U.S. patent application number 09/810378 was filed with the patent office on 2002-05-02 for diphenyl ether compounds useful in therapy.
Invention is credited to Andrews, Mark David, Hepworth, David, Middleton, Donald Stuart, Stobie, Alan.
Application Number | 20020052395 09/810378 |
Document ID | / |
Family ID | 27255641 |
Filed Date | 2002-05-02 |
United States Patent
Application |
20020052395 |
Kind Code |
A1 |
Andrews, Mark David ; et
al. |
May 2, 2002 |
Diphenyl ether compounds useful in therapy
Abstract
A compound of general formula (I), or pharmaceutically
acceptable salts, solvates or polymorphs thereof; wherein; R.sup.1
and R.sup.2, which may be the same or different, are hydrogen,
C.sub.1-C.sub.6alkyl, (CH.sub.2)m(C.sub.3-C.sub.6cycloalkyl)
wherein m =0, 1, 2 or 3, or R.sup.1 and R.sup.2 together with the
nitrogen to which they are attached form an azetidine ring; each
R.sup.3 is independently CF.sub.3, OCF.sub.3, C.sub.1-4alkylthio or
C.sub.1-C.sub.4alkoxy; n is 1, 2 or 3; and R.sup.4 and R.sup.5,
which may be the same or different, are: A-X, wherein A =--CH=CH--
or --(CH.sub.2)p-- where p is 0, 1 or 2; X is hydrogen, F, Cl, Br,
I, CONR.sup.6R.sup.7,SO.sub.2NR.sup.6R.sup.7,
SO.sub.2NHC(=O)R.sup.6, OH, C.sub.1-4alkoxy,
NR.sup.8SO.sub.2R.sup.9, NO.sub.2, NR.sup.6R.sup.11, CN,
CO.sub.2R.sup.10, CHO, SR.sup.10, S(O)R.sup.9 or SO.sub.2R.sup.10
R.sup.6, R.sup.7, R and R.sup.10 which may be the same or
different, are hydrogen or C.sub.1-6alkyl optionally substituted
independently by one or more R.sup.12; R.sup.9 is C.sub.1-6 alkyl
optionally substituted independently by one or more R.sup.12;
R.sup.11 is hydrogen, C.sub.1-6 alkyl optionally substituted
independently by one or more R.sup.12, C(O)R.sup.6,
CO.sub.2R.sup.9, C(O)NHR.sup.6 or SO.sub.2NR.sup.6R.sup.7; R.sup.12
is F, OH, CO.sub.2H, C.sub.3-6cycloalkyl, NH.sub.2, CONH.sub.2,
C.sub.1-6alkoxy, C.sub.1-6alkoxycarbonyl 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.sup.13; or R.sup.6 and R.sup.7, 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.sup.13;
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.sup.13; wherein R.sup.13 is hydroxy,
C.sub.1-C.sub.4alkoxy, F, C.sub.1-C.sub.6alkyl, haloalkyl,
haloalkoxy, --NH.sub.2, --NH(C.sub.1-C.sub.6alkyl) or
--N(C.sub.1-C.sub.6alkyl).sub.2; wherein when R.sup.1 and R.sup.2
are methyl, R.sup.4 and R.sup.5 are hydrogen and n is 1, R.sup.3is
not a --SMe group para to the ether linkage linking rings A and B.
1
Inventors: |
Andrews, Mark David; (Kent,
GB) ; Hepworth, David; (Kent, GB) ; Middleton,
Donald Stuart; (Kent, GB) ; Stobie, Alan;
(Kent, GB) |
Correspondence
Address: |
Paul H. Ginsburg
Pfizer Inc.
20th Floor
235 East 42nd Street
New York
NY
10017-5755
US
|
Family ID: |
27255641 |
Appl. No.: |
09/810378 |
Filed: |
March 16, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60197127 |
Apr 14, 2000 |
|
|
|
Current U.S.
Class: |
514/359 ;
514/383; 514/406; 514/520; 514/622; 548/255; 548/264.8;
548/367.4 |
Current CPC
Class: |
C07C 45/71 20130101;
C07D 295/096 20130101; C07C 217/58 20130101; C07C 47/55 20130101;
C07D 249/08 20130101; C07C 47/575 20130101; C07C 323/67 20130101;
C07C 323/32 20130101; C07C 2601/08 20170501; C07C 237/28 20130101;
C07C 255/43 20130101; C07C 311/05 20130101; C07C 229/38 20130101;
C07C 205/44 20130101; C07D 231/38 20130101; C07C 311/08 20130101;
C07D 249/06 20130101; C07D 295/192 20130101; C07C 323/20 20130101;
C07C 2601/02 20170501; C07D 231/12 20130101; C07C 317/32 20130101;
C07C 255/59 20130101; C07D 233/56 20130101; C07C 311/37
20130101 |
Class at
Publication: |
514/359 ;
514/383; 514/406; 514/520; 514/622; 548/367.4; 548/264.8;
548/255 |
International
Class: |
C07D 249/04 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 31, 2000 |
GB |
0007884.0 |
Claims
1. A compound of general formula (I), or a pharmaceutically
acceptable salt thereof: 198wherein; R.sup.1 and R.sup.2, which may
be the same or different, are hydrogen, C.sub.1-C.sub.6alkyl,
(CH.sub.2)m(C.sub.3-C.sub.- 6-cycloalkyl) wherein m=0 1, 2 or 3, or
R.sup.1 and R.sup.2 together with the nitrogen to which they are
attached form an azetidine ring; each R.sup.3 is independently
CF.sub.3, OCF.sub.3, C.sub.1-4alkylthio or C.sub.1-C.sub.4alkoxy; n
is1,2 or 3; and R.sup.4 and R.sup.5, which may be the same or
different, are: A-X, wherein A=--CH=CH-- or --(CH.sub.2).sub.p--
where p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I,
CONR.sup.6R.sup.7, SO.sub.2NR.sup.6R.sup.7, SO.sub.2NHC(=O)R.sup.6,
OH, C.sub.1-4alkoxy, NR.sup.8SO.sub.2R.sup.9, NO.sub.2,
NR.sup.6R.sup.11, CN, CO.sub.2R.sup.10, CHO, SR.sup.10, S(O)R.sup.9
or SO.sub.2R.sup.10; R.sup.6, R.sup.7, R.sup.8 and R.sup.10 which
may be the same or different, are hydrogen or C.sub.1-6alkyl
optionally substituted independently by one or more R.sup.12;
R.sup.9 is C.sub.1-6 alkyl optionally substituted independently by
one or more R.sup.12; R.sup.11 is hydrogen, C.sub.1-6 alkyl
optionally substituted independently by one or more R.sup.12,
C(O)R.sup.6, CO.sub.2R.sup.9, C(O)NHR.sup.6 or
SO.sub.2NR.sup.6R.sup.7; R.sup.12 is F, OH, CO.sub.2H,
C.sub.3-6cycloalkyl, NH.sub.2, CONH.sub.2, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl 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.sup.13; or
R.sup.6 and R.sup.7, 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.sup.13; or a 5- or
6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms
selected from N, S and 0, optionally substituted independently by
one or more R.sup.13; wherein R.sup.13 is hydroxy,
C.sub.1-C.sub.4alkoxy, F, C.sub.1-C.sub.6alkyl, haloalkyl,
haloalkoxy, --NH.sub.2, --NH(C.sub.1-C.sub.6alkyl) or
--N(C.sub.1-C.sub.6alkyl).sub.2; wherein when R.sup.1 and R.sup.2
are methyl, R.sup.4 and R.sup.5 are hydrogen, and n is 1, R.sup.3
is not a --SMe group para to the ether linkage linking rings A and
B.
2. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 and R.sup.2 which may be
the same or different, are hydrogen or C.sub.1-C.sub.6alkyl.
3. A compound according to claim 1 or a pharmaceutically acceptable
salt thereof, wherein each R.sup.3 is independently --CF.sub.3,
--OCF.sub.3, methylthio, ethylthio or methoxy.
4. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein at least one R.sup.3 is para to
the ether linkage linking ring A and B.
5. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein at least one R.sup.3 is
methylthio.
6. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.6 and R.sup.7, which may be
the same or different, are hydrogen, C.sub.1-C.sub.3alkyl
optionally substituted by hydroxy, --CONH.sub.2 or
C.sub.1-C.sub.3alkoxy.
7. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.8 is hydrogen, hydroxyethyl
or methyl.
8. A compound according to claim 9, or a pharmaceutically
acceptable salt thereof, wherein R.sup.9 is methyl, ethyl,
isopropyl, trifluoromethyl or methoxyethyl.
9. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein p is 1 or 0.
10. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4 and R.sup.5, which may be
the same or different, are --(CH.sub.2).sub.p--X, where p is 0, 1
or 2; X is hydrogen, hydroxy, CONR.sup.6R.sup.7,
SO.sub.2NR.sup.6R.sup.7, NR.sup.8SO.sub.2R.sup.9, SR.sup.10,
SOR.sup.9 or SO.sub.2R.sup.10; or a 5- or 6-membered heterocyclic
ring containing 1, 2 or 3 heteroatoms selected from N, S and O.
11. A compound according claims 1, or a pharmaceutically acceptable
salt thereof, wherein R.sup.4 and R.sup.5, which may be the same or
different, are: --(CH.sub.2).sub.p--X, where p is 0 or 1; X is
hydrogen, hydroxy, CONR.sup.6R.sup.7, SO.sub.2NR.sup.6R.sup.7 or
NR.sup.8SO.sub.2R.sup.9; wherein R.sup.6 and R.sup.7, which may be
the same or different, are hydrogen or C.sub.1-C.sub.3alkyl
optionally substituted by hydroxy, --CONH.sub.2 or
C.sub.1-C.sub.3alkoxy; R.sup.8 is hydrogen, hydroxyethyl or methyl;
or R.sup.9 is methyl, ethyl, isopropyl, trifluoromethyl or
methoxyethyl; or triazolyl, imidazolyl or pyrazolyl.
12. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4 and R.sup.5 are not both
hydrogen.
13. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4 is hydrogen.
14. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, selected from the group consisting of:
3-[(dimethylamino)methyl]-
-4-[4-(methylsulfanyl)phenoxy]benzene-sulfonamide;
3-[(dimethylamino)methy-
l]-N-methyl-4-[4-(trifluoromethyl)phenoxy]-benzenesulfonamide;
3-[(dimethylamino)methyl]-4-[4-(trifluoromethoxy)phenoxy]-benzene-sulfona-
mide; 3-[(dimethylamino)methyl]-N-[(2
R)-2-hydroxypropyl]-4-[4-(methylsulf-
anyl)-phenoxy]benzenesulfonamide; 3-[(dimethylamino)methyl]-N-[(1
S)-2-hydroxy-1-methylethyl]-4-[4-(methylsulfanyl)phenoxy]benzenesulfonami-
de;
3-[(dimethylamino)methyl]-N-(2-hydroxyethyl)-4-[4-(methylsulfanyl)-phe-
noxy]benzenesulfonamide;
3-[(dimethylamino)methyl]-4-[4-(methylsulfanyl)ph-
enoxy]benzonitrile;
3-[(dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy- ]benzamide;
3-[(dimethylamino)methyl]-4-[4-(trifluoromethoxy)phenoxy]benza-
mide;
3-[(methylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzamide;
N-{3-[(dimethylamino)methyl]-4-[4-(trifluoromethyl)phenoxy]phenyl}-methan-
esulfonamide;
4-[3-methoxy-4-(methylsulfanyl)phenoxy]-3-[(methylamino)meth-
yl]-benzamide;
N-methyl-3-[(methylamino)methyl]-4-[4-(methylsulfanyl)pheno-
xy]-benzamide;
3-[(dimethylamino)methyl]-4-[3-methoxy-4-(methylsulfanyl)ph-
enoxy]-benzamide; N-methyl-N-[2-[4-(methylsulfanyl)phenoxy]-5-(1 H-
1,2,3-triazol-1 -yl)benzyl]-amine;
N,N-methyl-N-[2-[4-(methylsulfanyl)phe- noxy]-5-(1 H-1
,2,4-triazol-1 -yl)benzyl]-amine; .>- ~N.
N-dimethyl-N-[2-[4-(methylsulfanyl)phenoxy]-5-(l1 H- 1,2,4-triazol-
1 -yl)benzyl]-amine; N-[2-[4-(methylsulfanyl)phenoxy]-5-(4 H- 1 ,2
,4-triazol-4-yl)benzyl]-N,N-dimethylamine; and N-{5-(3-amino-1
H-pyrazol-
1-yl)-2-[4-(methylsulfanyl)phenoxy]benzyl}-N-methylamine.
15. A pharmaceutical formulation containing a compound according to
claim 1, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable adjuvant, diluent or carrier.
16. The method of using a compound according to claim 1, or
pharmaceutically acceptable salts thereof, for the treatment or
prevention of a disorder in which the regulation of monoamine
transporter function is implicated.
17. The method according to claim 17 wherein the disorder is
depression, attention deficit hyperactivity disorder,
obsessive-compulsive disorder, post-traumatic stress disorder,
substance abuse disorders or sexual dysfunction.
18. The method according to claim 24 wherein the treatment is for
the treatment or prevention of premature ejaculation.
19. A method of treatment or prevention of a disorder in which the
regulation of monoamine transporter function is implicated,
comprising the administration of an effective amount of a compound
according to claim 1 or a pharmaceutically acceptable salt thereof,
to a patient in need of such treatment or prevention.
20. A method of treatment or prevention of premature ejaculation,
comprising the administration of an effective amount of a compound
according to claim 1 or a pharmaceutically acceptable salt thereof,
to a patient in need of such treatment or prevention.
21. A method of increasing ejaculatory latency which comprises the
administration of an effective amount of a compound according to
claim 1, or a pharmaceutically acceptable salt thereof, to a male
desiring increased ejaculatory latency.
22. A process for the preparation of a compound of general formula
(I); 199wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 and
n are as defined in claim 1 comprising reacting a compound of
general formula II 200under suitable reaction conditions to form a
compound of formula I wherein the suitable reaction conditions are:
i) where R.sup.4/R.sup.5 are halogen, by reaction of (II) with a
suitable halogenating agent in an inert solvent which does not
adversely affect the reaction; ii) where R.sup.4/R.sup.5 are
--NO.sub.2, by reaction of (II) with a suitable nitrating agent in
an inert solvent which does not adversely affect the reaction at,
or below, room temperature; or ii) where R.sup.4/R.sup.5 is
--SO.sub.2NR.sup.6R.sup.7 by reaction of an intermediate sulfonyl
chloride with the requisite amine of formula HNR.sup.6R.sup.7 in a
suitable solvent.
23. A process according to claim 22 for preparing compounds of
formula la, i.e compounds of formula I where R.sup.5 is
--SO.sub.2NR.sup.6R.sup.7; 201comprising a) reacting compounds of
formula II, optioanlly in a suitable solvent, with chlorosulfonic
acid to give compounds of formula (XII); 202followed by, b)
reaction with HNR.sup.6R.sup.7 to give compounds of formula
(Ia).
24. A process according to claim 23 wherein compounds of formula
(XII) are generated in situ and reacted with HNR.sup.6R.sup.7
without isolation.
25. A process according to claim 22 which further comprises the
step of preparing compounds of formula (II), by reacting compounds
of formula (III) 203with a compound of formula HNR.sup.1R.sup.2, or
with a suitable salt form thereof, together with a hydride reducing
agent in a suitable solvent, to form a compound of formula
(II).
26. A compound of formula (II) according to claim 22 with the
proviso that in compounds of formula (II) when R.sup.1 and R.sup.2
are methyl, and n is 1, R.sup.3is not a --SMe group para to the
ether linkage linking rings A and B.
27. A compound of formula (I), or a pharmaceutically acceptable
salt, solvates or polymorphs thereof, wherein R.sup.1, R.sup.2,
R.sup.3 and n are as defined in claim 1; and R.sup.4 and R.sup.5,
which may be the same or different, are --(CH.sub.2).sub.p--A',
wherein p is 0, 1 or 2 and A is a polar group.
28. A compound according to claim 27, wherein the polar group has a
6-value more negative than -0.1.
29. A compound of general formula (I): 204and pharmaceutically
acceptable salts or solvates thereof wherein: R.sup.1 and R.sup.2
independently represent H, C.sub.1-C.sub.6 alkyl,
(CH.sub.2).sub.m(C.sub.3-C.sub.6cyclo- alkyl) wherein m=0, 1, 2 or
3, or wherein NR.sup.1R.sup.2 together represent a 4-membered ring
wherein R.sup.1 and R.sup.2 together represent C.sub.3 alkyl;
R.sup.3 represents one or more groups selected from the group
including. CF.sub.3, OCF.sub.3, SR.sup.12 and C.sub.1-C.sub.4
alkoxy wherein R.sup.12 represents C.sub.1-C.sub.6 alkyl; and
R.sup.4 and R.sup.5 independently represent A-X wherein
A=--(CH.sub.2).sub.n--, wherein n represents 0, 1 or 2 and wherein
X represents: H, F, Cl, Br, 1, CONR.sup.6R.sup.7 or
SO.sub.2NR.sup.6R.sup.7- , OH, NR.sup.8SO.sub.2R.sup.9, NO.sub.2,
NR.sup.6R.sup.11, CN, CO.sub.2R.sup.10, CHO, S(O).sub.mR.sup.10
wherein m=0, 1 or 2 and wherein R.sup.6, R.sup.7, R.sup.8 and
R.sup.10 independently represent H or C.sub.1-6 alkyl, wherein
R.sup.9 represents C.sub.1-6 alkyl, R.sup.11 represents H,
C.sub.1-6 alkyl, C(O)R.sup.6, CO.sub.2R.sup.9, C(O)NHR.sup.6 or
SO.sub.2NR.sup.6R.sup.6 and wherein said C.sub.1-6 alkyl group is
optionally substituted by one or more groups selected from OH,
CO.sub.2H, C.sub.3-6 cycloalkyl, NH.sub.2, CONH.sub.2, C.sub.1-6
alkoxy, C16 alkoxycarbonyl and a 5- or 6-membered heterocyclic ring
containing 1, 2 or 3 heteroatoms selected from N, S and O; or
R.sup.4 and/or R.sup.5 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, R.sup.6 and R.sup.7 may, together with
the N atom to which they are attached, represent a pyrrolidine or
piperidine ring (which rings are optionally substituted by OH or
CONH.sub.2) or a morpholine ring (which is optionally substituted
by CONH.sub.2) with the with the proviso that both R.sup.4 and
R.sup.5 are not H.
Description
[0001] This invention relates to a series of 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. More 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.
[0002] According to a first aspect, the invention provides a
compound of general formula (I), or pharmaceutically acceptable
salts, solvates or polymorphs thereof; 2
[0003] wherein;
[0004] R.sup.1 and R.sup.2, which may be the same or different, are
hydrogen, C.sub.1-C.sub.6alkyl,
(CH.sub.2)m(C.sub.3-C.sub.6cycloalkyl) wherein m=0, 1, 2 or 3, or
R.sup.1 and R.sup.2 together with the nitrogen to which they are
attached form an azetidine ring;
[0005] each R.sup.3 is independently CF.sub.3, OCF.sub.3,
C.sub.1-4alkylthio or C.sub.1-C.sub.4alkoxy;
[0006] n is 1, 2 or 3; and
[0007] R.sup.4 and R.sup.5, which may be the same or different,
are:
[0008] A-X, wherein A=--CH=CH-- or --(CH.sub.2)p-- where p is 0, 1
or 2; X is hydrogen, F, Cl, Br, I, CONR.sup.6R.sup.7,
SO.sub.2NR.sup.6R.sup.7, SO.sub.2NHC(=O)R.sup.6, OH,
C.sub.1-4alkoxy, NR.sup.8SO.sub.2R.sup.9, NO.sub.2,
NR.sup.6R.sup.11, CN, CO.sub.2R.sup.10, CHO, SR.sup.10, S(O)R.sup.9
or SO.sub.2R.sup.10; R.sup.6, R.sup.7, R.sup.8 and R.sup.10 which
may be the same or different, are hydrogen or C.sub.1-6alkyl
optionally substituted independently by one or more R.sup.12;
R.sup.9 is C.sub.1-6 alkyl optionally substituted independently by
one or more R.sup.12; R.sup.11 is hydrogen, C.sub.1-6 alkyl
optionally substituted independently by one or more R.sup.12,
C(O)R.sup.6, CO.sub.2R.sup.9, C(O)NHR.sup.6 or
SO.sub.2NR.sup.6R.sup.7; R.sup.12 is F (preferably up to 3), OH,
CO.sub.2H, C.sub.3-6cycloalkyl, NH.sub.2, CONH.sub.2,
C.sub.1-6alkoxy, C.sub.1-6alkoxycarbonyl 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.sup.13; or R.sup.6 and R.sup.7, 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.sup.13;
or
[0009] 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.sup.13;
[0010] wherein R.sup.13 is hydroxy, C.sub.1-C.sub.4alkoxy, F,
C.sub.1-C.sub.6alkyl, haloalkyl, haloalkoxy, --NH.sub.2,
--NH(C.sub.1-C.sub.6alkyl) or --N(C.sub.1-C.sub.6alkyl).sub.2; and
wherein when R.sup.1 and R.sup.2 are methyl, R.sup.4 and R.sup.5
are hydrogen and n is 1, R.sup.3 is not a --SMe group para to the
ether linkage linking rings A and B.
[0011] 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.
[0012] 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, dioxolanyl, oxazolyl,
thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl,
pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl,
triazolyl, thiadiazolyl, pyranyl, pyridinyl, 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, quinolinyl,
quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl,
phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl.
The term heterocyclic should be similarly construed.
[0013] Preferably R.sup.1 and R.sup.2, which may be the same or
different, are hydrogen or C.sub.1-C.sub.6alkyl. More preferably
hydrogen or methyl.
[0014] Preferably each R.sup.3 is independently --CF.sub.3,
--OCF.sub.3, methylthio, ethylthio or methoxy.
[0015] Preferably at least one R.sup.3 is para to the ether linkage
linking ring A and B.
[0016] Preferably at least one R.sup.3 is methylthio.
[0017] Preferably R.sup.4 and R.sup.5, which may be the same or
different, are --(CH.sub.2)p--X, where p is 0, 1 or 2 (preferably 0
or 1); X is hydrogen, hydroxy, CONR.sup.6R.sup.7,
SO.sub.2NR.sup.6R.sup.7, NR.sup.8SO.sub.2R.sup.9, SR.sup.10,
SOR.sup.9 or SO.sub.2R.sup.10 wherein R.sup.6, R.sup.7, R.sup.8,
R.sup.9 and R.sup.10 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).
[0018] More preferably R.sup.4 and R.sup.5, which may be the same
or different, are: --(CH.sub.2)p--X, where p is 0 or 1; X is
hydrogen, hydroxy, CONR.sup.6R.sup.7, SO.sub.2NR.sup.6R.sup.7 or
NR.sup.8dSO.sub.2R.sup.9; wherein R.sup.6 and R.sup.7, which may be
the same or different, are hydrogen or C.sub.1,-C.sub.3alkyl
optionally substituted by hydroxy, --CONH.sub.2 or
C.sub.1-C.sub.3alkoxy (preferably methoxy); R.sup.8 is hydrogen,
hydroxyethyl or methyl; or R.sup.9 is methyl, ethyl, isopropyl,
trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or
pyrazolyl.
[0019] More preferably still R.sup.4 and R.sup.5 are not both
hydrogen. More preferably still R.sup.4 is hydrogen.
[0020] Preferably R.sup.6 and R.sup.7, which may be the same or
different, are hydrogen, C.sub.1-C.sub.3alkyl optionally
substituted by hydroxy, --CONH.sub.2 or C.sub.1-C.sub.3alkoxy
(preferably methoxy). More preferably R.sup.6 and R.sup.7, which
may be the same or different, are hydrogen or methyl, more
preferably still hydrogen.
[0021] When present, R.sup.12 is preferably oxadiazolyl, triazolyl,
imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl. More
preferably triazolyl, imidazolyl or pyrazolyl.
[0022] In the case where R.sup.6 and R.sup.7, 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.sub.2 or a morpholine ring which
may be substituted by CONH.sub.2.
[0023] Preferably R.sup.11 is hydrogen or C.sub.1-6 alkyl.
[0024] Preferably R.sup.8 is hydrogen, hydroxyethyl or methyl. More
preferably hydrogen.
[0025] Preferably R.sup.9 is methyl, ethyl, isopropyl,
trifluoromethyl or methoxyethyl. More preferably methyl or ethyl
(preferably methyl).
[0026] Preferably R.sup.10 is methyl or ethyl.
[0027] Preferably p is 1 or 0, more preferably 0.
[0028] Preferably R.sup.1 and R.sup.2, which may be the same or
different, are hydrogen or methyl; at least one R.sup.3 is para to
the ether linkage and is CF.sub.3, OCF.sub.3, methylthio, ethylthio
or methoxy; and
[0029] R.sup.4 and R.sup.5, which may be the same or different, are
(CH.sub.2).sub.p--X, where p is 0 or 1; X is hydrogen, hydroxy,
CONR.sup.6R.sup.7, SO.sub.2NR.sup.6R.sup.7,
NR.sup.8SO.sub.2R.sup.9, SR.sup.10, SOR.sup.9 or SO.sub.2R.sup.10
and wherein R.sup.6 and R.sup.7, which may be the same or
different, are hydrogen, C.sub.1-C.sub.3alkyl optionally
substituted by hydroxy, --CONH.sub.2 or C.sub.1-C.sub.3alkoxy
(preferably methoxy); or R.sup.6 and R.sup.7, 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 CONH.sub.2; R.sup.8 is hydrogen, hydroxyethyl or methyl
(preferably hydrogen); R.sup.9 is methyl, ethyl, isopropyl,
trifluoromethyl or methoxyethyl; and R.sup.10 is methyl or ethyl;
or an oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl,
pyridinyl or pyrimidinyl group.
[0030] More preferably R.sup.1 and R.sup.2, which may be the same
or different, are hydrogen or methyl; at least one R.sup.3 is para
to the ether linkage and is CF.sub.3, OCF.sub.3, methylthio,
ethylthio or methoxy, and at least one R.sup.3 is methylthio or
ethylthio; and
[0031] R.sup.4 and R.sup.5, which may be the same or different, are
--(CH.sub.2).sub.p--X, where p is 0 or 1; X is hydrogen, hydroxy,
CONR.sup.6R.sup.7, SO.sub.2NR.sup.6R.sup.7 or
NR.sup.8SO.sub.2R.sup.9; wherein R.sup.6 and R.sup.7, which may be
the same or different, are hydrogen, C.sub.1-C.sub.3alkyl
optionally substituted by hydroxy, --CONH.sub.2 or
C.sub.1-C.sub.3alkoxy (preferably methoxy); R.sup.8 is hydrogen,
hydroxyethyl or methyl; R.sup.9 is methyl, ethyl, isopropyl,
trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or
pyrazolyl.
