 400 MHz) 2.76
(6H, s), 3.21
11 ~ ~ (2H, t), 3.38 (2H, t), 4.39 (2H, s),
6.80 (1 H, d), 6.86
(1 H, d), 7.10 (1 H, s), 7.28 (3H,
m), 7.80 (1 H, d),
8.06 (1 H, s), 10.23 (1 H, br); MS
m/z (TS+) 365
(MH+)
EXAMPLE 24
3-f (Dimethylamino)methyll-4-('4-meth~rl-3-(methylsulfanyl)phenoxyl-
benzenesulfonamide
H2~ 9e2
SMe
The title compound was prepared from the secondary amine of Example 9 by the
method of Example 110; 8H (CD30D, 400 MHz) 2.27 (3H, s), 2.41 (3H, s), 2.61
(6H, s),
4.19 (2H, s), 6.76 (1 H, d), 6.88-6.93 (2H, m), 7.20 (1 H, d), 7.82 (1 H, d),
8.03 (1 H, d); MS
m/z (TSt) 367 (MH+).
EXAMPLE 25
N-(5-Methoxy-2-f3-methyl-4-(methylsulfanyl)phenox lby enzyll-N N-dimethylamine
Me0
~~\\~ N Men
f
Me
SMe
Dimethylamine hydrochloride (424 mg, 5.2 mmol), Et3N (725 p.L, 5.2 mmol), AcOH
(298
p,L, 5.2 mmol) and sodium triacetoxyborohydride (1.10 g, 5.2 mmol) were added
to a
solution of the aldehyde from Preparation 24 (1.00 g, 3.47 mmol) in THF (15
mL) and
DCM (15 mL) and the mixture was stirred at room temperature for 16 h. After
removing
the solvent in vacuo the residue was taken up in 2M HCI (20 mL) and washed
with ether
(2~e15 mL). The aqueous layer was basified with NaOH pellets and extracted
with DCM
(4x20 mL). The combined DCM extracts were washed with brine, dried (MgS04) and
evaporated. The residue was taken up in a small amount of DCM and treated with
1 M
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38
ethereal HCI to precipitate the HCI salt. This was filtered, washed with ether
and dried to
give a white solid (936 mg) contaminated with triethylamine hydrochloride.
This was
dissolved in 1 M NaOH (10 mL) and extracted with EtOAc (3x15 mL). The organic
extracts were washed with brine (10 mL), dried (MgS04) and evaporated before
being
re-dissolved in EtOAc and evaporated again. The residue was taken up in DCM
and
treated with 1 M ethereal HCI to precipitate the HCI salt, which was filtered,
washed with
ether and dried to give a white solid (635 mg, 52%); SH (CDCI3, 300 MHz) 2.35
(3H, s),
2.45 (3H, s), 2.79 (6H, s), 3.90 (3H, s), 4.21 (2H, s), 6.70 (1 H, d), 6.73 (1
H, s), 6.90 (2H,
m), 7.18 (1 H, d), 7.65 (1 H, s), 12.83 (1 H, brs); MS m/z (TS+) 318 (MH+).
Compounds of formula If, i.e. compounds of general formula I where R' and Rz
are
methyl, shown in Table 3 were prepared according to Example 25 from the
precursors
indicated.
R5
R,
Table 3
Example PrecursorR4 RS data
Y
Z
26 Prep 25 H F HCI salt: 8H (CDCI3, 300
MHz) 2.23
(6H, s), 3.41 (2H, s),
6.98 (2H, m),
7.34 (2H, m), 7.48 (1 H,
dd), 7.98
N r (1 H, d), 8.08 (1 H, d),
8.80 (1 H, s);
MS m/z (TS+) 297 (MH+)
27 Prep 39 H -NO~ 8H (CDCI3, 300 MHz) 2.32
(6H, s),
2.36 (3H, s), 2.47 (3H,
s), 3.60 (2H,
S), 6.80 (1 H, d), 6.87
(2H, d), 7.19
sme (1 H, d), 8.03 (1 H, d),
8.40 (1 H, d);
MS m/z (ES+) 333 (MH+)
28 Prep 38 H -NOZ Taken on crude at ~75%
purity; 8H
(CDCI3, 400 MHz) 2.33 (6H,
s),
3.24 (2H, m), 3.38 (2H,
m), 3.66
(2H, s), 6.76 (2H, m),
6.86 (1 H, m),
7.17 (1 H, d), 8.00 (1
H, dd), 8.37
(1 H, d)
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ExamplePrecursorR4 R5 data
I
/ Y
Z
29 Prep 26 H H 8H (CDC13, 300 MHz) 2.28
(6H, s),
~ 3.50 (2H, s), 7.03 (2H,
m), 7.20-
I 7.40 (3H, m), 7.52 (2H,
m), 7.98
N / (1 H, d), 8.09 (1 H, d),
8.81 (1 H, m);
MS m/z (TS+) 279 (MH+)
30 Prep 27 H H HCI salt: 8H (d6 DMSO,
300 MHz)
I ~ 2.77 (6H, d), 4.38 (2H,
d), 7.08 (1 H,
d), 7.36 (1 H, t), 7.52
(1 H, t), 7.62
(1 H, s), 7.80 (1 H, d),
7.91 (1 H, dd),
8.10 (1 H, d), 9.25 (1
H, s), 9.52 (1 H,
s); MS m/z (TS+) 280 (MH+)
31 Prep 29 H H Maleate salt: 8H (d6-DMSO,
300
MHz) 2.77 (6H, s), 4.33
(2H, s),
I / 5.98 (2H, s), 6.87 (1 H,
N d), 7.21 (1 H,
s-!~ dt), 7.30 (1 H, dd), 7.41
(1 H, dt),
7.58 (1 H, dd), 7.88 (1
H, d), 8.11
(1 H, d), 9.32 (1 H, s);
MS m/z 285
(MH~)
32 Prep 33 H Br HCI salt: SH (DMSO-d6,
400 MHz)
I ~ 2.77 (6H, d), 3.23 (3H,
m), 3.39
_ (2H, m), 4.32 (2H, d),
~ s 6.75 (2H, m),
7.03 (1 H, s), 7.26 (1
H, d), 7.57 (1 H,
dd), 7.87 (1 H, s), 10.06
(1 H, br, s);
MS m/z (ES+) 366 (MH+)
33 Prep 32 Br H ~H (CDC13, 400 MHz) 2.22
(6H, s),
I ~ 2.30 (3H, s), 2.41 (3H,
s), 3.41 (2H,
s), 6.76 (2H, m), 6.94
(1 H, s), 7.18
sMe (1 H, s), 7.21 (1 H, obs),
7.30 (1 H,
d); MS m/z (TS+) 366!368
(MH+)
EXAMPLE 34
3-f (Dimethylamino)methyl!-N-methyl-4-(6-auinolinyloxy)benzenesulfonamide
Mew
n~
H
Chlorosulfonic acid (106 ~L, 1.6 mmol) was added to a solution of Example 29
(50 mg,
0.16 mmol) in DCM (2 mL) and the mixture was stirred for 3 h at room
temperature.
Water (2 mL) was added, the mixture was adjusted to pH 6 with sat aq NaHCOs
and
extracted with DCM (2x5 mL). The organic extracts were dried (MgS04) and
filtered and
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8M methylamine in EtOH (0.3 mL) was added. After standing for 1 h the solvent
was
removed in vacuo and the residue was purified by column chromatography [Si02;
95:5:0.5 (DCM/ MeOH/ 880 NH3)]. The product was taken up in EtOAc and
converted to
the HCI salt by the addition of ethereal HCI. This gave the desired product as
a
5 hygroscopic solid (3 mg, 5%); 8H (CD30D, 300 MHz) 2.60 (3H, s), 2.99 (6H,
s), 4.60 (2H,
s), 7.21 (1 H, d), 7.96 (1 H, d), 8.04 (3H, m), 8.19 (1 H, s), 8.38 (1 H, d),
9.03 (1 H, d), 9.18
(1 H, d); MS m/z (TS+) 371 (MH+).
EXAMPLE 35
10 3-f(Methylamino)methyll-4-(6~uinolinyloxy)benzenesulfonamide
HZn
Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution of the
amine of
Example 48 (900 mg, 3.4 mmol) and triethylamine (1.9 mL, 13.6 mmol) in CHZCh
(15
mL) at 0°C and the mixture was stirred for 5 min. The solvent was
removed in vacuo and
15 the residue was partitioned between CH~Ch and water. The organic layer was
washed
with brine, dried (MgS04) and evaporated to give a yellow oil, which was used
without
further purification. This crude oil was taken up in CH~CI~ (20 mL), cooled to
0°C and
CIS03H (2.4 mL, 36.1 mmol) was added dropwise. The mixture was allowed to warm
to
room temperature and stirred for 4 h before being poured into ice water. The
mixture
20 was extracted with CHZCIZ (50 mL) and the organic layer was treated with a
saturated
solution of NH3 in MeOH (10 mL). After stirring for 4 h 1 M LiOH (20 mL) was
added and
stirring was continued overnight. Tlc analysis indicated reaction was
incomplete so
further 1 M LiOH (50 mL) was added and the mixture was stirred for 2 h. The
mixture
was acidified to pH 8 with 2M HCI and extracted with CHzCl2 (3X200 mL). The
combined
25 organic extracts were dried (MgS04) and evaporated and the residue was
triturated with
ether to give the title compound (500 mg, 43%) as a yellow solid; 8H (CDC13,
400 MHz)
2.46 (3H, s), 3.87 (2H, s), 6.93 (1 H, d), 7.25 (1 H, s), 7.39 (1 H, t), 7.42
(1 H, d), 7.78 (1 H,
d), 8.00-8.08 (2H, m), 8.12 (1 H, d), 8.86 (1 H, s); MS m/z (ES+) 344 (MH+).
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EXAMPLE 36
N-f5-Bromo-2-(2,3-dihydro-1-benzothien-5-yloxy)benzyll-IV-methylamine
Br ~ N~Me
\\~H
/ O
S
The aldehyde of Preparation 19 (1.10 g, 3.28 mmol) was dissolved in 8M
methylamine in
EtOH (4.1 mL, 32.8 mmol) and stirred for 5 h before the portionwise addition
of NaBH4
(372 mg, 9.83 mmol) over 30 min. EtOH (100 mL) was added and the reaction was
stirred for 16 h before being concentrated in vacuo. The residue was quenched
with 6M
HCI until pH 1 and the precipitated HCI salt was collected by filtration,
washed with water
(100 mL) and dried in vacuo to give a crystalline solid (1.04 g, 82%); 8H
(CDC13, 400
MHz) 2.62 (3H, s), 3.26 (2H, t), 3.41 (2H, t), 4.18 (2H, s), 6.66 (1 H, d),
6.90 (1 H, d), 7.03
(1 H, s), 7.19 (1 H, d), 7.39 (1 H, d), 7.80 (1 H, s); MS m/z (ESA) 350, 352
(MH+).
Compounds of formula Ig, i.e. compounds of general formula I where R' and R4
are
hydrogen and R2 is methyl, shown in Table 4 were prepared according to Example
36
from the precursors indicated. For those compounds which were isolated as the
free
base the reaction mixture was partitioned between 2M HCI and ether after
removal of
the reaction solvent in vacuo. The aqueous layer was then basified and
extracted with
DCM, the DCM layer being dried (MgSO4) and evaporated to give the desired
secondary
amine.
Me
Y
(~9)
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Table 4
ExamplePrecursorRS data
Y
Z
37 Prep 20 Br HCI salt: SH (d6-DMSO, 300
MHz) 2.48
(3H, s), 2.59 (3H, s), 4.18
(2H, s), 6.88
(1 H, d), 7.01 (1 H, d), 7.16
(1 H, d), 7.45
sMa (1 H, t), 7.59 (1 H, d), 7.91
(1 H, s); MS
m/z (TS+) 356, 358 (M H+)
38 Prep 21 Br 8H (CDC13, 400 MHz) 2.43 (3H,
s), 3.11
(2H, t), 3.78 (2H, s), 4.41
(2H, t), 6.44
(1 H, s), 6.51 (1 H, d), 6.77
(1 H, d), 6.98
(1 H, d), 7.31 (1 H, d), 7.55
(1 H, s); MS
m/z (ES+) 366, 368 (MH+)
39 Prep 22 Br &H (CDC13, 400 MHz) 2.41 (3H,
s), 2.45
(3H, s), 3.72 (2H, s), 6.77
(1 H d), 6.85
(1 H, d), 6.99 (1 H, s), 7.18
(1 H, d), 7.36
SMe (1 H, d), 7.59 (1 H, s); MS
m/z (TS+) 372,
374 (MH'~)
40 Prep 38 -NOZ 8H (CDC13, 300 MHz) 2.55 (3H,
s), 3.30
(2H, m), 3.43 (2H, m), 3.95
(2H, s), 6.80
s (2H, m), 6.91 (1 H, s), 7.22
(1 H, d), 8.05
s (1 H, d), 8.40 (1 H, s); MS
m/z (ES+) 317
(MH~)
41 Prep 36 -N02 8H (CDCI3, 400 MHz) 2.45 (3H,
S), 3.10
(2H, m), 3.86 (2H, s), 4.40
(2H, m), 6.53
o (2H, m), 6.80 (1 H, d), 7.01
(1 H, d), 8.00
SJ (1 H, d), 8.27 (1 H, s); MS
m/z (TS+) 333
(MH+)
42 Prep 40 -NOZ 8H (CDCI3, 400 MHz) 2.14 (2H,
m), 2.52
(3H, s), 2.93 (4H, t), 3.92
(2H, s), 6.78
s (1 H, d), 6.81 (1 H, d), 6.91
(1 H, s), 7.22
(1 H, d), 8.02 (1 H, dd),
8.29 (1 H, s); MS
m/z (TS+) 299 (MH+)
43 Prep 24 -OMe HCI salt: s,., (CDCI3, 300
MHz) 2.35 (3H,
s), 2.45 (3H, s), 2.60 (3H,
s), 3.84 (3H,
Me s), 4.17 (2H, s), 6.80 (1
H, d), 6.82 (1 H,
sMe s), 6.88 (2H, s), 7.15 (1
H, d), 7.42 (1 H,
s), 9.85 (2H, brs); MS m/z
(TS+) 304
(MH+)
44 Prep 23 Br 8H (CDC13, 300 MHz) 2.35 (3H,
s), 2.45
~ (6H, s), 3.77 (2H, s), 6.73
(2H, m), 6.80
~ (1 H, s), 7.19 (1 H, d), 7.32
(1 H, d), 7.57
sMe (1H, s); MS m/z (TS+) 352,
354 (MH+)
45 Prep 30 H HCI salt: ~,., (ds-DMSO, 400
MHz) 2.22
(3H, s), 2.42 (3H, s), 2.58
(3H, s), 4.18
a (2H, s), 6.78 (1 H, d), 6.96
(1 H, d), 6.99
sMe (1 H, s), 7.18 (1 H, t), 7.25
(1 H, d), 7.38
(1 H, t), 7.60 (1 H, d); MS
m/z (ES+) 274
(M H+)
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ExamplePrecursorR5 data
/ Y
Z
46 Prep 31 H HCI salt: 8H (CDC13, 400 MHz)
2.55 (3H,
brs), 3.21 (2H, t), 3.32 (2H,
m), 4.17
/ (2H, s), 6.76 (1 H, d), 6.84
(1 H, d), 6.99
(1 H, s), 7.04 (1 H, m), 7.12
(1 H, d), 7.28
(1 H, obs), 7.61 (1 H, d);
MS m/z (ESA)
272 (M H+)
47 Prep 28 H Maleate salt: 8H (DMSO-d6,
400 MHz)
2.60 (3H, s), 4.19 (2H, s),
5.99 (2H, s),
7.03 (1 H, d), 7.29 (1 H,
m), 7.37 (1 H, s),
7.45 (3H, m), 7.60 (1 H, d),
8.06 (1 H, d),
8.37 (1 H, d), 8.74 (2H, br),
8.83 (1 H,
dd); MS m/z 264 (MH+)
48 Prep 26 H SH (CDC13, 300 MHz) 2.64 (3H,
s), 4.25
(2H, s), 6.89 (1 H, d), 7.19
(1 H, t), 7.30-
7.41 (2H, m), 7.45 (1 H, s),
7.49 (1 H, d),
N r 7.69 (1 H, d), 8.08 (1 H,
d), 8.16 (1 H, d),
8.87 (1 H, d); MS m/z (ES+)
529 (2M+H+)
49 Prep 34 -CN HCI salt: 8H (CD30D, 400 MHz)
2.81
(3H, s), 3.30 (1 H, br), 4.42
(2H, s), 7.17
(1 H, br), 7.82 (1 H, br),
8.06 (1 H, br),
N / 8.11 (3H, br), 8.39 (1 H,
br), 9.18 (1 H,
br), 9.21 (1 H, br); MS mlz
(ES+) 290
(MH~)
- ~n~ nnetnyamme m Mec~H (z equiv.) and Ti(0'Pr)4 (2 equiv.) in EtOH (~0.1 M
soln of
aldehyde) were used in place of methylamine in EtOH. After isolation of the
free base it
was converted to the maleate salt by standard methods.