[0032] More preferably still R.sup.1 and R.sup.2, which may be the
same or different, are hydrogen or methyl; at least one R.sup.3 is
para to the ether linkage and is CF.sub.3, OCF.sub.3, methylthio or
methoxy, and at least one R.sup.3 is methylthio;
[0033] R.sup.4 is hydrogen, and
[0034] R.sup.5 is --(CH.sub.2).sub.9--X, where p is 0 or 1; X is
hydrogen, hydroxy, CONR.sup.6R.sup.7, SO.sub.2NR.sup.6R.sup.7 or
NR.sup.8SO.sub.2R.sup.9; wherein R.sup.6 and R.sup.7, which may be
the same or different, are hydrogen, C.sub.1-C.sub.3alkyl
optionally substituted by hydroxy, --CONH.sub.2 or
C.sub.1-C.sub.3alkoxy (preferably methoxy); R.sup.8 is hydrogen,
hydroxyethyl or methyl; R.sup.9 is methyl, ethyl, isopropyl,
trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or
pyrazolyl.
[0035] More preferably still R.sup.4 and R.sup.5 are not both
hydrogen.
[0036] 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.
[0037] 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.
[0038] Preferred compounds of formula (I) include:
[0039]
3-[(dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzenesulfo-
namide;
[0040]
3-[(dimethylamino)methyl]-N-methyl-4-[4-(trifluoromethyl)phenoxy]be-
nzene-sulfonamide;
[0041]
3-[(dimethylamino)methyl]-4-[4-(trifluoromethoxy)phenoxy]benzenesul-
fonamide;
[0042]
3-[(dimethylamino)methyl]-N-[(2R)-2-hydroxypropyl]-4-[4-(methylsulf-
anyl)-phenoxy]benzenesulfonamide;
[0043]
3-[(dimethylamino)methyl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-[4-(me-
thylsulfanyl)-phenoxy]benzenesulfonamide;
[0044]
3-[(dimethylamino)methyl]-N-(2-hydroxyethyl)-4-[4-(methylsulfanyl)p-
henoxy]-benzenesulfonamide;
[0045]
3-[(dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzonitrile-
;
[0046]
3-[(dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzamide;
[0047]
3-[(dimethylamino)methyl]-4-[4-(trifluoromethoxy)phenoxy]benzamide;
[0048]
3-[(methylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzamide;
[0049]
N-{3-[(dimethylamino)methyl]-4-[4-(trifluoromethyl)phenoxy]phenyl}--
methanesulfonamide;
[0050]
4-[3-methoxy-4-(methylsulfanyl)phenoxy]-3-[(methylamino)methyl]benz-
amide;
[0051]
N-methyl-3-[(methylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benza-
mide;
[0052]
3-[(dimethylamino)methyl]-4-[3-methoxy-4-(methylsulfanyl)phenoxy]-b-
enzamide;
[0053] N-methyl-N-[2-[4-(methylsulfanyl )phenoxy]-5-(1H-1 ,2,
3-triazol- 1-yl)benzyl]amine;
[0054]
N-methyl-N-[2-[4-(methylsulfanyl)phenox]-5-(1H-1,2,4-triazol-1-yl)b-
enzyl]amine;
[0055]
N,N-dimethyl-N-[2-[4-(methylsulfanyl)phenoxy]-5-(1H-1,2,4-triazol-1-
-yl)benzyl]-amine;
[0056]
N-[2-[4-(methylsulfanyl)phenoxy]-5-(4H-1,2,4-triazol-4-yl)benzyl]-N-
,N-dimethylamine; and
[0057]
N-{5-(3-amino-1H-pyrazol-1-yl)-2-[4-(methylsulfanyl)phenoxy]benzyl}-
-N-methylamine.
[0058] 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.
[0059] We have found that compounds of formula I which possess
these properties have a relatively polar group at R.sup.4/R.sup.5.
Therefore according to a further aspect, the invention provides a
compound of general formula I and pharmaceutically acceptable salts
thereof, wherein R.sup.1, R.sup.2, R.sup.3 and n are as defined in
the first aspect; and R.sup.4 and R.sup.5, which may be the same or
different, are --(CH.sub.2).sub.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 .pi.-value (see C Hansch and A Leo,
`Substituent Constants for Correlation Analysis in Chemistry and
Biology`, Wiley, N.Y., 1979). In this system, H has a .pi.-value of
0.00, --OCH.sub.3 has a .pi.-value of -0.02, and --SO.sub.2NH.sub.2
has a .pi.-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 90 -value: thus,
preferred groups have a-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 -1.0. Even when p is other
than zero in the above definition, the definition of A' is based on
the above reference as if p was zero.
[0060] The pharmaceutically or veterinarily acceptable salts of the
compounds of the invention 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 and diethanolamine
salts. For reviews on suitable pharmaceutical salts see Berge et
al, J. Pharm, Sci., 66, 1-19, 1977; Bighley et al, International
Journal of Pharmaceutics, 33 (1986), 201-217; and P L Gould,
Encyclopedia of Pharmaceutical Technology, Miarcel Debker Inc, New
York 1996, Volume 13, page 453-497.
[0061] The pharmaceutically acceptable solvates of the compounds of
the invention include the hydrates thereof.
[0062] Also included within the scope of the compound and various
salts of the invention are polymorphs thereof.
[0063] Preferred salts are the tartrate salts, particularly the
L-tartrate and the D-tartrate salts (and also the racemic
D/L-tartrate); the phosphate salt; the hydrochloride salt; the
citrate salt; and the sulfate salt. A further preferred salt is the
sodium salt (see Example 28).
[0064] Hereinafter compounds, their pharmaceutically acceptable
salts, their solvates or polymorphs, defined in any aspect of the
invention (except intermediate compounds in chemical processes) are
referred to as "compounds of the invention".
[0065] 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, chiral intermediate
compounds may be resolved and used to prepare chiral compounds of
the invention.
[0066] 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,
(X-pyridonyl.
[0067] The invention also includes radiolabelled compounds. 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.
[0068] 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).
[0069] 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 compounds of the
invention.
[0070] 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.
[0071] Compounds of the invention may be prepared, in known manner
in a variety of ways.
[0072] In the following reaction schemes and hereafter, unless
otherwise stated, R.sup.1 to R.sup.13, n, m and p are as defined in
the first aspect. These processes form further aspects of the
invention
[0073] Throughout the specification, general formulae are
designated by Roman numerals I, II, III, IV etc. Subsets of these
general formulae are defined as Ia, Ib, Ic etc., . . . IVa, IVb,
IVc etc.
[0074] Compounds of general formula (I) may be prepared from
compounds of general formula (II) by a variety of methodologies
(see Scheme 1), wherein L is a suitable leaving group such as
halogen (F, Cl, Br or I) or a sulfonate ester such as
trifluoromethanesulfonate or methanesulfonate, preferably L is F or
Cl. 3
[0075] For example:
[0076] i) Where R.sup.4/R.sup.5 are halogen, by reaction of (II)
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 as illustrated in
Example 16 herein;
[0077] ii) Where R.sup.4/R.sup.5 are --NO.sub.2, by reaction of
(II) with a suitable nitrating agent, such as an alkali metal
nitrate, in an inert solvent which does not adversely affect the
reaction at, or below, room temperature. Suitable nitrating agents
include trifluoromethanesulfonic acid/ potassium nitrate and
suitable inert solvents include trifluoroacetic acid, as
illustrated in Example 21 herein; or
[0078] iii) Transformation to the compounds of formula I where
R.sup.4/R.sup.5 is --SO.sub.2NR.sup.6R.sup.7 by reaction of an
intermediate sulfonyl chloride with the requisite amine of formula
HNR.sup.6R.sup.7 in a suitable solvent. Suitable solvents include
ethanol and the reactions are generally performed at or below room
temperature. For example, compounds of formula (la), where R.sup.5
is --SO.sub.2NR.sup.6R.sup.7, may be prepared via the intermediate
sulfonyl chlorides (XII) from compounds of formula (II) by reaction
of (II) with chlorosulfonic acid followed by reaction with
HNR.sup.6R.sup.7. Reaction conditions typically comprise low
temperature. The reaction can take place either neat, i.e. in the
absence of solvent, or in the presence of an inert solvent which
does not adversely affect the reaction. Suitable inert solvents
include dichloromethane and a typical reaction temperature is
0.degree. C., as illustrated in Example 28 herein. The intermediate
sulfonyl chloride (XII) may be isolated, purified and then reacted
with HNR.sup.6R.sup.7, alternatively it may be generated in situ,
without isolation, and then reacted with HNR.sup.6R.sup.7. 4
[0079] 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 (la)
by reacting compounds of formula (II) in a suitable solvent, with
chlorosulfonic acid to give compounds of formula (XII) followed by
reaction with HNR.sup.6R.sup.7 to give compounds of formula (Ia).
Preferably compounds of formula (XII) are generated in situ and
reacted with HNR.sup.6R.sup.7 without isolation.
[0080] Compounds of general formula (II) may in turn be prepared
from compounds of formula (III) by reaction with an amine of
general formula HNR.sup.1R.sup.2, or with a suitable salt form
thereof, together with a hydride reducing agent in a suitable
solvent. When either R.sup.1 or R.sup.2 is hydrogen, suitable
solvents include protic solvents such as ethanol, and sodium
borohydride is an appropriate reducing agent. When neither R.sup.1
or R.sup.2 are hydrogen, tetrahydrofuran/ dichloromethane is a
suitable solvent system and sodium tri(acetoxy)borohydride is a
suitable reducing agent. In such reactions the use of a salt form
of HNR.sup.1R.sup.2, such as the hydrochloride is preferable, and
an auxiliary base, to aid solubility of the HNR.sup.1R.sup.2 salt,
such as triethylamine may optionally be added.
[0081] Compounds of formula (III) may be prepared in turn from the
coupling of compounds of general formula (IV) with aldehyde
compounds of general formula (V). 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.
[0082] Alternatively, compounds of general formula (I) may be
prepared from compounds of general formula (VII) (See Scheme 2) in
analogous fashion to the preparation of (II) (see Scheme 1). 5
[0083] Compounds of general formula (VII) may be prepared from (VI)
and (IV) in an analogous fashion to the preparation of (Ill) (see
Scheme 1).
[0084] Alternatively, compounds of general formula (I) having a
particular R.sup.4/R.sup.5 substituent may be converted into other
compounds of formula (I) using known techniques. For example:
[0085] i) When R.sup.4/R.sup.5 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 (lI)catalyst in a high boiling
solvent at elevated temperatures. Suitable Pd catalysts include
palladium tetrakis(triphenylphosphine), suitable cyanide salts
include Zn(CN).sub.2 and suitable high boiling solvents which do
not adversely affect the reaction include dimethylformamide as
exemplified by Example 81 herein;
[0086] ii) When R.sup.4/R.sup.5 is halogen such as chloro, bromo or
iodo, it may be converted to --CH.sub.2CN via an intermediate
cyanoester. The intermediate cyanoesters are formed by reaction
with an .alpha.-cyanoacetate in the presence of a copper(I) salt
and a base, in a high boiling solvent at elevated temperatures.
Suitable .alpha.-cyanoacetates include ethyl .alpha.-cyanoacetate,
suitable copper(I) salts include copper(I) bromide, suitable bases
include potassium carbonate and suitable high boiling solvents
include dimethylsulfoxide. The intermediate cyanoesters may then be
hydrolysed and decarboxylated in one step by treatment with a
hydroxide salt in a high boiling solvent at elevated temperatures.
Suitable hydroxide salts include sodium hydroxide and suitable high
boiling solvents include aqueous dioxan, as exemplified by Example
89 herein;
[0087] iii) When R.sup.4/R.sup.5 is halogen such as chloro, bromo
or iodo, it may be converted to the corresponding sulfide --SR by
treatment with an alkyl thiolate salt and a Pd(0) or (II)catalyst,
in an inert high boiling solvent which does not adversely affect
the reaction, at elevated temperatures. Suitable alkyl thiolate
salts include sodium methanethiolate, suitable Pd catalysts include
palladium tetrakis(triphenylphosphine) and suitable inert high
boiling solvents include dimethylsulfoxide as exemplified by
Example 141 herein;
[0088] iv) When R.sup.4/R.sup.5 is halogen such as chloro, bromo or
iodo, it may be converted to the corresponding ester --CO.sub.2R by
treatment with carbon monoxide at high pressure with a Pd(0) or
(II) catalyst, in an alcohol solvent (ROH wherein R is
C.sub.1-C.sub.4 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 palladium tetrakis(triphenylphosphine), suitable
bases include triethylamine and suitable alcohol solvents include
methanol as exemplified by Example 151 herein;
[0089] v) When R.sup.4/R.sup.5 is halogen such as iodo, it may be
converted to the corresponding amide --CONR.sup.6R.sup.7 wherein
R.sup.6 and R.sup.7 are as previously defined herein, by treatment
with carbon monoxide, the corresponding amine of formula
HNR.sup.6R.sup.7 and a Pd(0)catalyst in an inert solvent which does
not adversely affect the reaction. Suitable catalysts include
palladium tetrakis(triphenylphosphin- e) and suitable solvents
include dimethylformamide. The reaction is preferably conducted at
an elevated temperature and pressure, as exemplified by Example 100
herein;
[0090] vi) When R.sup.4/R.sup.5 is halogen such as chloro, bromo or
iodo, it may be converted to --CH.sub.2CN by reaction with
tributyl(cyanomethyl)stannane [according to M. Kosugi, M. Ishiguro,
Y. Negishi, H. Sano, T. Migita, Chem. Lett., 1984, 1511-1512] and a
Pd-catalyst in a suitable solvent at elevated temperatures.
Suitable catalysts include bis(acetonitrile)dichloro-palladium(II)
and suitable solvents include m-xylene, as exemplified by Example
88 herein;
[0091] vii) When R.sup.4/R.sup.5 is halogen such as bromo, it may
be converted to a heterocyclic group, by treatment with copper
powder and the desired heterocyclic compound together with a base.
Suitable heterocyclic groups are defined herein before and include
1,2,3-triazoles, suitable bases include potassium carbonate and the
reaction is preferably carried out at elevated temperatures as
exemplified by Example 181 herein;
[0092] viii) When R.sup.4/R.sup.5 is halogen such as bromo, it may
be converted to an .alpha.,.beta.-unsaturated sulfonamide, by
treatment with vinylsulfonamide, 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 the presence of
tri(o-tolyl)phosphine, suitable bases include triethylamine and
suitable inert solvents include acetonitrile as exemplified by
Example 67 herein;
[0093] ix) When R.sup.4/R.sup.5 is halogen such as bromo, it may be
converted to an .alpha.,.beta.-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 the presence of tri(o-toiyl)phosphine, suitable bases
include triethylamine and suitable inert solvents include
acetonitrile as exemplified by Example 68 herein;
[0094] x) When R.sup.4/R.sup.5 is an .alpha.,.beta.-unsaturated
sulfonamide, it may be converted to
--CH.sub.2CH.sub.2SO.sub.2NH.sub.2, by treatment with a suitable
reducing agent at an appropriate temperature, in an inert solvent
which does not adversely affect the reaction. Suitable reducing
agents include tosyl hydrazide at elevated temperature and suitable
inert solvents include toluene as exemplified by Example 71
herein;
[0095] xi) When R.sup.4/R.sup.5 is nitro, it may be reduced to the
corresponding --NH.sub.2 group via treatment with a reducing agent
in a protic solvent at, or above, room temperature. Suitable
reducing agents include iron powder / calcium chloride, suitable
protic solvents include aqueous ethanol and at a typical reaction
temperature of from about 70.degree. C. to about 100.degree. C.,
preferably about 90.degree. C., as exemplified by Example 107
herein;
[0096] xii) When R.sup.4/R.sup.5 is --NH.sub.2, it may be converted
to the corresponding --NHSO.sub.2R.sup.9 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 methanesulfonic
anhydride, suitable bases include triethylamine and suitable inert
solvents include tetrahydrofuran as exemplified by Example 114
herein;
[0097] xiii) When R.sup.4/R.sup.5 is --NH.sub.2, it may be
converted to a triazole by treatment with
N'-[(dimethylamino)methylidene]-N,N-dimethylhy- drazonoformamide
and a suitable acid, in an inert solvent which does not adversely
affect the reaction, at elevated temperature. Suitable acids
include .rho.-toluenesulfonic acid and suitable solvents include
toluene as exemplified by Example 189 herein;
[0098] xiv) When R.sup.4/R.sup.5 is a --NHSO.sub.2R.sup.9 group, it
may be converted to the corresponding --NR.sup.8SO.sub.2R.sup.9
group via treatment with an alkylating agent and a base in a
suitable inert solvent. Examples of suitable alkylating agents
include 2-bromoethanol, suitable bases include potassium carbonate
and suitable inert solvents include acetonitrile, as exemplified by
Example 122 herein;
[0099] xv) When R.sup.4/R.sup.5 is a sulfonamide, it may be
converted to an acyl sulfonamide by treatment with an acylating
agent and a base in a solvent which does not adversely affect the
reaction. Suitable acylating agents include acetic anhydride,
suitable bases include triethylamine and suitable solvents include
dichloromethane as exemplified by Example 66 herein;
[0100] xvi) When R.sup.4/R.sup.5 is --CN, it may be converted to
the corresponding aldehyde by treatment with a hydride reducing
agent in an inert solvent which does not adversely affect the
reaction. Examples of suitable reducing agents include lithium
aluminium hydride and suitable inert solvents include
tetrahydrofuran. Such reactions are preferably carried out at low
temperature and in an inert atmosphere as exemplified by Example
157 herein;
[0101] xvii) When R.sup.4/R.sup.5 is a nitrile --CN, it may be
converted to the corresponding --C(O)NH.sub.2 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 91 herein. Oxidative
hydrolysis is preferably conducted with hydrogen peroxide in a
polar solvent such as dimethylsulfoxide in the presence of a
suitable base, such as potassium carbonate at, or below, room
temperature, as exemplified by Example 90 herein. Acidic hydrolysis
is preferably conducted with a strong acid, such as polyphosphoric
acid, at elevated temperatures, as exemplified by Example 92
herein;
[0102] xviii) When R.sup.4/R.sup.5 is --CN, it may be reduced to
the corresponding amine --CH.sub.2NH.sub.2 via treatment with a
hydride reducing agent, such as lithium aluminium hydride as
exemplified by Example 110 herein;
[0103] xix) When R.sup.4/R.sup.5 is --CHO, it may be reduced to the
corresponding alcohol --CH.sub.2OH via treatment with a reducing
agent in a suitable solvent. Examples of suitable reducing agents
include sodium borohydride, and suitable solvents include ethanol
as exemplified by Example 157 herein;
[0104] xx) When R.sup.4/R.sup.5 is, it may be converted to the
corresponding sulfoxide --S(O)R.sup.9 via low temperature treatment
with an oxidising agent such as oxone (RTM) or hydrogen peroxide in
a protic solvent as exemplified by Examples 145 or 149 herein;
[0105] xxi) When R.sup.4/ R.sup.5 is --SR.sup.10, it may be
converted to the corresponding sulfone --SO.sub.2R.sup.10 via low
temperature treatment with an oxidising agent such as oxone (RTM)
or hydrogen peroxide in a protic solvent as exemplified by Examples
146 and 150 herein;
[0106] xxii) When R.sup.4/R.sup.5 is an ester, it may be reduced to
the corresponding alcohol group --CH.sub.2OH via treatment with a
hydride reducing agent, such as lithium aluminium hydride, as
exemplified by Example 154 herein;
[0107] xxiii) When R.sup.4/R.sup.5 is an ester, it may be converted
to the corresponding acid --CO.sub.2H 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 Example 158
herein; and
[0108] xxiv) When R.sup.4/R.sup.5 is a carboxylic acid, it may be
converted to the corresponding amide --CONR.sup.6R.sup.7 by
treatment with a coupling agent, a base and an amine
HNR.sup.6R.sup.7 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 Example 159 herein.
[0109] Alternatively, compounds of general formula (I) having a
particular NR.sup.1R.sup.2 group may be converted into compounds of
general formula (I) having a different NR.sup.1R.sup.2 group. For
example:
[0110] i) compounds of formula (I) wherein either R.sup.1 or
R.sup.2 is hydrogen, can be converted into other compounds of
formula (I) wherein neither R.sup.1 nor R.sup.2 are hydrogen, by
reaction of the compound of formula (I) 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 183 herein; and
[0111] ii) compounds of formula (I) wherein R.sup.1 is hydrogen,
can be converted into other compounds of formula (I) wherein
R.sup.1 is methyl, by reaction of the compound of formula (I) 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 formylating agents include pentafluorophenyl
formate (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 128
herein.
[0112] Alternatively, compounds of general formula (I) may be
prepared from compounds of formula (VIII) (see Scheme 3) wherein L
is as defined for Scheme 1 and T is a group which can be converted
into CH.sub.2NR.sup.1R.sup.2. Examples of suitable T substituents
include: carboxy, alkoxycarbonyl, --CN and --C(O)NR.sup.1R.sup.2.
6
[0113] Methodologies for converting compounds of formula (VIII) to
(I), include:
[0114] i) where T is carboxy or alkoxycarbonyl, by reaction with an
amine of general formula NHR.sup.1R.sup.2 to form an amide followed
by reduction of the amide to provide a compound of formula (I).
Such compounds of general formula (I) may be further reacted with a
suitable aldehyde and hydride reducing agent, or a formylating
agent followed by a hydride reducing agent, to provide a compound
of formula (I);
[0115] ii) where T is --CN, by reduction to its corresponding amine
of formula --CH.sub.2NH.sub.2. To provide further compounds of
general formula (I), wherein either one or both of R.sup.1 or
R.sup.2 are not hydrogen, the amine can be further reacted with a
suitable aldehyde and hydride reducing agent, or a formylating
agent followed by a hydride reducing agent, to provide a compound
of formula (I); and
[0116] iii) where T is --C(O)NR.sup.1R.sup.2, by reduction to
provide an amine followed optionally by an appropriate conversion
of R.sup.1 and/or R.sup.2 if either is hydrogen into alternative
R.sup.1 and/or R.sup.2 groups via treatment with aldehyde with
subsequent reduction, or by treatment with a formylating agent
followed by a hydride reducing agent.
[0117] Compounds of general formula (VIII) may be prepared in turn
by the coupling of compounds of general formula (IX) 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 (V) in Scheme 1.
[0118] Compounds of general formula (IX) may be prepared in turn
from compounds of general formula (X) (see Scheme 4). 7
[0119] Compounds of formula (IX) may be prepared by aromatic
electrophilic substitution of compounds of formula (X) to give
compounds of formula IX directly. Alternatively compounds of
formula (IX) may be prepared in two or more steps; aromatic
electrophillic substitution of compounds of formula (X) to give
intermediate compounds which then undergo further reaction to give
compounds of formula (IX). The intermediate compounds may be
isolated or generated in sitiu without isolation. A preferred route
is shown in Scheme 5. 8
[0120] Compounds of formula (X) are reacted with sulfonyl chloride
to give compounds of formula (Xl) followed by reaction with
NHR.sup.6R.sup.7 to give compounds of formula (IXa).
[0121] A preferred route to compounds of formula (Ia) is shown in
Scheme 6. Preferred reaction conditions for the final step
involving reduction of compounds of formula (VIIIa) to compounds of
formula (Ia), are treatment with borane-tetrahydrofuran complex
(see Example 61.) 9
[0122] According to further aspects, the invention provides
compounds to formulae (II), (III), (VII), (VIII), (VIIIa) and (XII)
as defined above. In compounds of general formula (II) when R.sup.1
and R.sup.2are methyl, and n is 1, R.sup.3 is not a --SMe group
para to the ether linkage linking rings A and B.
[0123] Compounds of formulae (IV), (V), (VI) or (IX) are either
known and available from commercial sources or are available from
commercially available materials using known techniques.
[0124] 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 Inc, 1999. Example 121
provides an example of a protecting group strategy employed in the
synthesis of a compound of the present invention.
[0125] 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.
[0126] 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, Alzheimers disease, obsessive-compulsive disorder,
panic disorder, memory disorders (e.g. dementia, amnestic
disorders, and age-related cognitive decline (ARCD)), Parkinsons
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, Tourettes 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.
[0127] 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. 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`, 16th edition, p 1576, published by Merck Research
Laboratories, 1992].
[0128] Thus, according to further aspects, the invention
provides:
[0129] i) a compound of formula (I), as defined in the first
aspect, or pharmaceutically acceptable salts, solvates or
polymorphs thereof, for use as a pharmaceutical;
[0130] ii) the use of a compound of formula (I), as defined in the
first aspect, or pharmaceutically acceptable salts, solvates or
polymorphs thereof, 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;
[0131] iii) the use of a compound of general formula (I) as defined
in the first aspect, or pharmaceutically acceptable salts, solvates
or polymorphs thereof, in the manufacture of a medicament for the
treatment or prevention of premature ejaculation, and also provides
a method of treatment or prevention of premature ejaculation
comprising the administration of this compound to a patient in need
of such treatment or prevention;
[0132] 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 formula (I), as defined in the first aspect, or
pharmaceutically acceptable salts, solvates or polymorphs thereof,
to a patient in need of such treatment or prevention;
[0133] v) a method of increasing ejaculatory latency which
comprises the administration of an effective amount of a compound
of formula (I), as defined in the first aspect, or pharmaceutically
acceptable salts, solvates or polymorphs thereof, to a male
desiring increased ejaculatory latency; and
[0134] vi) a compound of formula (I), as defined in the first
aspect, or pharmaceutically acceptable salts, solvates or
polymorphs thereof, 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.
[0135] It is to be appreciated that all references herein to
treatment include curative, palliative and prophylactic
treatment.
[0136] 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 for the treatment of
premature ejaculation:
[0137] Alpha-blockers (e.g. phentolamine, doxazasim, tansulosin,
terazasin, prazasin and Example 19 of WO9830560;
[0138] Apomorphine - teachings on the use of apomorphine as a
pharmaceutical may be found in U.S. Pat. No. 5,945,117;
[0139] Dopamine D2 agonists (e.g. Premiprixal, Pharmacia Upjohn
compound number PNU95666);
[0140] Melanocortin receptor agonists (e.g. Melanotan II);
[0141] PGEI receptor agonists (e.g. alprostadil);
[0142] 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);
[0143] 5-HT3 antagonists (e.g. ondansetron and granisetron);
and
[0144] PDE inhibitors such as PDE2 (e.g.
erythro-9-(2-hydroxyl-3-nonyl)-ad- enine) 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-met-
hyl-4-oxo-7-propylimidazo[5,
1-f]-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl}- -4-ethylpiperazine
i.e. vardenafil / Bayer BA 38-9456) and IC351 (see structure below,
Icos Lilly). 10
[0145] 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.
[0146] 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 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.
[0147] 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 glycolate,
croscarmellose sodium and certain complex silicates, and
granulation binders such as polyvinylpyrrolidone,
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
sucrose, gelatin and acacia. Additionally, lubricating agents such
as magnesium stearate, stearic acid, glyceryl behenate and talc may
be included.
[0148] Solid compositions of a similar type may also be employed as
fillers in gelatin capsules. 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,
propylene glycol and glycerin, and combinations thereof.
[0149] 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 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.
[0150] 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.
[0151] 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.
[0152] 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).
[0153] Thus, for example, tablets or capsules of the compounds of
the invention or salts or solvates thereof may contain from 2.5 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
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
[0154] In general a tablet formulation could typically contain
between about 0.01 mg and 500 mg of a compound according to the
present invention (or a salt thereof) whilst tablet fill weights
may range from 50 mg to 1000 mg. An example formulation for a 10 mg
tablet is illustrated:
1 Ingredient % w/w Free acid, Free base or Salt of Compound 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.
[0155] 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.
[0156] 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.
[0157] The compounds of the invention may also be formulated for
delivery via an atomiser. Formulations for atomiser devices may
contain the following ingredients as solubilisers, emulsifiers or
suspending agents: water, ethanol, glycerol, propylene glycol, low
molecular weight polyethylene glycols, sodium chloride,
fluorocarbons, polyethylene glycol ethers, sorbitan trioleate,
oleic acid.
[0158] 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.
[0159] 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
benzalkonium chloride. Alternatively, they may be formulated in an
ointment such as petrolatum.
[0160] 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.
[0161] 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 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.
[0162] For oral or parenteral administration to human patients the
daily dosage levels of compounds of formula (I), and their
pharmaceutically acceptable salts, 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 0.4 g 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.
[0163] Oral administration is preferred. Preferably, administration
takes place shortly before an effect is required.
[0164] For veterinary use, a compound of the invention, or a
veterinarily acceptable salt thereof, or a veterinarily acceptable
solvate or pro-drug thereof, 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.
[0165] Thus according to a further aspect, the invention provides a
pharmaceutical formulation containing a compound of formula (i), as
defined in the first aspect, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable adjuvant, diluent or
carrier.
[0166] The invention is illustrated by the following non-limiting
Examples in which the following abbreviations and definitions are
used:
2 DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide br broad
Celite .RTM. filter agent, from Aldrich Chemical Company .delta.
chemical shift d doublet DCM dichloromethane DMPU
1,3-dimethyl-3,4,5,6-tetra- hydro-2(1H)-pyrimidinone DMSO
dimethylsulfoxide ES.sup.+ electrospray ionisation positive scan
ES.sup.- electronspray ionisation negative scan h hours m/z mass
spectrum peak HPLC High Pressure Liquid Chromatography min minutes
MS mass spectrum NMR nuclear magnetic resonance Oxone .RTM.
potassium peroxymonosulfate, from Aldrich Chemical Company q
quartet s singlet t triplet Tf trifluoromethanesulfonyl TFA
trifluoroacetic acid TFAA trifluoroacetic anhydride THF
tetrahydrofuran TLC thin layer chromatography TS.sup.+ thermospray
ionisation positive scan WSCDI
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride .DELTA.
heat
[0167] Where indicated, compounds were characterised as their
hydrochloride salts. A typical procedure for formation of
hydrochloride salts is given in Preparation 21. The procedure can
be carried out with other solvents e.g. diethyl ether or DCM.
[0168] The powder X-ray diffraction (PXRD) patterns were determined
using a Siemens D5000 powder X-ray diffractometer fitted with a
theta-theta goniometer, automatic beam divergence slits, a
secondary monochromator and a scintillation counter. The specimen
was rotated whilst being irradiated with copper K-alpha1 X-rays
(Wavelength=1.5046 Angstroms) filtered with a graphite
monochromator (.lambda.=0.15405 nm) with the X-ray tube operated at
40 kV/40 mA. The main peaks (in degrees 2 .theta.) of the PXRD
patterns for the various solid forms are illustrated.
[0169] Melting points were determined using a Perkin Elmer DSC7 at
a heating rate of 20.degree. C./minute.
EXAMPLES 1-15
[0170] Examples 1-15 were prepared according to the procedure
described in preparation 21 herein from the aldehyde indicated and
the appropriate amine.
3 11 Starting Example Material R.sup.4 R.sup.5 (R.sup.3).sub.n
R.sup.1 R.sup.2 Data 1 Prep. 2 H Br 3-CF.sub.3 Me Me
.delta..sub.H(CDCl.sub.3, 300MHz) 2.81(6H, s), 4.30(2H, s),
6.78(1H, d), 7.22 (1H, d), 7.25(1H, s), 7.43-7.57(3H, m), 8.07 (1H,
s); MSm/z(TS.sup.+) 374, 376(MH.sup.+). 2.sup.a Prep 3 H Br
4-CF.sub.3 --(CH.sub.2).sub.3-- .delta..sub.H(CDCl.sub.3, 300MHz)
(HCl salt) 2.34(1H, m), 2.80(1H, q), 3.92(2H, m), 4.27 (2H, s),
4.38(2H, m), 6.78(1H, d), 7.18(2H, d), 7.50(1H, d), 7.63 (2H, d),
7.98(1H, s), 13.20(1H, s); MSm/z (TS.sup.+)386, 388(MH.sup.+). 3
Prep 3 H Br 4-CF.sub.3 Me Me .delta..sub.H(CDCl.sub.3, 300MHZ) (HCl
salt) 2.82(6H, d), 4.28(2H, d), 6.82(1H, d), 7.13 (2H, d), 7.56(1H,
d), 7.65(2H, d), 8.05 (1H, s), 12.95(1H, s); MSm/z(TS.sup.+)374,
376 (MH.sup.+). 4.sup.c Prep 10 H F 4-SMe Me H
.delta..sub.H(CDCl.sub.- 3, 400MHz) (HCl salt) 2.46(3H, s),
2.60(3H, s), 4.18(2H, s), 6.78 (1H, m), 7.00(3H, m), 7.22(2H, m),
7.52(1H, dd), 9.84(2H, br); MS m/z(TS.sup.+)278(MH.sup.+). 5.sup.b
Prep 10 H F 4-SMe Et H .delta..sub.H(CDCl.sub.3, 400MHz) 1.08(3H,
t), 2.44(3H, s), 2.63(2H, q), 3.77 (2H, s), 6.80-6.92(4H, m),
7.18(1H, dd), 7.23 (2H, d); MSm/z(TS.sup.+) 292(MH.sup.+). 6.sup.a
Prep 10 H F 4-SMe --(CH.sub.2).sub.3-- .delta..sub.H(CDCl.sub.3,
300MHz) 2.03-2.12 (2H, m), 2.43 (3H, s), 3.30-3.29(4H, m), 3.56(2H,
m), 6.79- 6.90(4H, m), 7.17-7.23 (3H, m); MSm/z304 (MH.sup.+) 7
Prep 7 H Br 4-OCF.sub.3 Me Me .delta..sub.H(CDCl.sub.3, 300MHz)
2.23(6H, s), 3.42(2H, s), 6.78(1H, d), 6.91 (2H, m), 7.16(2H, m),
7.35(1H, dd), 7.65(1H, d); MSm/z(TS.sup.+)390 (MH.sup.+). 8 Prep 8
Br H 4-OCF.sub.3 Me Me .delta..sub.H(CDCl.sub.3, 300MHz) 2.25(6H,
s), 3.40(2H, s), 6.95(2H, d), 7.00 (1H, d), 7.20(2H, d), 7.28(1H,
dd), 7.38(1H, d); MSm/z(TS.sup.+)390 (MH.sup.+). 9 Prep 9 H Br
4-SMe Me Me .delta..sub.H(CDCl.sub.3, 300MHz) (HCl salt) 2.48(3H,
s), 2.82(6H, d), 4.30(2H, d), 6.70 (1H, d), 6.92(2H, d), 7.25(2H,
d), 7.42(1H, dd), 7.96(1H, d), 12.55 (1H, br); MSm/z(TS.sup.+)
352(MH.sup.+ 10 Prep10 H F 4-SMe Me Me .delta..sub.H(CDCl.sub.- 3,
300MHz) (HCl salt) 2.48(3H, s), 2.81(6H, in), 4.28(2H, m), 6.86
(3H, m), 7.06(1H, m), 7.18(1H, m), 7.70(1H, dd), 12.78(1H, br); MS
m/z(TS.sup.+)292(MH.sup.+). 11.sup.c Prep 5 Br H 4-CF.sub.3 Me H
.delta..sub.H(d.sub.6-DMSO, 400MHz) 2.53(3H, s), 4.10(2H, s),
7.16(1H, s), 7.26 (2H, d), 7.50(1H, d), 7.65(1H, d), 7.79(2H, d),
9.28(2H, brs); MS m/z360, 361(MH.sup.+) 12 Prep 5 Br H 4-CF.sub.3
Me Me .delta..sub.H(CD.sub.3OD, 300MHz) 2.93(6H, s), 4.84(2H, s),
7.16(1H, s), 7.30 (2H, d), 7.53(2H, dd), 7.78(2H, d); MSm/z
(TS.sup.+)374, 376(MH.sup.+). 13 Prep 14 Br H 4-SMe Me Me Free
base: .delta..sub.H(CDCl.sub.3, 400MHz)2.25(6H, s), 2.48(3H, s),
3.43(2H, s), 6.89(2H, d), 6.97 (1H, d), 7.23-7.28(3H, m), 7.33(1H,
d); MS m/z(TS.sup.+)352, 354 (MH.sup.+) 14 Prep 13 H OMe 4-SMe Me
Me HCl salt: .delta..sub.H(CD.sub.3OD, 400MHz)2.46(3H, s), 2.90(6H,
s), 3.83(3H, s), 4.34(2H, s), 6.92 (1H, d), 6.98(2H, d), 7.05(1H,
dd). 7.15(1H, dd), 7.31(2H, d); MS m/z(TS.sup.+)304, 340 (MH.sup.+)
15 Prep 18 OMe OMe 4-SMe Me Me HCl salt: .delta..sub.H(CD.sub.3OD,
400MHz)2.46(3H, s), 2.87(6H, s), 3.72(3H, s), 3.87(3H, s), 4.25
(2H, s), 6.60(1H, s), 6.97(2H, d), 7.13(1H, s), 7.31(2H, d); MS
m/z(TS.sup.+)334(MH.sup.+) .sup.aAzetidine hydrochloride was used
in place of Me.sub.2NH.HCl. .sup.bFree EtNH.sub.2 (as a 2M solution
in THF) was used as the amine component, THF alone was the reaction
solvent, and Et.sub.3N was omitted from the reaction mixture.
.sup.cMeNH.sub.2.HCl was used in place of Me.sub.2NH.HCl. AcOH(1
equiv. relative to Et.sub.3N) was an additional component of the
reaction mixture.
EXAMPLE 16
N-{5-lodo-2-[4-(trifluoromethoxy)phenoxy]benzyl}-N,N-dimethylamine
[0171] 12
[0172] To a stirred solution of the amine of preparation 23 (4.0 g,
12.9 mmol) in DCM (30 mL) at 0.degree. C. was added
trifluoromethanesulfonic acid (5.7 mL, 64.5 mmol) followed by
portionwise addition of N-iodosuccinimide (2.89 g, 12.9 mmol) over
15 min. After the addition was complete the mixture was allowed to
stir at 0.degree. C. for 30 min and then at 10.degree. C. for 1 h.
The reaction was quenched by the addition of aqueous sodium
hydroxide (2 M) and extracted three times with ethyl acetate. The
combined organic extracts were washed with sodium thiosulfate
solution, dried (MgSO.sub.4) and evaporated to a red oil which was
purified by flash chromatography [SiO.sub.2; DCM/ MeOH/ 880
NH.sub.3 (95:5:0.5)] to afford the desired iodide compound as a red
oil (4.16 g, 74%); .delta..sub.H (CDCI.sub.3, 400 MHz) 2.24 (6 H,
s), 3.40 (2 H, s), 6.64 (1 H, d), 6.92 (2 H, m), 7.16 (2 H, m),
7.53 (1 H, dd), 7.83 (1 H, d); MS m/z (TS.sup.+) 438
(MH.sup.+).
EXAMPLES 17-18
[0173] The following iodides were produced in an analogous fashion
to the reaction described for the preparation of Example 16.
4 13 Starting Example Material R.sup.1 R.sup.3 Data 17 Prep 26 H
OCF.sub.3 .delta..sub.H(CDCl.sub.3, 300MHz)1.88(1H, br), 2.43(3H,
s), 3.73(2H, s), 6.62(1H, d), 6.95(2H, m), 7.17 (2H, m), 7.53(1H,
dd), 7.77(1H, d); MSm/z (TS.sup.+)423(M.sup.+) 18 Prep 22 Me
CF.sub.3 .delta..sub.H(CDCl.sub.3, 400MHz)2.23(6H, s), 3.37(2H, s),
6.70(1H, d), 6.95(2H, d), 7.55(2H, d), 7.57(1H, dd), 7.88(1H, d);
MSm/z(TS.sup.30 )422(MH.sup.30 ).
EXAMPLE 19
N,N-Dimethyl-N-{2-[4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}amine
[0174] 14
[0175] The title compound was prepared from the aldehyde of
Preparation 19 according to the procedure used for preparation 21.
Acetic acid (1 equiv. relative to trethylamine) was an additional
component of the reaction mixture. .delta.H (CDCI.sub.3, 400 MHz)
2.33 (6 H, s), 2.50 (3 H, s), 3.60 (2 H, s), 6.79 (1 H, d), 6.98 (2
H, d), 7.29 (2 H, d), 8.03 (1 H, dd), 8.39 (1 H, d); MS m/z
(TS.sup.+) 319 (MH.sup.+).
EXAMPLE 20
N-Methyl-N-{5-nitro-2-[4-(trifluoromethyl)phenoxy]benzyl}amine
[0176] 15
[0177] The aldehyde of preparation 20 (5.0 g, 16.07 mmol) was
dissolved in a solution of monomethylamine in ethanol (ca. 8 M) (20
mL, 160 mmol), and the mixture stirred for 30 min at room
temperature to form an orange solution. Sodium borohydride (3.0 g,
80 mmol) was added portionwise over 10 min and stirring continued
for 30 min, by which time the solution had become dark red. The
reaction was quenched by cautiously pouring the reaction mixture
into hydrochloric acid (2 M, 100 mL). The mixture was basified by
pouring this solution into a large excess of potassium carbonate to
give a mixture with ca. pH 10, which was extracted with ethyl
acetate (3.times.70 mL). The combined organic fractions were dried
(MgSO.sub.4) and evaporated to an orange oil which was filtered
through a short plug of silic, eluting with DCM/ methanol/ 880
ammonia (93:7:1). After evaporation, the residue was further
purified by flash chromatography [SiO.sub.2; pentane/ ethyl acetate
(2:1) to elute non-basic materials followed by DCM/ methanol/ 880
ammonia (93:7:1)] to afford the desired amine compound as a yellow
oil (3.08 g, 59%); .delta..sub.H (CDCI.sub.3, 400 MHz) 2.49 (3 H,
s), 3.89 (2 H, s), 6.89 (1 H, d), 7.12 (2 H, d), 7.67 (2 H, d),
8.10 (1 H, dd), 8.40 (1 H, d); MS m/z (TS.sup.+) 327
(MH.sup.+).
EXAMPLE 21
N,N-Dimethyl-N-{5-nitro-2-[4-(trifluoromethyl)phenoxy]benzyl}amine
[0178] 16
[0179] Trifluoromethanesulfonic acid (500 .mu.L) was added dropwise
to a solution of the amine of preparation 22 (504 mg, 1.71 mmol) in
TFA (4.5 mL) at 0.degree. C. under nitrogen followed by potassium
nitrate (173 mg, 1.71 mmol). The mixture was stirred at 0.degree.
C. for 75 min then poured onto ice and basified with sodium
hydroxide pellets. The aqueous mixture was extracted with ethyl
acetate and the organic extract was washed with brine, dried
(MgSO.sub.4) and concentrated in vacuo. The residue was purified by
flash chromatography [SiO.sub.2; DCM/ methanol/ 880 ammonia
(99:1:0.5)] to give the desired nitro compound (400 mg, 69%) as
yellow oil; OH (CDCI.sub.3, 300 MHz) 2.30 (6 H, s), 3.55 (2 H, s),
6.92 (1 H, d), 7.08 (2 H, d), 7.65 (2 H, d), 8.10 (1 H, dd), 8.45
(1 H, d); MS m/z (TS.sup.+) 341 (MH.sup.+).
EXAMPLE 22
N,N-Dimethyl-N-{5-nitro-2-[4-(trifluoromethoxy)phenoxy]benzyl}amine
[0180] 17
[0181] The reaction of example 21 was repeated under similar
conditions using the amine of preparation 23 to provide the title
nitro compound. .delta..sub.H (CDCI.sub.3, 400 MHz) 2.33 (6 H, s),
3.58 (2 H, s), 6.83 (1 H, d), 7.05 (2 H, m), 7.25 (2 H, m), 8.06 (1
H, d), 8.41 (1 H, s); MS m/z (TS.sup.+) 357 (MH.sup.+).
EXAMPLE 23
N-{5-Bromo-2-[4-(methylsulfanyl)phenoxy]benzyl}-N-methylamine
[0182] 18
[0183] The bromoaldehyde of preparation 9 (39.0 g, 120 mmol), was
dissolved in monomethylamine (7.37 mL, 33% in ethanol) and the
solution stirred for 10 min before the addition of sodium
borohydride (6.8 g, 180 mmol). The reaction mixture was stirred for
3 hrs at room temperature before being added cautiously to 3 M HCI.
After the addition was complete the mixture was left for 10 min
before adjusting the pH to 14 with sodium hydroxide (3 M). The
aqueous phase was extracted with ethyl acetate and the organic
layer washed with brine, dried (MgSO.sub.4) and evaporated. The
resulting oil was taken up in diethyl ether and treated with excess
hydrochloric acid (1 M in di ethyl ether). The salt was collected
by filtration and washed with DCM. The washed solid was partitioned
between ethyl acetate and sodium hydroxide (3 M), the organic layer
separated, washed with brine, dried and evaporated to a colourless
oil (24.6 g, 61%); .delta..sup.H (CDCI.sub.3, 300 MHz) 2.43 (3 H,
s), 2.47 (3 H, s), 3.76 (2 H, s), 6.72 (1 H, d), 6.87 (2 H, d),
7.24 (2 H, d), 7.30 (1 H, dd), 7.54 (1 H, d); MS m/z (TS.sup.+)
338/ 340 (MH.sup.+).
EXAMPLES 24-27
[0184] A series of secondary amines was prepared from the requisite
aldehyde using the procedure described for example 23.
5 19 Starting Example material R.sup.4 R.sup.5 (R.sup.3).sub.n Data
24 Prep 8 Br H 4-OCF.sub.3 HCl salt: .delta..sub.H(CDCl.sub.3,
400MHz)2.59(3H, s), 4.16(2H, s), 6.88(1H, s), 7.18-7.29(5H, m),
7.59(1H, d), 9.82(2H, brs); MSm/z (TS.sup.+)376, 378(MH.sup.+) 25
Prep 13 H OMe 4-SMe HCl salt: .delta..sub.H(CD.sub.3OD,
300MHz)2.47(3H, s), 2.75(3H, s), 3.82(3H, s), 4.20(2H, s), 6.95(4H,
m), 7.10(1H, dd), 7.30(2H, d); MSm/z(TS.sup.+)304(MH.sup.+) 26 Prep
16 H Br 3-OMe Free base: .delta..sub.H(CDCl.sub.3, 400MHz)2.43(3H,
4-SMe s), 2.46(3H, s), 3.77(2H, s), 3.87(3H, s), 6.48(1H, dd),
6.56(1H, s)6.78(1H, d), 7.15(1H, d), 7.33(1H, dd), 7.57(1H, d);
MSm/z(TS.sup.+)368/370(MH.sup.+) 27 Prep 17 H Br 3-CF.sub.3 Free
base: .delta..sub.H(CDCl.sub.3, 300MHz)2.44(3H, 4-SMe s), 2.51(3H,
s), 3.75(2H, s), 6.78(1H, d), 7.03(1H, dd), 7.39(2H, t), 7.61(1H,
s)
EXAMPLE 28
3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzenesulfonamide
[0185] 20
[0186] Chlorosulfonic acid (48.1 mL, 724 mmol) was added cautiously
to a solution of the compound of preparation 21 (19.8 g, 72.4 mmol)
in DCM (290 mL) cooled to 0.degree. C. and the mixture was stirred
for 4 h before being poured into ice-water (1000 mL) and extracted
with DCM (300 mL). This crude solution of sulfonyl chloride was
treated with saturated ethanolic ammonia (1160 mL) and stirred at
room temperature overnight before being concentrated in vacuo. The
reaction was repeated twice more under identical conditions and the
material from the three runs was combined. Purification of the
combined residues by flash chromatography [SiO.sub.2; (MeOH/ 880
NH.sub.3) (9:1)} (0.fwdarw.5%) in DCM] gave a clean sample of the
desired sulfonamide (3.96 g, 5%) as well as slightly contaminated
sulfonamide (19.73 g, 26%). For pure free base; .delta..sub.H
(CDCI.sub.3, 300 MHz) 2.24 (6 H, s), 2.48 (3 H, s), 3.56 (2 H, s),
5.25 (2 H, br), 6.81 (1 H, d), 6.92 (2 H, d), 7.27 (2 H, d), 7.70
(1 H, dd), 8.04 (1 H, d); MS m/z (TS.sup.+) 353 (MH.sup.+). Each
sample was converted to the hydrochloride salt by stirring a
suspension in diethyl ether with excess ethereal hydrochloric acid
for 30 mins, the precipitate was collected and dried, and then
recrystallised from hot ethanol/ ethyl acetate (1:1) (m.p.
193-194.degree. C.) to afford 2.69 g and 15.63 g of the
hydrochloride of the desired sulfonamide from each batch
respectively; .delta..sub.H (d.sub.6-DMSO, 400 MHz) 2.48 (3 H, s),
2.78 (6 H, s), 4.43 (2 H, s), 6.86 (1 H, d), 7.19 (2 H, d),
7.31-7.38 (4 H, m), 7.82 (1 H, dd), 8.11 (1 H, dd), 10.44 (1 H,
brs); MS m/z(TS.sup.+) 353 (MH.sup.+).
[0187] Alternatively, the title compound can be prepared via the
secondary amine of Example 42, which itself is also available by
borane reduction of the amide from preparation 31 using the method
described for Example 61. 21
[0188] Alternatively the title compound may be prepared as
follows:
[0189] A solution of the hydrochloride salt of the title product
from preparation 21 (113 g) in dichloromethane (1130 mL) was slowly
added to a solution of chlorosulfonic acid (428 g) in
dichloromethane (230 mL) keeping the temperature between 0 and
5.degree. C. After 1 h at 0-5.degree. C., the reaction mixture was
quenched slowly into 5% trifluoroacetic acid in water (1200 mL),
keeping the temperature between 0-10.degree. C. The two phases were
separated and the dichloromethane layer removed in vacuo to give an
oil. Acetonitrile (1360 mL) was added and to this solution was
slowly added POCI.sub.3 (140 g). The resulting slurry was heated at
reflux at which point it became a solution. After 1 h the reaction
mixture was cooled to room temperature and quenched into ice/water
(1200 mL) keeping the temperature below 20.degree. C. The mixture
was extracted with dichloromethane (1.times.1400 mL and 1.times.400
mL) and the combined extracts stirred at room temperature while
adding aqueous ammonia (250 mL). After 1 h the layers were
separated and the aqueous layer further extracted with
dichloromethane (400 ml). The combined dichloromethane layers were
concentrated in vacuo. Water (539 ml) was added and to this mixture
was added aquesou sodium hydroxide solution (108 ml; 46-48%w/w) and
the slurry stirred for 1 h at room temperature and a further 1 h at
10.degree. C. The solid was filtered and reslurried in water (500
mL) and the pH adjusted to 6-6.5 by addition of 1:1,
water:concentrated hydrochloric acid. The resulting slurry was
stirred for 1 h at 10.degree. C. or below. The solid was filtered,
washed with water (107 mL) and the damp solid reslurried in 9:1,
water:acetone (289 mL:32 mL) for 1 h below 10.degree. C. This
slurry was filtered and dried in a vacuum oven at 50.degree. C.
overnight. A solution of the above solid in acetone (565 mL) was
slurried with carbon (Norit SX plus, 50%w/w) filtered and treated
with another charge of carbon (Norit SX plus, 50%w/w). This was
again filtered and the solution concentrated, replacing with water
(1130 mL). The slurry was granulated, filtered and vacuum dried
overnight to give the product as a white solid (78.6 g, 61%), m.p.
119.degree. C.
[0190] The main peaks (in degrees 2 .theta.) of the PXRD pattern
are as follows:
6 Angle Intensity Angle Intensity Angle Intensity 2-Theta .degree.
% 2-Theta .degree. % 2-Theta .degree. % 4.891 9.6 22.267 89.7
31.964 9.2 8.221 2.3 23.305 14.4 32.738 10.2 10.305 7.8 23.964 49.6
33.161 17.6 10.416 20.3 24.686 7.6 35.203 11.0 11.476 46.3 25.192
13.2 35.316 11.4 14.720 36.6 25.593 16.5 35.534 11.7 16.301 11.6
26.177 10.5 35.858 11.5 16.581 43.1 26.650 26.0 36.427 12.2 18.011
43.8 27.744 7.6 36.820 8.0 19.373 44.3 28.098 37.9 38.360 11.1
19.668 51.3 29.737 6.1 39.471 8.4 20.568 18.3 30.262 12.9 39.996
9.6 20.943 19.7 30.814 9.9 40.984 9.9 21.235 77.6 31.141 7.8 41.907
9.7 21.509 100.0 31.493 15.5 43.787 10.2
[0191] Alternatively the title compound may be prepared as
follows:
[0192] Chlorosulfonic acid (706 mL) was added very slowly to a cold
(-5.degree. C. to 0.degree. C.) solution of the title product from
preparation 21 (290 g, 1.06 mol) in dichloromethane (2.9 L) The
reaction mixture was stirred at 0.degree. C. overnight. The mixture
was added slowly into 3 M HCI (2.9 L) keeping the temperature
between -5 and 0.degree. C. Dichloromethane (2.9 L) was added and
the layers separated. Aqueous ammonia (580 mL) was added to the
dichloromethane layer at 0.degree. C., and stirred overnight. Water
was added (2 L) and the layers separated The aqueous layer was
washed with dichloromethane. The dichloromethane layers were
combined and concentrated under vacuum to give a brown oil which
solidified on standing. The residue was purified by flash
chromatography [SiO.sub.2; DCM:0-6% (MeOH:NH.sub.3, 9:1)] to give a
pale yellow solid which was further purified by stirring in 9:1,
water:acetone (1.3). The slurry was filtered, washed and dried
overnight in a vacuum oven at 55.degree. C. to give the product as
a white solid (57 g, 15%), m.p. 129.degree. C.
[0193] The main peaks (in degrees 2 .theta.) of the PXRD pattern
are as follows
7 Angle Intensity Angle Intensity Angle Intensity 2-Theta .degree.
% 2-Theta .degree. % 2-Theta .degree. % 8.807 4.7 23.265 17.5
34.425 4.3 9.088 20.6 23.876 4.3 35.326 3.3 11.580 4.4 24.416 4.6
35.750 6.0 11.887 2.5 24.640 8.4 36.189 2.8 14.068 8.5 25.318 10.2
36.715 4.1 14.489 1.9 25.622 3.4 36.946 7.0 14.978 8.5 26.077 6.6
37.500 4.2 15.918 2.2 26.746 20.8 38.534 3.1 16.558 2.3 26.974 6.8
39.065 4.4 17.021 8.3 27.259 13.4 39.468 5.3 18.254 100.0 27.948
13.6 39.695 4.3 18.787 8.0 29.197 4.1 40.850 5.1 19.388 4.2 29.530
11.1 41.596 6.5 19.759 4.2 30.284 6.7 42.460 6.9 20.079 5.2 30.952
11.5 43.120 7.2 20.476 72.1 31.779 3.4 43.506 4.5 20.743 5.2 32.224
6.0 44.103 5.1 21.323 76.2 32.690 5.4 44.530 3.9 22.005 8.8 33.708
2.6
The Intermediate Sulfonyl Chloride
3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzenesulfonyl
chloride
[0194] In the above methods of preparing Example 28, the
intermediate sulfonyl choride was not isolated, but was generated
in situ. This is the preferred method of preparing Example 28.