EXAMPLE 50
(2L1-3-f4-(2,3-Dihydro-1-benzothien-6-yloxy)-3-f(dimethylamino)methyllphenyl
propenamide
HaN
A mixture of the bromide of Example 32 (400 mg, 1.10 mmol), acrylamide (156
mg, 2.19
mmol), triethylamine (0.38 mL, 2.74 mmol), palladium II acetate (12.5 mg, 0.06
mmol)
and tri-o-tolylphosphine (33.4 mg, 0.11 mmol) in acetonitrile (15 mL) was
heated at
reflux for 72 h. After cooling to room temperature the solvent was removed in
vacuo and
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the residue was partitioned between EtOAc (50 mL) and 2M HCI (50 mL). The
aqueous
phase was basified with 2M NaOH and extracted with EtOAc (3x50 mL). The
combined
basic extracts were dried (MgS04) and evaporated. The residue was purified by
column
chromatography [Si02; 96:4:0.5 (DCM/ MeOH/ 880 NH3) increasing polarity to
90:10:1]
to give the title compound (196 mg, 50%) as a beige foam; 8H (CDCI3, 400 MHz)
2.28
(6H, s), 3.24 (2H, t), 3.38 (2H, t), 3.51 (2H, s), 5.73 (2H, br), 6.42 (1 H,
d), 6.59 (1 H, dd),
6.82 (2H, m), 7.10 (1 H, d), 7.32 (1 H, d), 7.60 (1 H, d), 7.69 (1 H, s); MS
m/z (ES+) 355
(MH+).
EXAMPLE 51
~~2,3-Dihydro-1-benzothien-6-yloxy)-3-[(dimethylamino)methyllphen
rLl)propanamide
HEN
A solution of Sml~ in THF (0.1 M, 21.9 mL, 2.19 mmol) was added to a solution
of the
alkene of Example 50 (194 mg, 0.55 mmol) in THF (5 mL) under nitrogen followed
by
water (1 mL). After stirring at room temperature for 10 min the reaction was
quenched
with 6M NaOH (10 mL) and stirred for 30 min. The organic phase was separated
and the
aqueous phase was extracted with EtOAc (2x20 mL). The combined organic layers
were
dried (MgS04) and evaporated to an oil, which was purified by column
chromatography
[Si02; 93:7:1 (DCM/ MeOH/ 880 NH3) increasing polarity to 90:10:1] to give the
title
compound (90 mg, 46%); 8H (CDCI3, 400 MHz) 2.25 (6H, s), 2.54 (2H, t), 2.97
(2H, t),
3.22 (2H, t), 3.36 (2H, t), 3.42 (2H, s), 5.20-5.46 (2H, br), 6.54 (1 H, d),
6.73 (1 H, s), 6.81
(1 H, d), 7.05 (2H, m), 7.31 (1 H, s); MS m/z (TS+) 357 (MH+).
Compounds of formula If, i.e. compounds of general formula I where R' and R2
are
methyl, shown in Table 5 were prepared according to Preparation 50 from the
precursors indicated.
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n5
9e2
Y
(I~
Table 5
Example PrecursorR4 R5 data
I
Y
Z
52 Example H -COZMe 8N (CDCI3, 400 MHz)
2.29 (6H,
32 I ~ s), 3.26 (3H, m), 3.39
(2H, m),
~ s 3.54 (2H, s), 3.89 (3H,
s), 6.62
(1 H, d), 6.84 (2H,
m) 7.13 (1 H,
d),.7.86 (1 H, d), 8.12
(1 H, s);
MS m/z (TS~) 344 (MH+)
53 Example -COZMe H 8H (CDCI3, 400 MHz)
2.24 (6H,
33 I ~ s), 2.33 (3H, s), 2.42
(3H, s),
a 3.48 (2H, S), 3.82 (3H,
s), 6.73
sMe (2H, m), 7.14 (1 H,
d), 7.50
(1 H, s), 7.55 (1 H,
d), 7.78 (1 H,
d); MS m/z (TS~) 346
(MH~)
5 Compounds of formula If, i.e. compounds of general formula I where R' and R2
are
methyl, shown in Table 6 were prepared according to Preparation 55 from the
precursors indicated.
Table 6
Example PrecursorR4 R5 data
Y
Z
54 Example H -COZH ~H (CD30D, 400 MHz) 2.95
(6H, s),
52 I ~ 3.29 (2H, m), 3.42 (2H,
m), 4.52 (2H,
~ s s), 6.80 (1 H, d), 6.89
(1 H, d), 7.03
(1 H, s), 7.29 (1 H, d),
8.06 (1 H, d),
8.23 (1 H, s); MS m/z (TS+)
330 (MH+)
Example -COSH H 8,., (CD30D, 400 MHz) 2.27
(3H, s),
(~80% 55 I ~ 2.42 (3H, s), 2.88 (6H,
s), 4.43 (2H,
purity) ~ Me s), 6.95 (2H, m), 7.26 (1
H, m), 7.42
sMe (2H, m), 7.72 (1 H, m)
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Compounds of formula If, i.e. compounds of general formula I where R' and Rz
are
methyl, shown in Table 7 were prepared according to Preparation 59 from the
precursors indicated.
Table 7
ExamplePrecursorR4 R5 data
I
Y
Z
56 Example H -CONHZ 5,., (CDCI3, 400 MHz) 2.27
(6H, s),
54 I ~ 3.25 (2H, m), 3.38 (2H,
m), 3.54
~ s (2H, s), 5.90-6.38 (2H,
br), 6.59
(1 H, d), 6.80 (1 H, s),
6.86 (1 H, d),
7.11 (1 H, d), 7.71 (1
H, d), 7.92 (1 H,
s); MS m/z (TS*) 329 (MH*)
57 Example -CONH2 H HCI salt: 8H (CD30D, 400
MHz)
55 I ~ 2.32 (3H, s), 2.43 (3H,
s), 2.94 (6H,
M s), 4.47 (2H, s), 6.98
(2H, br), 7.27
sMe (1 H, br), 7.36 (1 H, br),
7.62 (1 H,
br); MS m/z (TS*) 331 (MH*)
Compounds of formula If, i.e. compounds of general formula I where R' and R2
are
methyl, shown in Table 8 were prepared according to Preparation 69 from the
precursors indicated
Table 8
ExamplePrecursorR4 R5 data
I
Y
Z
58 Example H -CH~OH HCI salt: 8H (DMSO-ds,
400 MHz)
52 I ~ 2.76 (6H, s), 3.22 (2H,
m), 3.40
s (2H, m), 4.30 (2H, s),
4.49 (2H, s),
5.27 (1 H, br, s), 6.68
(1 H, d), 6.83
(1 H, d), 6.97 (1 H, s),
7.25 (1 H, d),
7.37 (1 H, d), 7.60 (1
H, s), 10.07
(1 H, br); MS m/z (TS*)
316 (MH*)
59 Example -CH~OH H HCI salt: bH (CD30D, 400
MHz)
53 I ~ 2.34 (3H, s), 2.46 (3H,
s), 2.90 (6H,
s), 4.40 (2H, s), 4.55
(2H, s), 6.89
sMe (1 H, s), 6.95 (2H, m),
7.18 (1 H, d),
7.28 (1 H, d), 7.50 (1
H, d); MS m/z
(TS*) 318 (MH+)
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EXAMPLE 60
4-(2,3-Dihydro-1-benzothien-5-yloxy)-3-f(methylamino)met~llbenzamide
0
\ H~Me
O
S
The protected amine of Preparation 59 (317 mg, 0.76 mmol) was dissolved in a
saturated solution of HCI in DCM (25 mL) at 0°C and left for 1 h before
being neutralised
by the addition of 10% aq K2C03 (25 mL). Water (50 mL) was added and the
layers were
separated. The aqueous layer was extracted with DCM (25 mL) and the combined
organic layers were dried (MgSO~) and evaporated. The resulting oil was
dissolved in
EtOAc (10 mL) and treated with 1 M ethereal HCI (1 mL). The white precipitate
was
collected by filtration and dried in vacuo to give the desired product (211
mg, 77%); 8H
(CD30D, 400 MHz) 2.77 (3H, s), 3.35 (2H, obs), 3.39 (2H, t), 4.34 (2H, s),
6.79 (1 H, d),
6.90 (1 H, dd), 7.02 (1 H, s), 7.21 (1 H, d), 7.83 (1 H, d), 8.00 (1 H, s); MS
m/z (TS~) 315
(MH~).
Compounds of formula Ig, i.e. compounds of general formula I where R' and R4
are
hydrogen and RZ is methyl, shown in Table 9 were prepared according to Example
60
from the precursors indicated.
R5 Me
Y
(1g)
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Table 9
Ex Prec RS data
I
/ Y
Z
61 Prep HCI salt: bH (CDC13, , ,
61 400 MHz) 2.77 (3H d)
3.35 (2H, obs), 3.36 (3H, s),
3.39 (2H, t),
/ 3.51 (4H, s), 4.35 (2H, s),
6.80 (1 H, d),
ome s 6.90 (1 H, dd), 7.01 (1 H, s),
7.21 (1 H, d),
7.79 (1 H, d), 7.96 (1 H, s);
MS m/z (TS+)
373 (MH+)
62 Prep HCI salt: ~,., (CD30D, 400 MHz)
60 2.77 (3H,
s), 2.88 (3H, s), 3.35 (2H,
obs), 3.39 (2H,
Me / t), 4.35 (2H, s), 6.79 (1 H,
d), 6.90 (1 H, dd),
s 7.01 (1 H, s), 7.20 (1 H, d),
7.78 (1 H, d),
7.96 (1 H, s); MS m/z (TS+)
329 (MH+)
63 Prep HCI salt: 8H (ds-DMSO, 300 MHz)
62 ~ ~ 2.52 (3H,
HZN obs), 2.61 (3H, s), 4.21 (3H,
s), 6.90 (1 H,
d), 7.07 (1 H, d), 7.19 (1 H,
d), 7.40 (1 H,
sMe brs), 7.48 (1 H, t), 7.92 (1
H, d), 7.96 (1 H,
s), 8.21 (1 H, s); MS m/z (TS+)
321 (MNH4+)
64 Prep HCI salt: 8H (ds-DMSO, 300 MHz)
63 2.52 (3H,
obs), 2.60 (3H, s), 2.79 (3H,
d), 4.21 (2H,
Me / F s), 6:89 (1 H, d), 7.07 (1 H,
d), 7.19 (1 H, d),
sane 7.48 (1 H, t), 7.85 (1 H, d),
8.19 (1 H, s),
8.48 (1 H, d); MS m/z (TS+)
335 (MH+)
65 Prep HCI salt: &H (d6-DMSO, ,
64 II 300 MHz) 2.52 (3H
obs), 2.60 (3H, s), 3.27 (3H,
/ F s), 3.46 (4H,
m), 4.22 (2H, s), 6.91 (1 H,
d), 7.08 (1 H, d),
oMe sMe 7.20 (1 H, d), 7.50 (1 H, t),
7.89 (1 H, d),
8.10 (1 H, s), 8.58 (1 H, brs);
MS m/z (TS+)
379 (MH+)
66 Prep HCI salt: 8,., (d6-DMSO, 300
65 MHz) 2.52 (3H,
HxN ' I ~ obs), 2.60 (3H, t), 4.11 (2H,
s+H20), 6.82
/ ci (1H, d), 7.21 (1H, d), 7.40
(3H, s+d), 7.88
sMe (1 H, d), 7.96 (1 H, brs), 8.21
(1 H, s); MS
m/z (ES+) 337 (MH+)
67 Prep ~ HCI salt: sH (ds-DMSO, 300 MHz)
66 2.52 (3H,
HN ~ obs), 2.60 (3H, t), 2.79 (3H,
d), 4.22 (2H,
I t), 6.94 (1 H, d), 7.22 (1 H,
/ c~ d), 7.40 (2H,
SMe s+d), 7.83 (1 H, d), 8.19 (1
H, d), 8.46 (1 H,
d); MS m/z (ES+) 351 (MH+)
68 Prep ~ 8H (CDCi3, 400 MHz) 2.41 (3H,
67 s), 3.08
(2H, m), 3.80 (2H, s), 4.37
(2H, m), 5.94-
/ 0 6.36 (2H, brd), 6.46 (1 H, s),
6.49 (1 H, d),
sJ 6.81 (1 H, d), 6.96 (1 H, d),
7.65 (1 H, d),
7.86 (1H, s); MS m/z (TS+) 331
(MH+)
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Ex Prec RS data
I
Y
Z
69 Prep HCI salt: SH (CDC13, 400 MHz)
68 2.42 (3H, s),
3.08 (2H, m), 3.44-3.50 (4H,
m), 3.80 (2H,
o s), 4.40 (2H, m), 6.45 (1 H,
s), 6.49 (1 H, d),
oMe sJ 6.62 (1 H, brs), 6.83 (1 H,
d), 6.96 (1 H, d),
7.62 (1 H, d), 7.78 (1 H, s);
MS m/z (TS+)
390 (MH+)
70 Prep Hod HCI salt: ~H (d6-DMSO, 300 MHz)
70 2.48 (3H,
s), 2.58 (3H, s), 4.12 (2H,
s), 4.50 (2H, d),
5.32 (1 H, t), 6.92 (2H, m),
7.03 (1 H, dd),
sMe 7.39 (1 H, dd), 7.46 (1 H, d),
7.60 (1 H, s);
MS m/z (TS+) 308 (MH+)
71 Prep Nod HCI salt: 8H (d6-DMSO, 300 MHz)
69 2,52 (3H,
obs), 2.58 (3H, t), 4.10 (2H,
s+Hz0), 4.48
ci (2H, s), 6.94 (1 H, d), 7.11
(1 H, d), 7.21
sMe (1 H, s), 7.25 (2H, m), 7.57
(1 H, s); MS m/z
(ES+) 324 (MH+)
72 Prep -C---N HCI salt: 8H (ds-DMSO, 300 MHz)
49 2.52 (3H,
s), 2.60 (3H, s), 4.24 (2H,
s), 6.94 (1 H, d),
7.04 (1 H, d), 7.28 (1 H, d),
7.50 (1 H, t),
sMe 7.86 (1 H, d), 8.08 (1 H, s);
MS m/z (TS~)
303 (MH+)
73 Prep ,~. HCI salt: 8H (CDCI3, 300 MHz)
73 2.48 (3H, s),
Me~S~H~ I ~ 2.64 (3H, s), 2.99 (3H, s),
4.23 (2H, s),
4.30 (2H, d), 6.40 (1H, br),
6.81-6.89 (3H,
sMe m), 7.26-7.35 (2H, ObS), 7.92
(1 H, S); MS
m/z (ES+) 385 (MH+), (ES') 383
(M-H+)
74 Prep Hod HCI salt: SH (CD30D, 400 MHz)
71 2.30 (3H,
s), 2.44 (3H, s), 2.73 (3H,
s), 4.25 (2H, s),
Me 4.59 (2H, s), 6.81 (1 H, d),
6.88-6.92 (2H,
sMe m), 7.24 (1 H, d), 7.37 (1 H,
d), 7.46 (1 H, s);
MS m/z (ES+) 304 (MH+)
75 Prep ,.. HCI salt: sH (CD30D, 300 MHz)
72 2.37 (3H,
Me'S~H~ ~ s), 2.48 (3H, s), 2.78 (3H,
s), 2.96 (3H,s),
I 4.27 (2H, S), 4.31 (2H, s),
6.85 (1 H, d),
sMe 6.92-7.00 (2H, m), &.31 (1 H,
d), 7.41 (1 H,
d), 7.57 (1 H, s); MS m/z (ES~)
381 (MH+),
(ES-) 379 (M-H+)
76 Prep ~s HCI salt: 8,., (CD30D, 400 MHz)
75 2.29 (3H,
s), 2.41 (3H, s), 2.43 (3H,
s), 3.76 (2H, s),
4.30 (2H, S), 6.72-6.79 (3H,
m), 7.12 (1 H,
sMe br), 7.27 (2H, obs); MS m/z
(ES+) 435
(MH+), (ES-) 433 (M-H+)
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EXAMPLE 77
N-f4-!(Dimeth lard. mino~methyll-3-(3-methyl-4-
(methylsulfanyl)phenoxy]benzyl~methanesulfonamide
NMe~
H
Mew ,N
~S\ O
O O
rI
Me
SMe
5 Example 77 was prepared from the Boc protected sulfonamide of Preparation 74
by the
method of Example 60 ;NCI salt: 8H (CD30D, 400 MHz) 2.29 (3H, s), 2.42 (3H,
s), 2.82
(3H, s), 2.89 (6H, s), 4.17 (2H, s), 4.39 (2H, s), 6.39 (3H, m), 7.19 (1 H,
d), 7.24 (1 H, d),
7.48 (1 H, d); MS m/z (TS+) 395 (MH+).
10 EXAMPLE 78
3-[(Methylamino)methyll-4-f3-methyl-4-(meth Isulfanyl)aohenoxy]benzonitrile
NC ~ N~Me
H
O
/ I
Me
SMe
Zn(CN)2 (700 mg, 5.96 mmol) and Pd(PPh3)~ (1.97 g, 1.7 mmol) were added to a
solution of the bromide of Example 44 (3.0 g, 8.52 mmol) in DMF (20 mL) and
the
15 mixture was heated at 100°C for 17 h. The reaction was cooled to
room temperature,
diluted with water (100 mL) and extracted with ether (2x100 mL then 3x50 mL).
The
combined organic layers were washed with water (3x50 mL), dried (MgSO4) and
evaporated to a yellow oil. Initial purification by column chromatography
[SiO~; 95:5:0.5
(DCM/ MeOHI 880 NH3)] was unsuccessful so the material was re-chromatographed
20 [Si02; 50% pentane in 95:5:0.5 (DCM/ MeOH/ 880 NH3) increasing polarity to
0%
pentane] to give the product (1.275 g, 50%) as a pale yellow oil. A sample was
taken up
in DCM (5 mL) and treated with 1M ethereal HCI to give the HCI salt as a white
powder
which was collected by filtration; 8H (CDCI3, 300 MHz) 2.35 (3H, s), 2.47 (6H,
s), 3.88
(2H, s), 6.79 (1 H, d), 6.87 (2H, m), 7.20 (1 H, d), 7.46 (1 H, d), 7.72 (1 H,
s); MS m/z (TS+)
25 299 (MH+).