However, in the course of a repeat experiment, a portion of the
intermediate sulfonyl choride was isolated; .sup.1H NMR
.delta..sub.H (d.sub.6--DMSO, 300 MHz) 3.6 (3 H, br s), 4.3 (6 H,
br s), 8.3 (1 H, br s), 8.6 (2 H, brs), 8.9 (2 H, brs), 9.2 (1 H,
brs), 9.4 (1 H, brs). .sup.1H NMR .DELTA..sub.H (d6--DMSO+D.sub.2O,
300 MHz) 2.4 (3 H, s), 2.8 (6 H, s), 6.8 (1 H, d), 7.1 (2 H, d),
7.4 (2 H. d), 7.7 (1 H, dd), 7.9 (1 H, s).
[0195] Salts
[0196] i) L-Tartrate salt
[0197] A solution of L-tartaric acid (2.81, 18.7 mmol) in water (6
mL) was added to a hot (40.degree. C.) solution of the title
product (6.0, 17.0 mmol) in acetone (54 mL). The slurry was then
heated at 60.degree. C. for 30 min, and allowed to cool to room
temperature. After stirring at room 15 temperature for 1-2 h, the
mixture was cooled to 0.degree. C. After a further 3 h, the mixture
was filtered, washed with acetone (2.times.10 mL), and dried in a
vacuum oven at 55.degree. C. overnight to give the desired salt as
a white crystalline solid (8.4 g, 98%), m.p. 179.degree. C.
[0198] The main peaks (in degrees 2 .theta.) of the PXRD pattern
are as follows:
8 Angle Intensity Angle Intensity Angle Intensity 2-Theta .degree.
% 2-Theta .degree. % 2-Theta .degree. % 4.330 21.9 25.156 12.0
34.663 6.7 12.165 5.6 25.787 6.1 35.071 5.6 12.425 10.1 26.057 12.4
35.674 15.2 12.543 5.4 26.114 14.5 35.788 14.7 13.218 12.7 26.408
11.6 36.228 10.7 14.368 6.3 26.642 25.5 36.517 8.6 14.463 6.3
26.830 25.4 36.975 13.3 16.849 7.3 27.130 26.7 37.618 17.4 17.149
57.2 27.540 12.6 37.799 19.7 17.469 49.5 28.001 20.7 38.242 16.2
17.623 66.1 29.122 17.7 38.882 15.5 18.498 9.5 29.772 28.7 39.432
8.1 19.403 47.2 30.394 13.5 39.577 9.0 20.422 12.4 30.983 12.8
40.198 18.4 20.733 15.7 31.259 32.9 41.451 8.2 20.923 28.2 32.085
14.6 42.109 14.6 21.914 100.0 32.258 9.5 42.816 8.7 23.542 19.0
32.818 5.2 43.969 11.5 23.776 20.0 33.433 6.5 44.213 14.2 24.958
30.8 34.085 20.3 11.9
[0199] ii) D-Tartrate salt
[0200] A solution of D-tartaric acid (2.81 g, 18.7 mmol) in water
(6 mL) was added to a hot (40.degree. C.) solution of the title
compound (6.0, 17.0 mmol) in acetone (54 mL). The slurry was then
heated at 60.degree. C. for 30 min, and allowed to cool to room
temperature. After stirring at room temperature for 1-2 h, the
mixture was cooled to 0.degree. C. After a further 3 h, the mixture
was filtered, washed with acetone (2.times.10 mL), and dried in a
vacuum oven at 55.degree. C. overnight to give the desired salt as
a white crystalline solid (8.4 g, 98%), m.p. 182.degree. C.
[0201] The main peaks (in degrees 2 .theta.) of the PXRD pattern
are as follows:
9 Angle Intensity Angle Intensity Angle Intensity 2-Theta .degree.
% 2-Theta .degree. % 2-Theta .degree. % 4.320 23.3 25.153 11.8
34.701 5.1 12.147 5.0 25.776 5.4 35.066 4.9 12.414 11.1 26.058 7.2
35.693 13.8 12.539 4.8 26.135 11.8 35.794 11.5 13.219 11.9 26.405
10.1 36.241 11.5 14.368 5.8 26.635 25.4 36.525 8.5 14.480 6.0
26.825 24.3 37.044 8.8 16.854 7.0 27.133 27.8 37.632 15.2 17.161
58.2 27.547 13.3 37.806 18.8 17.452 52.8 28.005 19.1 38.264 15.3
17.631 68.8 29.125 18.2 38.880 14.1 18.516 8.5 29.788 26.8 39.454
9.1 19.407 50.3 30.408 12.2 39.542 8.4 20.425 12.3 30.984 10.2
40.193 17.2 20.733 17.0 31.273 26.4 41.530 5.8 20.912 26.5 32.093
12.5 42.108 12.1 21.919 100.0 32.268 7.5 42.854 5.2 23.566 20.2
32.821 4.8 43.930 7.9 23.787 17.5 33.461 5.4 44.243 11.7 24.974
32.1 34.084 17.3
[0202] iii) Hydrochloride Salts
[0203] a) Lower melting point form
[0204] A solution of hydrochloric acid /isopropanol (7.02 M, 0.41
mL, 2.86 mmol) was added to a solution of the title compound (1.0
g, 2.84 mmol) in methyl ethyl ketone (10 mL). After stirring at
room temperature for 3 h the mixture was filtered, washed and dried
in a vacuum oven at 55.degree. C. overnight to give the desired
salt, m.p. 176.degree. C.
[0205] The main peaks (in degrees 2 .theta.) of the PXRD pattern
are as follows:
10 Angle Intensity Angle Intensity Angle Intensity 2-Theta %
2-Theta % 2-Theta % 4.365 10.4 18.749 23.5 25.485 37.9 8.758 22.3
19.031 42.1 26.443 40.8 11.591 19.0 19.374 20.8 26.634 36.1 13.184
10.0 20.096 47.2 27.345 13.4 14.438 20.5 20.904 15.0 27.846 34.0
14.522 14.2 21.408 20.4 29.280 17.9 14.948 10.6 21.710 74.1 30.117
13.9 15.512 18.7 22.012 100.0 31.281 21.4 15.886 9.7 22.157 42.7
33.336 16.5 16.716 23.7 22.485 27.9 34.024 11.0 16.975 36.5 22.614
31.6 35.172 16.2 17.568 22.3 23.967 11.9 37.237 14.6 18.506 16.4
24.503 19.6 11.4
[0206] b) Higher melting point form
[0207] A solution of hydrochloric acid /isopropanol (7.02 M, 0.41
mL, 2.86 mmol) was added to a solution of the title compound (1.0
g, 2.84 mmol) in methyl ethyl ketone (1 OmL). After stirring 5 at
room temperature for 7 h the mixture was filtered, washed and dried
in a vacuum oven at 55.degree. C. overnight to give the desired
salt, m.p. 192.degree. C.
[0208] The main peaks (in degrees 2 .theta.) of the PXRD pattern
are as follows:
11 Angle Intensity Angle Intensity Angle Intensity 2-Theta %
2-Theta % 2-Theta % 6.511 1.5 23.777 8.7 33.939 10.0 10.198 2.6
24.218 19.1 34.326 6.5 11.969 2.9 24.288 24.1 35.190 6.6 12.081 6.0
25.086 20.8 36.183 6.9 12.500 2.1 25.973 6.2 36.674 5.9 12.948 17.7
26.342 13.0 37.061 4.8 14.111 2.6 26.825 13.8 37.365 4.3 15.313 4.9
27.357 8.2 37.918 3.9 16.477 13.2 27.600 5.7 38.491 7.4 16.587 15.0
27.942 5.2 38.680 5.6 17.261 3.8 28.322 20.0 39.283 2.9 18.009 22.0
28.895 13.7 39.915 3.9 19.104 15.6 30.097 9.2 40.271 6.8 20.174
100.0 30.192 10.2 40.686 7.4 21.435 11.7 30.567 11.1 41.448 4.9
21.961 26.1 31.493 7 3 42 435 5 3 22.554 4.7 31.776 4.8 43.170 4.3
22.860 21.3 32.417 17.4 43.612 11.1 23.059 11.2 32.931 5.5 12.1
23.126 13.5 33.516 7.5 44.077 5.8 23.425 17.0
[0209] iv) Citrate Salt
[0210] Citric acid (0.30 g, 1.56 mmol) was added to a solution of
the title compound (0.50 g, 1.42 mmol) in acetone (5 mL). After
stirring at room temperature for 3 h the mixture was 5 filtered,
washed and dried in a vacuum oven at 55.degree. C. overnight to
give the desired salt, m.p. 110.degree. C.
[0211] The main peaks (in degrees 2 .theta.) of the PXRD pattern
are as follows:
12 Angle Intensity Angle Intensity Angle Intensity 2-Theta %
2-Theta % 2-Theta % 5.516 11.7 17.246 39.6 23.513 48.2 5.731 25.7
17.307 44.3 24.114 39.9 7.279 7.7 17.587 52.4 24.737 50.0 9.057 8.2
18.186 44.3 25.403 38.8 10.733 25.1 19.089 100.0 25.986 37.5 11.522
15.3 19.596 51.9 26.182 42.2 11.957 13.8 19.815 68.6 27.333 23.8
13.115 11.2 20.286 56.9 30.030 31.2 13.429 12.2 20.553 81.1 30.250
40.4 14.311 13.3 20.713 63.0 30.396 39 5 14.702 23.6 21.342 34.4
31.830 24.5 16.515 17.8 21.666 42.6 34.066 27.4 16.813 17.6 21.830
51.1 37.320 23.2
[0212] v) Sulfate Salt
[0213] Concentrated sulfuric acid (0.04 mL) was added to a solution
of the title compound (0.50 g, 1.42 mmol) in acetone (5 mL). After
stirring at room temperature for 2 h, the mixture was stirred at
0.degree. C. for a further 3 h. The mixture was then filtered,
washed and dried overnight in a vacuum oven at 55.degree. C. to
give the desired salt as a white solid (0.31 g, 48%), m.p.
233.degree. C.
[0214] The main peaks (in degrees 20) of the PXRD pattern are as
follows:
13 Angle Intensity Angle Intensity Angle Intensity 2-Theta .degree.
% 2-Theta .degree. % 2-Theta .degree. % 4.770 7.1 21.291 9.5 29.923
15.5 9.354 10.5 21.610 45.1 31.761 10.5 9.906 8.0 22.019 11.0
32.221 8.3 12.435 6.2 22.611 52.2 32 690 9 0 14.406 12.9 23.168
12.2 33.983 9.3 16.040 8.2 23.567 39.0 34.610 10.2 16.563 3.4
23.855 16.6 35.098 11.2 17.145 26.5 24.096 12.7 35.420 16.7 17.322
48.9 24.521 33.7 36.212 9.4 17.945 7.3 24.951 53.7 36.942 14.4
18.292 35.2 25.341 9.7 37.618 9.6 18.794 100.0 25.790 13.6 38.349 9
9 19.234 7.1 26.276 13.5 38.856 11.6 19.780 46.3 26.815 12.8 39.126
8.3 20.026 50.0 28.030 22.5 40.321 10.0 20.365 10.9 28.739 21.7
40.948 12.5 20.513 11.6 29.274 8.8 7.5
[0215] vi) Phosphate Salt
[0216] Phosphoric acid (4.63 mL, 67.7 mmol) was added dropwise to a
suspension of the title compound (21.7 g, 61.6 mmol) in water (149
mL). The slurry was then heated on a steam bath 5 until a clear
solution was produced. This solution was then allowed to cool to
room temperature and stirred for 2 h. The mixture was then cooled
to 0.degree. C., and stirred for a further 3 h. The precipitate was
filtered, washed with water (2.times.50 mL) and dried in a vacuum
oven at 55.degree. C. overnight to give the desired salt as a white
crystalline solid (23.1 g, 83%), m.p. 196.degree. C.
[0217] The main peaks (in degrees 2 .theta.) of the PXRD are as
follows:
14 Angle Intensity Angle Intensity Angle Intensity 2-Theta.degree.
% 2-Theta.degree. % 2-Theta.degree. % 4.336 18.7 22.157 13.9 31.877
5.7 11.698 8.5 22.729 22.5 32.521 13.0 13.047 14.5 23.034 16.2
32.702 6.9 13.479 9.4 23.219 17.3 33.213 7.2 14.330 13.5 23.506
79.0 33.960 8.9 15.217 69.4 23.915 11.9 34.334 10.5 15.440 10.6
25.456 17.3 34.717 22.6 16.205 12.4 25.691 27.0 35.586 10.7 17.440
70.9 26.317 12.5 36.184 16.7 17.899 5.4 26.508 21.9 36.722 6.8
18.300 30.6 26.838 14.9 37.819 64 18.750 22.5 26.976 25.5 38.412
8.7 19.120 12.6 27.115 22.6 38.773 13.3 19.740 100.0 27.971 32.6
39.078 9.5 19.930 30.8 28.902 12.5 39.848 11.5 20.291 15.6 29.351
8.6 40.076 10.7 20.581 58.2 29.987 22.1 41.269 9.9 21.617 39.9
31.022 8.0 43.921 12.8 21.832 10.4 31.368 11.6 9.8
EXAMPLES 29-60
[0218] The following sulfonamides were prepared in an analogous
fashion to that described herein for Example 28, replacing ammonia
with the requisite amine where appropriate.
15 22 Starting Example Material R.sup.6 R.sup.7 R.sup.1 R.sup.3
Data 29 Prep 27 Me Me H CF.sub.3 .delta..sub.H(CDCl.sub.3, 400 MHz)
2.45 (3H, s), 2.75 (6H, s), 3.85 (2H, s), 6.96 (1H, d), 7.07 (2H,
d), 7.64 (3H, d), 7.88 (1H, s); MS m/z (ES.sup.+) 389 (MH.sup.+).
30 Prep 22 Me H Me CF.sub.3 .delta..sub.H(CDCl.sub.3, 400 MHz) 2.59
(2H, s), 2.97 (3H, s), 4.58 (1H, s), 4.81 (6H, s), 7.08 (1H, d),
7.40 (2H, d), 7.80 (2H, d), 7.92 (1H, d), 8.15 (1H, s) 31 Prep 22
23 H Me CF.sub.3 .delta..sub.H(CDCl.sub.3, 300 MHz) 2.31 (6H, s),
3.18 (2H, t), 3.56 (2H, s), 3.68 (2H, t), 6.97 (1H, d), 7.06 (2H,
d), 7.63 (2H, d), 7.78 (1H, d), 8.12 (1H, s); MS m/z (TS.sup.+) 419
(MH.sup.+) 32 Prep 22 Me Me Me CF.sub.3 .delta..sub.H(CDCl.sub.3,
300 MHz) 2.77 (6H, s), 2.83 (6H, s), 4.20 (2H, s), 6.96 (1H, d),
7.22 (2H, d), 7.71 (2H, d), 7.78 (1H, d), 8.18 (1H, s); MS m/z
(TS.sup.+) 403 (MH.sup.+). 33 Prep 22 H H Me CF.sub.3
.delta..sub.H(CDCl.sub.3, 300 MHz) 2.28 (6H, s), 3.54 (2H, s), 6.98
(1H, d), 7.04 (2H, d), 7.61 (2H, d), 7.80 (1H, d), 8.16 (1H, s); MS
m/z (TS.sup.+) 375 (MH.sup.+). 34 Prep 27 Me H H CF.sub.3
.delta..sub.H(CDCl.sub.3, 300 MHz) 2.44 (3H, s), 2.68 (3H, s), 3.84
(2H, s), 6.94 (1H, d), 7.08 (2H, d), 7.62 (2H, d), 7.76 (1H, d),
8.00 (1H, s), MS m/z (TS.sup.+) 375 (MH.sup.+). 35 Prep 26 H H H
--OCF.sub.3 .delta..sub.H(CDCl.sub.3, 300 MHz) 2.48 (3H, s), 2.65
(3H, br), 3.89 (2H, s), 6.84 (1H, d), 7.03 (2H, m), 7.23 (2H, m),
7.77 (1H, dd), 8.03 (1H, d); MS m/z (TS.sup.+) 377 (MH.sup.+). 36
Prep 23 H H Me --OCF.sub.3 .delta..sub.H(d.sub.6-DMSO, 300 MHz)
(HCl salt) 2.80 (6H, s), 4.43 (2H, s), 6.98 (1H, d), 7.37 (4H, m),
7.50 (2H, m), 7.86 (1H, dd), 8.13 (1H, d), 10.18 (1H, br); MS m/z
(TS.sup.+) 391 (MH.sup.+). 37 Prep 23 Me H Me OCF.sub.3
.delta..sub.H(d.sub.6-DMSO, 300 MHz) 2.43 (3H, d), 2.80 (6H, s),
4.46 (2H, s), 6.99 (1H, d), 7.37 (2H, m), 7.48 (3H, m), 7.80 (1H,
dd), 8.12 (1H, d), 10.37 (1H, br); MS m/z (TS.sup.+) 405 (MH.sup.+)
38 (HCl salt) Prep 28 24 H H SMe .delta..sub.H(DMSO-D.sub.6, 400
MHz) 2.47 (3H, s), 2.63 (3H, s), 2.79 (2H, q), 3.36 (2H, m), 4.29
(2H, s), 4.71 (1H, t), 6.86 (1H, d), 7.17 (2H, d), 7.38 (2H, d),
7.60 (1H, t), 7.75 (1H, dd), 8.01 (1H, d), 8.95 (2H, br); MS m/z
(ES.sup.+) 383 (MH.sup.+). 39 (HCl salt) Prep 28 25 Me H SMe
.delta..sub.H(DMSO-D.sub.6, 400 MHz) 2.48 (3H, s), 2.61 (3H, s),
2.72 (3H, s), 3.00 (2H, t), 3.49 (2H, m), 4.29 (2H, s), 4.83 (1H,
t), 6.83 (1H, d), 7.21 (2H, d), 7.38 (2H, d), 7.71 (1H, dd), 8.03
(1H, d), 9.37 (2H, br), MS m/z (ES.sup.+) 397 (MH.sup.+) 40 (HCl
salt) Prep 28 26 H H SMe .delta..sub.H(DMSO-D.sub.6, 400 MHz) 1.51
(2H, m), 2.48 (3H, s), 2.61 (3H, s), 2.79 (2H, m), 3.35 (2H, m),
4.28 (2H, s), 4.44 (1H, br), 6.85 (1H, d), 7.19 (2H, d), 7.37 (2H,
d), 7.53 (1H, t), 7.74 (1H, dd), 8.02 (1H, d), 9.11 (2H, br); MS
m/z (ES.sup.+) 397 (MH.sup.+). 41 Prep 28 27 H H SMe
.delta..sub.H(CD.sub.3OD, 300 MHz) 1.00 (3H, d), 2.43 (3H, s), 2.48
(3H, s), 3.26-3.34 (2H, m), 3.38-3.46 (1H, m), 3.89 (2H, s), 6.87
(1H, d), 7.04 (2H, d), 7.35 (2H, d), 7.72 (1H, dd), 7.92 (1H, d);
MS m/z (ES.sup.+) 397 (MH.sup.+). 42 Prep 28 H H H SMe
.delta..sub.H(CDCl.sub.3, 400 MHz) 2.49 (HCl salt) (6H, s), 3.89
(2H, s), 6.81 (1H, d), 6.96 (2H, d), 7.29 (2H, d), 7.72 (1H, dd),
7.99 (1H, d); MS m/z (TS.sup.+) 339 (MH.sup.+). 43 Prep 28 Me H H
SMe .delta..sub.H(CDCl.sub.3, 400 MHz) 2.49 (3H, s), 2.50 (3H, s),
2.65 (3H, s), 3.90 (2H, s), 6.82 (1H, d), 6.97 (2H, d), 7.30 (2H,
d), 7.66 (1H, dd), 7.91 (1H, d); MS m/z (TS.sup.+) 353 (MH.sup.+).
44 Prep 28 Me Me H SMe .delta..sub.H(CD.sub.3OD, 400 MHz) (HCl
salt) 2.49 (3H, s), 2.70 (6H, s), 2.83 (3H, s), 4.45 (2H, s), 6.86
(1H, d), 7.16 (2H, d), 7.41 (2H, d), 7.78 (1H, dd), 7.98 (1H, d);
MS m/z (TS.sup.+) 367 (MH.sup.+). 45 Prep 21 Me H Me SMe
.delta..sub.H(CD.sub.3OD, 400 MHz) (HCl salt) 2.51 (3H, s), 2.55
(3H, s), 2.97 (6H, s), 4.57 (2H, s), 6.96 (1H, d), 7.17 (2H, d),
7.41 (2H, d), 7.86 (1H, dd), 8.06 (1H, d); MS m/z (ES.sup.+) 368
(MH.sup.+). 46 (HCl salt) Prep 21 28 H Me SMe
.delta..sub.H9CD.sub.3OD, 400 MHz) 1.15 (3H, d), 2.52 (3H, s), 2.84
(2H, m), 3.00 (6H, s), 3.76 (1H, m), 4.56 (2H, s), 6.95 (1H, d),
7.16 (2H, d), 7.40 (2H, d), 7.89 (1H, dd), 8.06 (1H, d); MS m/z
(ES.sup.+) 412 (MH.sup.+). 47 (HCl salt) Prep 21 29 Me Me SMe
.delta..sub.H(CD.sub.3OD, 400 MHz) 2.51 (3H, s), 2.84 (3H, s), 2.97
(6H, s), 3.17 (2H, t), 3.68 (2H, t), 4.57 (2H, s), 6.97 (1H, d),
7.17 (2H, d), 7.40 (2H, d), 7.85 (1H, dd), 8.06 (1H, d); MS m/z
(ES.sup.+) 412 (MH.sup.+). 48 (HCl salt) Prep 21 30 H Me SMe
.delta..sub.H(CD.sub.3OD, 400 MHz) 2.51 (3H, s), 2.96 (6H, s), 3.06
(2H, t)(, 3.25 (3H, s), 3.39 (2H, t), 4.55 (2H, s), 6.95 (1H, d),
7.16 (2H, d), 7.40 (2H, d), 7.89 (1H, d), 8.06 (1H, d); MS m/z
(ES.sup.+) 412 (MH.sup.+). 49 (HCl salt) Prep 21 31 H Me SMe
.delta..sub.H(CD.sub.3OD, 400 MHz) 1.02 (3H, d), 2.51 (3H, s), 2.96
(6H, s), 3.30 (3H, m), 4.55 (2H, s), 6.94 (1H, d), 7.16 (2H, d),
7.40 (2H, d), 7.90 (1H, dd), 8.09 (1H, d); MS m/z (ES.sup.+) 412
(MH.sup.+). 50 Prep 21 Et H Me SMe .delta..sub.H(CD.sub.3OD, 400
MHz) (HCl salt) 1.08 (3H, t), 2.51 (3H, s), 2.91 (2H, q), 2.97 (3H,
s), 4.56 (2H, s), 6.95 (1H, d), 7.16 (2H, d), 7.40 (2H, d), 7.87
(1H, dd), 8.06 (1H, d); MS m/z (ES.sup.+) 382 (MH.sup.+). 51 (HCl
salt) Prep 21 32 H Me SMe .delta..sub.H(CD.sub.3OD, 400 MHz) 0.11
(2H, m), 0.44 (2H, m), 0.86 (1H, m), 2.51 (3H, s), 2.76 (2H, d),
2.96 (6H, s), 4.56 (2H, s), 6.94 (1H, d), 7.16 (2H, d), 7.40 (2H,
d), 7.88 (1H, dd), 8.06 (1H, d); MS m/z (ES.sup.+) 408 (MH.sup.+).
52 (HCl salt) Prep 21 33 H Me SMe .delta..sub.H(CD.sub.3OD, 400
MHz) 1.15-1.63 (6H, m), 1.81 (2H, m)(, 2.51 (3H, s), 2.96 (6H, s),
3.50 (2H, s), 4.55 (2H, s), 6.93 (1H, d), 7.15 (2H, d), 7.39 (2H,
d), 7.93 (1H, dd), 8.09 (1H, d); MS m/z (ES.sup.+) 452 (MH.sup.+).