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EXAMPLE 79
3-f (Methylamino meth Ir~1-4-[3-methyl-4-(meth IsulfanyJ~henoxy]benzamide
HZN
A mixture of the nitrite of Example 78 (404 mg, 1.35 mmol) and KOH (304 mg,
5.42
mmol) in tert-butanol (10 mL) was heated at reflux for 1 h under N2. After
cooling to room
temperature the solvent was removed in vacuo and the residue was partitioned
between
water (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (4 x
20
mL) and the combined organic layers were washed with brine, dried (MgS04) and
evaporated. The residue was purified by column chromatography [SiO~; 93:7:1
(DCMi
MeOHI 880 NH3)] to give the desired product (376 mg, 88%) as a white foam; 8H
(CDCI3,
300 MHz) 2.35 (3H, s), 2.47 (3H, s), 2.49 (3H, s), 3.88 (2H, s), 5.90-6.30
(2H, brs), 6.82
(3H, m), 7.19 (1 H, d), 7.70 (1 H, d), 7.90 (1 H, s); MS m/z (TS+) 317 (MH+).
Compounds of formula Ih, i.e. compounds of general formula I where R' and R2
are
methyl and R'' is hydrogen, shown in Table 10 where prepared according to
Example 12
from the precursors indicated.
R5
fez
Y
(1h)
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Table 10
ExamplePrecursorRS data
Iw
Y
Z
80 Example 8H (CD30D, 400 MHz) 2.91
~ (6H, s),
60 H2N I a 3.35 (2H, obs), 3.38 (2H,
t), 4.45
(2H, s), 6.81 (1 H, d),
6.90 (1 H, d)
,
7.03 (1 H, s), 7.21 (1 H,
d), 7.86 (1 H,
d), 8.03 (1 H, s); MS m/z
(TS+) 329
(M H+)
81 Example 8H (CD30D, 400 MHz) 2.90-2.99
~ (9H,
62 MeNN ~ m), 3.35 (2H, obs), 3.43
(2H
t), 4.50
~ ,
(2H, s), 6.88 (1 H, d),
6.97 (1 H, d),
7.07 (1 H, s), 7.28 (1 H,
d), 7.85 (1 H,
d), 8.03 (1 H, s); MS m/z
(TS+) 343
(M H+)
82 Example bH (CDCI3, 400 MHz) 2.90
~ ~ (6H, brm),
61 HN ~ 3.35 (2H, obs), 3.37 (2H,
brm), 3.51
(4H, brm), 4.43 (2H, brs),
6.80-6.94
s (2H, brd , 7.01 1 H, brs
, 7.20 1 H
( ) ( ,
brs), 7.82 (1 H, brs), 7.98
(1 H, brs);
MS m/z (TS+) 387 (MH+)
83 Example sH (CDCI3, 300 MHz) 2.29
63 ~ ~ (6H, s),
H2N ~ 2.47 (3H, s), 3.51 (2H,
s), 6.73 (2H,
s), 6.97 (1 H, d), 7.30
(1 H, t), 7.79
sMe (1 H, d), 7.97 (1 H, s);
MS m/z (TS+)
335 (MNH4+)
84 Example 8 CDCI3, ,
~ H ( 300 MHz) 2.29 (6H, s)
~
64 HN ~ 2.46 (3H, s), 3.02 (3H,
d), 3.54 (2H,
Me s F s), 6.20 (1 H, brs), 6.69
(2H, m), 6.97
sMe (1 H, d), 7.30 (1 H, t),
7.75 (1 H, d),
7.91 (1 H, s); MS m/z (TS+)
349
(MH+)
85 Example HCI salt: 8H (CDCI3, 300
~ ~ MHz) 2.49
65 HN ! (3H, s), 2.94 (6H, s), 3.42
(3H, s),
3.65 (4H, m), 4.33 (2H,
s), 6.79 2H,
oMe sMe d), 6.96 (1 H, d), 7.35
(1 H, t), 7.39
(1 H, brs), 7.98 (1 H, d),
8.68 (1 H, s);
MS m/z (TS+) 393 (MH+)
86 Example 8 CDCI3, ,
~ ,.i ( 400 MHz) 2.38 (6H,
~ s)
66 ~ ~ 2,47 (3H, s), 3.53 (2H,
H2N s), 6.88 (2H
I ,
ci d), 7.03 (1 H, s), 7.19
(1 H, d), 7.77
SMe (1 H, d), 7.95 (1 H, s);
MS m/z (ES+)
351 (MH+)
87 Example 8H (CDCI3, 400 MHz) 2.27
~ (6H, s),
67 HN ~ 2.46 (3H, s), 3.01 (3H,
d), 3.50 (2H
~ ,
Me ~ c~ s), 6.19 (1 H, brs), 6.88
(2H, m), 7.00
sMe (1 H, s), 7.19 (1 H, d),
7.72 (1 H, d),
7.85 (1 H, s); MS m/z (ES+)
365
(M H+)
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Example PrecursorR5 data
I
/ Y
Z
88 Example ~ HCI salt: 8H (CDC13, 400
~ MHz) 2.25
68 ~ ~ (6H, s), 3.07 (2H, s), 3.49
HzN (2H, s),
I / 4.37 (2H, m), 5.47-6.22 (2H,
brd),
sJ 6.44 (1 H, s), 6.49 (1 H,
d), 6.86 (1 H,
d), 6.95 (1 H, d), 7.68 (1
H, d), 7.87
(1 H, s); MS m/z (TS+) 346
(MH+)
89 Example HCI salt: 8H (CD30D, 400
~ ~ MHz) 2.91
69 Hr~ (6H, s), 3.13 (2H, s), 3.27
I (3H, s),
/ 0 4.39 (2H, s), 4.46 (2H, s),
6.64 (2H,
oMe sJ s+d), 6.87 (1 H, d), 7.08
(1 H, d), 7.95
(1 H, d), 8.00 (1 H, s);
MS m/z (TS+)
403 (MH+)
90 Example N~ HCI salt: 8H (d6-DMSO, 300
MHz)
70 ~ 2.46 (3H, s), 2.74 (6H, s),
I 4.29 (2H,
/ F s), 4.51 (2H, s), 5.32 (1
H, brs), 6.93
snna (2H, d), 7.08 (1 H, d), 7.41
(2H, m),
7.63 (1 H, s); MS m/z (TS+)
322
(MH+)
91 Example N~ HCI salt: 8H (d6 DMSO, 400
MHz)
71 ~ 2.52 (3H, obs), 2.76 (6H,
s), 4.09
I (2H, s), 4.49 (2H, s), 5.32
/ o, (1 H, brs),
sm,e 6.87 (1 H, d), 7.08 (1 H,
d), 7.26 (1 H,
s), 7.38 (2H, m), 7.60 (1
H, s); MS
m/z (ES+) 338 (MH+)
92 Example -C-_-N HCI salt: 8H (CDCI3, 400
MHz) 2.35
78 ~ (3H, s), 2.48 (3H, s), 2.87
(6H, d),
I 4.39 (2H, d), 6.85 (1 H,
/ Me d), 6.90 (1 H,
sMe d), 6.93 (1 H, dd), 7.21
(1 H, d), 7.60
(1 H, d), 8.17 (1 H, s);
MS m/z (TS+)
313 (MH+)
93 Example -C---N HCI salt: 8H (d6-DMSO, 300
MHz)
72 ~ 2.49 (3H, obs), 2.79 (6H,
s), 4.41
I (2H, s), 6.97 (1 H, d), 7.14
/ F (1 H, d),
sMa 7.32 (1 H, d), 7.49 (1 H,
t), 7.87 (1 H,
d), 8.22 (1 H, s); MS m/z
(TS+) 317
(M H+)
94 Example H HCI salt: SH (ds-DMSO, 400
MHz)
45 ~ 2.23 (3H, s), 2.42 (3H, s),
2.76 (6H,
I S), 4.34 (2H, S), 6.80 (1
/ Me H, d), 7.97
sMa (1 H, dd), 7.00 (1 H, s),
7.19 (1 H, t),
7.24 (1 H, d), 7.40 (1 H,
t), 7.67 (1 H,
d); MS m/z (ES+) 288 (MH+)
95 Example H HCI salt: 8H (CDCI3, 400
MHz) 2.74
46 ~ (6H, s), 3.22 (2H, m), 3.38
(2H, m),
I / 4.26 (2H, s), 6.71 (1 H,
d), 6.80 (2H,
s brm), 7.15 (2H, brm), 7.32
(1 H, d),
7.79 (2H, d); MS m/z (ES+)
286
(MH+)
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Example PrecursorR5 data
I
Y
Z
96 Example ... HCI salt: 8,., (CD30D, 300
MHz) 2.46
73 "~e S~H'~I ~ (3H, s), 3.93 (6H, s), 3.97
(3H, s),
4.24 (2H, s), 4.42 (2H,
s), 6.91-7.00
sMe (3H, m), 7.41-7.54 (2H,
m), 7.61 (1 H,
s); MS m/z (TS+) 399 (MH+),
(ES-)
397 (M-H+)
97 Example ..~ HCI salt: ~H (CD30D, 400
MHz) 2.31
75 Me S~H'~I ~ (3H, s), 2.43 (3H, s), 2.86-2.94
(9H,
a Me m), 4.22 (2H, s), 4.39 (2H,
s), 6.83
sMe (1 H, d) 6.89-6.94 (2H,
m), 7.26 (1 H,
d), 7.40 (1 H, d), 7.54
(1 H, s); MS m/z
(ES-) 393 (M-H+)
98 Example H~ HCI salt: 8H (CD30D, 300
MHz) 2.36
74 I a (3H, s), 2.47 (3H, s), 2.98
(6H, s),
Me 4.43 (2H, s), 4.63 (2H,
s), 6.89 (1 H,
sMe d), 6.91-7.00 (2H, m), 7.30
(1 H, d),
7.43 (1 H, d), 7.55 (1 H,
s); MS m/z
(ES+) 318 (MH+)
99 Example ... HCI salt: SH (CD30D, 300
MHz) 2.39
76 ~F3 S~H I ~ (3H, s), 2.47 (3H, s), 2.85
(6H, s),
4.32 (2H, S), 4.44 (2H,
S), 6.80-6.86
sMe (3H, m), 7.21 (1 H, d),
7.35 (1 H, d),
8.08 (1 H, s); MS m/z (ES+)
449
(MH+), (ES-) 447 (M-H+)
100 Example ~ 8H (CD30D, 400 MHz) 2.26
~ ~ (6H, s),
102 H2N I 3.58 (2H, s), 6.97 (1 H,
d), 7.35 (1 H,
d), 7.46 (1 H, dd), 7.54
(1 H, d), 7.80
N a (1 H, d), 8.03 (2H, m),
8.20 (1 H, d),
8.74 (1 H, d); MS m/z (TS+)
322
(MH+)
Example 94 was also prepared as follows.
A solution of the product from Preparation 30 (200 g, 0.78 mol) in DCM (1.4 L)
was
added to THF (1.4 L). To this mixture was added dimethylamine hydrochloride
(69.5 g,
0.85 mol) and triethylamine (235 g, 2.33 mol) successively. The temperature
was
adjusted to 20 °C and after 3 h sodium triacetoxyborohydride (246 g,
1.16 mol) was
added (After 20 h, if the reaction has completed, continue with work up;
otherwise see
note below). Dichloromethane (2 L) was added and a solution of 8% sodium
bicarbonate
(0.9 L) was added over 0.5 h. The layers were separated and the organic layer
washed
with water (1 L). The layers were again separated and the organic layer was
concentrated. Ethyl acetate (0.27 L) was added and the solvent removed
replacing with
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fresh ethyl acetate (800 ml). The solution was then cooled to below 5
°C and 7.02 M
HCI/IPA (0.117 L, 0.82 mol) added whist the temperature was maintained below
10 °C.
After stirring for 1 h at below 5 °C, the slurry was filtered, washed
with ethyl acetate (3 x
0.2 L) and dried in a vacuum oven at 50 °C overnight to give the
desired product as a
5 powdery solid (141.5 g, 56%). [Note: if reaction hasn't completed after 20h.
Add another
portion of dimethylamine hydrochloride (13g, 0.16mo1) and triethylamine
(43.4g,
0.43mo1) successively. After 2h at room temperature add sodium
triacetoxyborohydride
{46g, 0.22mo1). Leave for a further 20h and then work up as above].
10 Compounds of formula Ii, i.e. compounds of general formula I where R2 is
methyl, R4 is
hydrogen and R5 is -C(=O)NH2, shown in Table 11 were prepared according to
Example
79 form the precursors indicated.
a
15 Table 11
ExamplePrecursorR' data
I
Y
Z
101 Example Me 8H (CDC13, 300 MHz) 2.30 (6H,
s), 2.35
92 I ~ (3H, s), 2.46 (3H, s), 3.58
(2H, s), 5.60-
Me 5.80 (1 H, brs), 6.00-6.20 (1
H, brs), 6.32
sMe (3H, m), 7.19 (1 H, m), 7.71
(1 H, d), 7.90
(1 H, s); MS m/z (TS+) 331 (MH+)
102 Example H SH (CDCI3, 400 MHz) 2.43 (3H,
s), 3.84
49 I ~ (2H, s), 6.94 (1 H, d), 7.20
(1 H, d), 7.34-
7.39 (1 H, m), 7.43 (1 H, dd),
7.70 (1 H, d),
N s 7.91 (1 H, s), 7.99 (1 H, d),
8.09 (1 H, d),
8.82 (1 H, d); MS m/z (ES+)
309 (MH+)
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EXAMPLE 103
N~5-Amino-2-(3-meth~rl-4-(methyfsulfanyl)phenoxylbenzyl)-N,N-dimethylamine
HzN ~ ~ NMez
O
Me
SMe
A mixture of the vitro compound of Example 27 (2.0 g, 6 mmol), Fe powder (2.51
g, 44.9
mmol) and CaCl2 (300 mg, 2.7 mmol) in EtOH (20 mL) and water (4 mL) was heated
at
reflex for 20 h. After cooling to room temperature the solvent was removed in
vacuo and
the residue was partitioned between brine (100 mL) and ether (100 mL). The
aqueous
layer was extracted with ether (50 mL) and the combined organic layers were
dried
(MgS04) and evaporated to give the product (1.47 g; 81 %) as an orange oil; SH
(CDCI3,
300 MHz) 2.22 (6H, s), 2.32 (3H, s), 2.40 (3H, s), 3.33 (2H, s), 6.59 (1 H,
dd), 6.60-6.75
(2H, m), 6.78 (1 H, dd), 6.94 (1 H, s), 7.10-7.20 (3H, m); MS m/z (ES+) 303
(MH+).
EXAMPLE 104
N-[5-Amino-2-(2,3-dihydro-1-benzothien-5-yloxy)benz,Lrll-N,N-dimeth lame
H2N
ez
The title compound was prepared from the vitro compound of Example 28 by the
method
of Example 103; sH (CDCI3, 400 MHz) 2.20 (6H, s), 3.16 (2H, t), 3.30 (4H, m),
3.54 (2H,
br), 6.53 (1 H, dd), 6.60 (1 H, d), 6.71 (2H, m), 6.79 (1 H, d), 7.01 (1 H,
d); MS m/z (ES+)
301 (MH+).
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EXAMPLE 105
N-[3-(Aminomethyl)-4-(2,3-dihydro-1,4-benzoxathiin-6-yloxy)pheny1l-
methanesulfonamide
H
Me~1~01 N NH2
O
S
~J
The nitrite of Preparation 95 (720 mg, 1.99 mmol) was dissolved in a 1 M
solution of
BH3.THF in THF (10 mL, 10 mmol) and the mixture was heated at reflux for 3 h.
After
cooling to room temperature the reaction was quenched by the cautious addition
of
MeOH (10 mL). The solvent was evaporated, the residue was treated with 6M HCI
(10
mL) and heated at reflux for 1 h. After cooling, the mixture was basified with
2M NaOH
and the pH was adjusted to 7 with sat aq NH4CI. The mixture was extracted with
EtOAc
(3x50 mL) and DCM (2x50 mL) and the combined organic layers were dried (MgS04)
and evaporated to give a beige foam (685 mg, 94%) which was used without
further
purification; 8H (CDCI3, 400 MHz) 3.00 (3H, s), 3.13 (2H, m), 3.87 (2H, s),
4.40 (2H, m),
6.62 (1 H, d), 6.67 (1 H, s), 6.79 (2H, d), 7.08 (1 H, d), 7.25 (1 H, d); MS
m/z (TS+) 367
(M H+).
Compounds of formula Ij, i.e. compounds of general formula I where R', R~ and
R4 are
hydrogen and R5 is -NRB-SOZMe, shown in Table 12 were prepared according to
Example 105 from the precursors indicated
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58
Table 12
ExamplePrecursor R8 data
Y
Z
106 Prep H sH (CDCI3, 300 MHz) 2.47 (3H, s),
96 3.02 (3H, s),
3.08 (3H, br), 3.85 (2H, s), 6.87
(2H, m), 6.99
ci (1 H, d), 7.15 (1 H, dd), 7.20
(1 H, d), 7.30 (1 H,
sMe d); MS m/z (ES') 371 (M-H+)
107 Prep H Used crude in a subsequent step:
97 8H (CD30D,
400 MHz) 2.37 (3H, s), 2.95 (3H,
s), 3.75 (2H,
s), 6.58 (1 H, d), 6.71 (2H, m),
6.89 (1 H, d), 7.15
SMe (1 H, dd), 7.28 (1 H, obs)
108 Prep Me Used crude in a subsequent step:
100 8H (CDCI3,
300 MHz) 2.36 (3H, s), 2.46 3H,
s), 2.90 (3H,
~Me S), 3.36 (3H, 5), 3.93 (2H, S),
6.83 (3H, m), 7.20
sMe (2H, m), 7.42 (1 H, d).
109 Prep H 8H (CD30D, 400 MHz) 2.24 (3H, s),
99 2.40 (3H, s),
2.97 (3H, s), 3.80 (2H, s), 6.60
(1 H, d), 6.81-
SMe 6.87 (2H, m), 7.08-7.17 (2H, m),
7.29 (1 H, d);
Me MS m/z (ES+) 353 (MH+), (ES') 351
(M-H+)
EXAMPLE 110
N-f4-(2,3-Dihydro-1,4-benzoxathiin-6-yloxy)-3-~(methylamino)methyllphen
methanesulfonamide
,Me
Me' ISOI I 'H
0 0
o f
s
o~
Dicyclohexylcarbodiimide (460 mg, 2.23 mmol) was added to a solution of
pentafluorophenol (413 mg, 2.24 mmol) in ether (10 mL) followed by formic acid
(95 ~.L,
2.5 mmol). The mixture was stirred for 2 h and then filtered, washing the
residue with
ether. The filtrate was concentrated to ~5 mL and a solution of the primary
amine of
Example 105 (411 mg, 1.1 mmol) in DCM (10 mL) was added. The mixture was
stirred
for 16 h then concentrated to an oily residue. This crude oil was taken up in
a solution of
BH3.THF in THF (1 M, 20 mL, 20 mmol) and heated at reflux for 1.5 h under N2.
After
cooling to room temperature the reaction was quenched by the cautious addition
of
MeOH (10 mL) and then concentrated in vacuo. The oily residue was treated with
6M
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HCI and heated at reflux for 30 min. After cooling to room temperature the
mixture was
basified with aq K2C03 and extracted with DCM (3x). The combined organic
extracts
were dried (MgS04) and evaporated. The residue was purified by column
chromatography [SiOa; 90:10:1 (DCM/ MeOH/ 880 NH3)] to give a colourless oil
which
was taken up in EtOAc (20 mL) and treated with 1 M ethereal HCI (2 mL). After
stirring
for 1.5 h the solid was collected by filtration to give the title product (282
mg, 60%); 8H
(CD30D, 400 MHz) 2.78 (3H, s), 2.98 (3H, s), 3.18 (2H, m), 4.29 (2H, s), 4.39
(2H, m), a
6.74 (1 H, d), 6.80-6.90 (3H, m), 7.22 (1 H, d), 7.44 (1 H, s); MS m/z (TS+)
381 (MH+).
Compounds of formula Ik, i.e. compounds of general formula I where R' and R4
are
hydrogen, R2 is methyl and RS is -NHSO~Me, shown in Table 13 were prepared
according to Example 110 from the precursors indicated.
O~S~~ ~ ,Me
Me'o
0
Y
Z
(1k)
Table 13
Example Precursor data
I
Y
Z
111 Example 8H (CDCI3, 400 MHz) 2.40 (6H, s),
2.99 (3H, s),
107 ~ 3.70 (2H, s), 6.64 (2H, t), 6.88
(1 H, d)
7.15 (1 H
~ ,
,
d), 7.25 (2H, s); MS m/z (TS+) 371
(MH+)
SMe
11,2 Example HCI salt: 8H (CD30D, 400 MHz) 2.55
(3H, s),
106 ~ 3.82 (3H, s), 3.04 (3H, s), 4.32
(2H, s), 6.97
~ (1 H, d), 7.11 (1 H, d), 7.23 (1
H, s), 7.30 (1 H, d),
sMe 7.39 (1 H, d), 7.56 (1 H, s); MS
m/z (TS+) 387
(M H+)
113 Example HCI salt: 8H (CD30D, 400 MHz) 2.24
(3H, s),
109 ~ ~ 2.39 (3H, s), 2.76 (3H, s), 2.93
(3H, s), 4.25
SMe (2H, s), 6.69 (1 H, d), 6.82 (1
H, d), 6.93 (1 H, s),
Me 7.17 (1 H, d), 7.21 (1 H, d), 7.43
(1 H, s); MS m/z
(ES+) 367 (MH+), (ES') 365 (M-H~)
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Compounds of formula Im, i.e. compounds of general formula I where R' and R4
are
hydrogen, R~ is methyl and R5 is -NRBSO~Me, shown in Table 14 were prepared
according to Example 110 from the precursors indicated.
M
1e
(lm)
5
Table 14
Example PrecursorRa data
I
Y
Z
114 Prep 85 H HCI salt: 8H (CDC13, 400 MHz)
2.09 (2H,
m), 2.73 (3H, s), 2.88 (4H,
t), 3.00 (3H, s),
I ~ 4.21 (2H, s), 6.80 (2H, m),
6.88 (1 H, s),
7.19 (1 H, d), 7.34 (1 H, d),
7.75 (1 H, s);
MS m/z (TS+) 347 (MH+)
115 Prep 84 H HCI salt: 8H (ds-DMSO, 400 MHz)
2.20
I ~ (3H, s), 2.40 (3H, s), 2.55
(3H, s), 2.97
(3H, S), 4.08 (2H, S), 6.80
(1 H, d), 6.87
sMe (1 H, d), 6.91 (1 H, s), 7.14
(1 H, d), 7.20
(1 H, d), 7.39 (1 H, s); MS
m/z (TS~) 367
(M H+)
116a Prep 88 Me 8H (CDCI3, 300 MHz) 2.17 (3H,
s), 2,37
~ (3H, s), 2.48 (3H, s), 2.62
(3H, s), 2.97
I (3H, s), 3.34 (3H, s), 4.23
(2H, s), 6.79
sMe (1 H, d), 6.94 (2H, s), 7.35
(2H, m), 7.81
(1 H, s); MS m/z (TS+) 381 (MH+)
117 Prep 89 " HCI salt: 8H (CDC13, 400 MHz)
2.29 (3H,
~ s), 2.39 (3H, s), 2.42 (3H,
s), 2.94 (3H, s),
I 3.60 (2H, t), 3.74 (2H, t),
3.79 (2H, s),
5Me 6.78 (3H, m), 7.14 (2H, m),
7.41 (1 H, s);
MS m/z (TS+) 410 (MH+)
118 Prep 87 H 8H (CDC13, 400 MHz) 2.42 (3H,
s), 2.58-
2.79 (2H, br}, 2.94 (3H, s),
3.08 (2H, m),
3.71 (2H, s), 4.38 (2H, m),
6.39 (1 H, s),
s J 6.47 (1 H, d), 6.82 (1 H, d),
6.94 (1 H, d),
7.07 (1 H, d), 7.18 (1 H, s);
MS m/z (TS+)
381 (MH+)
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Example PrecursorR8 data
Y
Z
119 Prep 86 H 8H (CD30D, 400 MHz) 2.80 (3H,
s), 3.00
(3H, s), 3.27 (2H, m), 3.40
(2H
m)
4.28
,
,
(2H, m), 6.85 (2H, m), 7.00
(1 H, s), 7.20
s (1 H, d), 7.24 (1 H, dd), 7.47
(1 H, d); MS
m/z (TS+) 365 (MH+)
a - Also made from Example 108 by the method of Example 110.
Compounds of formula In, i.e. compounds of general formula I where R' and R2
are
methyl, R4 is hydrogen, and R5 is -NRBSO~Me, shown in Table 15 were prepared
according to Example 12 from the precursors indicated.
(1n)
Table 15
Example PrecursorR8 Data
I~
Y
Z
120 Example H HCI salt: 8H (CD3OD, 400 MHz)
2.42 (3H,
111 ~ ~ s), 2.89 (6H, s), 2.98 (3H, s),
4.37 (2H, s),
6.88 (2H, m), 6.97 (1 H, d),
7.28 (1 H, d),
sMa 7.39 (1 H, t), 7.48 (1 H, s);
MS m/z (TS+) 385
(M H+)
121 Example H 8H (CDCI3, 400 MHz) 3.00 (3H,
s), 3.13 (2H,
(from 105 ~ ~ m), 3.87 (2H, s), 4.40 (2H, m),
6.62 (1 H, d),
primary ~ S 6.67 (1 H, s), 6.79 (2H, d),
7.08 (1 H, d), 7.25
amine) o f (1H, d); MS m/z (TS+) 367 (MH+)
122 Example H HCI salt: 8H (CD30D, 400 MHz)
2.49 (3H,
(from 106 ~ s), 2.93 (6H, s), 3.00 (3H, s),
4.41 (2H, s),
primary ~ 6.95 (1 H, d), 7.07 (1 H, d),
~ ~, 7.21 (1 H, s), 7.33
amine) sMe (2H, m), 7.54 (1 H, s); MS m/z
(TS~) 395
(M H+)
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Example PrecursorR$ Data
I
Y
z
123 Example H HCI salt: 8H (CDCI3, 400 MHz)
2.12 (2H, m),
114 ~ 2.81 (6H, s), 2.91 (4H, t), 3.13
(3H, s), 4.25
(2H, s), 6.73 (1 H, d), 6.83
(2H, m), 7.10
(1 H, d), 7.39 (1 H, d), 7.90
(1 H, s); MS m/z
(TS+) 360 (MH+)
124 Example H 8H (CDC13, 400 MHz) 2.22 (6H,
s), 2.98 (3H,
118 ~ s), 3.07 (2H, m), 3.41 (2H, s),
4.38 (2H, m),
~ 6.36 (1 H, s), 6.45 (1 H, d),
6.86 (1 H, d), 6.92
sJ (1 H, d), 7.12 (1 H, d), 7.27
(1 H, s); MS m/z
(TS~) 395 (MH+)
125 Example " HCI salt: 8,., (CDCI3, 300 MHz)
2.38 (3H, s),
117 ~ ~ 2.48 (3H, s), 2.86 (6H, brs),
3.15 (3H, s),
~ 3.73 (2H, brs), 3.87 (2H, brs),
Me 4.35 (2H,
sMe brs), 6.82 (3H, brs), 7.20 (2H,
m), 7.41 (1 H,
d); MS m/z (TSt) 425 (MH+)
126 Example Me HCI salt: 8,., (CD3OD, 400 MHz)
2.29 (3H,
(from 108 ~ s), 2.43 (3H, s), 2.89 (3H, s),
2.91 (6H, s),
primary ~ 3.26 (3H, s), 4.42 (2H, s), 6.84
~ Me (1 H, d), 6.97
amine) SMa (2H, m), 7.27 (1 H, d), 7.47
(1 H, dd), 7.60
(1 H, d); MS m/z (TS+) 395 (MH+)
127 Example H HCI salt: sH (CD30D, 400 MHz)
2.27 (3H,
(from 109 ~ ~ s), 2.42 (3H, s), 2.94 (6H, s),
2.99 (3H, s),
primary ~ SMQ 4.42 (2H, s), 6.77 (1 H, d),
6.89 (1 H, d), 6.99
amine) Me (1 H, s), 7.19 (1 H, d), 7.28
(1 H, dd), 7.50
(1 H, s); MS m/z (TS~) 381 (MH+),
(ES+) 381
(MH+), (ES-) 379 (M-H+)
EXAMPLE 128
N-{31(Dimethylamino)methyll-4-[3-methyl-4-(methylsulfanyl)phenoxy1-
phen~3methanesulfonamide
Ae2
Me
Methanesulfonyl chloride (371 p.L, 4.79 mmol) was added to a solution of the
aniline of
Example 103 (725 mg, 2.4 mmol) and Et3N (1 mL, 7.17 mmol) in DCM (10 mL) at
0°C.
After stirring at 0°C for 1 h the reaction was allowed to warm to room
temperature before
the solvent was removed in vacuo. 2M NaOH (10 mL) was added to the residue and
the
mixture was stirred overnight. The resulting clear solution was neutralised by
the addition
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of sat aq NH4C1 and extracted with DCM (2x30 mL). The combined organic layers
were
dried (MgS04) and evaporated to give an oil. This was taken up in EtOAc (10
mL), the
HCI salt was precipitated by the addition of 1 M ethereal HCI and the product
(669 mg,
67%) was collected by filtration; 8H (ds-DMSO, 400 MHz) 2.23 (3H, s), 2.42
(3H, s), 2.75
(6H, s), 3.04 (3H, s), 4.38 (2H, s), &.84 (1 H, d), 6.93 (1 H, d), 6.98 (1 H,
s), 7.17-7.25 (2H,
m), 7.50 (1H, s); MS m/z (ES+) 381 (MH+).
Compounds of formula Ip, i.e. compounds of general formula I where R' and R2
are
methyl, R4 is hydrogen, and R5 is -NHS02R9, shown in Table 16 were prepared
according to Example 128 from the precursors indicated.
R8
O~ ,N ,Me
Me'ti I \ H
Y
z
(1p)
Table 16
Example Precursor R9 data
I
Y
Z
129 Example Me HCI salt: 8H (CD30D, 400 MHz) 2.92 (6H,
104 ~ ~ s), 2.99 (3H, s), 3.26 (2H, t), 3.40 (2H, t),
4.41 (2H, s), 6.88 (2H, d), 7.00 (1 H, s), 7.10
s (1 H, d), 7.27 (1 H, d), 7.50 (1 H, s); MS m/z
(TS+) 381 (MH+)
130 Example Et HCI salt: 8H (ds-DMSO, 400 MHz) 1.21 (3H,
103 ~ ~ t), 2.23 (3H, s), 2.42 (3H, s), 2.74 (6H, s),
Me 3.16 (2H, q), 4.26 (2H, S), 6.92 (1 H, d), 6.92
sMe (1 H, d), 6.98 (1 H, s), 7.18-7.25 (2H, m),
7.51 (1 H, s); MS m/z (ES+) 395 (MH+)
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PREPARATIONS
PREPARATION 1
5-(Aminosulfon~)-2-fluoro-N-methylbenzamide
NHMe
HzNOzS /
F
To a solution of 5-(aminosulfonyl)-2-fluorobenzoic acid [prepared according to
Chem.
Pharm. Bull. 1995, 43, 582-7] (22.98 g, 105 mmol) in THF (500 mL) at room
temperature
under nitrogen was added carbonyldiimidazole (17 g, 105 mmol). After stirring
for 2.25 h
a solution of methylamine in THF (2M, 70 mL, 140 mmol) was added dropwise and
the
reaction was allowed to stir for 18 h. The crude reaction mixture was
concentrated to a
low volume and EtOAc (150 mL) was added to the resulting thick oil. This
mixture was
stirred and a granular precipitate formed which was collected by filtration.
This crude
product, contaminated with imidazole, was suspended in DCM (300 mL) and heated
at
reflux for 5 h. After cooling to room temperature the mixture was filtered to
give the
desired product (19.8 g, 81%).containing <2% wiw imidazole;'H NMR 8H (300 MHz,
d4-
MeOH) 2.97 (3H, s), 7.40 (1 H, t), 8.05 (1 H, m), 8.29 (1 H, d); MS rn/z (TS+)
250 (MNH4+).
PREPARATION 2
3-Chloro-4-(methylsulfanyl)phenol
OH
CI
SMe
(i) Preparation of 2-chloro-1-(methylsulfany~-4-nitrobenzene
To a solution of 4-fluoro-3-chloronitrobenzene (27 g, 156 mmol) in DMF (150
mL) at
room temperature was added 5-tert-butyl-4-hydroxy-2-methylphenyl sulfide (100
mg)
followed by sodium thiomethoxide (NaSMe) (10 g, 143 mmol) and the reaction was
stirred for 6h. The DMF was removed in vacuo and the residue was partitioned
between
ether (1 L) and water (1 L). The ether layer was washed with water (1 L) and
brine (1 L),
dried (MgS04) and the solvent was removed under reduced pressure. The residue
was
purified by column chromatography (SiOz; DCM: pentane 1:5 increasing polarity
to 3:7)
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to give the title compound (15.22 g, 49%) as a yellow solid; 8H (400 MHz,
CDC13) 2.53
(3H, s), 7.20 (1 H, d), 8.09 (1 H, dd), 8.20 (1 H, d).
iii) Preparation of 3-chloro-4-(methylsulfanyl)aniline
To a mixture of the above compound (14.08 g, 69 mmol) in acetic acid (300 mL)
and
5 water (60 mL) was added Fe powder (23 g, 412 mmol) and the reaction mixture
was
swirled until all the starting material had dissolved. The mixture was left to
stand for 1.5 h
and the acetic acid was then removed under reduced pressure. The residue was
taken
up in sat NaHC03 (aq) (500 mL) and EtOAc (500 mL) and filtered through
Arbocel~. The
layers were separated, the aqueous phase was extracted with EtOAc (300 mL) and
the
10 combined organics were washed with brine, dried (MgS04) and the solvent was
removed
in vacuo to give the title compound (11.52 g, 96%) as a beige solid; 8H (400
MHz, CDCI3)
2.38 (3H, s), 3.66 (2H, br), 6.53 (1 H, dd), 6.70 (1 H, d), 7.12 (1 H, d); MS
m/z (ES+) 174
(MH+).
(iii) Preparation of 3-chloro-4-(meth Isy ulfianyl)phenol
15 The above aniline (11.5 g, 66.2 mmol) was dissolved in the minimum THF (~15
mL) and
water (500 mL) was added with vigorous stirring, followed by conc HZS04 (25
mL). The
mixture was cooled in an ice-water bath and a solution of NaNOa (5.0 g, 72.5
mmol) in
iced water (10 mL), was added via pipette under the surface of the reaction
mixture. The
reaction was stirred at 0°C for 1.5 h and the resulting yellowlbrown
solution was
20 decanted from the remaining solid into a dropping funnel containing ice
0200 g). This
solution was added at a steady rate over 7 min to a vigorously stirred mixture
of
Cu(N03)~ (230 g, 0.99 mol) and Cu20 (8.52 g, 67.4 mmol) in water (1 L) at room
temperature. After the addition was complete the mixture was stirred for a
further 15 min
before being extracted with ether (500 mL). The residual redibrown solid in
the reaction
25 flask was taken up in MeOH (100 mL) and diluted with ether (300 mL) before
being
poured into the aqueous layer from above. The ether layer was separated and
the
combined organic layers were extracted with 1 M NaOH (3 x 100 mL). The aqueous
extracts were acidified with conc. HCi and then extracted with ether (2 x 150
mL). The
ether layers were then washed with brine, dried (MgS04) and the solvent was
removed
30 in vacuo to give the phenol (5.465 g, 47%) as a brown crystalline solid; 8H
(400 MHz,
CDC13) 2.44 (3H, s), 5.08 (1 H, br), 6.77 (1 H, d), 6.93 (1 H, d), 7.18 (1 H,
d); MS m/z (ES-)
173 (M-H+).