53 Prep 21 34 H Me SMe .delta..sub.H(CDCl.sub.3, 400 MHz) 1.10 (3H,
d), 2.31 (6H, s), 2.50 (3H, s), 3.37 (2H, m), 3.49 (1H, m), 3.60
(2H, s), 4.78 (1H, br), 6.84 (1H, d), 6.94 (2H, d), 7.29 (2H, d),
7.70 (1H, dd), 8.05 (1H, s), MS m/z (TS.sup.+) 411 (MH.sup.+) 54
Prep 21 --CH.sub.2CH.sub.2CH.sub.2-- Me SMe
.delta..sub.H(CDCl.sub.3, 400 MHz) 2.11 (HCl salt) (2H, m), 2.51
(3H, s), 2.98 (6H, s), 3.58 (1H, m), 3.79 (3H, t), 4.60 (2H, s),
7.02 (1H, d), 7.18 (2H, d), 7.41 (2H, d), 7.88 (1H, d), 8.07 (1H,
s); MS m/z (T.sup.+) 393 (MH.sup.+) 55 Prep 21 35 H Me SMe
.delta..sub.H(CDCl.sub.3, 400 MHz) 2.32 (6H, s), 2.48 (3H, s), 3.30
(2H, s), 3.52 (2H, s), 3.68 (2H, s), 6.88 (1H, d), 7.03 (2H, d),
7.35 (2H, d), 7.72 (1H, d), 7.93 (1H, s); MS m/z (ES.sup.+) 410
(M.sup.+) 56 Prep 21 36 H Me SMe .delta..sub.H(CDCl.sub.3, 400 MHz)
1.15 (3H, d), 2.31 (6H, s), 2.49 (3H, s), 2.80 (1H, dd), 3.09 (1H,
d), 3.23 (1H, t), 3.59 (2H, s), 3.85 (1H, m), 5.16 (1H, br), 6.82
(1H, d), 6.95 (2H, d), 7.29 (2H, d), 7.66 (1H, d), 8.02 (1H, s); MS
m/z (ES.sup.+) 413 (MH.sup.+) 57 (HCl salt) Prep 21 37 H Me SMe
.delta..sub.H(CD.sub.3OD, 400 MHz) 1.66 (2H, m), 2.51 (3H, s), 2.97
(6H, m), 3.30 (1H, s), 3.57 (2H, t), 4.57 (2H, s), 6.95 (1H, d),
7.16 (2h, d), 7.39 (2H, d), 7.87 (1H, dd), 8.08 (1H, s); MS m/z
(ES.sup.+) 411 (MH.sup.+) 58 (HCl salt) Prep 21 38 H Me SMe
.delta..sub.H(CD.sub.3OD, 400 MHz) 2.51 (3H, s), 2.96 (6H, s), 3.00
(2H, t), 4.56 (2H, t), 4.97 (2H, s), 6.94 (1H, d), 7.16 (2H, d),
7.40 (2H, d), 7.88 (1H, dd), 8.09 1H, s); MS m/z (ES.sup.+) 411
(MH.sup.+) 59 Prep 21 Me Me Me SMe .delta..sub.H(CD.sub.3OD, 400
MHz) 2.51 (HCl salt) (3H, s), 2.72 (6H, s), 2.96 (6H, s), 4.57 (2H,
s), 6.99 (1H, d), 7.17 (2H, d), 7.40 (2H, d), 7.83 (1H, dd), 8.02
(1H, s); MS m/z (ES.sup.+) 381 (M.sup.+) 60 Prep 29 H H Me SEt
.delta..sub.H(d.sub.6-DMSO, 400 MHz) (HCl salt) 1.22 (3H, t), 2.78
(6H, s), 2.97 (2H, q), 4.42 (2H, s), 6.91 (1H, d), 7.17 (2H, d),
7.39 (2H, s), 7.42 (2H, d), 7.83 (1H, dd), 8.07 (1H, s); MS m/z
(ES.sup.+) 367 (MH.sup.+)
EXAMPLE 61
4-[4-Methoxy-3-(methylsulfanyl)phenoxy]-3-[(methylamino)methyl]-benzenesul-
fonamide
[0219] 39
[0220] Borane-tetrahydrofuran complex (1 M in THF, 10 mL, 10 mmol)
was added dropwise to the amide from preparation 32 (450 mg, 1.18
mmol). The mixture was then stirred at reflux for 4 hours. After
cooling to room temperature the reaction was quenched by the
addition of methanol (10 mL) and the mixture evaporated to a white
foam. This residue was treated with hydrochloric acid (6 M, 10 mL)
and the mixture heated to reflux once more for 1 hour. After
cooling to room temperature the mixture was neutralised to pH ca. 7
by treatment with excess sodium hydroxide (2 M) and then saturated
aqueous ammonium chloride. The mixture was then extracted with
ethyl acetate (3.times.50 mL), DCM (2.times.50 mL) and the combined
organics were dried (MgSO.sub.4) and evaporated to a colourless
oil. This oil was redissolved in ethyl acetate (20 mL) and treated
with 1 M hydrochloric acid in diethyl ether (2 mL, 2 mmol) to form
the hydrochoride salt which was collected by filtration and dried
(346 mg, 73%); .delta..sub.H (CD.sub.3OD, 400 MHz) 2.34 (3 H, s),
2.78 (3 H, s), 3.86 (3 H, s), 4.39 (2 H, s) 6.83 (1 H, d), 6.90 (1
H, m), 6.98 (2 H, m), 7.84 (1 H, dd), 8.01 (1 H, d); MS m/z
(ES.sup.+) 369 (MH.sup.+).
EXAMPLES 62-63
[0221] The following sulfonamides were prepared in an analogous
fashion to that in Example 61 starting from the appropriate
amide.
16 40 Starting Example Material (R.sup.3).sub.n Data 62 Prep 30
3-OMe (248 mg, 43%); .delta..sub.H(DMSO-D.sub.6, 400MHz)2.35(3H,
s), (HCl salt) 4-SMe 2.60(3H, s), 3.76(3H, s), 4.24(2H, s),
6.75(1H, dd), 6.84(1H, d), 6.90(1H, d), 7.19(1H, d), 7.31(2H, s),
7.77(1H, d), 8.00(1H, s), 9.10(2H, br); MSm/z(TS.sup.+)
369(MH.sup.+). 63 Prep 33 3-CF.sub.3 HCl salt:
.delta..sub.H(d.sub.6-DMSO, 400MHz)2.38(3H, s), 3.08(3H, (HCl salt)
4-SMe s), 4.50(2H, s), 6.87(1H, d), 6.97(2H, d), 7.11(2H, brs),
7.43(2H, d), 7.58(1H, d); MSm/z(ES.sup.+)407(MH.sup.+)
[0222] The sulfonamide of example 42 can also be prepared using
this method starting from the amide of preparation 31.
EXAMPLES 64-65
[0223] The following tertiary amine sulfonamides were prepared via
reductive methylation using the method described for Example 178
and the appropriate secondary amine as starting material.
17 41 Starting Example Material (R.sup.3).sub.n .sup.1H NMR Data 64
Example 62 3-OMe .delta..sub.H(CDCl.sub.3, 400MHz)2.27(6H, s),
2.40(3H, s), 3.55 4-SMe (2H, s), 3.82(3H, s), 6.53(2H, m), 6.84(1H,
d), 7.13 (1H, d), 7.70(1H, dd), 8.04(1H, d); MSm/z(ES.sup.+)383
(MH.sup.+). 65 Example 61 3-SMe .delta..sub.H(CD.sub.3OD,
400MHz)2.38(3H, s), 2.96(6H, s), 3.89 (HCI salt) 4-OMe (3H, s),
4.51(2H, s), 6.92(2H, m), 7.01(2H, m), 7.94 (1H, d), 8.05(1H, s);
MSm/z(TS.sup.+)383(MH.sup.+).
[0224] The product of example 28 can also be prepared by this
method from the secondary amine of example 42.
EXAMPLE 66
N-Acetyl-3-[(dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]-benzenesu-
lfonamide
[0225] 42
[0226] Triethylamine (399 .mu.L, 2.86 mmol) was added to a solution
of the sulfonamide from example 28 (500 mg, 1.3 mmol) in DCM (5 mL)
followed by acetyl chloride (102 .mu.L, 1 43 mmol). The mixture was
stirred at room temperature for 16 h and then the solvent was
removed in vacuo. The residue was purified by column chromatography
[SiO.sub.2, DCM 100% increasing polarity to 15% (1:7
NH.sub.4OH:MeOH) in DCM] to give a crystalline solid (438 mg, 86%);
.delta..sub.H (DMSO-D.sub.6, 400 MHz) 1.83 (3 H, s), 2.31 (6 H, s),
2.46 (3 H, s), 3.68 (2 H, s), 6.83 (1 H, d), 7.03 (2 H, d), 7.32 (2
H, d), 7.71 (1 H, d), 7.99 (1 H, s); MS m/z (ES.sup.+) 395
(MH.sup.+).
EXAMPLE 67
(E)-2-{3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl}-ethe-
nesulfonamide
[0227] 43
[0228] The bromide from Example 9 (2.0 g, 5.68 mmol),
vinylsulfonamide (1.22 g, 11.35 mmol), palladium acetate (64 mg,
0.28 mmol, 5 mol%), tri(o-tolyl)phosphine (173 mg, 0.57 mmol, 10
mol%), and triethylamine (1.98 mL, 14.19 mmol) were combined in
acetonitrile (50 mL) and heated at reflux under nitrogen for 20 h.
After cooling to room temperature the reaction mixture was
evaporated onto silica gel and then chromatographed [SiO.sub.2;
(EtOAc/ MeOH/ 880 NH.sub.3; 100:5:0.5)/ pentane; 3:1.fwdarw.1:0] to
afford the desired title compound as a yellow powder (1.26 g, 59%)
Free base: .delta..sub.H(CDCI.sub.3, 300 MHz) 2.28 (6 H, s), 2.49
(3 H, s), 3.52 (2 H, s), 6.80-6.95 (4 H, m), 7.25-7.31 (3 H, m),
7.48 (1 H, d), 7.68 (1 H, s); MS m/z (TS.sup.+) 379 (MH.sup.+).
EXAMPLES 68-70
[0229] The reaction described in Example 67 was repeated using the
appropriate alkene and aryl bromide components to provide the
following alkenes.
18 44 Starting Example material R.sup.5 R.sup.4 Data 68.sup.a
Example 9 45 H Free base: .delta..sub.H(CDCl.sub.3, 400MHz)2.30
(6H, s), 2.48(3H, s), 3.50(2H, s), 5.43 (2H, bs), 6.40(1H, d),
6.82(1H, d), 6.90 (2H, d), 7.27(2H, d), 7.34(1H, dd), 7.61 (1H, d),
7.69(1H, d); MSm/z(TS.sup.+)343 (MH.sup.+). 69.sup.a Example 13 H
46 Free base: .delta..sub.H(CDCl.sub.3, 300MHz)2.26 (6H, s),
2.48(3H, s), 3.49(2H, s), 5.49 (2H, bs), 6.32(1H, d), 6.88(2H, d),
700 (1H, s), 7.27(3H, m), 7.50(1H, d), 7.53 (1H, d);
MSm/z(TS.sup.+)343(MH+). 70 Example 13 H 47 Free base:
.delta..sub.H(CDCl.sub.3, 300MHz)2.26 (6H, s), 2.46(3H, s),
3.50(2H, s), 6.79 (1H, d), 6.88(2H, d), 6.94(1H, d), 7.25 (3H, m),
7.41(1H, d), 7.52(H, d); MS m/z(TS.sup.+)379(MH.sup.+).
.sup.aAcrylamide was used as the alkene coupling partner in these
examples.
EXAMPLE
2-{3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]-phenyl}ethanesu-
lfonamide
[0230] 48
[0231] The vinylsulfonamide from example 67 (1.26 g, 3.33 mmol) was
heated together with tosyl hydrazine (6.20 g, 33.3 mmol) in toluene
at reflux for 5 h. After cooling to rt the solvent was evaporated
and the residue partitioned between EtOAc (50 mL) and sat.
NaHCO.sub.3 (50 mL). The organic layer was separated, washed with
water (20 mL), brine (20 mL) and then dried (MgSO.sub.4) and
evaporated. The residue was purified by flash chromatography
[SiO.sub.2; (EtOAc/ MeOH/ 880 NH.sub.3; 100:5:0.5)/ pentane;
3:1.fwdarw.1:0] to afford the desired product as a cream powder
(1.055 g, 83%); Free base: .delta..sub.H(CD.sub.3OD, 400 MHz) 2.27
(6 H, s), 2.47 (3 H, s), 3.09-3.13 (2 H, m), 3.30-3.36 (2 H, m),
3.50 (2 H, m), 6.83 (1 H, d), 6.87 (2 H, d), 7.19 (1 H, d), 7.27 (2
H, d), 7.35 (1 H, s); MS m/z (TS.sup.+) 381 (MH.sup.+).
EXAMPLE 72
2-{4-[(Dimethylamino)methyl]-3-[4-(methylsulfanyl)phenoxy]phenyl}-ethanesu-
lfonamide
[0232] 49
[0233] The title sulfonamide was prepared in an analogous fashion
to that in Example 71 from the vinylsulfonamide of Example 70. Free
base: .delta..sub.H(CDCI.sub.3, 300 MHz) 2.25 (6 H, s), 2.48 (3 H,
s), 3.08 (2 H, m), 3.33 (2 H, m), 3.44 (2 H, m), 4.57 (2 H, brs),
6.73 (1 H, s), 6.86 (2 H, d), 6.98 (1 H, dd), 7.25 (2 H, d), 7.41
(1 H, d); MS m/z (TS.sup.+) 381 (MH.sup.+).
EXAMPLE 73
[0234]
3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenol
50
[0235] The methylether from example 14 (500 mg, 1.65 mmol) was
mixed with hydrogen bromide in acetic acid (30%, 3 mL) and aqueous
hydrogen bromide (48%, 200 microlitres), and the mixture heated at
reflux overnight under a nitrogen atmosphere. After cooling to room
temperature the mixture was evaporated under reduced pressure and
the residue partitioned between saturated aqueous sodium
bicarbonate (20 mL) and DCM (30 mL). The organic layer was
separated and the aqueous layer re-extracted with DCM (4.times.30
mL). The combined organic fractions were washed with brine, dried
(MgSO.sub.4) and evaporated to a dark oil. Purification by repeated
flash chromatography, first with [silica; DCM/ methanol 880 ammonia
(95:5:0.5)] and then [SiO.sub.2; DCM/ methanol/ 880 ammonia
(97:3:0.3)] gave partially purified material. This material was
dissolved in hydrochloric acid (2 M) and washed with diethyl ether
(3.times.5 mL). The aqueous layer was basified with sat.
NaHCO.sub.3(aq) (10 mL) and re-extracted with DCM (4.times.10 mL).
The organic fractions were combined and evaporated to a residue
which was further purified by flash chromatography [SiO.sub.2; DCM/
methanol/ 880 ammonia (95:5:0.5)]. This furnished the desired
phenol as a white solid (141 mg, 30%); .delta..sub.H (CDCI.sub.3,
400 MHz) 2.25 (6 H, s), 2.42 (3 H, s), 3.40 (2 H, s), 6.71 (1 H,
m), 6.79 (3 H, d), 6.89 (1 H, s), 7.25 (2 H, d); MS m/z (TS.sup.+)
290 (MH.sup.+)
EXAMPLE 74
3-[(Methylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenol
[0236] 51
[0237] The title compound was prepared from the methyl ether of
Example 25 by the method described for Example 73. .delta..sub.H
(CDCI.sub.3, 400 MHz) 2.35 (3 H, s), 2.43 (3 H, s), 3.59 (2 H, s),
6.70 (1 H, s), 6.80 (2 H, m), 6.83 (2 H, d), 7.25 (2 H, d); MS m/z
(TS.sup.+) 276 (MH.sup.+)
EXAMPLE 75
3-(3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl0propanami-
de
[0238] 52
[0239] THF (20 mL) was saturated with NH.sub.3 and cooled to
-60.degree. C. The hydrazide from preparation 68 (756 mg, 1.47
mmol) was added followed by lead tetraacetate (1.30 g, 2.94 mmol)
in DCM (15 mL) dropwise. The reaction was stirred at -60 .degree. C
under a nitrogen atmosphere for 3 hours, then allowed to warm to
room temperature overnight. The solvent was removed by evaporation
giving an orange residue which was diluted with aqueous sodium
hydroxide (2 M) (50 mL) and extracted with ethyl acetate
(2.times.50 mL). The combined organic layers were washed with water
(20 mL), brine (30 mL), dried (MgSO.sub.4) and evaporated to an
orange oil. Purifcation by HPLC [phenomonex Luna C.sub.8
150.times.21.2 mm, 5 .mu.M; 0.1% aqueous diethylamine/ methanol
(gradient)] led to an oil which was partitioned between sodium
hydroxide (1 M) and diethyl ether (10 mL). The organic layer was
separated, washed with water (10 mL), dried (MgSO.sub.4) and
evaporated to a clear oil of the title compound which solidified
after drying under vacuum (264 mg, 52%); Free base: 67
.sub.H(CDCI.sub.3, 400 MHz) 2.25 (6 H, s), 2.48 (3 H, s), 2.54 (2
H, t), 2.95 (2 H, t), 3.42 (2 H, s), 5.39 (2 H, brs), 6.81 (1 H,
d), 6.85 (2 H, d), 7.07 (1 H, d), 7.25 (2 H, d), 7.33 (1 H, s); MS
m/z (TS.sup.+) 345 (MH.sup.+)
EXAMPLE 76
3-{4-[(Dimethylamino)methyl]-3-[4-(methylsulfanyl)phenoxy]phenyl}propanami-
de
[0240] The title amide was prepared from the hydrazide of
Preparation 69 using the method described in Example 75. 53
[0241] Free base: .delta..sub.H(CDCI.sub.3, 400 MHz) 2.23 (6 H, s),
2.48 (5 H, m), 2.90 (2 H, t), 3.40 (2 H, s), 5.35 (2 H, brs), 6.75
(1 H, s), 6.85 (2 H, d), 6.98 (1 H, d), 7.25 (2 H, d), 7.38 (1 H,
d); MS m/z (TS.sup.+) 345 (MH.sup.+) EXAMPLE 77
2-Bromo-5-[(methylamino)methyl]-4-[4-(trifluoromethoxy)phenoxy]-benzenesul-
fonamide
[0242] 54
[0243] (i) Formation of the trifluoroacetamide:
N-{4-bromo-2-[4-(trifluoro-
methoxy)phenoxy]benzyl}-2,2,2-trifluoro-N-methylacetamide
[0244] The bromide derivative from example 24 (1.31 g, 3.2 mmol)
was dissolved in DCM (12 mL), treated with triethylamine (1.77 mL,
13.9 mol) and the solution cooled to 0.degree. C.
[0245] Trifluoroacetic anhydride (897 .mu.L, 6.3 mmol) was added
dropwise over 5 minutes and stirring was continued for a further 30
minutes. The reaction was quenched by the addition of water (20 mL)
and the organic layer was separated. The aqueous layer was
re-extracted with DCM (20 mL) and the combined organic fractions
dried (MgSO.sub.4) and evaporated to a clear oil:
.delta..sub.H(CDCI.sub.3, 400 MHz, 2 rotomers visible) 3.00 [3 H, s
(minor rotomer)], 3.17 (3 H, s), 4.66 (2 H, s), 4.69 [2 H, s(minor
rotomer)]. 6.97-7.02 (3 H, m), 7.22-7.27 (4 H, m); MS m/z
(TS.sup.+) 489, 491 (MNH.sub.4.sup.+).
[0246] (ii) Synthesis of sulfonamide:
N-{5-(aminosulfonyl)-4-bromo-2-[4-(t-
rifluoromethoxy)phenoxy]benzyl}-2,2,2-trifluoro-N-methylacetamide
[0247] The trifluoroacetamide from stage (i) (used without further
purification) was dissolved in TFA (6 mL) and chlorosulfonic acid
was added (2.1 mL, 31.7 mmol). The mixture was 20 stirred overnight
at room temperature and then quenched by pouring cautiously onto
ice-water. A white solid precipitated and was collected by
filtration and then dissolved in DCM, dried (MgSO.sub.4), filtered
and evaporated to a yellow oil. The oil was treated with saturated
NH.sub.3 in ethanol (30 mL) and after 30 minutes, the solvents were
evaporated. Purification of the residue by flash chromatography
[SiO.sub.2; DCM, MeOH, 880 NH.sub.3 (93:7:1)] afforded the desired
sulfonamide as a white solid (825 mg, 47%);
.delta..sub.H(CDCI.sub.3, 400 MHz, 2 rotomers visible) 3.04 (3 H,
s, minor rotomer), 3.10 (3 H, s), 4.72 (2 H, s), 4.75 (2 H, s,
minor rotomer), 5.15 (2 H, brs), 7.04-7.09 (3 H, m), 7.24-7.35 (2
H, m), 8.00 (1 H, s, minor rotomer), 8.09 (1 H, s); MS m/z
(TS.sup.+) 568, 570 (MNH.sub.4.sup.+).
[0248] (iii) Hydrolysis of trifluoroacetamide group:
2-bromo-5-[(methylamino)methyll-4-[4-(trifluoromethoxy)phenoxy]benzenesul-
fonamide
[0249] The sulfonamide from stage (ii) was dissolved in ethanol (10
mL) and treated with 1 M LiOH.sub.(aq) (20 mL). The mixture was
stirred for 10 minutes before being evaporated to remove 10 most of
the ethanol. The aqueous mixture resulting was extracted with
diethyl ether (2.times.50 mL) and the combined extracts washed with
brine (100 mL), dried (MgSO.sub.4) and evaporated to a white solid
(550 mg, 81%); .delta..sub.H(CDCI.sub.3, 400 MHz) 2.46 (3 H, s),
3.84 (3 H, s), 7.05 (2 H, d), 7.06 (1 H, s), 7.27 (2 H, d), 8.20 (1
H, s); MS mlz (TS.sup.+) 455,457 (MH.sup.+).
EXAMPLE 78
5-[(Methylamino)methyl]-2-(methylsulfanyl)-4-[4-(trifluoromethoxy)phenoxy]-
-benzenesulfonamide
[0250] 55
[0251] The sulfonamide from example 77 (510 mg, 1.1 mmol) was
dissolved in DMSO (3 mL) and treated with palladium
tetrakis(triphenylphosphine) (129 mg, 0.11 mmol) and sodium
methanethiolate (157 mg, 2.2 mmol). The mixture then was heated at
100.degree. C. under a nitrogen atmosphere for 18 h. After cooling
to room temperature the mixture was partitioned between water and
diethyl ether (50 mL each). The ether layer was separated and the
organic layer re-extracted with diethyl ether (2.times.25 mL). The
combined organic fractions were dried (MgSO.sub.4) and evaporated
to an orange oil. Purification by flash chromatography [SiO.sub.2;
DCM/ MeOH/ 880 NH.sub.3 (93:7:1)] gave a white solid (286 mg, ca
60%) which was shown by H-NMR to be a 60:40 mixture of desired
product: starting bromide. A portion of this sample was further
purified by HPLC [Magellen C18 15*21.12 cm column, 0.2%
diethylamine.sub.(aq)/ acetonitrile (50:50), flow rate 20 mL/ min]
to afford the desired title compound (retention time 8.2 min) as a
white solid (22.1 mg); .delta..sub.H(CDCI.sub.3, 400 MHz) 2.32 (3
H, s), 2.37 (3 H, s), 3.75 (2 H, s), 6.83 (1 H, s), 7.12 (2 H, d),
7.32 (2 H, d), 8.00 (1 H, s); MS m/z (TS.sup.+) 423 (MH.sup.+).
EXAMPLES 79-80
2-bromo-5-[(dimethylamino)methyl]-4-[4-(trifluoromethoxy)phenoxy]-benzenes-
ulfonamide (Example 79) and
5-[(dimethylamino)methyl]-2-(methylsulfanyl)-4-[4-(trifluoromethoxy)phenox-
y]-benzenesulfonamide (Example 80)
[0252] 56
[0253] The mixture of bromo- and methylsulfanyl- sulfonamides
obtained from the reaction of Example 78 prior to the HPLC
purification (136 mg, ca. 0.3 mmol) was dissolved in DCM (2 mL) and
treated with formaldehyde (37% aqueous) (80 .mu.L, 3 equivs). The
reaction mixture was stirred for 30 minutes before the addition of
sodium tri(acteoxy)borohydride (273 mg, 1.3 mmol). After stirring
for a further 1 hour, the mixture was evaporated, quenched by the
addition of hydrochloric acid (2 M) and the pH made slightly basic
by the addition of aqueous sodium hydroxide (2 M). The mixture was
extracted with ether (2.times.30 mL), the combined organic
fractions were dried (MgSO.sub.4) and evaporated to a colourless
oil. Purification by flash chromatography [silica; 97:3:0.3 (DCM/
methanol/ 880 ammonia)] afforded a white foam, which upon
dissolution in diethyl ether and dilution with pentane formed a
white powder. This material was shown by .sup.1H NMR to be a 50:50
mixture of Example 79 and 80. This sample was further purified by
HPLC [Magellen C18 15*21.12 cm column, 0.2% diethylamine.sub.(aq)/
acetonitrile (50:50), flow rate 20 mL/min] to afford Example 79
(retention time: 12.02 min, 15 mg], and Example 80 (retention time:
12.56 min, 25.6 mg):
[0254] Example 79: 15 mg, free base: .delta..sub.H(CDCI.sub.3, 400
MHz) 2.26 (6 H, s), 3.56 (2 H, s), 7.08 (1 H, s), 7.13 (1 H, d),
7.33 (1 H, d), 8.16 (1 H, s); MS m/z (TS.sup.+) 469, 471
(MH.sup.+).
[0255] Example 80: 25.6 mg, hydrochloride salt:
.delta..sub.H(CD.sub.3OD, 400 MHz) 2.30 (3 H, s), 2.88 (6 H, s),
4.40 (2 H, brs), 6.80 (1 H, s), 7.28 (2 H, d), 7.40 (2 H, d), 8.14
(1 H, d); MS m/z (TS.sup.+) 437 (MH.sup.+).
EXAMPLE 81
3-[(Methylamino)methyl]-4-[4-(trifluoromethoxy)phenoxy]benzonitrile
[0256] 57
[0257] The product of Example 17 (2.46 g, 5.8 mmol) was dissolved
in DMF (30 mL) together with palladium tetrakis(triphenylphosphine)
(0.538 g, 0.47 mmol) and zinc(II) cyanide (478 mg, 4.1 mmol). The
reaction mixture was stirred and heated at 100.degree. C. for 12 h.
After cooling to room temperature the reaction mixture was poured
into water and extracted three times with ethyl acetate. The
combined organic extracts were dried (MgSO.sub.4) and evaporated to
a brown oil. The residue was purified by flash chromatography
[SiO.sub.2; DCM/ methanol/880 ammonia (95:5:0.5-90:10:1)]. The
resulting material was recolumned [SiO.sub.2; ethyl acetate/
methanol/ 880 ammonia (95:5:0.5)] to leave an off white solid. The
material was further purified by trituration with ethyl
acetate/diethyl ether followed by drying under vacuum to give the
desired nitrile compound as an off white solid (1.2 g, 64%);
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.67 (3 H, s), 4.24 (2 H, s),
6.77 (1 H, d), 7.32 (4 H, m), 7.58 (1 H, d), 8.02 (1 H, s); MS m/z
(TS.sup.+) 323 (MH.sup.+).
EXAMPLES 82-86
[0258] A series of nitrites was prepared from the requisite aryl
halides (iodides or bromides) by the procedure described for the
preparation of Example 81.
19 58 Starting Example Material R.sup.5 R.sup.4 R.sup.3 Data 82
Example H NC-- --CF.sub.3 .delta..sub.H(CDCl.sub.3, 400 MHz) 12
2.25 (6H, s), 3.48 (2H, s), 6.99 (2H, d), 7.17 (1H, s), 7.48 (1H,
d), 7.61 (2H, d), 7.68 (1H, d); MS m/z (TS.sup.+) 321 (MH.sup.+).
83 Example NC-- H --CF.sub.3 .delta..sub.H(CDCl.sub.3, 300 MHz) 18
2.28 (6H, s), 3.50 (2H s), 6.91 (1H, d), 7.05 (2H, d), 7.51 (1H,
d), 7.62 (2H, d), 7.87 (1H, d); MS m/z (TS.sup.+) 321 (MH.sup.+).
84 Example NC-- H --OCF.sub.3 .delta..sub.H(CDCl.sub.3, 400 MHz) 16
2.30 (6H, s), 3.53 (2H, s), 6.83 (1H, d), 7.00 (2H, m); 7.23 (2H,
m), 7.47 (1H, m), 7.83 (1H, s); MS m/z (TS.sup.+) 337 (MH.sup.+) 85
Example NC-- H --SMe .delta..sub.H(CDCl.sub.3, 400 MHz) 9 2.30 (6H,
s), 2.50 (3H, s), 3.57 (2H, s), 6.80 (1H, d), 6.95 (2H, d), 7.30
(2H, d), 7.45 (1H, dd), 7.82 (1H, d); MS m/z (TS.sup.+) 299
(MH.sup.+) 86 Example H NC-- --OCF.sub.3 .delta..sub.H(CDCl.sub.3,
300 MHz) 8 2.24 (6H, s), 3.50 (2H, s), 6.93 (2H, d), 7.20 (2H, d),
7.37-7.48 (2H, m), 7.63 (1H, d); MS m/z (TS.sup.+) 337
(MH.sup.+)
EXAMPLE 87
3-[(Methylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzonitrile
[0259] 59
[0260] The title nitrile was prepared from the bromide of example
23 according to the eocedure described for example 81;
.delta..sub.H(DMSO-D.sub.6, 300 MHz) 2.47 (3 H, s), 2.62 (3 H, s),
4.25 (2 H, s), 6.81 (1 H, d), 7.18 (2 H, d), 7.40 (2 H, d), 7.81 (1
H, dd), 8.06 (1 H, d), 9.03 (2 H, br); MS m/z (TS.sup.+) 285
(MH.sup.+).
EXAMPLE 88
{3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl~acetonitril-
e
[0261] 60
[0262] A mixture of the bromide of Example 9 (1.5 g, 4.26 mmol),
tributyl(cyanomethyl)stannane [prepared according to M. Kosugi, M.
Ishiguro, Y. Negishi, H. Sano, T. Migita, Chem. Lett., 1984,
1511-1512] (2.1 g, 6.36 mmol), tri-o-tolylphosphine (78 mg, 0.26
mmol), bis(acetonitrile)dichloropalladium(II) (33 mg, 0.13 mmol)
and m-xylene (20 mL) was stirred at 120.degree. C. under nitrogen
for 16 h. After cooling to room temperature the solvent was removed
in vacuo and the residue was purified by flash chromatography
[SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3 (97:3:0.5)] to give the desired
compound (895 mg, 67%) as a yellow oil; .delta..sub.H(CDCI.sub.3,
400 MHz) 2.27 (6 H, s), 2.47 (3 H, s), 3.46 (2 H, s), 3.74 (2 H,
s), 6.87 (3 H, m), 7.18 (1 H, d), 7.25 (2 H, d), 7.45 (1 H, s); MS
m/z (TS.sup.+) 313.
EXAMPLE 89
{3-[(Dimethylamino)methyl]-4-[4-(trifluoromethoxy)phenoxy]phenyl}aceto
nitrile
[0263] Step 1. Preparation of intermediate cyanoester 61
[0264] A mixture of the iodide compound of example 16 (1.03 g, 2.37
mmol), CuBr (1.70 g, 11.8 mmol), a-cyanoethyl acetate (1.337 g,
11.83 mmol) and potassium carbonate (3.29 g, 23.7 mmol) in DMSO (30
mL) was heated at 120.degree. C. under nitrogen for 2 h. After
cooling to room temperature the mixture was partitioned between
ether and saturated aqueous ammonium chloride. The organic layer
was washed with brine, dried (MgSO.sub.4) and concentrated in
vacuo. The residue was purified by flash chromatography [SiO.sub.2;
DCM/ MeOH (98:2)] to give the desired intermediate cyanoester (410
mg, 41%); .delta..sub.H(CDCI.sub.3, 400 MHz) 1.27 (3 H, t), 2.22 (6
H, s), 3.46 (2 H, s), 4.23 (2 H, q), 4.64 (1 H, br), 6.89 (1 H, d),
6.92 (2 H, d), 7.18 (2 H, d), 7.33 (1 H, d), 7.60 (1 H, s); MS m/z
(TS.sup.+) 423 (MH.sup.+).
[0265] Step 2. Ester hydrolysis/ decarboxylation to provide the
desired nitrile compound
{3-[(dimethylamino)methyl]-4-[4-(trifluoromethoxy)phenox-
y]phenyllacetonitrile
[0266] Sodium hydroxide (39 mg, 0.97 mmol) was added to a solution
of the intermediate cyanoester (410 mg, 0.97 mmol) in dioxane (40
mL) and the mixture was heated at reflux for 2 h. After cooling to
room temperature the reaction mixture was partitioned between ether
and water. The organic layer was washed with brine, dried
(MgSO.sub.4) and concentrated in vacuo. The residue was purified by
flash chromatography [SiO.sub.2; DCM/ MeOH (97:3)] to give the
desired nitrile compound (141 mg, 41%); .delta..sub.H(CDCI.sub.3,
400 MHz) 2.25 (6 H, s), 3.43 (2 H, s), 3.75 (2 H, s), 6.85-6.97 (3
H, m), 7.13-7.24 (3 H, m), 7.46 (1 H, s); MS m/z (TS.sup.+) 351
(MH.sup.+).
EXAMPLE 90
4-[(Dimethylamino)methyl]-3-[4-(trifluoromethyl)phenoxy]benzamide
[0267] 62
[0268] The nitrile compound of Example 82 (300 mg, 0.94 mmol) was
dissolved in DMSO (2 mL) and potassium carbonate (43 mg, 0.3 mmol)
was added followed by H.sub.2O.sub.2 (30%, 0.2 mL). The reaction
was stirred at room temperature for 30 min before being diluted
with water (5 mL) and being extracted with diethyl ether
(2.times.10 mL). The combined ether layers were dried with
MgSO.sub.4 and evaporated to an oil. This residue was purified by
flash chromatography [SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3 (93:7:1)]
to afford the desired amide compound as a colourless solid (258 mg,
78%); .delta..sub.H(CDCI.sub.3, 300 MHz) 2.24 (6 H, s), 3.45 (2 H,
s), 5.60-6.00 (2 H, 2.times.brs), 6.98 (2 H, d), 7.44 (1 H, s),
7.54-7.64 (4 H, m); MS m/z (TS.sup.+) 339 (MH.sup.+).
EXAMPLE 91
3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzamide
[0269] 63
[0270] The nitrile compound of Example 85 (60 mg, 0.2 mmol) was
dissolved in tert-butanol, potassium hydroxide (45 mg, 0.8 mmol)
was added and the mixture refluxed under nitrogen for 1 h. The
mixture was cooled and diluted with water and EtOAc. The organic
layer was separated, washed with brine, dried (MgSO.sub.4) and
evaporated to a pale yellow gum. Purification by flash
chromatography [SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3 (95:5:1)]
afforded the desired amide as a white powder (39 mg, 61%); .sup.8H
(CDCI.sub.3, 400 MHz) 2.30 (6 H, s), 2.50 (3 H, s), 3.57 (2 H, s),
5.60 (1 H, br), 6.00 (1 H, br), 6.86 (1 H, d), 6.92 (2 H, d), 7.27
(2 H, d), 7.73 (1 H, dd), 7.93 (1 H, s); MS m/z (TS.sup.+) 317
(MH.sup.+).
EXAMPLE 92
2-(3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl}acetamide
[0271] 64
[0272] A mixture of the nitrile compound of Example 88 (100 mg,
0.32 mmol) and polyphosphoric acid (750 mg) was heated at
110.degree. C. under nitrogen for 75 min. After cooling to room
temperature sodium hydroxide (2 M) was added and the resulting
mixture was extracted with ethyl acetate (3 times). The combined
organic extracts were dried (MgSO.sub.4) and concentrated in vacuo.
The residue was purified by flash chromatography [DCM/ MeOH/880
NH.sub.3 (93:7:1.fwdarw.90:10:1)] to give the desired primary amide
compound (58 mg, 55%); .sup.6 H (CDCI.sub.3, 400 MHz) 2.25 (6 H,
s), 2.45 (3 H, s), 3.45 (2 H, s), 3.55 (2 H, s), 5.63 (1 H, br),
5.76 (1 H, br), 6.87 (3 H, m), 7.15 (1 H, d), 7.25 (2 H, d), 7.40
(1 H, s); MS m/z (TS.sup.+) 331 (MH.sup.+).
EXAMPLES 93-97
[0273] A series of primary amides was prepared by application of
the appropriate hydrolysis conditions on the requisite nitrites
according to the reactions described in Examples 90, 91 or
20 65 Hydrolysis Starting Example procedure Material R.sup.5
R.sup.3 R.sup.1 Data 93 (Ex. 90) Example 81 66 OCF.sub.3 H
.delta..sub.H (CDCl.sub.3, 400 MHz) 2.45 (3H, s), 3.82 (2H, s),
6.18 (1H, br), 6.46 (1H, br), 6.83 (1H, d), 6.99 (2H, m), 7.20 (2H,
m), 7.72 (1H, dd), 7.93 (1H, d); MS m/z (TS.sup.+) 341 (MH.sup.+).
94 (Ex. 90) Example 84 67 OCF.sub.3 Me .delta..sub.H (CDCl.sub.3,
300 MHz) 2.28 (6H, s) 3.53 (2H, S), 5.70 (1H, br), 6.09 (1H, br)
6.91 (1H, d), 6.98 (2H, m), 7.20 (2H, m), 7.78 (1H, dd), 7.96 (1H,
d); MS m/z (TS.sup.+) 355 (MH.sup.+). 95 (Ex. 90) Example 83 68
CF.sub.3 Me .delta..sub.H (CDCl.sub.3, 400 MHz) 2.27 (6H, s), 3.50
(2H, s), 6.96 (1H, d), 7.00 (2H, d), 7.58 (2H, d), 7.78 (1H, dd),
8.00 (1H, s); MS m/z (TS.sup.+) 339 (MH.sup.+). 96 (Ex. 90) Example
89 69 OCF.sub.3 Me .delta..sub.H (CDCl.sub.3, 400 MHz) 2.28 (6H,
s), 3.46 (2H, s), 3.58 (2H, s), 5.51 (2H, brs), 6.88 (1H, d), 6.92
(2H, d), 7.12-7.20 (3H, m), 7.42 (1H, s); MS m/z (TS.sup.+) 369
(MH.sup.+). 97 (Ex. 91) Example 87 70 SMe H .delta..sub.H
(DMSO-D.sub.6, 300 MHz) 2.30 (3H, s), 2.47 (3H, s), 3.72 (2H, s),
6.79 (1H, d), 6.96 (2H, d), 7.28 (3H, m), 7.74 (1H, d), 7.86 (1H,
br), 8.00 (1H, s); MS m/z (TS.sup.+) 303 (MH.sup.+)
EXAMPLE 98
4-[(Dimethylamino)methyl]-3-[4-(trifluoromethoxy)phenoxy]benzamide
[0274] 71
[0275] A mixture of the bromide compound of Example 8 (500 mg, 1.28
mmol), paladium (II) chloride (7 mg, 0.04 mmol), triphenylphosphine
(20 mg, 0.08 mmol), hexamethyidisilazane (1.08 mL, 5.12 mmol) and
DMPU (5 mL) was heated at 120.degree. C. under carbon monoxide (100
psi pressure) for 16 h. At this point TLC analysis indicated no
change, so palladium tetrakis(triphenylphosphine) (200 mg, 0.17
mmol) and sodamide (500 mg, 12.8 mmol) were added and the reaction
was heated at 120.degree. C. under carbon monoxide (100 psi
pressure) for a further 16 h. Methanol was added and the mixture
was concentrated in vacuo to give a black oil. This was partitioned
between ethyl acetate and sodium hydroxide solution (1 M), the
organic layer was washed with water (3 times) and brine, dried
(MgSO.sub.4) and concentrated in vacuo. The residue was purified by
repeated flash chromatography on silica to give the desired primary
amide compound (33 mg, 7%) as a pale yellow powder;
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.25 (6 H, s), 3.50 (2 H, s),
5.50 (1 H, br), 5.90 (1 H, br), 6.95 (2 H, d), 7.17 (2 H, d), 7.39
(1 H, s), 7.55 (1 H, d), 7.58 (1 H, d); MS m/z (TS.sup.+) 355
(MH.sup.+).
EXAMPLES 99-100
4-[(dimethylamino)methyl]-N-methyl-3-[4-(trifluoromethoxy)phenoxy]benzamid-
e (Example 99) and
4-[(dimethylamino)methyl]-N,N-dimethyl-3-[4-(trifluoromethoxy)phenoxy]-ben-
zamide (Example 100)
[0276] 72
[0277] The bromide compound of Example 8 (500 mg, 1.28 mmol) was
dissolved in DMF (10 mL) together with monomethylamine (2 M in THF,
6.4 mL, 12.8 mmol), triethylamine (446 .mu.L, 3.2 mmol), and
palladium tetrakis(triphenylphosphine) (75 mg, 0.06 mmol). The
reaction mixture was placed in a bomb, carbon monoxide was
introduced to a pressure of 50 psi, and the mixture heated at
100.degree. C. overnight. The pressure was released and further
palladium catalyst added (100 mg, 0.09 mmol) together with extra
monomethylamine in THF (3 mL, 6 mmol). Carbon monoxide was then
introduced to a pressure of 100 psi and the mixture heated again
overnight at 120.degree. C. After releasing the pressure a further
load of palladium catalyst was added (130 mg, 0.1 mmol) and the
mixture heated at 120.degree. C. under 100 psi of carbon monoxide
for a further 4 h. After this time, in order to drive the reaction
to completion (as judged by TLC analysis) further batches of
palladium catalyst (200 mg, 0.17 mmol) and methylamine in THF (6.4
mL, 12.8 mmol) were added. The reaction mixture was then heated at
120.degree. C. under 100 psi of carbon monoxide for a further 60 h.
After releasing the pressure for the final time the solvents were
evaporated under reduced pressure to leave an orange oil. The oil
was basified with sodium hydroxide (1 M) and extracted with ethyl
acetate. The organic extract was washed with water (x3), brine,
dried over MgSO.sub.4 and then evaporated to an orange oil.
Purification by repeated flash chromatography [SiO.sub.2; MeOH
(2.5%-5%) in DCM containing 0.5% 880 NH.sub.3] to afford the
methylamide compound as a colourless oil which slowly crystallised
upon standing (105 mg, 23%) and the corresponding dimethylamide
material as a colourless oil (130 mg, 27%).
EXAMPLE 99
[0278] .delta..sub.H(CDCI.sub.3, 400 MHz) 2.26 (6 H, s), 2.98 (3 H,
d), 3.50 (2 H, s), 6.00 (1 H, br), 6.95 (2 H, d), 7.17 (2 H, d),
7.33 (1 H, s), 7.50 (1 H, d), 7.58 (1 H, d); MS m/z (TS.sup.+) 369
(MH.sup.+).
EXAMPLE 100
[0279] .delta..sub.H(CDCI.sub.3, 400 MHz) 2.27 (6 H, s), 2.95 (3 H,
br), 3.05 (3 H, br), 3.47 (2 H, s), 6.95 (2 H, d), 6.96 (1 H, s),
7.15 (2 H, d), 7.20 (1 H, d), 7.50 (1 H, d); MS m/z (TS.sup.+) 383
(MH.sup.+).
EXAMPLES 101-106
[0280] A series of mono- and di-methyl amines were prepared in an
analogous fashion to the reactions described for the preparation of
Examples 99 and 100, starting from the requisite bromides or
iodides. In each case the reaction was performed at such a
temperature and pressure, and with sufficient catalyst to ensure
complete consumption of starting materials.
21 73 Starting Example Material R.sup.5 R.sup.4 R.sup.3 Data 101
Example 7 74 H --OCF.sub.3 .delta..sub.H (CDCl.sub.3, 400 MHz) 2.27
(6H, s), 3.01 (3H, d), 3.51 (2H, s), 6.19 (1H, br), 6.89 (1H, d),
6.97 (2H, m), 7.18 (2H, m), 7.70 (1H, dd), 7.86 (1H, d); MS m/z
(TS.sup.+) 369 (MH.sup.+) 102 Example 7 75 H --OCF.sub.3
.delta..sub.H (CDCl.sub.3, 400 MHz) 2.24 (6H, s), 3.00 (3H, br),
3.07 (3H, br) 3.48 (2H, s), 6.89 (1H, d), 6.95 (2H, m) 7.17 (2H,
m), 7.34 (1H, dd), 7.58 (1H, d); MS m/z (TS.sup.+) 383 (MH.sup.+)
103 (HCl salt) Example 3 76 H --CF.sub.3 .delta..sub.H (CDCl.sub.3,
400 MHz) 2.82 (6H, s), 3.14 (6H, s), 4.30 (2H, s), 6.94 (1H, d),
7.16 (2H, d), 7.57 (1H, d), 7.65 (2H, d), 8.00 (1H, s), 13.00 (1H,
s); MS m/z (TS.sup.+) 367 (MH.sup.+). 104 Example 3 77 H --CF.sub.3
.delta..sub.H (CDCl.sub.3, 300 MHz) 2.11 (6H, s), 2.99 (3H, d),
3.43 (2H, s), 6.26 (1H, brs), 6.92-7.00 (3H, m), 7.57 (2H, d), 7.74
(1H, dd), 7.86 (1H, d); MS m/z (TS.sup.+) 353 (MH.sup.+). 105
Example 12 H 78 --CF.sub.3 .delta..sub.H (CDCl.sub.3, 300 MHz) 2.14
(6H, s), 2.84 (2H, d), 3.37 (2H, s), 6.65 (1H, brs), 6.89 (2H, d),
7.37 (1H, s), 7.50-7.44 (3H, m), 7.59 (1H, d); MS m/z (TS.sup.+)
353 (MH.sup.+). 106 Example 12 H 79 --CF.sub.3 .delta..sub.H
(CDCl.sub.3, 400 MHz) 2.14 (6H, s), 2.96 (3H, brs), 3.06 (3H, brs),
3.43 (2H, s), 6.97-7.00 (3H, m), 7.26 (1H, m), 7.56 (3H, d); MS m/z
(TS.sup.+) 367 (MH.sup.+).
EXAMPLE 107
N-{5-Amino-2-[4-(trifluoromethyl)phenoxy]benzyl}-N,N-dimethylamine
[0281] 80
[0282] A mixture of the nitro compound of Example 21 (400 mg, 1.18
mmol), iron powder (591 mg, 10.6 mmol) and calcium chloride (65 mg,
0.59 mmol) in 85% aqueous ethanol (15 mL) was heated at reflux for
18 h. The reaction mixture was cooled to room temperature and
filtered through Celite.RTM., washing thoroughly with ethanol and
then ethyl acetate. The solvent was removed in vacuo and the
residue was purified by flash chromatography [SiO.sub.2; DCM/ MeOH/
880 NH.sub.3 (95:5:0.5)] to give the desired aniline compound (299
mg, 82%) as a beige solid; .delta..sub.H(CDCI.sub.3, 300 MHz) 2.20
(6 H, s), 3.27 (2 H, s), 3.63 (2 H, brs), 6.60 (1 H, dd), 6.80 (1
H, d), 6.87 (1 H, d), 6.90 (2 H, d), 7.50 (2 H, d); MS m/z
(TS.sup.+) 310 (MH.sup.+).
EXAMPLES 108-109
[0283] A range of anilines was prepared from the requisite nitro
compounds using the conditions described in Example 107. Data for
these compounds are presented below.
22 81 Starting Example Material R.sup.3 Data 108 108 Example 22
--OCF.sub.3 .delta..sub.H (CDCl.sub.3, 400 MHz) 2.22 (6H, s), 3.30
(2H, s), 3.62 (2H, br), 6.59 (1H, dd), 6.78 (1H, d), 6.83 (3H, m),
7.10 (2H, d); MS m/z (TS.sup.+) 327 (MH.sup.+) 109 Example 19 --SMe
.delta..sub.H (CDCl.sub.3, 400 MHz) 2.26 (6H, s), 2.44 (3H, s),
3.36 (2H, s), 3.61 (2H, br), 6.58 (1H, dd), 6.79 (3H, m), 6.87 (1H,
d), 7.22 (2H, m); MS m/z (TS.sup.+) 289 (MH.sup.+)
EXAMPLE 110
N-{5-(Aminomethyl)-2-[4-(trifluoromethoxy)phenoxy]benzyl}-N,N-dimethylamin-
e
[0284] 82
[0285] A solution of lithium aluminium hydride in THF (1 M, 7.1 mL,
7.1 mmol) was added dropwise to a solution of the nitrile compound
of Example 84 (2.40 g, 7.14 mmol) in THF (50 mL) at room
temperature under nitrogen and stirred overnight. A further
addition of lithium 10 aluminium hydride in THF was made (1 M, 7.1
mL, 7.1 mmol) and the mixture was heated at reflux for 1 h, before
being cooled to room temperature and quenched cautiously with
water. The mixture was dried (MgSO.sub.4), filtered (washing
thoroughly with THF) and the filtrate and washings concentrated in
vacuo. Purification of the residue by flash chromatography
[SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3 (90:10:1.fwdarw.84:14:2)] gave
the desired amine compound (1.95 g, 80%) as a reddish oil;
.delta..sub.H(CDCI.sub.3, 400 MHz) 1.73, (2 H, br), 2.26 (6 H, s),
3.43 (2 H, s), 3.87 (2 H, s), 6.90 (3 H, m), 7.13 (2 H, d), 7.20 (1
H, dd), 7.43 (1 H, d); MS m/z (TS.sup.+) 341 (MH.sup.+).
EXAMPLES 111-113
[0286] The general reaction of example 110 was repeated to produce
a series of amines from the requisite nitrile precursors.
23 83 Starting Example Material R.sup.5 R.sup.4 R.sup.3 Data 111
Example 85 84 H --SMe .delta..sub.H (CDCl.sub.3, 400 MHz) 2.24 (6H,
s), 2.45 (3H, s), 3.43 (2H, s), 3.85 (2H, s), 6.86 (3H, m), 7.17
(1H, dd), 7.23 (2H, m), 7.41 (1H, d); MS m/z (TS.sup.+) 303
(MH.sup.+) 112 (2xHCl salt) Example 83 85 H --CF.sub.3
.delta..sub.H (d.sub.6-DMSO, 400 MHz) 2.74 (6H, s), 4.00 (2H, brs),
4.29 (2H, s), 7.07 (1H, d), 7.16 (2H, d), 7.60 (1H, d), 7.80 (2H,
d), 7.85 (1H, s), 8.47 (3H, brs), 10.68 (1H, brs); MS m/z
(TS.sup.+) 325 (MH.sup.+). 113 Example 86 H 86 --OCF.sub.3
.delta..sub.H (CDCl.sub.3, 300 MHz) 1.53 (2H, brs), 2.23 (6H, s),
3.41 (2H, s), 3.82 (2H, s), 6.85-6.94 (3H, m), 7.07-7.19 (3H, m),
7.43 (1H, d); MS m/z (TS.sup.+) 341 (MH.sup.+)
EXAMPLE 114
[0287]
N-(3-[(Dimethylamino)methyl]-4-[4-(trifluoromethyl)phenoxy]phenyl}
methanesulfonamide 87
[0288] A solution of the aniline compound of Example 107 (295 mg,
0.95 mmol) in THF (10 mL) was treated sequentially with
triethylamine (397 .mu.L, 2.85 mmol) and methanesulfonic anhydride
(331 mg, 1.9 mmol), and the mixture stirred at room temperature for
1 h. The reaction was then quenched by the addition of 1 M sodium
hydroxide and the mixture left to stir for 30 min before being
extracted with ethyl acetate. The organic layer was washed with
brine, dried (MgSO.sub.4) and evaporated to a brown oil.
Purification by flash chromatography [SiO.sub.2; DCM/ MeOH/ 880
NH.sub.3 (95:5:1)] afforded the desired methanesulfonamide compound
as a colourless oil which crystallised on standing to give a white
solid (291 mg, 79%); .delta..sub.H(CDCI.sub.3, 400 MHz) 2.22 (6 H,
s), 3.05 (3 H, s), 3.39 (2 H, s), 6.95 (2 H, d), 6.95 (1 H, d),
7.21 (1 H, dd), 7.37 (1 H, d), 7.58 (2 H, d); MS m/z (TS.sup.+) 389
(MH.sup.+).
EXAMPLES 115-120
[0289] A series of methanesulfonamides was prepared from the
requisite aniline or amine by similar procedures to that described
in Example 114. In some cases methanesulfonyl chloride was used in
place of the anhydride and/ or DCM was used as solvent.
24 88 Starting Example Material R.sup.4 R.sup.5 R.sup.3 Data 115
Example H --CH.sub.2NHSO.sub.2CH.sub.3 --CF.sub.3 .delta..sub.H
(CDCl.sub.3, 400 MHz) 112 2.14 (6H, s), 2.93 (3H, s), 3.40 (2H, s),
4.34 (2H, d), 4.66 (1H, brs), 6.95 (3H, d), 7.27 (1H, d), 7.51(1H,
s), 7.56 (2H, d); MS m/z (TS.sup.+) 403 (MH.sup.+). 116 Example H
--NHSO.sub.2CH.sub.3 --OCF.sub.3 .delta..sub.H (CDCl.sub.3, 400
MHz) 108 2.26 (6H, s), 3.02 (3H, s), 3.43 (2H, s), 6.91 (3H, m),
7.18 (3H, m), 7.34 (1H, d); MS m/z (TS.sup.+) 405 (MH.sup.+) 117
Example H --CH.sub.2NHSO.sub.2CH.su- b.3 --OCF.sub.3 .delta..sub.H
(CDCl.sub.3, 400 MHz) 110 2.24 (6H, s), 2.92 (3H, s), 3.43 (2H, s),
4.32 (2H, d), 4.65 (1H, br), 6.90 (3H, m), 7.17 (2H, m), 7.25 (1H,
m), 7.48 (1H, s); MS m/z (TS.sup.+) 419 (MH.sup.+) 118.sup.b
Example H --NHSO.sub.2CH.sub.3 --SMe .delta..sub.H (CD.sub.3OD, 300
MHz) 109 2.48 (3H, s), 2.93 (6H, s), 3.00 (3H, s), 4.83 (2H, s),
6.90 (1H, d), 7.06 (2H, m), 7.31, (1H, dd), 7.37 (2H, m), 7.52 (1H,
d); MS m/z (TS.sup.+) 367 (MH.sup.+) 119.sup.a Example H
--CH.sub.2NHSO.sub.2CH.sub.3 --SMe .delta..sub.H (d.sub.6-DMSO, 400
MHz) (HCl salt) 111 2.46 (3H, s), 2.76 (6H, d), 2.88 (3H, s), 4.13
(2H, d), 4.33 (2H, d), 6.80 (1H, d), 7.06 (2H, d), 7.33 (2H, d),
7.38 (1H, d), 7.57 (1H, t), 7.61 (1H, s), 10.28 (1H, br); MS m/z
(TS.sup.+) 381 (MH.sup.+) 120 113 --CH.sub.2NHSO.sub.2CH.sub.3 H
--OCF.sub.3 HCL salt: (d.sub.6-DMSO, 400 MHz) 2.73 (6H, s), 2.81
(3H, s), 4.11 (2H, d), 4.29 (2H, s), 6.91 (1H, s), 7.20 (3H, m),
7.43 (2H, d), 7.60 (1H, t), 7.65 (1H, d), 10.18 (1H, brs); MS m/z
(TS.sup.+) 419 (MH.sup.+) .sup.aNeSO.sub.2Cl (1 equivalent) was
used in place of (MeSO.sub.2).sub.2O and DCM was used as solvent.
.sup.bExcess MeSO.sub.2Cl was used in place of (MeSO.sub.2).sub.2O
and DCM was the solvent. After work up in the usual fashion the
crude product (largely bis-mesylate) was redissolved in 1,4-dioxan
and treated with excess 2M NaOH.sub.(aq). After stirring overnight
the solvent was removed in vacuo and the residue partitioned
between saturated NH.sub.4Cl.sub.(aq) and DCM. Extraction and
purification was effected in the usual way.