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PREPARATION 3
3-Fluoro-4-(methylsuffanyl)phenol
OH
F
SMe
This compound was prepared using a similar method to that described above for
Preparation 2 starting from commercially available 3,4-difluoronitrobenzene;
8H (CDCl3,
300 MHz) 2.40 (3H, s), 5.03 (1 H, br), 6.60 (2H, m), 7.27 (1 H, m obscured);
MS m/z (ES-)
157 (M-H+).
PREPARATION 4
2.3-Dihydro-1.4-benzoxathiin-6-of
off
s
of
1,2-Dibromoethane (2.3 mL, 26.7 mmol) and KZC03 (8.21 g, 59.4 mmol) were
slurried in
acetone (250 mL) and a solution of 2-sulfanyl-1,4-benzenediol (prepared
according to J.
Org. Chem. 1990, 55, 2736) (4.22 g, 29.7 mmol) in acetone (50 mL) was added
over 4 h
to the stirred mixture. Once the addition was complete stirring was continued
for a
further 10 h before the solvent was removed in vacuo. The residue was
partitioned
between water (50 mL) and EtOAc (50 mL), the aqueous layer was extracted with
EtOAc
(50 mL) and the combined organic layers were dried (MgSO4) and evaporated.
Purification of the residue by column chromatography [Si02; 9:1
(pentane/EtOAc)] gave
the title compound (2.48 g, 55%) as a pale orange oil; 8H (CDCI3, 400 MHz)
3.08 (2H,
m), 4.31 (2H, m), 4.44 (1 H, s), 6.42 (1 H, d), 6.49 (1 H, s), 6.66 (1 H, d);
MS m/z (ES-) 167
(M-H+).
PREPARATION 5
2.3-Dih~dro-1,4-benzoxathiin-7-of
OH
O
SJ
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The title compound was prepared in a similar manner to the compound of
Preparation 4
starting from 4-sulfanyl-1,3-benzenediol (prepared according to J. Org. Chem.
1979, 26,
4971-4973); bH (CDCI3, 400 MHz) 3.05 (2H, t), 4.37 (2H, t), 6.32 (1H, s), 6.35
(1H, d),
6.84 (1 H, d); MS m/z (TS+) 169 (MH+).
PREPARATION 6
1, 3-Dihydro-2-benzofuran-5-of
OH
O
1,3-Dihydro-2-benzofuran-5-amine (prepared according to US4000286) (2.7 g, 20
mmol)
was dissolved in a mixture of water (300 mL) and conc. H2S04 (21 mL), cooled
to 0°C
and NaN02 (1.43 g, 20.7 mmol) in water (10 mL) was added over 15 min. After
stirring at
0°C for 1 h the mixture was allowed to stir at 10°C for 30 min
and urea was added until a
negative test with starch/KI paper was observed. The solution was then poured
over 2
min into a mixture of water (180 mL) and conc. H~S04 (12.6 mL) at 90°C
and stirred at
this temperature for 1.5 h. The hot mixture was filtered then allowed to cool
to room
temperature. The aqueous mixture was extracted with EtOAc (2 x 100 mL) and the
combined organic layers were dried (MgS04) and evaporated to give the title
phenol
(974 mg, 36%) as a cream solid; bH (CDCI3, 400 MHz) 5.03 (4H, s), 6.71 (2H,
m), 7.08
(1 H, d).
PREPARATION 7
2.3-Dihydro-1-benzothiophen-6-of
OH
S
(i) Preparation of 2 3-dihydro-1-benzothiophen-6-of 1,1-dioxide
A suspension of 2,3-dihydro-1-benzothiophen-6-amine 1,1-dioxide [prepared
according
to J. Am. Chem. Soc. 1955, 77, 5939] (15.73 g, 85.8 mmol) in water (500 mL)
and conc.
H~S04 (35 mL) was warmed until solution was achieved. The mixture was cooled
to 0°C
and a solution of NaN02 (6.22 g, 90 mmol) in water (15 mL) was then added over
5 min.
The reaction was stirred at 0°C for 1 h then urea was added, to remove
excess nitrite,
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until a negative test with starch/KI paper was obtained. The mixture was
allowed to
warm to room temperature then added with stirring to a mixture of conc. H~S04
(55 mL)
and water (750 mL) at 90°C. The reaction was re-heated to 90°C
and stirred at this
temperature for 30 min. The hot reaction mixture was filtered through Arbocel~
then
stirred at room temperature overnight. The aqueous mixture was extracted with
ether
(2.5 L) and then EtOAc (5 x 500 mL) and the combined organic layers were dried
(MgS04) and evaporated to give the desired phenol (12.7 g, 80%) which was used
without further purification; 8H (CDCI3, 400 MHz) 3.30 (2H, m), 3.50 (2H, m),
7.05 (1 H,
m), 7.14 (1 H, s), 7.23 (1 H, m); MS m/z (ES-) 183 (M-H+).
(ii) Preparation of 2,3-dihydro-1-benzothiophen-6-of
A solution of the sulfone from stage (i) (4.84 g, 26.3 mmol) in toluene (100
mL) and THF
(70 mL) was added to a solution of DIBAL in toluene (1M, 100 mL, 100 mmol) and
the
mixture was then heated at reflux for 16 h. After cooling to room temperature
EtOH (75
mL) was added cautiously followed by water (100 mL) with stirring. 6M HCI was
added
to the resulting thick suspension and the organic layer was separated. The
aqueous
layer was extracted with EtOAc (3 X 150 mL) and the combined organic layers
were
dried (MgS04) and evaporated to a beige solid. Purification by column
chromatography
[Si02; DCM/ MeOH/ 880 NH3 (97:3:0.25) increasing polarity to (95:5:0.5)]
afforded the
desired title phenol as a beige solid (1.85 g, 53%); SH (CD3OD, 400 MHz) 3.13
(2H, t),
3.30 (2H, m), 6.41 (1 H, d), 6.60 (1 H, s), 6.98 (1 H, d); MS m/z (ES-) 151 (M-
H+).
PREPARATION 8
5-(Aminosulfonyl)-2-[3-methyl-4-(methylsulfanyl)phenoxy]-N-methylbenzamide
HZ
The fluoroamide of Preparation 1 (732 mg, 3.15 mmol) was treated with 4-
(methylthio)-
m-cresol (commercially available) (535 mg, 3.47 mmol) and potassium carbonate
(457
mg, 3.31 mmol) in DMF (10 mL). The mixture was heated at 100 °C for 5
hours. The
solvent was removed by evaporation under reduced pressure and the residue was
treated with 2M HCI (10 mL). The resulting suspension was extracted several
times with
dichloromethane. The combined dichloromethane layers contained a suspension
and
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were evaporated to a solid residue. The residue was triturated with ether (5
mL) and the
remaining solid was washed with ether (3x10 mL) to give an off-white solid
(765 mg,
66%). SH (300 MHz, d6-DMSO) 2.28 (3H, s), 2.48 (3H, s), 2.70 (3H, d), 6.90 (1
H, d), 7.02
(1 H, d), 7.03 (1 H, s), 7.30 (1 H, d), 7.35 (2H, s), 7.79 (1 H, d), 8.10 (1
H, d), 8.30 (1 H, m);
MS m/z (TS+) 367 (MH+), 385 (MNH4+).
PREPARATIONS 9-18
Compounds of formula Va, i.e. compounds of general formula V where T is
-C(=O)NHMe, R4 is hydrogen and R5 is -SOZNH2, shown in Table 17 were prepared
according to Preparation 8 using the sulfonamide of Preparation 1 and the
phenol
indicated.
0
o,s o
H N~ ~ ~ ~NHMe
z
Y
Z
(Va)
Table 17
PreparationPrecursor data
phenol
'~ Y
Z
9 Synth. 8H (ds-DMSO,400 MHz) 2.80 (3H, d),
3.20 (2H,
Gommun. ~ ~ t), 3,40 (2H, t), 6.90 (1 H, m),
7.05 (1 H, s), 7.25
1991, 21, ~ (1 H, d), 7.35 (1 H, s), 7.80 (1
H, m), 8.10 (1 H, s),
959-964 s 8.30 (1 H, brs); MS m/z (TS+) 365
(MH+)
10 Prep 5 8H (CD30D, 400 MHz) 2.92 (3H, s),
3.17 (2H,
m), 4.41 (2H, m), 6.60-6.70 (2H,
m), 6.97 (1 H,
d), 7.18 (1 H, d), 7.90 (1 H, d),
8.31 (1 H, s); MS
s J m/z (TS+) 381 (M H+)
11 Prep 3 sH (CD30D, 400 MHz) 2.43 (3H, s),
2.97 (1 H, s),
6.89 (2H, m), 7.00 (1 H, d), 7.39
(1 H, br), 7.88
~' F (1 H, brd), 8.23 (1 H, s); MS m/z
(ES+) 371 (MH+)
SMe
12 Prep 2 8H (CD30D, 400 MHz) 2.85 (3H, s),
2.99 (3H, s),
6.99 (1 H, d), 7.09 (1 H, d), 7.22
(1 H, s), 7.37
~ (1 H, d), 7.92 (1 H, d), 8.28 (1
H, s); MS m/z (ES+)
sMe 387 (MH+)
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PreparationPrecursor data
phenol
Y
Z
13 Prep 4 8H (CD30D, 400 MHz) 2.87 (3H, brs),
3.13 (2H,
brs), 4.37 (2H, brs), 6.73 (1 H,
I brs), 6.82 (3H,
~ s m), 7.82 (1 H, s), 8.28 (1 H, brs);
MS m/z (ES+)
of 381 (MH+)
14 Prep 6 SH (ds-DMSO, 400 MHz) 2.79 (3H,
s), 4.98 (4H,
brs), 6.92 (1 H, d), 7.04 (1 H,
d), 7.09 (1 H, s)
,
a 7.37 (3H, m), 7.79 (1 H, m), 8.10
(1 H, s), 8.30
o (1H, s); MS m/z (TS+) 349 (MH+)
15 Commercial 8H (CD30D, 400 MHz) 2.08 (2H, m),
2.90 (7H,
m), 6.84 (2H, m), 6.97 (1 H, s),
7.23 (1 H
d)
,
,
7.81 (1 H, d), 8.31 (1 H, s); MS
m/z (TS~) 347
(M H+)
16 Tetrahedron Product used without purification
1982, 38, _
2721 & ~ SMe
Synthesis Me
1982, 475
17 ~ Prep 101 8H (CD30D, 400 MHz) 2.88 (3H, s),
4.20 (4H, s),
6.89 (1 H, d), 6.97 (1 H, d), 7.01
(1 H, s), 7.30
(1 H, d), 7.84 (1 H, d), 8.28 (1
H, s); MS m/z (TS+)
s 382 (MNH~+)
18 Prep 7 SH (DMSO-d6, 400 MHz) 2.78 (3H,
d), 3.23 (2H,
m), 3.40 (2H, m), 6.75 (1 H, dd),
6.90 (1 H, d),
S 7.02 (1 H, s), 7.27 (1 H, d), 7.34
(1 H, d), 7.80
(1 H, d), 8.10 (1 H, s), 8.26 (1
H, br, d); MS m/z
(ES-) 363 (M-H+)
PREPARATION 19
5-Bromo-2-(2,3-dihydro-1-benzothien-5-yloxy)benzaldehyde
Br / ~ ~ o
0
s
5 A mixture of 5-bromo-2-fluorobenzaldehyde (1.08 g, 5.32 mmol), 5-hydroxy-2,3-
dihydrobenzothiophene (prepared as described in Synth. Common. 1991, 21, 959-
964)
(808 mg, 5.31 mmol) and KzCO3 (1.47 g, 10.6 mmol) in DMF (5 mL) was heated at
90°C
for 16 h. After cooling to room temperature the mixture was partitioned
between water
(50 mL) and ether (50 mL), the aqueous layer being extracted with ether (50
mL). The
10 combined organic extracts were washed with water (50 mL), dried (MgS04) and
evaporated. The residue was purified by column chromatography [SiOz; 9:1
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(pentanelEtOAc)], then triturated with ether, to give the product (1.1 g, 62%)
as a pale
yellow solid; 8H (CDCI3, 400 MHz) 3.28 (2H, t), 3.41 (2H, t), 6.78 (1 H, d),
6.84 (1 H, d),
6.92 (1 H, s), 7.20 (1 H, d), 7.58 (1 H, d), 8.00 (1 H, s), 10.43 (1 H, s).
Compounds of general formula II shown in Table 18 were prepared according to
Preparation 19 by reacting the phenol indicated with the required 2-
fluorobenzaldehyde.
In most cases the crude reaction product after aqueous work-up was used
directly in
subsequent steps without further purification.
R5 ~ ~ O
R4
Y
Z
Table 18
PreparationPrecursor R4 R5 data
Phenol
Y
Z
Prep 3 H Br 8H (CDCI3, 300 MHz) 2.48
(3H, s),
6.81 (3H, m), 7.37 (1 H,
t), 7.64
(1 H, d), 8.06 (1 H, s),
10.39 (1 H, s);
SMe MS m/z (TS+) 358, 360 (MNH~+)
21 Prep 5 H Br 8,., (CDCI3, 400 MHz) 3.13
(2H, m),
4.42 (2H, m), 6.55 (1 H,
s), 6.59
o (1 H, d), 6.81 (1 H, d),
7.04 (1 H, d),
sJ 7.59 (1 H, d), 8.01 (1
H, s), 10.40
(1 H, s)
22 Prep 2 H Br 8H (CDCI3, 400 MHz) 2.43
(3H, s),
6.78 (1 H, d), 6.94 (1
H, d), 7.08
i ci (1 H, s), 7.19 (1 H, d),
7.59 (1 H, d),
sMe 8.00 (1 H, s)
23 commercialH Br sH (CDCI3, 300 MHz) 2.35
(3H, s),
2.49 (3H, s), 6.78 (1 H,
d), 6.90
(2H, s), 7.22 (1 H, d),
7.59 (1 H, d),
SMe 8.05 (1 H, s), 10.45 (1
H, s); MS m/z
(TS+) 356, 354 (MNH4+)
24 commercialH Me0 8H (CDC13, 300 MHz) 2.35
(3H, s),
2.45 (3H, s), 3.87 (3H,
s), 6.82
(1 H, d), 6.83 (1 H, S),
6.92 (1 H, d),
sMe 7.13 (1 H, dd), 7.19 (1
H, d), 7.40
(1 H, d), 10.40 (1 H, s);
MS m/z
- (TS+) 389 (MH+)
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PreparationPrecursor R4 R5 data
Phenol
Y
Z
25 commercialH F &H (CDCI3, 300 MHz) 7.02
(1 H, dd),
7.21 (1 H, s), 7.30 (1
H, m)
7.40
,
(1 H, m), 7.54 (1 H, d),
7.66 (1 H,
dd), 8.01 (1 H, d), 8.18
(1 H, d),
8.88 (1 H, d), 10.43 (1
H, s); MS m/z
(ES+) 268 (MH+)
26 commercialH H 8N (CDCl3, 400 MHz) 6.97
(1 H, d),
7.21-7.27 (2H, m), 7.38
(1 H, dd),
r 7.49-7.58 (2H, m), 7.92-8.01
(2H,
m), 8.11 (1 H, d), 8.83
(1 H, d),
10.50 (1 H, s); MS m/z
(ES+) 272
(MNa+), (ES-) 248 (M-H+)
27 J. Chem. H H sH (CDCI3, 300 MHz) 7.08
(1 H, d),
Soc. 1952, ~ ~ 7.36 (2H, m), 7.65 (1 H,
m), 7.79
4985-4993 ~ (1 H, dd), 8.01 (1 H, d),
8.13 (1 H, d),
~ 9.29 (1 H, d), 10.45 (1
H, s); MS m/z
(TS+) 251 (MH+)
28 commercialH H 8H (CDC13, 400 MHz) 7.09
(1 H, d),
7.28 (1 H, m), 7.35 (1
H, m), 7.40
(1 H, m), 7.50 (1 H, br),
7.59 (1 H,
w ~ m), 7.86 (1 H, dd), 7.99
(1 H,. dt),
8.15 (1 H, d), 8.86 (1
H, m), 10.46
(1 H, s); MS m/z 250 (MH+)
29 Chem. H H 8,.i (CDCi3, 400 MHz) 6.91
(1 H, d),
Pharm. ~ ~
2
.
, N (1 H, m)H8. 2
Bull., ( H, d)(
1978; 8.95 (1 H,
s),
26, 1443 s!~ 10.5 (1 H, s); MS m/z 256
(MH+)
30 commercialH H bH (CDC13, 300 MHz) 2.35
(3H, s),
3.44 (3H, s), 6.87 (3H,
m), 7.17
-' Me (2H, m), 7.50 (1 H, t),
7.92 (1 H, dd),
sMe 10.52 (1 H, s); MS m/z
(TS+) 259
(MH+)
31 Synth. H H ~H (CDC13, 400 MHz) 3.26
(2H, t),
Commun. ~ 3.39 (2H, m), 6.85 (2H,
~ t), 6.92
1991, 21, i
(1 H, s), 7.18 (2H
m), 7.48 (1 H
t)
,
959-964 S ,
,
7.92 (1 H, d), 10.51 (1
H, s); MS m/z
(TS+) 257 (MH+)
32 commercialBr H 8H (CDC13, 400 MHz) 2.36
(3H, s),
2.44 (3H, s), 6.88 (2H,
m), 6.96
(1 H, S), 7.18-7.25 (2H,
obs), 7.77
sMe (1 H, d), 10.43 (1 H, s)
33 Prep 7 H Br s,., (CDCI3, 400 MHz) 3.27
(2H, m),
3.42 (2H, m), 6.67 (1 H,
d), 6.80
~ s (1 H, d), 6.90 (1 H, s),
71.6 (1 H, d),
7.58 (1 H, d), 8.01 (1
H, s), 10.41
(1 H, s); MS m/z (TS+)
354 (MNH4~)
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PreparationPrecursor R4 R5 data
Phenol
/ Y
z
34a commercialH CN 8H (DMSO-ds, 300 MHz) 6.26
(1 H,
d), 6.43 (1 H, d), 7.49
(1 H, d), 7.65-
~ 7.71 (2H, m), 7.88 (1 H,
d), 8.07
N / (1 H, d), 8.17 (1 H, s),
8.73 (1 H, d),
8.89 (1 H, s); MS m/z (ES-)
273 (M-
H), (ES~) 275 (MH+)
- 4-Fluoro-3-formylbenzonitrile was synthesised according to Synth. Common.
1997,
27(7), 1199 and J. Org. Chem. 1961, 26, 2522.
The product from Preparation 30 was also prepared as follows.
Potassium carbonate (334.1 g, 2.42 mol) and 4-(methylthio)-m-cresol (273.4 g,
1.77
mol) were added successively to DMF (2 L). 2-Fluorobenzaldehyde (200 g, 1.61
mol)
was then added to the slurry and the mixture heated in the range 100-110
°C. After 48 h
the reaction mixture was allowed to cool to room temperature and wafer (1.2 L)
added.
The solution was cooled to below 10 °C and the pH adjusted to 5 with
concentrated HCI
(0.37 L), keeping the temperature below 10 °C. Water (0.15 L) and
dichloromethane
(0.9 L) were added and the mixture stirred. The layers were separated and the
organic
layer was washed with water (4 x 0.75 L). The solvent was distilled to
azeotropically
remove the water. Fresh dichloromethane was added as required. The dry
dichloromethane solution was then concentrated in vacuo to give the crude
product as
an oil (422 g, 100%).
Compounds of formula IX shown in Table 19 were prepared according to
Preparation
19, using either 2-chloro-5-nitrobenzaldehyde or 2-chloro-5-nitrobenzonitrile
with the
phenol indicated. For these reactions a shorter reaction time (ca. 2-3 h) was
usually
sufficient to achieve good conversion. In most cases the crude reaction
product after
aqueous work-up was used directly in subsequent steps without further
purification.
o2N ~w
Y
z
px>
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Table 19
PreparationPrecursor W data
I
Y
Z
35 Prep 3 -C---N sH (CDC13, 400 MHz) 2.48
(3H, s),
6.85-6.95 (3H, m), 7.28 (1
H, t), 8.30
-' F (1 H, d), 8.52 (1 H, s)
SMe
36 Prep 5 8H CDC13, , ,
( 400 MHz) 3.14 (2H d) 4.43
(2H, d), 6.62 (2H, m), 6.92
(1 H, d),
7.08 (1 H, d), 8.27 (1 H,
~ d), 8.72 (1 H, s),
s 10.51 (1 H, s); MS m/z (TS+)
318 (MH+)
37 Prep 2 -C---N 8H (CDCI3, 300 MHz) 2.55
(3H, s), 6.94
(1 H, d), 7.09 (1 H, dd),
7.22 (1 H, d),
, 7.27 (1 H, d), 8.36 (1 H,
dd), 8.60 (1 H,
sMe d); MS m/z (TS+) 338 (MNH4+)
38 Synth. p 8H (CDC13, 400 MHz) 3.29
~ (2H, m),
Common. ~N ~ 3.42 (2H, m), 6.88 (2H, m),
6.96 (1 H,
1991, 21, I ./ s), 7.23 (1 H, d), 8.26 (1
H, d), 8.75 (1 H,
959-964 s s), 10.54 (1 H, s)
39 commercial 8H (CDCI3, 400 MHz) 2.38
(3H, s), 2.50
(3H, s), 6.92 (1 H, d), 6.99
(2H, m),
Me 7.24 (1 H, d), 8.28 (1 H,
dd), $.78 (1 H,
sMe d), 10.57 (1 H, s)
40 commercial i;H (CDC13, 400 MHz) 2.18
(2H, m),
2.95 (4H, t), 6.90 (2H, m),
7.29 (1 H, d),
8.27 (1 H, d), 8.79 (1 H,
s), 10.59 (1 H,
s); MS m/z (TS+) 301 (MNH4+)
41 Prep 4 -C---N 8H (CDCI3, 400 MHz) 3.18
(2H, t), 4.44
(2H, t), 6.76 (1 H, d), 6.86
(1 H, s), 6.92
s s (2H, d), 8.32 (1 H, d), 8.57
(1 H, s); MS
o f m/z (TS+) 332 (MNH4+)
42 commercial-C---N 8H (CDCI3, 400 MHz) 2.32
(3H, s), 2.47
(3H, s), 6.87 (1 H, d), 6.94
(2H, m),
Me 7.21 (1 H, d), 8.26 (1 H,
dd), 8.51 (1 H,
Me d); MS m/z (TS+) 318 (MNH4+)
43 Tetrahedron-C---N 8,., (CDCI3, 400 MHz) 2.31
(3H, s), 2.41
1982, 38, ~ (3H, s), 6.76 (1 H, dd),
I 6.85 (2H, m),
2721 & ~ SMe 7.19 (1 H, d), 8.24 (1 H,
dd), 8.53 (1 H,
Synthesis Me d); MS mlz (TS+) 318 (MNH4+)
1982, 475
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PREPARATION 44
tent-ButylS-bromo-2-(2,3-dihydro-1-benzothien-5~rlox benzyl(methyl)carbamate
0II
Br \ N~OtBu
Me
S
The hydrochloride salt of Example 36 (1.04 g, 2.7 mmol) was slurried in DCM
(12 mL)
5 and Et3N (750 ~.L, 5.38 mmol) was added, followed by di-tert butyl
dicarbonate (766 mg,
3.51 mmol). After stirring at room temperature for 20 min the reaction was
quenched by
the addition of 0.2M HCI (20 mL). The well shaken mixture was separated and
the
aqueous layer was extracted with DCM (10 mL). The combined organic layers were
dried (MgS04) and evaporated to give the product (assumed quantitative yield)
as a
10 colourless oil which was used without further purification; 8H (CDCI3, 400
MHz) 1.56 (9H,
s), 2.82-2.98 (3H, brd), 3.23 (2H, t), 3.40 (2H, t), 4.44 (2H, brd), 6.71 (2H,
d), 6.79 (1 H,
s), 7.12 (1 H, d), 7.29 (1 H, d), 7.39 (1 H, s).
Compounds of formula X shown in TabIe.20 were prepared according to
Preparation 44
15 starting from the precursors indicated.
0
Br \ N~~~Bu
C Me
Y
Z
(X)
Table 20
PreparationPrecursor data
/ Y
Z
45 Example 8H (CDC13, 400 MHz) 1.41 (9H, brs),
2.81 (3H, m),
38 ~ 3.07 (2H, m), 4.36 (4H, m), 6.38
(1 H, s)
6.43
I ,
/ (1 H, d), 6.71 (1 H, d), 6.92 (1
H, d), 7.26 (1 H, d),
+
7.34 (1 H, s); MS m/z (ES
) 468 (MH+)
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PreparationPrecursor~' data
I
Y
Z
46 Exarnple SH (CDCl3, 400 MHz) 1.48 (9H, s),
2.41 (3H, s),
39 I ~ 2,82 (3H, brd), 4.39 (2H, brd), 6.73
(1 H, d), 6.80
(1 H, d), 6.93 (1 H, s), 7.04 (1
H, d), 7.32 (1 H, d),
sMe 7.39 (1 H, s); MS m/z (TS+) 474 (MH+)
47 Example bH (CDCl3, 300 MHz) 1.46 (9H, brs),
2.46 (3H, s),
37 ~ 2.89 (3H, brs), 4.41 (2H, brs), 6.68
(2H, m), 6.82
I (1 H, d), 7.27 (1 H, obs), 7.40 (1
H, d), 7.43 (1 H, s);
sMe MS m/z (TS+) 458 (MH~)
48 Example 8H (CDCI3, 300 MHz) 1.45 (9H, br)
2.38 (3H, s),
44 I ~ 2.44 (3H, s), 2.90 (3H, br), 4.47
(2H, br), 6.70-
Me 6.81 (3H, m) 7.20 (1 H, d), 7.24-7.58
(2H, m)
SMe
PREPARATION 49
tent-Butyl 5-cyano-2-f3-fluoro-4-(methylsulfanyl)phenoxylbenzyl-
(methyl)carbamate
0
NC /
N~O~Bu
\~ Me
F
SMe
The title compound was prepared from the bromide of Preparation 47 by the
method of
Example 78 ;8H (CDCI3, 300 MHz) 1.48 (9H, brs), 2.50 (3H, s), 2.93 (3H, brs),
4.55 (2H,
brs), 6.79 (2H, m), 6.88 (1 H, d), 7.35 (1 H, t), 7.53 (1 H, d), 7.59 (1 H,
s); MS m/z (TS+)
403 (MHt).
PREPARATION 50
Methyl 3~f(tert-buto~icarbon rLl)(methyl)aminolmethyl;-42,3-dihydro-1-
benzothien-5-
yloxy)benzoate
0 0
Me0 ~ ~ N"OtBu
O Me
S
A mixture of the bromide of Preparation 44 (1.22 g, 2.7 mmol), Et3N (1.13 mL,
8.11
mmol) and dichlorobis(triphenylphosphine)palladium (II) (190 mg, 0.27 mmol) in
MeOH
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(14 mL) was heated at 80°C under 100 psi pressure of CO for 18 h.
Analysis by tlc
indicated the reaction was not complete so a further portion of catalyst (190
mg, 0.27
mmol) was added and the mixture was heated at 100°C under 100 psi
pressure of CO
for 24 h. The mixture was diluted with EtOAc (20 mL) and filtered through a
pad of silica
gel, eluting with excess EtOAc. The solvent was removed in vacuo and the
residue was
partitioned between EtOAc (50 mL) and a 2:1 mixture of water:880 NH3 (50 mL).
The
aqueous layer was extracted with EtOAc (25 mL) and the combined organic layers
were
dried (MgS04) and evaporated. Purification by column chromatography [SiO~; 4:1
(pentane/EtOAc)] gave the product (970 mg, 84%) as an oil; 8H (CDCI3, 400 MHz)
1.42
(9H, s), 2.90 (3H, brs), 3.22 (2H, t), 3.38 (2H, t), 3.84 (3H, s), 4.50 (2H,
brd), 6.74 (2H,
d), 6.82 (1 H, s), 7.13 (1 H, d), 7.82 (1 H, d), 7.93 (1 H, brd); MS m/z (ES+)
430 (MH+).
Compounds of formula XI shown in Table 21 were prepared according to
Preparation 50
starting from the precursors indicated.
0
O'Bu
Y
~xi>
Table 21
PreparationPrecursor data
/ Y
Z
51 Prep 45 8H (CDC13, 400 MHz) 1.42 (9H, s),
2.86 (2H, m),
~ 3.07 (2H, m), 3.85 (3H, s), 4.37
(2H, m), 4.48
I (2H, m), 6.48 (2H, m), 6.79 (1 H,
/ o d), 6.97 (1 H, d),
SJ 7.83 (1 H, d), 7.95 (1 H, s); MS
m/z (ES+) 446
(M H+)
52 Prep 46 sH (CDCI3, 400 MHz) 1.43 (9H, brs),
2.47 (3H, s),
2.88 (3H, brd), 3.90 (3H, s), 4.51
(2H, brd), 6.81
I / ~, (1 H, d), 6.91 (1 H, d), 7.06 (1
H, s), 7.20 (1 H, d),
SMe 7.89 (1 H, d), 7.98 (1 H, brd); MS
m/z (TS+) 469
(MNH4+)
53 Prep 47 8H (CDCI3, 300 MHz) 1.47 (9H, brs),
2.46 (3H, s),
2.91 (3H, brs), 3.94 (3H, s), 4.52
I (2H, brs), 6.78
/ F (2H, m), 6.91 (1 H, d), 7.35 (1 H,
m), 7.92 (1 H, d),
SMe 8.02 (1 H, brs); MS m/z (TS+) 453
(MNH4+)
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PreparationPrecursor data
I
s r
z
54 Prep 48 8H (CDC13, 300 MHz) 1.44 (9H, s),
2.37 (3H, s),
I ~ 2.47 (3H, s), 2.94 (3H, br), 3.90
(3H, s), 4.73
Me (2H, br), 6.79-6.87 (3H, m), 7.20
(1 H,d), 7.86
sMe (1 H,d), 8.00 (1 H, br); MS m/z (ES+)
454 (MNa+)
PREPARATION 55
~~(tert-Butoxycarbonyl)(methyl)aminolmethyl~-4-(2,3-dihydro-1-benzothien-5-
yloxy)benzoic acid
HO 'otBu
A solution of the ester of Preparation 50 (970 mg, 2.26 mmol) in THF (20 mL)
and 1 M
LiOH (20 mL) was heated at reflux for 16 h. After cooling to room temperature
the THF
was removed in vacuo, the residue was neutralised with sat aq NH4CI and the
mixture
was extracted with DCM (100 mL) and then ether (100 mL). The combined organic
layers were dried (MgS04) and evaporated to give a white foam (960 mg) which
was
used without further purification; 8,., (CDCI3, 400 MHz) 1.30 (9H, s), 2.78
(3H, brs), 3.20
(2H, brs), 3.38 (2H, t), 4.41 (2H, m), 6.62 (2H, m), 6.78 (1 H, m), 7.10 (1 H,
m), 7.84 (1 H,
m), 7.99 (1 H, m); MS m/z (ES-) 414 (M-H).
Compounds of formula XII shown in Table 22 were prepared according to
Preparation
55 from the precursors indicated.
Ho 'o'au
txu~
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Table 22
PreparationPrecursor data
I
Y
Z
56 Prep 51 8N (CDCI3, 400 MHz) 1.26 (9H,
s), 2.74 (3H,
~ s), 3.02 (2H, m), 4.31 (4H, m),
6.38 (2H
m)
I ,
,
6.64 (1 H, d), 6.87 (1 H, d),
7.68 (1 H, brs),
SJ 7.78 (1 H, brs); MS m/z (ES-)
430 (M-H+)
57 Prep 52 8H (CDCI3, 400 MHz) 1.44 (9H,
brs), 2.49
(3H, s), 2.92 (3H, brd), 4.57
(2H, brd), 6.82
I o (1 H, d), 6.94 (1 H, d), 7.08
~, (1 H, s), 7.21 (1 H,
sMe d), 7.97 (1 H, d), 8.04 (1 H,
brd); MS m/z (ES-)
436 (M-H+)
58 Prep 53 8H (CDC13, 300 MHz) 1.46 (9H,
brs), 2.49
(3H, s), 2.93 (3H, brs), 4.57
I (2H, brs), 6.77
~ F (2H, m), 6.92 (1 H, d), 7.32 (1
H, t), 7.99 (1 H,
sMe d), 8.08 (1 H, brs); MS m/z (ES-)
420 (M-H+)
PREPARATION 59
tent-Butyl 5-(aminocarbonyl)-2-(2,3-dihydro-1-benzothien-5-ylo~)benz,~l-
(methyl)carbamate
0 0II
HZN ~ \ N' _QiBu
Me
o
\,
S
Et3N (267 ~,L, 1.92 mmol), HOBt.H~O (129 mg, 0.84 mmol) and WSCDI (191 mg, 1.0
mmol) were added to a solution of the acid of Preparation 55 (318 mg, 0.77
mmol) in
DCM (10 mL) and the mixture was stirred for 1 h before the addition of a
saturated
solution of NH3 in THF (2 mL). After stirring for a further 16 h the reaction
was diluted
with wafer (50 mL), 0.2M HCI (20 mL) and DCM (25 mL). The organic layer was
separated and the aqueous layer was extracted with DCM (25 mL). The combined
organic layers were dried (MgS04) and evaporated to give a white foam (assumed
quantitative yield) which was used without further purification; bH (CDCI3,
400 MHz) 1.44
(9H, s), 2.91 (3H, br), 3.27 (2H, t), 3.40 (2H, t), 4.54 (2H, br), 6.75-6.88
(3H, m), 7.18
(1 H, d), 7.68 (1 H, d), 7.74 (1 H, s).
Compounds of formula XIII shown in Table 23 were prepared according to
Preparation
59 from the precursors indicated.