EXAMPLE 121
[0290]
N-{3-[(Methylamino)methyl]-4-[4-(trifluoromethyl)phenoxy]phenyl}-me-
thanesulfonamide 89
[0291] Step 1. Protection of Amine
[0292] The amine compound of Example 20 (3.08 g, 9.44 mmol) was
dissolved in DCM (20 mL) and then DMAP (50 mg, 0.41 mmol) and
triethylamine (5.26 mL, 37.8 mmol) were added. The solution was
cooled to 0.degree. C. before the dropwise addition of TFAA (2.76
mL, 18.9 mmol) over 10 min. The reaction was allowed to reach room
temperature and stirred for a further 20 min, then quenched by the
addition of methanol (3 mL). The quenched mixture was poured into 1
M hydrochloric acid (50 mL), the organic layer separated and then
the aqueous layer further extracted with DCM (2.times.30 mL). The
combined organic fractions were dried (MgSO.sub.4) and evaporated
to a slightly impure yellow oil (4.60 g) of the desired
trifluoroacetamide, which was not purified any further. Two amide
rotomers were visible in the .sup.1H NMR spectrum. Data is given
for the major rotomer only; .delta..sub.H(CDCI.sub.3, 400 MHz) 3.23
(3 H, s), 4.79 (2 H, s), 6.92 (1 H, d), 7.16 (2 H, d), 7.70 (2 H,
d), 8.16 (1 H, dd), 8.23 (1 H, d); MS m/z (TS.sup.+) 440
(M+NH.sub.4.sup.+).
[0293] Step 2. Iron Reduction to Aniline
[0294] The crude oil of Step 1 was dissolved in 85% aqueous ethanol
(38 mL) together with calcium chloride (471 mg, 4.24 mmol) and iron
powder (4.75 g, 85 mmol) was added. The mixture was heated at
reflux for 18 h and then allowed to cool to room temperature. The
mixture was filtered through a plug of arbocel.RTM. (washing
through with DCM) and then evaporated to an oil. The oil was
purified by passing through a plug of silica gel, eluting with
DCM/methanol/ 880 NH.sub.3 (93:7:1), followed by evaporation to a
yellow oil (3.35 g) of the desired aniline. Two amide rotomers were
visible in the .sup.1H NMR spectrum, which showed the material to
be ca. 90% pure. Data is given for the major rotomer only;
.delta..sub.H(CDCI.sub.3, 400 MHz) 3.04 (3 H, s), 4.51 (2 H, s),
6.66 (2 H, m), 6.84 (1 H, dd), 6.92 (2 H, d), 7.53 (2 H, d).
[0295] Step 3. Sulfonamide formation-hydrolysis
[0296] The crude oil from Step 2 was dissolved in DCM (34 mL) and
triethylamine (9.48 mL, 68 mmol) was added followed by
methanesulfonyl chloride (2.64 mL, 34 mmol) dropwise. The mixture
was stirred for a further 30 min before being quenched by the
addition of sodium hydroxide (2 M; 20 mL). The organic phase was
separated and the aqueous layer was extracted further with DCM
(2.times.30 mL). The combined organic fractions were dried
(MgSO.sub.4) and evaporated to an oil which was purified by flash
chromatography [SiO.sub.2; MeOH (0.fwdarw.10%) in DCM] and the
resulting oil dissolved in methanol (50 mL) and treated with sodium
hydroxide (2.5 g). The mixture was stirred at room temperature
overnight and then at reflux for 1 h. After cooling to room
temperature the mixture was acidified by the addition of acetic
acide (4 mL) and then 880 ammonia was added (100 mL). The organic
layer was separated and the aqueous layer extracted with DCM
(2.times.50 mL). The combined organic fractions were dried
(MgSO.sub.4) and evaporated to an orange oil. The oil was extracted
into hydrochloric acid (2 M) (100 mL) and the aqueous layer washed
with diethyl ether (2.times.50 mL). The acid was neutralised by
pouring cautiously into 880 ammonia (200 mL) and the mixture
extracted with DCM (3.times.100 mL). After drying (MgSO.sub.4) and
evaporation the residue was purified by flash chromatography
[SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3 (93:7:1)] to afford the desired
sulfonamide compound as a solid (330 mg, 10%) which was further
purified by trituration with diethyl ether/ pentane to afford the
desired sulfonamide compound as a cream powder (250 mg); .delta.
(CDCI.sub.3, 400 MHz) 2.43 (3 H, s), 3.02 (3 H, s), 3.71 (2 H, s),
6.93 (1 H, d), 6.94 (2 H, d), 7.18 (1 H, dd), 7.31 (1 H, d), 7.57
(2 H, d); MS m/z (TS.sup.+) 375 (MH.sup.+).
EXAMPLE 122
[0297]
N-{3-[{Dimethylamino)methyl]-4-[4-(trifluoromethyl)phenoxy]phenyl}--
N-(2-hydroxyethyl)methanesulfonamide 90
[0298] The methanesulfonamide compound of Example 114 (131 mg, 0.34
mmol), 2-bromoethanol (36 .mu.L, 0.51 mmol), and potassium
carbonate (70 mg, 0.51 mmol) were heated at reflux in acetonitile
(2 mL). After 1.5 h a further portion of 2-bromoethanol (20 .mu.L,
0.28 mmol) was added and refluxing continued for a further 2.5 h.
After cooling to room temperature the mixture was evaporated to a
yellow oil. Purification of the mixture by flash chromatography
afforded the desired hydroxyethyl sulfonamide compound as a
colourless oil (28 mg, 19%) in addition to returned starting
material (methanesulfonamide of Example 67) (19.4 mg, 15%) and
mixed fractions (58 mg). Desired compound:
.delta..sub.H(CDCI.sub.3, 300 MHz) 2.23 (6 H, s), 3.00 (3 H, s),
3.43 (2 H, s), 3.70 (2 H, t), 3.85 (2 H, t), 6.95 (1 H, d), 7.00 (2
H, dd), 7.28 (1 H, dd), 7.58 (1 H, d), 7.59 (2 H, d); MS m/z
(TS.sup.+) 433 (MH.sup.+).
EXAMPLE 123
N-{3-(Aminomethyl)-4-[4-(methylsulfanyl)phenoxy]phenyl}-N-(2-hydroxyethyl)-
-methanesulfonamide
[0299] 91
[0300] Borane-tetrahydrofuran complex (1 M soln in THF, 7.5 mL, 7.5
mmol) was added to a solution of the nitrile from preparation 66
(1.9 g, 5.02 mmol) in THF (40 .mu.L) under N.sub.2 and the mixture
was heated at reflux for 20 h. TLC analysis indicated starting
material remaining so a further portion of borane-tetrahydrofuran
complex (1 M soln in THF, 7.5 mL, 7.5 mmol) was added and reflux
was continued for 2 h. After cooling to room temperature
hydrochloric acid (6 M; 10 mL) was added and the mixture was heated
at reflux for 1 h. The mixture was re-cooled, basified with sodium
hydroxide (2 M) and extracted with ethyl acetate (100 mL), the
organic extract being washed with brine, dried (MgSO.sub.4) and
evaporated. The residue was taken up in ethyl acetate (50 mL) and
extracted with hydrochloric acid (2 M) (50 mL+2.times.25 mL). The
combined aqueous extracts were basified with sodium hydroxide (5 M)
(50 mL) and extracted with DCM (3.times.40 mL), the organic
extracts being dried (MgSO.sub.4) and evaporated. The residue was
purified by column chromatography [SiO.sub.2; DCM/methanol/880
NH.sub.3 (95:5:0.5)) to give the title compound;
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.44 (3 H, s), 2.97 (3 H, s),
3.67 (2 H, t), 3.79 (2 H, m), 3.88 (2 H, s), 6.78 (1 H, d), 6.91 (2
H, d), 7.15 (1 H, dd), 7.23 (2 H, d), 7.39 (1 H, d); MS m/z
(ES.sup.+) 383 (MH.sup.+).
EXAMPLE 124
N-{3-(Aminomethyl)-4-[4-(methylsulfanyl)-3-(trifluoromethyl)phenoxy]phenyl-
}-methanesulfonamide
[0301] 92
[0302] The title compound was prepared from the nitrile of
preparation 64 using the method described for Example 123
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.48 (3 H, s), 3.01 (3 H, s),
3.87 (2 H, s), 6.93 (1 H, d), 7.05 (1 H, d), 7.17 (1 H, d), 7.27 (1
H, obs), 7.30 (1 H, s), 7.39 (1 H, d); MS m/z (TS.sup.+) 407
(MH.sup.+).
EXAMPLE 125
[0303]
N-{3-(Aminomethyl)-4-[4-(methylsulfanyl)phenoxy]phenyl}methanesulfo-
namide 93
[0304] Lithium aluminium hydride (1 M soin in THF, 6 mL, 6 mmol)
was added to a solution of the nitrile of preparation 62 (1.01 g,
3.02 mmol) in THF (30 mL) under nitrogen and the mixture was heated
at reflux for 3 h. After cooling to room temperature the reaction
was quenched by the cautious addition of sodium hydroxide (2 M; 2
mL). The reaction mixture was dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue was purified by column
chromatography [SiO.sub.2; DCM/MeOH/880 NH.sub.3 (93:7:1)] to give
an off-white powder (805 mg, 79%); .delta..sub.H(DMSO-D.sub.6, 400
MHz) 2.39 (3 H, s), 2.47 (3 H, s), 2.93 (3 H, s), 3.58 (2 H, s),
6.82 (3 H, m), 7.02 (1 H, dd), 7.21 (2 H, d), 7.35 (1 H, d); MS m/z
(TS.sup.+) 339 (MH.sup.+).
EXAMPLE 126
[0305]
N-{3-(Aminomethyl)-4-[4-(methylsulfanyl)phenoxy]phenyl}-N-methylmet-
hanesulfonamide 94
[0306] Lithium aluminium hydride (1 M soln in THF, 15 mL, 15 mmol)
was added to a solution of the nitrile of preparation 65 (2.75 g,
7.89 mmol) in THF (50 mL) under N.sub.2 and the mixture was heated
at reflux for 2 h. After cooling to room temperature the reaction
was quenched by the cautious addition of sodium hydroxide (2 M; 3
mL). After stirring for 10 min the reaction mixture was dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified by multiple column chromatography [SiO.sub.2; DCM/(10% 880
ammonia in methanol) 94:6] to give the product as an oil (783 mg,
28%). A sample was taken up in DCM and converted to the HCI salt by
the addition of 1 M ethereal HCI. Removal of the solvent and drying
in vacuo gave an off-white foam; .delta..sub.H(DMSO-D.sub.6, 400
MHz) 2.44 (3 H, s), 2.95 (3 H, s), 3.16 (3 H, s), 4.04 (2 H, q),
6.74 (1 H, d), 7.04 (2 H, d), 7.31 (3 H, m), 7.60 (1 H, s), 8.30 (3
H, br); MS mz (ES.sup.+) 353 (MH.sup.+).
EXAMPLE 127
[0307]
N-{3-(Aminomethyl)-4-[3-methoxy-4-(methylsulfanyl)phenoxy]phenyl}-m-
ethanesulfonamide 95
[0308] The procedure for example 126 was repeated using the product
of preparation 63 to provide the title amine;
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.33 (3 H, s), 2.94 (3 H, s),
3.78 (3 H, s), 3.93 (2 H, s), 6.50 (1 H, dd), 6.67 (1 H, s),
7.12-7.18 (2 H, m), 7.33 (1 H, d).
EXAMPLE 128
N-{3-[(Methylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl}methane-sul-
fonamide
[0309] 96
[0310] Formic acid (55 .mu.L, 1.46 mmol) was added to a solution of
pentafluorophenol (240 mg, 1.30 mmol) in ether (5 mL) at 0.degree.
C. followed by dicyclohexylcarbodiimide (270 mg, 1.31 mmol). The
mixture was stirred at 0.degree. C. for 15 min and at room
temperature for 2 h before being filtered, the residue being washed
with ether. The ethereal solution of pentafluorophenyl formate was
added to a suspension of the amine from Example 125 (221 mg, 0.65
mmol) in DCM (7 mL) and the mixture was stirred at room temperature
for 18 h before being diluted with DCM (40 mL) and washed with sat.
aq NaHCO.sub.3 (50 mL). The organic layer was dried and evaporated
to give a crude formamide which was used without further
purification. The crude formamide (0.65 mmol) was taken up in dry
THF (10 mL), borane-tetrahydrofuran complex (1 M soln in THF, 2 mL,
2 mmol) was added and the mixture was heated at reflux for 1.5 h.
After cooling to room temperature hydrochloric acid (6 M; 5 mL) was
added and the mixture was stirred for 15 min before being
neutralised with satuarated aqueous sodium bicarbonate solution (50
mL). The aqueous mixture was extracted with DCM (2.times.30 mL) and
the organic extracts were dried (MgSO.sub.4) and evaporated.
Purification of the residue by column chromatography [SiO.sub.2;
EtOAc/MeOH/880 NH.sub.3 (95:5:0.5 increasing polarity to 90:9:1)]
gave the product as a colourless oil. This was taken up in DCM (5
mL) and converted to the hydrochloride salt by the addition of 1 M
ethereal hydrochloric acid. Removal of the solvent and drying in
vacuo gave an off-white foam (218 mg, 86%);
.delta..sub.H(CD.sub.3OD, 300 MHz) 2.48 (3 H, s), 2.77 (3 H, s),
2.99 (3 H, s), 4.28 (2 H, s), 6.87 (1 H, d), 7.06 (2 H, d), 7.25 (1
H, dd), 7.35 (2 H, d), 7.49 (1 H, d); MS m/z (ES.sup.+) 353
(MH.sup.+).
EXAMPLES 129-131
[0311]
[0312] Examples 129-131 were prepared from the requisite primary
amines according to the method described for Example 128.
25 97 Starting Example Material R.sup.5 (R.sup.3).sub.n Data 129
(HCl salt) Example 126 98 4-SMe .delta..sub.H (CD.sub.3OD, 300 MHz)
2.48 (3H, s), 2.78 (3H, s), 2.93 (3H, s), 3.29 (3H, s), 4.32 (2H,
s), 6.88 (1H, d), 7.09 (2H, d), 7.38 (2H, d), 7.47 (1H, dd), 7.59
(1H, d); MS m/z (ES.sup.+) 367 (MH.sup.+). 130 Example 123 99 4-SMe
.delta..sub.H (CDCl.sub.3, 300 MHz) 2.45 (3H, s), 2.48 (3H, s),
2.99 (3H, s), 3.69 (2H, m), 3.82 (4H, m), 6.81 (1H, d), 6.94 (2H,
d), 7.20 (1H, dd), 7.28 (2H, d), 7.44 (1H, d); MS m/z (TS.sup.+)
397 (NH.sup.+). 131 Example 127 100 3-OMe, 4-SMe .delta..sub.H
(CD.sub.3OD, 400 MHz) 2.39 (3H, s), 2.79 (3H, s), 3.99 (3H, s),
3.83 (3H, s), 4.29 (2H, s), 6.65 (1H, dd), 6.77 (1H, d), 6.91 (1H,
d), 7.19 (1H, d), 7.25 (1H, dd), 7.47 (1H, d); MS m/z (TS.sup.+)
400 (MNH.sub.4.sup.+)
EXAMPLE 132
[0313]
N-{3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl}-N-
-(2-hydroxyethyl)methanesulfonamide 101
[0314] Formaldehyde (37% aq soln, 600 .mu.L, 7.39 mmol) was added
to a solution of the amine of Example 123 (450 mg, 1.18 mmol) in
DCM (15 mL) and THF (5 mL) and the mixture was stirred for 15 min
before sodium triacetoxyborohydride (1.0 g, 4.72 mmol) was added
portionwise over 15 min. The mixture was stirred for 18 h before
being poured into aqueous potassium carbonate (10%; 50 mL) and
extracted with DCM (2.times.30 mL). The organic layer was dried
(MgSO.sub.4) and evaporated, and the residue was purified by column
chromatography [SiO.sub.2; DCM/MeOH/880 NH.sub.3 (90:9:1)] to give
the product as an oil. This was taken up in DCM and converted to
the hydrochloride salt by the addition of 1 M ethereal hydrochloric
acid Removal of the solvent and drying in vacuo gave an off-white
foam (362 mg, 69%); .delta..sub.H (CDCI.sub.3, 400 MHz) 2.50 (3 H,
s), 2.86 (6 H, d), 3.12 (3 H, s), 3.70 (2 H, m), 3.84 (2 H, m),
4.31 (2 H, d), 6.82 (1 H, d), 6.96 (2 H, d), 7.30 (2 H, d), 7.41 (1
H, dd), 8.18 (1 H, d), 12.5 (1 H, br); MS m/z (ES.sup.+) 411
(MH.sup.+).
EXAMPLE 133-136
[0315] The examples below were prepared from the requisite primary
amine by the method described in Example 132.
26 102 Starting Example Material R.sup.5 (R.sup.3) data 133 Example
127 103 3-OMe, 4-SMe .delta..sub.H (CD.sub.3OD, 400 MHz) 2.39 (3H,
s), 2.92 (6H, s), 2.98 (3H, s), 3.84 (3H, s), 4.41 (2H, s), 6.65
(1H, dd), 6.77 (1H, d), 6.93 (1H, d), 7.22 (1H, d), 7.29 (1H, dd),
7.51 (1H, d); MS m/z (TS.sup.+) 397 (MH.sup.+) 134 Example 124 104
3-CF.sub.3, 4-SMe HCl salt: .delta..sub.H (d.sub.6-DMSO, 400 MHz)
2.55 (3H, s), 2.76 (6H, d), 3.05 (3H, s), 4.28 (2H, d), 6.97 (1H,
d), 7.22 (1H, d), 7.31 (1H, d), 7.45 (1H, s), 7.59 (1H, d), 9.88
(1H, s), 10.25 (1H, brs) 135 Example 192 --Cl 4-SMe .delta..sub.H
(CDCl.sub.3, 400 MHz) 2.49 (3H, s), 2.81 (6H, s), 4.27 (2H, s),
6.79 (1H, d), 6.94 (2H, d), 7.27 (2H, d), 7.31 (1H, dd), 7.80 (1H,
d); MS m/z (TS.sup.+) 308. 310 (MH.sup.+). 136 (HCl salt) Example
126 105 4-SMe .delta..sub.H (CDCl.sub.3, 400 MHz) 2.50 (3H, s),
2.82 (6H, d), 3.01 (3H, s), 3.38 (3H, s), 4.30 (2H, d), 6.81 (1H,
d), 6.95 (2H, d), 7.30 (2H, d), 7.44 (1H, d), 8.21 (1H, s), 12.92
(1H, br); MS m/z (TS.sup.+) 381 (MH.sup.+).
EXAMPLE 137
[0316]
N-(3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl}-2-
-methoxyethanesulfonamide 106
[0317] The aniline of Example 109 (350 mg, 1.08 mmol) was dissolved
in DCM (10 mL) and treated with 4,4-dimethylaminopyridine (132 mg,
1.08 mmol), triethylamine (0.68 mL, 4.86 mmol) and
2-(methoxy)ethylsulfonyl chloride [prepared according to EP
0446845]. The reaction mixture was stirred at room temperature
overnight The mixture was evaporated to remove volatiles and the
residue treated with sodium hydroxide (2 M; 5 mL) and dioxan (5
mL). The mixture was stirred for 3 hours and then evaporated once
more to remove most of the dioxan. The aqueous residue was
extracted with dichloromethane (2.times.30 mL) and the combined
extracts dried (MgSO.sub.4) and evaporated. The residue was
purified by flash chromatography [SiO.sub.2; DCM/ MeOH
(95:5.fwdarw.90:10)] to afford the title compound, which was
isolated as the HCI salt (20 mg, 4%); HCI salt: .DELTA..sub.H
(CD.sub.3OD, 400 MHz) 2.44 (3 H, s), 2.88 (6 H, s), 3.28 (3 H, s),
3.30 (2 H, t), 3.74 (2 H, t), 4.38 (2 H, s), 6.85 (1 H, d), 7.02 (2
H, d), 7.25 (1 H, dd), 7.31 (2 H, d), 7.48 (1 H, d); MS m/z
(ES.sup.+) 411 (MH.sup.+).
EXAMPLE 138
[0318]
N-{3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl}-e-
thanesulfonamide 107
[0319] The title compound was prepared from the aniline of Example
109 according to the general procedure described in example 114,
using ethanesulfonyl chloride in place of methanesulfonyl chloride.
HCI salt:.quadrature..delta..sub.H (d.sub.6-DMSO, 300 MHz) 1.20 (3
H, t), 2.47 (3 H, s), 2.75 (6 H, s), 4.30 (1 H, brs), 6.85 (1 H,
d), 7.06 (2 H, d), 7.22 (1 H, dt), 7.37 (2 H, d), 7.53 (1 H, m),
9.84 (1 H, s), 10.50 (1 H, brs); MS m/z (ES.sup.+) 381
(MH.sup.+)
EXAMPLE 139
[0320]
N-{3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl}-2-
-propanesulfonamide 108
[0321] The compound was prepared from the aniline of Example 109
according to the general procedure described in example 114, using
2-propylsulfonyl chloride in place of methanesulfonyl chloride. HCI
salt: .delta..sub.H (d.sub.6-DMSO, 400 MHz) 1.23 (6 H, d), 2.45 (3
H, s), 2.73 (6 H, d), 3.33 (1 H, m), 4.28 (2 H, d), 6.87 (1 H, d),
7.04 (1 H, d), 7.22 (1 H, dd), 7.54 (1 H, d), 9.83 (1 H, s), 10.30
(1 H, brs); MS m/z (ES.sup.+) 395 (MH.sup.+)
EXAMPLE 140
[0322]
N-{3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl}-(-
trifluoro)methanesulfonamide 109
[0323] The aniline from example 109 (300 mg, 0.9 mmol) was
dissolved in DCM (10 mL) and treated with trifluoromethanesulfonic
anhydride (169 .mu.L, 1.02 mmol) at 0.degree. C. The mixture was
stirred at this temperature for 3 hours and then the solvents
removed by evaporation. The residue was purified by flash
chromatography [SiO.sub.2; DCM/ MeOH (100:0.fwdarw.90:10)] to
afford a yellow solid. Trituration with DCM afforded the title
compound as a white solid (80 mg, 21%); Free base: .delta..sub.H
(d.sub.6-DMSO, 400 MHz) 2.40 (3 H, s), 2.70 (6 H, s), 4 10 (2 H,
s), 6.67 (1 H, d), 6 89 (2 H, d), 7.00 (1 H, dd), 7.09 (1 H, s),
7.24 (2 H, d), 9.33 (1 H, brs); MS m/z (TS.sup.+) 421
(MH.sup.+).
EXAMPLE 141
[0324]
N,N-Dimethyl-N-{5-(methylsulfanyl)-2-[4-(trifluoromethoxy)phenoxy]b-
enzyl}amine 110
[0325] A solution of the bromide compound of Example 7 (1.6 g, 4.1
mmol) and palladium tetrakis(triphenylphosphine) (237 mg, 0.21
mmol) in DMSO (40 mL) was stirred at 100.degree. C. under nitrogen
for 90 min. Sodium thiomethoxide (575 mg, 8.2 mmol) was added in
one portion and the reaction was stirred at 100.degree. C. for 64
h. After cooling to room temperature the reaction mixture was
poured into water and extracted with ethyl acetate (4 times). The
combined organic extracts were dried (MgSO.sub.4) and concentrated
in vacuo. The residue was purified by flash chromatography
[SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3 (97:3:0.5.fwdarw.93:7:1)]. The
relevant fractions were combined and repurified by flash
chromatography [SiO.sub.2; ethyl acetatelmethanol/ 880 ammonia
(96:4:0.4)] to give the desired sulfide compound (930 mg, 63%);
.delta..sub.H (CDCI.sub.3, 400 MHz) 2.24 (6 H, s), 2.49 (3 H, s),
3.39 (2 H, s), 6.87 (3 H, m), 7.14 (3 H, m), 7.42 (1 H, s); MS m/z
(TS.sup.+) 358 (MH.sup.+ ).
EXAMPLES 142-144
[0326] The reaction described in Example 141 was repeated under
similar conditions to provide a series of sulfides from the
requisite bromide or iodide. Data for these compounds are compiled
below.
27 111 Starting Example Material R.sup.5 R.sup.4 R.sup.3 .sup.1H
NMR Data 142 Example H --SMe --OCF.sub.3 .delta..sub.H (CDCl.sub.3,
400 MHz) 2.23 (6H, s), 2.42 8 (3H, s), 3.39 (2H, s), 6.79 (1H, s),
6.90 (2H, d), 7.05 (2H, d), 7.15 (2H, d), 7.39 (1H, d); 358
(MH.sup.+) 143 Example MeS-- H --CF.sub.3 .delta..sub.H
(CDCl.sub.3, 400 MHz) 2.06 (6H, s), 2.50 18 (3H, s), 3.36 (2H, s),
6.90 (1H, d), 6.93 (2H, d), 7.17 (1H, d), 7.44 (1H, s), 7.53 (2H,
d); MS m/z (ES.sup.+) 342 (MH.sup.+). 144 Example H EtS--
--CF.sub.3 .delta..sub.H (CDCl.sub.3, 400 MHz) 1.29 (3H, t), 2.22
12 (6H, s), 2.89 (2H, q), 3.33 (2H, s), 6.90 (1H, s), 6.95 (2H, d),
7.14 (1H, d), 7.41 (1H, d), 7.56 (2H, d); MS m/z (TS.sup.+) 356
(MH.sup.+).
EXAMPLES 145-146
[0327]
N,N-Dimethyl-N-{5-(methylsulfonyl)-2-[4-(trifluoromethoxy)phenoxy]b-
enzyl}amine (Example 145) and
[0328]
N,N-dimethyl-N-{5-(methylsulfinyl)-2-(4-(trifluoromethoxy)phenoxy]b-
enzyl}amine 112
[0329] Oxone.RTM. (1.54 g, 2.50 mmol) was added to a solution of
the compound of Example 141 (900 mg, 2.52 mmol) in THF (4 mL),
isopropyl alcohol (20 mL) and water (2 mL) at 0.degree. C. The
mixture was stirred at 0-5.degree. C. for 15 min then allowed to
warm to room temperature over 25 min before being quenched with
sodium hydroxide (2 M). The aqueous mixture was extracted with
ethyl acetate (3 times) and the combined organic extracts were
dried (MgSO.sub.4) and concentrated in vacuo. The residue was
purified by flash chromatography [SiO.sub.2; DCM/methanol/ 880
ammonia (97:3:0.5.fwdarw.93:7:1)] to give two major products.
Fractions containing the higher running product were combined and
repurified by flash chromatography [SiO.sub.2; ethyl
acetate/methanol/ 880 ammonia (96:4:0.4)] to give the sulfone of
Example 145 (473 mg, 48%) as a colourless solid; .delta..sub.H
(CDCI.sub.3, 400 MHz) 2.30 (6 H, s), 3.07 (3 H, s), 3.58 (2 H, s),
6.92 (1 H, d), 7.02 (2 H, m), 7.25 (2 H, m), 7.78 (1 H, dd), 8.12
(1 H, d); MS m/z (TS.sup.+) 390 (MH.sup.+).
[0330] Fractions containing the lower running product were combined
and repurified by flash chromatography [SiO.sub.2; EtOAc/ MeOH/ 880
NH.sub.3 (95:5:0.5)] to give the sulfoxide of Example 146 (64 mg,
7%) as a colourless oil; .delta..sub.H (CDCI.sub.3, 400 MHz) 2.29
(6 H, s), 2.76 (3 H, s), 3.56 (2 H, s), 6.99 (3 H, m), 7.20 (2 H,
m), 7.57 (1 H, dd), 7.78 (1 H, d); MS m/z (TS.sup.+) 374
(MH.sup.+).