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~OtBu
(X111)
Table 23
PreparationPrecursorR5 data
Y
Z
60 Prep 55 II 8H (CDCI3, 400 MHz) 1.43
(9H, s),
Me~H~ ~ 2,83-3.00 (6H, m), 3.24
(2H, t),
I 3.39 (2H, t), 4.51 (2H,
brs), 6.70-
s 6.85 (3H, m), 7.15 (1
H, d), 7.62
(1 H, d), 7.68 (1 H, s)
61 Prep 55 8H (CDCI3, 400 MHz) 1.46
(9H, s),
NN ~ ~ 2.89 (3H, br), 3.24 (2H,
t), 3.37-
3.43 (5H, m), 3.56 (2H,
t), 3.63
~
oMe s (2H, m), 4.54 (2H, br),
6.46 (1 H,
br), 6.75-6.86 (3H, m),
7.16 (1 H,
d), 7.62 (1 H, d), 7.69
(1 H, s)
62 Prep 58 SH (ds-DMSO, 400 MHz)
1.29 (9H,
N2N~ ~ a br), 2.40 (3H, s), 2.75
(3H, s),
4.39 (2H, s), 6.78 (1
H, d), 6.91
sMe (2H, m), 7.23 (1 H, br),
7.36 (1 H,
t), 7.78 (2H, m), 7.90
(1 H, br); MS
m/z (TS+) 438 (MNH4+)
63 Prep 58 8H (CDC13, 400 MHz) 1.41
(9H, s),
Me~H~ I ~ 2.40
( 3H, s), 2.92 (3H, brs),
2.98
(3H, d), 4.45 (2H, brs),
6.10 (1 H,
sMe brs), 6.67 (2H, m), 6.88
(1 H, d),
7.27 (1 H, obs), 7.63
(2H, m); MS
m/z (TS+) 452 (MNH4+)
64 Prep 58 8H (CDCI3, 400 MHz) 1.40
(9H, s),
2.40 (3H, s), 2.81 (3H,
brs), 3.35
(3H, s), 3.53 (2H, m),
3.61 (2H,
onne sMa m), 4.44 (2H, brs), 6.45
(1 H, brs),
6.66 (2H, m), 6.87 (1
H, d), 7.29
(1 H, d), 7.64 (1 H, d),
7.72 (1 H, s);
MS m/z (TS+) 479 (MH+)
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PreparationPrecursorR5 data
I \
Y
Z
65 Prep 8H (CDC13, 400 MHz) 1.43
57 (9H,
HZN~ ~ ~ brs), 2.47 (3H, s), 2.90
(3H, brd),
4.52 (2H, brs), 6.87 (1
H, d), 6.91
SMe (1 H, d), 7.03 (1 H, s),
7.10 (1 H, d),
7.72 (1 H, d), 7.78 (1
H, s); MS m/z
(ES') 435 (M-H+)
66 Prep II 8H (CDCI3, 400 MHz) 1.42
57 (9H,
Me~H~ I ~ b rs), 2.47 (3H, s), 2.88
(3H, brd),
3.00 (3H, d), 4.48 (2H,
brs), 6.16
SMe (1 H, brd), 6.85 (2H,
m), 7.01 (1 H,
s), 7.19 (1 H, d), 7.67
(2H, m); MS
m/z (ES-) 449 (M-H+)
67 Prep 8H (CDC13, 400 MHz) 1.42
56 (9H, s),
HzN~ I ~ 2.86 (3H, m), 3.08 (2H,
m), 3.97
(2H, m), 4.48 (2H, brs),
5.86-6.27
(2H, brs), 6.45 (1 H,
s), 6.49 (1 H,
d), 6.82 (1 H, d), 6.96
(1 H, d),
7.64 (1 H, d), 7.71 (1
H, s); MS m/z
(TS+) 331 (MH+-Boc)
68 Prep 8H (CDCI3, 400 MHz) 1.26
56 (9H, s),
I ~ 2.74 (3H, s), 3.02 (2H,
m), 4.31
a (4H, m), 6.38 (2H, m),
6.64 (1 H,
oMe sJ d), 6.87 (1 H, d), 7.68
(1 H, brs),
7.78 (1 H, brs); MS m/z
(ES-) 430
(M_H+)
PREPARATION 69
tent-Butyl 2-f 3-chloro-4-(methylsulfanyl)pheno~~hydroxymethyl)benzyl-
(methyl)carbamate
0
HO ~ ~ N~O~Bu
/~\~Me
CI
SMe
A solution of LiAIH4 in THF (1 M, 2 mL, 2 mmol) was added dropwise to a
solution of the
ester of Preparation 52 (452 mg, 1 mmol) in THF (10 mL) under N2. Once the
reaction
was judged complete by tlc analysis, ether (10 mL) was added and the excess
LiAlH4
was quenched by the cautious addition of 2M NaOH. The organic layer was
separated,
washed with brine, dried (MgSO4) and evaporated. Purification of the residue
by column
chromatography [SiO~; 39:1 (DCM/MeOH) j gave the desired alcohol (200 mg, 47%)
as a
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gummy white solid; 8H (CDC13, 400 MHz) 1.41 (9H, brs), 1.80 (1 H, brs), 2.43
(3H, s),
2.81 (3H, brd), 4.42 (2H, brd), 4.66 (2H, s), 6.82 (1 H, d), 6.88 (1 H, d),
6.96 (1 H, s), 7.16
(1 H, d), 7.27 (2H, obs); MS m/z (ES+) 446 (MNa+).
Compounds of formula XIV shown in Table 24 were prepared according to
Preparation
69 starting from the precursors indicated.
HO
Table 24
PreparationPrecursor data
z
70 Prep 53 8H (CDCI3, 400 MHz) 1.39 (9H,
brs), 1.99
(1 H, brs), 2.39 (3H, s), 2.78
(3H, brd), 4.39
(2H, brs), 4.62 (2H, d), 6.61
(2H, t), 6.88 (1 H,
SMe d), 7.20-7.30 (3H, m+CHC13); MS
m/z (TS~) .
408 (MH+)
71 Prep 54 5H (CDCI3, 300 MHz) 1.45 (9H,
s), 2.34 (3H,
s), 2.46 (3H, s), 2.90 (3H, br),
4.49 (2H, s),
-' Me 4.67 (2H, s), 6.72-6.81 (2H, m),
6.85 (1 H, d),
sMe 7.18 (1 H, d), 7.21-7.30 (2H,
obs); MS m/z
(TS'~) 404 (MH+)
PREPARATION 72
tent-Butyl 3-(f(tert-butox car~rbonyl)(methyl)aminolmeth rL.l~,[3-methyl-4-
(methylsulfanyl)phenoxylbenzyl methylsulfonyl)carbamate
0 0 0
.... ~
Me'S~N I ~ N~O~Bu
tBuO' '/G v _O Me
Me
sMe
A solution of diethyl azodicarboxylate (505 wL, 3.21 mmol) in THF (5 mL) was
added
dropwise to a solution of tent-butyl methylsulfonylcarbamate (synthesised
according to
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83
Tetrahedron Lett. 1994, 35, 379-380) (655 mg, 3.36 mmol), the alcohol of
Preparation
71 (1.226 g, 3.04 mmol) and triphenylphosphine (880 mg, 3.36 mmol) in THF (15
mL) at
0°C. The reaction was stirred at 0°C for 2 h then diluted with
EtOAc (80 mL) and washed
with 10% aq. I<ZCO3 (100 mL). The organic layer was washed with brine, dried
(MgS04)
and evaporated. The residue was purified by column chromatography [Si02; 1:4
EtOAc:pentane] to give the title compound (1.406 g, 80%) as a colourless oil;
sH (CDCI3,
300 MHz) 1.45 (9H, s), 1.52 (9H, s), 2.38 (3H, s), 2.44 (3H, s), 2.83 (3H, s),
3.22 (3H, s),
4.49 (2H, s), 4.85 (2H, s), 6.74-6.83 (3H, m), 7.18-7.29 (3H, obs); MS m/z
(TS+) 481
(MHO-BOC).
PREPARATION 73
tart-But~r~[(tart-butoxycarbonyl)(methyl)aminolmefihyl~[3-fluoro-4-
(methylsulfanyl~phenoxylbenzyl(methylsulfon rLl)carbamate
0 0
....
Me'S~N O'Bu
'Bu0"
The title compound was prepared from the alcohol of Preparation 70 by the
method of
Preparation 72; 8H (CDCI3, 300 MHz) 1.44 (9H, s), 1.52 (9H, s), 2:44 (3H, s),
2.82 (3H,
s), 3.23 (3H, s), 4.45 (2H, s), 4.87 (2H, s), 6.61-6.70 (2H, m), 6.90 (1 H,
d), 7.25-7.33
(3H, m); MS m/z (ES+) 607 (MNa+).
PREPARATION 74
tent-Buyl 4-f (dimethylamino)methyl]-3-f3-methyl-4-
(methylsulfanyl)phenoxy]benzyl(methylsulfon rLl)carbamate
'Buoy
'~f Ie2
O\SiN
~~I
Me
Me
The title compound was prepared from the alcohol of Example 59 by the method
of
Preparation 72. The crude product was not purified by column chromatography
but taken
on directly to the next step; 8H (CDCI3, 400 MHz) 1.39 (9H, s), 2.22 (6H, s),
2.28 (3H, s),
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2.38 (3H, s), 3.07 (3H, s), 3.42 (2H, s), 4.76 (2H, s), 6.72 (2H, m), 6.79 1
H, s), 7.07 (1 H,
d), 7.12 (1 H, d), 7.40 (1 H, obs).
PREPARATION 75
tent-But I~ylf2-f3-methyl-4-(methylsulfany~phenox~5-
(f [(trifluorometh~ sulfonyllamino methyl)benzyllcarbamate
0 0 0 o c o
's' ~ ~s'
CF3 ~~ ~ ~ N O~Bu CF3 ~ I OtBu
O Me
Me Me
SMe
2
The title compound was prepared from the alcohol of Preparation 71 by the
method of
Preparation 72 using trifluoromethanesulfonamide instead of tent-butyl
methylsulfonylcarbamate. The desired product was contaminated with tent-butyl
5-((~3-
{[(tent-butoxycarbonyl)(methyl)amino]methyl)-4-[3-methyl-4-
(methylsulfanyl)phenoxy]benzyl)[(trifluoromethyl)sulfonyl]amino}methyl)-2-[3-
methyl-4-
(methylsulfanyl)phenoxy]benzyl(methyl)carbamate and was taken on as a mixture;
MS
m/z (ES-) 533 (M-H~)
Compounds of formula XV shown in Table 25 were prepared according to
Preparation
44 using the precursors indicated.
0Ii
~o~Bu
Y
(XU)
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Table 25
PreparationPrecursor data
I
Y
Z
76 Example 8H (CDCI3, 400 MHz) (major rotamer)
1.51
41 ~ (9H, s), 2.92 (3H, s), 3.10
(2H, m), 4.40
I (2H, m), 4.52 (2H, br), 6.53
s o (2H, m), 6.81
sJ (1 H, m), 7.03 (1 H, d), 7.97-8.21
(2H, m);
MS m/z (TS+) 433 (MH+)
77 Example ~H (CDCI3, 300 MHz) 1.50 (9H,
br), 2.99
40 ~ (3H, s), 3.29 (2H, m), 3.43
(2H, m), 4.60
I (2H, br), 6.81 (2H, m), 6.91
(1 H, s), 7.22
(1 H, d), 8.04 (1 H, d), 8.21
(1 H, br)
78 Example bH (CDCI3, 400 MHz) 1.56 (9H,
s), 2.15
42 ~ (2H, m), 2.85-3.00 (7H, m),
4.60 (2H, brd),
I 6.78 (2H, m), 6.87 (1 H, s),
7.12 (1 H, d),
8.03 (1 H, d), 8.10 (1 H, s);
MS m/z (TS+)
399 (MH+)
PREPARATION 79
tent-Buyl methyl(2-[3-methyl-4-(methylsulfanyl}phenoxyl-5-
nitrobenzLrl}carbamate
N ~OII
o° ~~ ~ N~O~Bu
~Me
Me
5 sMe
N-Methyl-~2-f3-methyl-4-(meth Isulfanyl)phenoxY]-5-nitrobenzyl~amine and ~2-~3-
methyl-4-~methylsulfanyl)phenoxy]-5-nitrophenyl} methanol.
To a suspension of the aldehyde of Preparation 39 (21.0 g, 69.2 mmol) in EtOH
(100
mL) was added 8M methylamine in EtOH (86.5 ml, 692 mmol). A solution was given
and
10 after stirring for a short time a precipitate was observed. This was re-
dissolved by the
addition of THF (100 mL), the solution was cooled to 0°C and NaBH4
(7.85 g, 208 mmol)
was then added. The reaction was allowed to warm slowly to room temperature
and
stirred overnight before the solvent was removed in vacuo. The residue was
taken up in
water (150 mL) and ether (150 mL), and 2M HCI was added cautiously until pH 1.
The
15 layers were separated and the aqueous layer was washed with ether (2X100
mL). The
combined organic extracts were dried and evaporated to give ~2-[3-methyl-4-
(methylsulfanyl)phenoxy]-5-nitrophenyl}methanol (18.9 g, 89%) as a yellow
solid; 8H
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(CDC13, 400 MHz) 2.35 (3H, s), 2.48 (3H, s), 4.90 (2H, s), 6.79 (1 H, d), 6.89
(1 H, s), 6.91
(1 H, d), 7.22 (1 H, d), 8.07 (1 H, dd), 8.41 (1 H, d).
The aqueous layer from above was neutralised by pouring onto excess solid
K2C03. The
basic solution was extracted with ether (2x100 mL) and these ether extracts
were dried
(MgSO4) and evaporated to give N-methyl-N-(2-[3-methyl-4-
(methylsulfanyl)phenoxy]-5-
nitrobenzyl}amine (1.65 g, 7.5%) as an orange oil; MS m/z (ES~) 319 (MH+).
N-Methyl-N-f2-f3-methyl-4-(methylsulfanyl)phenox~,-5-nitrobenzylfamine from~2-
('3-
methyl-4-(methylsulfan rLllphenoxy]-5-nitro~henyl; methanol.
Methanesulfonyl chloride (4.81 mL, 61.9 mmol) was added slowly to a solution
of (2-[3-
methyl-4-(methylsulfanyl)phenoxy]-5-nitrophenyl}methanol (18.9 g, 61.9 mmol)
and Et3N
(9.5 mL, 68.2 mmol) in DCM (60 mL). The mixture was stirred at room
temperature for 3
h then poured into water and extracted with DCM (3 times). The combined
organic
extracts were dried (MgS04) and evaporated to give a dark, viscous oil. This
oil was
taken up in DCM (50 mL) and 8M methylamine in EtOH (200 mL, 1.6 mol) was added
followed by Et3N (10 mL, 71.7 mmol). After stirring for 18 h the mixture was
concentrated
in vacuo to give crude amine which was used without further purification.
tent-Butyl methylf2-f3-methyl-4-(methylsulfanyl)phenoxy~-5-
nitrobenzyl~carbamate
The crude amine from above was dissolved in DCM (100 mL) at 0°C and
Et3N (11.4 mL,
81.8 mmol) was added, followed by di-tert-butyl dicarbonate (15.0 g, 68.7
mmol). The
reaction was allowed to warm to room temperature and stirred for 16 h before
being
concentrated in vacuo. The residue was partitioned between EtOAc and water and
the
aqueous Payer was extracted with EtOAc (2 times). The combined organic layers
were
dried (MgS04) and evaporated. The residue was purified by column
chromatography
(Si02; 1St column - 3% MeOH in DCM; 2"d column EtOAc:pentane 1:3) to give the
title
compound (14.2 g, 54%) as a yellow oil; &,., (CDCI3, 400 MHz) 1.44 (9H, s),
2.32 (3H, s),
2.44 (3H, s), 2.95 (3H, s), 4.56 (2H, br), 6.75 (1 H, d), 6.84 (2H, m), 7.17
(1 H, d), 8.00
(1 H, d), 8.18 (1 H, br); MS m/z (TS+) 419 (MH+).
Compounds of formula XVI shown in Table 26 were prepared according to Example
103
from the precursors indicated
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O
~ N"OtBu
\~~~~Me
O
Y
Z
(XVI)
Table 26
PreparationPrecursor data
I
Y
Z
80 Prep 77 8H (CDCI3, 300 MHz) 1.50 (9H,
br), 2.80
I ~ (3H, br), 3.20 (2H, m), 2.37
(2H, m), 3.60
(2H, br), 4.40 (2H, s), 6.50-6.80
(5H, m),
s 7.05 (1 H, d); MS m/z (ES+) 387
(MH+)
81 Prep 78 3H (CDCI3, 400 MHz) 1.42 (9H,
s), 2.05 (2H,
I ~ m), 2.80 (7H, m), 4.37 (2H, s),
6.50-6.65
(3H, m), 6.69 (1 H, s), 6.78
(1 H, d), 7.08
(1 H, d); MS m/z (TS+) 369 (MH+)
82 Prep 76 8H (CDCI3, 400 MHz) 1.43 (9H,
s), 2.88 (3H,
~ br), 3.07 (2H, m), 3.59 (2H,
br), 4.30 (2H,
I s), 4.36 (2H, m), 6.32 (1 H,
~ o s), 6.40 (1 H, d),
sJ 6.49-6.65 (2H, m), 6.75 (1 H,
d), 6.88 (1 H,
d); MS m/z (TS+) 403 (MH+)
83 Prep 79 8H (CDCI3, 300 MHz) 1.47 (9H,
s), 2.33 (3H,
~ s), 2.40 (3H, s), 2.82 (3H, br),
3.60 (2H, s),
I 4.35 (2H, S), 6.50-6.77 (4H,
m), 6.80 (1 H,
sons d), 7.16 (1H, d); MS m/z (TS+)
389 (MH+)
PREPARATION 84
tent-Butyl met~lf2-[3-methyl-4-(methylsulfanyl)phenoxyl-5-
f (methylsulfonyl)amin~benzyl)carbamate
M O S; ~ otBu
O
Methanesulfonyl chloride (4.16 mL, 53.7 mmol) was added dropwise to a solution
of the
aniline of Preparation 83 (9.5 g, 24.5 mmol) and Et3N (7.5 mL, 53.8 mmol) in
DCM (50
mL) at 0°C. After stirring at 0°C for 30 min the reaction was
allowed to warm to room
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8$
temperature before the solvent was removed in vacuo. 2M NaOH (50 mL) was added
to
the residue and the mixture was stirred for 30 min. The mixture was extracted
with
EtOAc and the organic layer was washed with brine, dried (MgS04) and
evaporated to
give an oil. Purification by column chromatography [Si02; 97.5:2.5:0.25
(DCM/MeOH/880 NH3)] gave the product (9.0 g, 79%) as a brown foam; 8H (CDCI3,
300
MHz) 1.43 (9H, brs), 2.35 (3H, s), 2.42 (3H, s), 2.88 (3H, brs), 3.01 (3H, s),
4.46 (2H,
brs), 6.76 (2H, d+s), 6.83 (1 H, d), 7.16 (1 H, s), 7.20 (2H, brs); MS m/z
(ES+) 467 (MH+)
Compounds of formula XVII shown in Table 27 were prepared according to
Preparation
84 from the precursors indicated.
0
~°;s'~ I ~ N~o'Bu
O ~Me
O
Y
z
(XVI I)
Table 27
PreparationPrecursor data
I
a Y
z
85 Prep 81 8H (CDC13, 400 MHz) (rotamers)
1.44 and
~ 1.48 (9H, 2xs), 2.10 (2H, quintet),
2.88 (7H,
I m), 3.00 (3H, s), 4.49 (2H, br),
a 6.23 (1 H, br),
6.72 (1 H, d), 6.81 (1 H, s),
6.83 (1 H, d), 7.13
(3H, m); MS m/z (TS+) 347 (MH+-Boc)
86 Prep 80 Product used without purification.
I
a
s
87 Prep 82 8H (CDC13, 400 MHz) (rotamers)
1.40 and
~ 1.44 (9H, 2xs), 2.80 and 2.85
(3H, 2xs), 2.95
I (3H, s), 3.07 (2H, m), 4.38 (2H,
a o m), 6.36 (1 H,
SJ s), 6.44 (1 H, d), 6.84 (1 H,
d), 6.92 (1 H, d),
7.12 (2H, m); MS m/z (TS+) 498
(MNH4+)
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PREPARATION 88
tent Butyl methylf2-j3-methyl-4-(methylsulfanyl~phenoxyl-5-[meth I(methyl-
suifo~l)aminolbenz rLl}carbamate
Me o
I
Me~S~N
0,10
Mel (1.07 mL, 17.2 mmol) was added dropwise to a mixture of the sulfonamide of
Preparation 84 (2.0 g, 4.3 mmol) and KzC03 (592 mg, 4.3 mmol) in CH3CN (10 mL)
under N~. The mixture was stirred for 16 h and then partitioned between EtOAc
(50 mL)
and 2M NaOH (50 mL). The organic layer was washed with brine, dried (MgSO4)
and
evaporated. The residue was purified by column chromatography [Si02; 590:10:1
(DCM/MeOH/880 NH3)] to give the product (1.23 g, 60%) as a yellow oil; 8H
(CDCI3, 300
MHz) 1.45 (9H, s), 2.34 (3H, s), 2.42 (3H, s), 2.86 (3H, s), 2.90 (3H, s),
3.28 (3H, s),
4.49 (2H, s), 6.80 (3H, br), 7.18 (3H, m); MS m/z (TS+) 498 (MNH4+).
PREPARATION 89
tent-Butyl5-[(2-hydroxyethyl)(methylsulfonyl)aminol-2-f3-meth
(methylsulfanyl)phenoxylbenzyl(methyl)carbamate
OH
O
Mew ,N ~ N~~tgu
o BSO ~ / O Me
Me
SMe
2-Bromoethanol (1.34 mL, 18.9 mmol) was added to a mixture of the sulfonamide
of
Preparation 84 (2.0 g, 4.3 mmol) and KZC03 (2.605 g, 18.8 mmol) in CH3CN (10
mL)
under N~. The mixture was heated at reflux for 16 h, cooled and then
partitioned
between EtOAc (50 mL) and 2M NaOH (50 mL). The organic layer was washed with
brine, dried (MgS04) and evaporated. The residue was purified by column
chromatography [Si02; 390:10:1 (DCM/MeOHl880 NH3)] to give the product (524
mg,
24%) as a pink foam; 8H (CDC13, 300 MHz) 1.42 (9H, s), 2.37 (3H, s), 2.43 (3H,
s), 2.91
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(3H, s), 2.98 (3H, s), 3.68 (2H, brs), 3.79 (2H, d), 4.49 (2H, s), 6.81 (3H,
m), 7.19 (3H,
m); MS m/z (TS+) 528 (MNH4+).
PREPARATION 90
5 5-Amino-2-(2,3-dihydro-1,4-benzoxathin-6-yloxy~benzonitrile
Fe powder (930 mg, 16.7 mmol) was added to the nitro compound of Preparation
41
(740 mg, 2.38 mmol) in AcOH (5 mL) and water (1 mL) and the mixture was
stirred at
room temperature for 16 h. The solvent was removed in vacuo, the residue was
taken up
10 in EtOAc (50 mL) and 10% aq KzC03 (50 mL) and filtered through Arbocel~.
The
organic layer was separated and the aqueous layer was extracted with EtOAc (50
mL).
The combined organic extracts were dried (MgS04) and evaporated to a brown
foam
(670 mg, 99%) which was used without further purification; sH (CDCI3, 400 MHz)
3.18
(2H, m), 4.36 (2H, m), 6.60-6.70 (2H, m), 6.70-6.80 (3H, m), 6.85 (1 H, s); MS
m/z (TS+)
15 302 (MNH4+)
Compounds of formula Vb, i.e. compounds of formula V where T is cyano, R4 is
hydrogen and R5 is amino, shown in Table 28 were prepared according to
Preparation
90 from the precursors indicated.
H2N ~ CN
f~
0
~I
Y
Z
20 (vb)
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91
Table 28
PreparationPrecursor data
I
/
Y
Z
91 Prep 35 8,., (CDC13, 400 MHz) 2.40 (3H,
s), 6.62-
~ 6.72 (2H, m), 6.80-6.90 (3H,
m), 7.28 (1 H,
1 d)
SMe
92 Prep 37 8H (CDC13, 300 MHz) 2.47 (3H,
s), 3.83
~ (2H, br), 6.83-6.94 (4H, m),
7.01 (1 H, s),
I 7.19 (1 H, d); MS m/z (TS+)
308 (MNH4+)
SMe
93 Prep 42 8H (CDC13, 400 MHz) 2.30 (3H,
s), 2.40
(3H, s), 3.84 (2H, br), 6.77
I (4H, m), 6.85
~'' (1 H, s), 7.13 (3H, d); MS m/z
Me (TS+) 288
sMe (MNH4+)
PREPARATION 94
5-Amino-2-f4-methyl-3-(methylsulfanyllphenoxyjbenzonitrile
cN
0
SMe
Me
The title compound was prepared from the nitro compound of Preparation 43 by
the
method of Example 103; 8H (CDCI3, 400 MHz) 2.27 (3H, s), 2.41 (3H, s), 3.66
(2H, br),
6.62 (1 H, d), 6.79 (2H, s), 6.82 (1 H, s), 6.89 (1 H, s), 7.08 (1 H, d); MS
m/z (ES+) 293
(MNa+), (ES') 269 (M-H+).
Compounds of formula Vc, i.e. compounds of formula V where T is cyano, R4 is
hydrogen and R5 is -NHSOZMe, shown in Table 29 were prepared according to
Preparation 84 from the precursors indicated.
o°s~
Me' II
O
(Vc)
Z
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92
Table 29
PreparationPrecursor data
I
Y
Z
95 Prep 90 sH (CDCI3, 400 MHz) 2.98 (3H,
s), 3.10 (2H,
I ~ m), 4.39 (2H, m), 6.67 (1 H,
dd), 6.76 (1 H,
s s), 6.81 (1 H, d), 7.33 (1 H,
dd), 7.49 (1 H, s);
of MS m/z (TS+) 380 (MNH4+)
96 Prep 92 8H (CDCI3, 300 MHz) 2.51 (3H,
s), 3.06 (3H,
~ s), 6.52 (1 H, br), 6.92 (1 H,
d), 7.02 (1 H,
I dd), 7.14 (1 H, d), 7.24 (1 H,
d), 7.41 (1 H,
sMa dd), 7.57 (1 H, d); MS m/z (ES+)
391 (MNa+)
97 Prep 91 bH (CDCI3, 400 MHz) 2.43 (3H,
s), 3.02 (3h,
S), 6.41 (1 H, brs), 6.72-6.85
(2H, m), 6.92
I / F (1 H, d), 7.28 (1 H, t), 7.38
(1 H, d), 7.51 (1 H,
sMe s); MS m/z (ES+) 351 (MH+)
98 Prep 93 8H (CDCI3, 400 MHz) 2.19 (3H,
s), 2.42 (3H,
~ s), 2.99 (3H, s), 6.81 (1 H,
d), 6.86 (2H, m),
I 7.15 (1 H, d), 7.33 (1 H, d),
Me 7.51 (1 H, s); MS
sMe m/z (TS+) 366 (MNH4+)
99 Prep 94 8H (CDCI3, 400 MHz) 2.31 (3H,
s), 2.43 (3H,
I ~ s), 3.02 (3H, s), 6.61 (1 H,
s), 6.72 (1 H, dd),
SMe 6.83 (1 H, d), 6.88 (1 H, s),
7.17 (1 H, d), 7.37
Me (1 H, dd), 7.55 (1 H, s); MS
m/z (TS+) 366
(MNH4+)
PREPARATION 100
N-f 3-Cyano-4-[3-methyl-4-(methylsulfany,phenoxylphenLrl~-N-
methylmethanesulfonamide
Me
I
MeSOz
The title compound was prepared from the sulfonamide of Preparation 98 by the
method
of Preparation 88; sH (CDCI3, 400 MHz) 2.31 (3H, s), 2.44 (3H, s), 2.83 (3H,
s), 3.27 (3H,
s), 6.79 (1 H, d), 6.88 (2H, m), 7.17 (1 H, d), 7.44 (1 H, dd), 7.58 (1 H, d);
MS m/z (ES+)
385 (MNa+).
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PREPARATION 101
1, 3-Dihydro-2-benzothiophen-5-o!
OH
S
Preparation of j4-(allyloxy~-2-(h dy roxymethyl)phenyllmethanol
Dimethyl 4-(allyloxy)phthalate (prepared according to Inouye, M.; Tsuchiya,
K.; Kitao, T.
Angew. Chem. 1992, 104, 198-200 (See also Angew. Chem., Int. Ed. Engl., 1992,
204-
205)j (9.9 g, 38 mmol) was dissolved in THF (40 mL) and cooled to 0°C
before the
dropwise addition of lithium aluminium hydride (1 M in THF, 77 mL, 77 mmol)
over 10
min. The mixture was then allowed to stir at room temperature for 3 h before
being
quenched cautiously by the addition of water (1.4 mL) followed by 2M NaOH (1.4
mL).
Excess MgSO4 was then added followed by water until a granular precipitate
formed (ca.
5 mL). The mixture was then filtered and evaporated to a brown oil (7.1 g, ca.
95%). 'H
NMR showed the material to be of ca. 85% purity. It was used directly in the
next stage
without. further purification; 8H (CDCI3, 400 MHz) 2.C3 (1 H, brs), 2.91 (1 H,
brs), 4.52 (2H,
m), 4.67 (4H, m), 5.26 (1 H, dd), 5.38 (1 H, dd), 5.97-6.09 (1 H, m), 6.80 (1
H, dd), 6.92
(1 H, d), 7.22 (1 H, d).
(ii) Preparation of 5-(allyloxy)-1,3-dihydro-2-benzothiophene
Crude diol from stage (i) (3.5 g, 18 mmol) was dissolved in DCM (60 mL) and
treated
with Et3N (10 mL, 72 mmol) and the solution was cooled to 0°C.
Methanesulfonyl
chloride (4.2 mL, 54 mmol) was added dropwise and the solution was stirred for
1 h
being allowed to reach room temperature. The reaction was then quenched by the
addition of water followed by 2M HCI (50 mL). The DCM layer was separated and
the
aqueous layer was re-extracted with DCM (50 mL). The combined organic
fractions were
washed with water (50 mL), dried (MgS04) and concentrated to a volume of ca.
30 mL.
Benzyltriethylammonium chloride (1 g) was added followed by a solution of
sodium
sulfide (5 g, 91 mmol) in water (50 mL). The mixture was stirred rapidly under
a nitrogen
atmosphere for 15 h. The organic layer was separated and the aqueous layer was
re-
extracted with DCM (50 mL). The combined organic layers were dried (MgS04) and
evaporated to a yellow oil. Flash chromatography afforded two fractions; the
first was
pure product and the second product contaminated with dimeric material.
Trituration of
the second fraction caused crystallisation of the dimeric material which was
removed by
filtration. The filtrate was combined with the first chromatography fraction
to afford the
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94
desired product (800 mg, 23%); 8H (CDC13, 400 MHz) 4.16 (2H, s), 4.19 (2H, s),
4.48
(2H, m), 5.26 (1 H, d), 5.37 (1 H, d), 5.95-6.06 (1 H, m), 6.74 (2H, m), 7.09
(1 H, d).
Sill) Preparation of 1,3-dihydro-2-benzothiophen-5-of
The allyl ether from stage (ii) (800 mg, 4.16 mmol) was dissolved in THF (10
mL) and
treated with palladium tetrakis(triphenylphosphine) (481 mg, 0.42 mmol)
followed by
sodium borohydride (944 mg, 25 mmol). The mixture was then heated to 45
°C and
stirred at this temperature for 15 h. After cooling to room temperature the
THF was
evaporated and the residue partitioned between 2M NaOH solution (25 mL) and
diethyl
ether (25 mL). The aqueous layer was separated and the organic layer re-
extracted with
2M NaOH solution (25 mL). The combined aqueous layers were neutralised to pH 7-
8
with concentrated hydrochloric acid and extracted with EtOAc (2 x 25 mL). The
combined organic extracts were dried (MgSO4) and evaporated to a clear oil of
the title
phenol which solidified upon standing (540 mg, 85%); 4.14 (2H, s), 4.17 (2H,
s), 6.63-
6.68 (2H, m), 7.04 (1 H, d).
Biological Activity
A number of compounds were tested for biological activity by their ability to
inhibit the
uptake of serotonin by human serotonin transporters as follows.
(l) Cell Culture
Human embryonic kidney cells (HEK-293) stably transfected with either the
human serotonin transporter (hSERT), noradrenaline transporter (hNET) or
dopamine transporter (hDAT) were cultured under standard cell culture
techniques (cells were grown at 37°C and 5% COZ in DMEM-culture media
(supplemented with 10% dialysed foetal calf serum (FCS), 2mM I-glutamine and
250p,g/ml geneticin)). Cells were harvested for the assay to yield a cell
suspension of 750,000 cells/ml.
(l) Determination of inhibitor potenc~r
All test compounds were dissolved in 100% DMSO and diluted down in assay
buffer to give appropriate test concentrations. Assays were carried out in 96-
well
filter bottom plates. Cells (7500 cells/assay well) were pre-incubated in
standard
assay buffer containing either test compound, standard inhibitor or compound
vehicle (1 % DMSO) for 5 minutes. Reactions were started by addition of either
3H-Serotonin, 3H-Noradrenaline or 3H-Dopamine substrates. All reactions were
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carried out at room temperature in a shaking incubator. Incubation times were
5
minutes for the hSERT and hDAT assays and 15 minutes for the hNET assay.
Reactions were terminated by removal of the reaction mixture using a vacuum
manifold followed by rapid washing with ice cold assay buffer. The quantity of
3H-
5 substrate incorporated into the cells was then quantified.
Assay plates were dried in a microwave oven, scintillation fluid added, and
radioactivity measured. Potency of test compounds was quantified as ICSO
values
(concentration of test compound required to inhibit the specific uptake of
10 radiolabelled substrate into the cells by 50%).
Standard Assay Buffer Composition:
Trizma hydrochloride (26mM)
NaCI (124mM)
15 KCI (4.5mM)
KH2P04 (1.2mM)
MgC12.6H~0 (1.3mM)
Ascorbic acid (1.136mM)
Glucose (5.55mM)
20 pH 7.40
CaCl2 (2.3mM)
Pargyline (100p.M)
Note: The pH of the buffer was adjusted to 7.40 with 1 M NaOH before addition
25 of CaCl2 and pargyline.
(iv) Summary of Assay Parameters
hSERT hDAT hNET
Assay Assay Assay
Cell concentration 75,000 75,000 75,000
per
assay well.
Substrate Concentration.3H-5HT 3H-Dopamine3H-Noradrenaline
(50nM) (200nM) (200nM)
Incubation time 5 5 15
(minutes)
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Compounds having a serotonin re-uptake inhibition (SRI) ICSO value of less
than or equal
to 100nM include the title compounds of Examples 1-6, 8-23, 25, 26, 29-32, 34-
36, 43,
45-49, 51, 56-102, 109-130.
Compounds having an serotonin re-uptake inhibition (SRI) ICSO value of less
than or
equal to 100nM and which are more than 10-fold as potent in the inhibition of
serotonin
re-uptake than in the inhibition of dopamine re-uptake or noradrenaline re-
uptake include
the title compounds of Examples 1-6, 9-13, 16-19, 21, 22, 25, 26, 29-32, 34-
36, 43, 45,
47-49, 51, 57-88, 90-1 O2, 109-121, 123, 124, 127, 129.
Compounds having an serotonin re-uptake inhibition (SRI) ICSO value of less
than or
equal to 100nM and which are more than 100-fold as potent in the inhibition of
serotonin
re-uptake than in the inhibition of dopamine re-uptake or noradrenaline re-
uptake include
the title compounds of Examples 1, 2, 4, 5, 9, 12, 13, 16-19, 21, 22, 25, 26,
29-32, 34-
36, 43, 45, 48, 49, 58-80, 83-88, 90, 92-97, 99-102, 111-113, 115-118, 120,
123, 124,
127.
Compounds having an serotonin re-uptake inhibition (SRI) ICSO value of less
than or
equal to 50nM and which are more than 100-fold as potent in the inhibition of
serotonin
re-uptake than in the inhibition of dopamine re-uptake and noradrenaline re-
uptake
include the title compounds of Examples 1, 2, 4, 9, 12, 17, 18, 26, 29, 30,
36, 43, 45, 48,
49, 60-66, 68-75, 78, 79, 90, 92-94, 100, 102, 116, 118, 124.
In particular, the title compound of Example 16 had a serotonin re-uptake
inhibition (SRI)
ICSO of 4.7 nM; the title compound of Example 29 had a serotonin re-uptake
inhibition
(SRI) ICSO of 2.0 nM; and the title compound of Example 62 had a serotonin re-
uptake
inhibition (SRI) ICSO of 3.7 nM.