EXAMPLES 147-148
[0331] The reaction of Examples 145 and 146 was repeated to provide
the sulfoxides of Examples 147 and 148 from the corresponding
sulfides.
28 113 Starting Example Material R.sup.5 R.sup.4 R.sup.3 Data 147
Example --SOMe H CF.sub.3 .delta..sub.H (CDCl.sub.3, 400 MHz) 2.25
(6H, s), 2.75 143 (3H, s), 3.49 (2H, s), 7.01 (2H, d), 7.06 (1H,
d), 7.57-7.60 (3H, m), 7.80 (1H, s); MS m/z (TS.sup.+) 358
(MH.sup.+). 148 Example H --SOEt CF.sub.3 .delta..sub.H
(CDCl.sub.3, 400 MHz) 1.16-1.20 (3H, m), 144 2.25 (6H, s), 2.63
(1H, dq), 2.87 (1H, dq), 3.43-3.49 (2H, m), 6.98 (2H, d), 7.23 (1H,
s), 7.38 (1H, d), 7.57 (2H, d), 7.68 (1H, d); MS m/z (TS.sup.+) 372
(MH.sup.+).
EXAMPLE 149
[0332]
N,N-Dimethyl-N-{4-(methylsulfinyl)-2-[4-(trifluoromethoxy)phenoxy]b-
enzyl}amine 114
[0333] Hydrogen peroxide (30%, 76 .mu.L, 0.67 mmol) was added
dropwise to a solution of the sulfide compound of Example 142 (240
mg, 0.67 mmol) in TFA (2 mL) at 0.degree. C. under nitrogen. After
stirring at 0.degree. C. for 30 min the reaction mixture was
diluted with water and carefully basified with sodium hydroxide
pellets. The mixture was extracted with ethyl acetate and the
organic extract was washed with brine, dried (MgSO.sub.4) and
concentrated in vacuo. The 10 residue was purified by flash
chromatography [SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3
(97:2.5:0.5.fwdarw.95:5:0.5)] to give the desired sulfoxide
compound (142 mg, 57%) as a colourless oil; .delta..sub.H
(CDCI.sub.3, 400 MHz) 2.27 (6 H, s), 2.70 (3 H, s), 3.50 (2 H, s),
6.95 (2 H, d), 7.19 (2H ,d), 7.21 (1 H, s), 7.37 (1 H, d), 7.67 (1
H, d); MS m/z (TS.sup.+) 374 (MH.sup.+).
EXAMPLE 150
[0334]
N,N-Dimethyl-N-{4-(methylsulfonyl)-2-[4-(trifluoromethoxy)phenoxy]b-
enzyl}amine 115
[0335] Hydrogen peroxide (30%, 160 .mu.L, 1.41 mmol) was added
dropwise to a solution of the sulfide compound of Example 142 (252
mg, 0.71 mmol) in TFA (2 mL) at 0.degree. C. under nitrogen. After
stirring at 0.degree. C. for 60 min and room temperature for 30 min
a further portion of hydrogen peroxide (80 mL, 0.71 mmol) was added
and the mixture was stirred at room temperature for another 6 hrs.
The reaction mixture was diluted with aqueous sodium hydroxide (1
M) and carefully basified further with sodium hydroxide pellets.
The mixture was extracted with ethyl acetate and the organic
extract was washed with brine, dried (MgSO.sub.4) and concentrated
in vacuo. The residue was purified by flash chromatography
[SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3 (99:1:0.5.fwdarw.98:2:0.5) to
give the desired sulfone compound (183 mg, 67%) as a colourless
oil; .delta..sub.H(CDCI.sub.3, 400 MHz) 2.30 (6 H, s), 3.00 (3 H,
s), 3.55 (2 H, s), 6.97 (2 H, d), 7.20 (2 H, d), 7.42 (1 H, s),
7.70 (1 H, s), 7.78 (1 H, d) 390 (MH.sup.+).
EXAMPLE 151
[0336] Methyl
3-[(dimethylamino)methyl]-4-[4-(trifluoromethyl)phenoxy]benz- oate
116
[0337] The iodide compound of Example 18 (2.0 g, 4.75 mmol) was
dissolved in methanol (30 mL) and treated with triethylamine (0.98
mL, 7.04 mmol) and palladium tetrakis(triphenylphosphine) (0.28 g,
0.25 mmol). The reaction mixture was placed under an atmosphere of
carbon monoxide (100 psi) and heated to 80.degree. C. with
stirring. After 6 h the pressure was released and the reaction
mixture allowed to cool to room temperature. The mixture was
diluted with brine and extracted with ethyl acetate to provide,
after drying with MgSO.sub.4 and evaporation, an orange solid.
Purification by flash chromatography [SiO.sub.2; MeOH/880 NH.sub.3;
(10:1) (1.fwdarw.3%) in DCM] gave the desired ester compound as an
orange oil (1.66 g, 99%); .delta..sub.H(CDCI.sub.3, 400 MHz) 2.27
(6 H, s), 3.49 (2 H, s), 3.91 (3 H, s), 6.83 (1 H, d), 7.03 (2 H,
d), 7.60 (2 H, d), 7.93 (1 H, dd), 8.19 (1 H, d); MS m/z (TS.sup.+)
354 (MH.sup.+).
EXAMPLE 152
[0338] Methyl
3-[(dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzo- ate
117
[0339] The reaction of example 151 was repeated in a similar
fashion with the bromide of Example 9 to provide the title ester.
Free base: .delta..sub.H(CDCI.sub.3, 400 MHz) 2.47 (9 H, s), 3.78
(2 H, s), 3.87 (3 H, s), 6.80 (1 H, d), 6.95 (2 H, d), 7.26 (2 H,
d), 7.88 (1 H, d), 8.17 (1 H, d); MS m/z (TS.sup.+) 354
(MH.sup.+).
EXAMPLE 153
[0340] Methyl
3-[(methylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzoat- e
118
[0341] The title ester was prepared from the bromide of example 23
using the procedure described for example 151;
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.46 (3 H, s), 2.49 (3 H, s),
3.86 (2 H, s), 3.89 (3 H, s), 6.79 (1 H, d), 6.95 (2 H, d), 7.29 (2
H, d), 7.86 (1 H, dd), 8.07 (1 H, d); MS m/z (TS.sup.+) 318
(MH.sup.+).
EXAMPLE 154
[0342]
{3-[(Dimethylamino)methyl]-4-[4-(trifluoromethyl)phenoxy]phenyl}met-
hanol 119
[0343] A solution of lithium aluminium hydride in THF (1 M, 7 mL, 7
mmol) was added dropwise to a stirring solution of the ester
compound of Example 151 (1.66 g, 4.7 mmol) in THF (25 mL) at room
temperature under nitrogen. The mixture was stirred for 3 h before
being diluted with ether (100 mL) and quenched by the cautious
addition of sodium hydroxide (2 M) (approximately 1 mL). The
mixture was stirred for 10 min before being dried (MgSO.sub.4),
filtered and concentrated in vacuo. Purification of the residue by
flash chromatography {SiO.sub.2; [(MeOH/ 880 NH.sub.3) 9:1] in DCM
(2% .fwdarw.4%)] gave the desired alcohol compound (0.7 g, 48%);
Example 90: .delta..sub.H(CDCI.sub.3, 400 MHz) 2.13 (6 H, s), 3.39
(2 H, s), 4.70 (2 H, s), 6.93-6.98 (3 H, m), 7.30 (1 H, d),
7.52-7.56 (3 H, m); MS m/z (TS.sup.+) 326 (MH.sup.+).
EXAMPLE 155
[0344]
{3-[([Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl}met-
hanol
[0345] The reaction of example 154 was repeated using the ester
compound of Example 152 to produce the title alcohol. 120
[0346] Free base: .delta..sub.H(CDCI.sub.3, 400 MHz) 2.06 (6 H, s),
2.43 (3 H, s), 4.30 (2 H, d), 4.47 (2 H, s), 6.80 (1 H, d), 7.03 (2
H, d), 7.31 (2 H, d), 7.34 (1 H, m), 7.60 (1 H, d); MS m/z (ES+)
304 (MH.sup.+)
EXAMPLE 156
[0347]
{3-[(Methylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]phenyl}methan-
ol 121
[0348] The title alcohol was prepared from the ester of example 153
using the procedure described for example 154;
.delta..sub.H(DMSO-D.sub.6, 400MHz) 2.45 (3 H, s), 2.57 (3 H, s),
4.15 (2 H, s), 4.47 (2 H, s), 5.26 (1 H, br), 6.78 (1 H, d), 7.01
(2 H, d), 7.33 (3 H, m), 7 54 (1 H, s), 8.86 (2 H, br), MS m/z
(ES.sup.+) 290 (MH.sup.+). reaction was neutralised with
hydrochloric acid (2 M) and extracted with DCM. The organic
extracts were dried (MgSO.sub.4) and evaporated to a white foam of
the title carboxylic acid (4.80 g, 95%); .delta..sub.H(CD.sub.3OD,
400 MHz) 2.48 (3 H, s), 2.56 (6 H, s), 3.94 (2 H, s), 6.80 (1 H,
d), 7.00 (2 H, d), 7.33 (2 H, d), 7.94 (1 H, d), 8.09 (1 H, s); MS
m/z (ES.sup.+) 318 (MH.sup.+).
EXAMPLE 159
[0349]
3-[(Dimethylamino)methyl]-N-methyl-4-[4-(methylsulfanyl)phenoxy]ben-
zamide 122
[0350] The product from example 158 (480 mg, 1.51 mmol) WSCDI (377
mg, 2 mmol), HOBt.H.sub.2) (255 mg, 1.66 mmol) and triethylamine
(0.53 mL, 3.78 mmol) were dissolved in DCM (0.03 M). After stirring
for 30 min, MeNH.sub.2 (condensed, 2 mL) was added and the mixture
stirred for a further 12 h. The mixture was then evaporated and the
residue partitioned between ethyl acetate and water. The organic
layer was separated and the aqueous layer re-extracted with ethyl
acetate (3 times). The combined organic layers were dried
(MgSO.sub.4) and evaporated to a yellow oil, which was purified by
flash chromatography [SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3 (93:7:1)].
The desired title amide was isolated as its hydrochloride salt (285
mg, 63%); Free base: .delta..sub.H(CDCI.sub.3, 400 MHz) 2.12 (6 H,
s), 2.41 (3 H, s), 2.92 (3 H, d), 3.46 (3 H, s), 6.78 (1 H, brd),
6.84 (2 H, d), 7.20 (2 H, d), 7.63 (1 H, dd), 7.82 (1 H, d); MS m/z
(ES+) 331 (MH.sup.+)
EXAMPLES 160-168
[0351] The following amides were prepared in an analogous fashion
to that in Example 159 from the the carboxylic acid of Example 158
and the appropriate amine.
29 123 Example --NR.sup.6R.sup.7 Data 160 124 Free base:
.delta..sub.H (CDCl.sub.3, 400 MHz) 2.27 (6H, s), 2.49 (3Hm, s),
3.50 (2H, s), 3.59 (2H, m), 3.81 (2H, t), 6.82 (1H, d), 6.90 (2H,
d), 7.08 (1H, t), 7.25 (2H, d), 7.67 (1H, d), 7.90 (1H, s); MS m/z
(ES.sup.+) 361 (MH.sup.+) 161 125 HCl salt: .delta..sub.H
(CDCl.sub.3, 400 MHz) 2.78 (6H, s), 3.24 (3H, s), 4.39 (2H, s),
6.80 (1H, d), 7.16 (2H, d), 7.37 (2H, d), 7.88 (1H, d), 8.18 (1H,
s), 8.53 (1H, s); MS m/z (TS.sup.+) 375 (MH.sup.+) 162 126 HCl
salt: .delta..sub.H (d.sub.6-DMSO, 400 MHz) 1.12 (3H, d), 2.47 (3H,
s), 2.79 (6H, d), 3.29-3.46 (2H, m), 3.99 (1H, m), 4.41 (2H, d),
6.80 (1H, d), 7.13 (2H, d), 7.36 (2H, d), 7.89 (1H, d), 8.11 (1H,
d), 8.23 (1H, s), 10.17 (1H, brs); MS m/z (ES.sup.+) 375 (MH.sup.+)
163 127 HCl salt: .delta..sub.H (d.sub.6-DMSO, 400 MHz) 1.12 (3H,
d), 2.48 (3H, s), 2.80 (6H, d), 3.29-3.46 (2H, m), 3.99 (1H, m),
4.40 (2H, d), 6.81 (1H, d), 7.13 (2H, d), 7.36 (2H, d), 7.89 (1H,
d), 8.08 (1H, d), 8.25 (1H, s), 10.29 (1H, brs); MS m/z (ES.sup.+)
375 (MH.sup.+ 164 128 HCl salt: .delta..sub.H (d.sub.6-DMSO, 400
MHz) 2.48 (3H, s), 2.77 (6H, d), 3.4-3.60 (8H, brm), 4.38 (2H, d),
6.79 (1H, d), 7.15 (2H, d), 7.35 (2H, d), 7.46 (1H, d), 7.77 (1H,
s), 10.62 (1H, brs); MS m/z (ES.sup.+) 387 (MH.sup.+) 165 129 HCl
salt: (d.sub.6DMSO, 400 MHz) 1.10 (3H, t), 2.48 (3H, s), 2.78 (6H,
d), 3.27 (2H, m), 4.40 (2H, d), 6.68 (1H, d), 7.14 (2H, d), 7.36
(2H, d), 7.85 (1H, d), 8.21 (1H, s), 8.47 (1H, t), 10.30 (1H, brs);
MS m/z (ES.sup.+) 345 (MH.sup.+) 166 130 HCl salt: .delta..sub.H
(d.sub.6-DMSO, 400 MHz) 0.22 (2H, s), 0.61 (2H, m), 1.08 (1H, m),
2.51 (3H, s), 3.15 (2H, m), 4.41 (2H, s), 6.81 (1H, d), 7.16 (2H,
d), 7.37 (2H, d), 7.88 (1H, d), 8.18 (1H, s), 8.53 (1H, s); MS m/z
(TS.sup.+) 371 (MH.sup.+) 167 131 Free base: .delta..sub.H
(CDCl.sub.3, 400 MHz) 2.27 (6H, s), 2.48 (3H, s), 3.55 (2H, s),
4.16 (2H, d), 5.95 (1H, brs), 6.38 (1H, brs), 6.86 (1H, d), 6.91
(2H, d), 7.18-7.31 (3H, m), 7.73 (1H, d), 7.97 (1H, s); MS m/z
(ES.sup.+) 374 (MH.sup.+) 168 132 HCl salt: .delta..sub.H
(d.sub.6-DMSO, 400 MHz) 1.73-1.97 (2H, m), 2.78 (6H, m), 3.26 (1H,
d), 3.35 (1H, d), 4.27 (1H, d), 4.40 (2H, d), 6.77 (1H, d), 7.15
(2H, d), 7.36 (2H, d), 7.58 (1H, m), 7.88 (1H, s), 10.21 (1H, brs;
MS m/z (ES.sup.+) 387 (MH.sup.+).
EXAMPLE 169
[0352]
4-[3-Methoxy-4-(methylsulfanyl)phenoxy]-3-[(methylamino)methyl]benz-
amide 133
[0353] The Boc-protected amine of preparation 53 (280 mg, 0.65
mmol) was dissolved in DCM (10 mL) and the solution cooled to
0.degree. C. Hydrogen chloride gas was bubbled through the solution
for 15 minutes and then the solution was evaporated to dryness. The
residue was co-evaporated several times using DCM/ethyl acetate
(1:1) and then diethyl ether. The product was obtained as a white
solid which was dried under vacuum (240 mg, ca.100%); HCI salt:
.delta..sub.H(CD.sub.3OD, 400 MHz) 2.37 (3 H, s), 2.77 (3 H, s),
3.82 (3 H, s), 4.35 (2 H, s), 6 73 (1 H, dd), 6.80 (1 H, d), 6.84
(1 H, d), 7.36 (1 H, d), 7.86 (1 H, dd), 8.03 (1 H, d); MS m/z
(TS.sup.+) 333 (MH.sup.+).
EXAMPLES 170-176
[0354] A series of amides was prepared in an analogous fashion to
that in example 169 from the requisite Boc-protected amines.
30 134 Starting Example material R.sup.5 (R.sup.3).sub.n data 170
Prep 47 135 4-SMe HCl salt: .delta..sub.H(CDCl.sub.3, 300
MHz)2.47(3H, s), 2.49(3H, s), 3.39(3H, s), 3.58(2H, t), 3.66(3H,
t), 3.84(2H, s), 6.48(1H, brs), 6.83(1H, d), 6.93(2H, d), 7.29(2H,
d), 7.64(1H, d), 7.81(1H, s); MSm/z(TS.sup.+) 361(MH+) 171 Prep 48
136 4-SMe HCl salt: .delta..sub.H(CDCl.sub.3, 300 MHz)2.46(3H, s),
2.47(3H, s), 3.60(2H, in), 3.80(2H, m), 3.85(2H, s), 6.80-6.87(2H,
m), 6.94 (2H, d), 7.30(2H, s), 7.67(1H, d), 7.85 (1 H, s);
MSm/z(TS+)347 (MH+) 172 Prep 49 137 4-SMe Free base:
.delta..sub.H(CDCl.sub.3, 300 MHz)2.49 (3H, s), 2.50(3H, s),
3.88(2H, s), 4.17 (2H, d), 6.82(1H, d), 6.93-7.00(3H, m), 7.29(2H,
d), 7.70(1H, d), 7.91(1H, s); MSm/z(TS.sup.+)360(MH.sup.+) 173 Prep
50 138 4-SMe Free base: .delta..sub.H(CDCl.sub.3, 400 MHz)1.18 (3H,
d), 2.45(3H, s), 2.46(3H, s), 3.62 (1H, dd), 3.75(1H, dd), 3.91(2H,
s), 4.20-4.28 (1H, m), 6.23(1H, brd), 6.79(1H, d), 6.89(2H, d),
7.23(2H, d), 7.61(1H, d), 7.79(1H, s); MSm/z(TS.sup.+)361(MH.sup.+)
174 Prep 51 139 4-SMe Free base: .delta..sub.H(CDCl.sub.3, 400
MHz)1.23 (3H, d), 2.44(6H, s), 2.46(3H, s), 3.62 (1H, dd), 3.76(1H,
dd), 3.91(2H, s), 4.20-4.28 (1H, m), 6.34(1H, brd), 6.79(1H, d),
6.88(2H, d), 7.25(2H, d), 7.62(1H, d), 7.81(1H, s);
MSm/z(TS.sup.+)361(MH.sup.+) 175 Prep 52 140 4-SMe HCl salt:
.delta..sub.H(CD.sub.3OD, 400 MHz)2.49(3H, s), 2.80(3H, s),
2.91(3H, s), 4.37(2H, s), 6.83(1H, d), 7.12(2H, d), 7.38(2H, d),
7.81(1H, d), 8.00(1H, s); MSm/z(TS.sup.+) 318(MH.sup.+) 176 Prep 54
141 3-OMe, 4-SMe HCl salt: .delta..sub.H(CD.sub.3OD, 400
MKz)2.38(3H, s), 2.77(3H, s), 2.91(3H, s), 3.81(3H, s), 4.35(2H,
s), 6.72(1H, dd), 6.79(1H, d), 6.85(1H, d), 7.23(1H, d), 7.78(1H,
dd), 7.96(1H, d); MSm/z(TS.sup.+)347(MH.sup.+)
EXAMPLE 177
[0355]
3-[(Methylamino)methyl]-4-[4-(methylsulfanyl)-3-(trifluoromethyl)ph-
enoxy]-benzamide 142
[0356] The Boc-protected amine of preparation 46 (396 mg, 0.842
mmol) was treated with hydrochloric acid (4 M) in dioxan (5 mL) and
stirred for 1.5 hours. The solvent was removed by evaporation and
the residue basified by the addition of saturated aqueous sodium
bicarbonate solution and then extracted with DCM (4.times.10 mL).
The combined organic extracts were washed with brine (10 mL) dried
(MgSO.sub.4) and evaporated to a yellow oil. This oil was purified
by flash chromatography [SiO.sub.2; DCM/ MeOH/ 880
NH.sub.3(93:7:1)] to afford the title amide as a white foam (208
mg, 66%). Free base: .delta..sub.H(CDCI.sub.3, 400 MHz) 2.45 (3 H,
s), 2.51 (3 H, s), 3.82 (2 H, s), 6.84 (1 H, d), 7.10 (1 H, d),
7.31 (1 H, s), 7.40 (1 H, d), 7 72 (1 H, dd), 7.91 (1 H, s); MS m/z
(TS.sup.+) 371 (MH.sup.+).
EXAMPLE 178
[0357]
3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)-3-(trifluoromethyl)-
-phenoxy]benzamide 143
[0358] The amide from example 177 (105 mg, 0.28 mmol) was suspended
in DCM (3 mL) and treated with formaldehyde (37% aqueous, 35 .mu.L,
0.425 mmol). The mixture was stirred for 30 minutes (dissolution
had occurred by this stage) and then treated with sodium
tri(acetoxy)borohydride (120 mg, 0.567 mmol). The reaction was
stirred overnight and then diluted with water (5 mL), basified with
880 ammonia (1 mL) and extracted with DCM (3.times.10 mL). The
combined organic extracts were washed with brine (5 mL), dried
(MgSO.sub.4) and evaporated to a white solid. Purification by flash
chromatography [siO.sub.2; DCM, MeOH, 880 NH.sub.3 (95:5:0.5)]
afforded the title amide as a white powder (85 mg, 78%); Free base:
.delta..sub.H (CDCI.sub.3, 400 MHz) 2.24 (6 H, s), 2.46 (3 H, s),
3.50 (2 H, s), 5.47-6.15 (2 H, brm), 6.85 (1 H, d), 7.03 (1 H, d),
7.23 (1 H, s), 7.35 (1 H, d), 7.71 (1 H, d), 7.90 (1 H, s); MS m/z
(TS.sup.+) 385 (MH.sup.+)
EXAMPLES 179-180
[0359] The following amides were prepared in an analogous fashion
to that in example 178 from the requisite secondary amine.
31 144 Starting Example Material R.sup.6 (R.sup.3).sub.n data 179
Example 169 H 3-OMe, .delta..sub.H(CD.sub.3OD, 400MHz)2.41(3H, s),
2.97(6H, s), 4-SMe 3.86(3H, s), 4.54(2H, s), 6.77(1H, dd), 6.85
(1H, d), 6.91(1H, d), 7.28(1H, d), 7.93(1H, dd), 8.10(1H, d);
MSm/z(TS.sup.+)347(MH.sup.+) 180 Example 176 Me 3-OMe,
.delta..sub.H(CDCl.sub.3, 400MHz)2.44(3H, s), 2.87(6H, s), 4-SMe
3.00(3H, d), 3.85(3H, s), 4.35(2H, s), 6.56(2H, in), 6.88(1H, d),
7.16(1H, d), 7.58(1H, brd), 7.94(1H, dd), 8.61(1H,d);
MSm/z(TS.sup.+)361 (MH.sup.+)
EXAMPLES 181 and 182
[0360] N-Methyl-N-[2-[4-(methylsulfanyl)phenoxy]-5-(1 H-
1,2,3-triazol- 1-yl)benzyl]amine (Example 181) and
[0361] N-methyl-N-[2-[4-(methylsulfanyl)phenoxy]-5-(2
H-1,2,3-triazol-2-yl)benzyl]amine (Example 182) 145
[0362] The bromide of Example 23 (2.0 g, 6 mmol) was mixed with
copper powder (378 mg, 6 mmol) 1,2,3-triazole (ca. 5 g, excess),
and potassium carbonate (828 mg, 6 mmol) were heated together at
160.degree. C. for 48 h. After cooling to room temperature the
reaction mixture 15 was partitioned between sodium hydroxide (3 M)
and ethyl acetate. The organic layer was separated and washed with
sodium hydroxide (3 M) (3 x), water, and brine, before being dried
(MgSO.sub.4) and evaporated. The resulting residue was purified by
flash chromatography [SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3
(97.5:2.5:0.25)] to afford, separately, the 1-substitiuted triazole
derivative compound of Example 181 and the 2-substituted isomer
compound of Example 182. The hydrochloride salt of each was
precipitated by treatment with ethereal hydrochloric acid (1 M
solution, excess).
[0363] Example 181 (mono-hydrochloride salt) (270 mg, 13%);
.delta..sub.H(d.sub.6-DMSO, 400 MHz) 2.50 [3 H, s(obsc.)], 2.64 (3
H, t), 4.27 (2 H, t), 6.97 (1 H, d), 7.14 (2 H, d), 7.36 (2 H, d),
7.87 (1 H, dd), 7.99 (1 H, s), 8.26 (1 H, d), 8.76 (1 H, s), 9.16
(2 H, brs); MS m/z (TS.sup.+) 327 (MH.sup.+).
[0364] Example 182 (bis-hydrochloride salt) (400 mg, 17%);
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.50 (3 H, s), 2.67 (3 H, brs),
4.18 (2 H, brs), 6.95 (1 H, d), 7.15 (2 H, d), 7.27 (2 H, d), 7.74
(2 H, s), 7.96 (1 H, dd), 8.35 (1 H, d), 9.92 (2 H, brs); MS m/z
(TS.sup.+) 327 (MH.sup.+).
EXAMPLE 183
[0365] N,N-Dimethyl-N-[2-[4-(methylsulfanyl)phenoxy]-5-(2
H-1,2,3-triazol-2-yl)benzyl]amine 146
[0366] The triazole derivative hydrochloride salt of Example 182
(400 mg, 1.1 mmol) was suspended in DCM (30 mL) and formaldehyde
(37% aqueous) (ca. 0.2 mL, ca. 5.5 mmol) was added followed by
sodium tris(acetoxy)borohydride (1.16 g, 5.5 mmol). The reaction
mixture was stirred at room temperature for 1 h and then
partitioned between sodium hydroxide (3 M) and DCM. The organic
layer was separated and the aqueous layer extracted further with
DCM (4 x). The combined organic fractions were washed with brine,
dried (MgSO.sub.4), and evaporated to give the title compound as a
colourless oil (290 mg, 70%); .delta..sub.H(CDCI.sub.- 3, 400 MHz),
2.44 (3 H,s), 2.49 (6 H, s), 3.75 (2 H, brs), 6.93 (2 H, d), 6.98
(1 H, d), 7.26 (2 H, d), 7.80 (2 H, s), 7.85 (1 H, dd), 8.26 (1 H,
d); MS m/z (TS.sup.+) 341 (MH.sup.+).
EXAMPLE 184
[0367] N,N-Dimethyl-N-[2-[4-(methylsulfanyl)phenoxy]-5-(1
H-1,2,3-triazol-1-yl)benzyl]-amine 147
[0368] The title compound was prepared from the product of example
181 in an analogous fashion to that used for the preparation of the
compound of Example 183 (108 mg, 52%); .delta..sub.H (CDCI.sub.3,
400 MHz) 2.18 (6 H, s), 2.44 (3 H, s), 3.48 (2 H, brs), 6.97 (2 H,
d), 7 06 (1 H, d), 7.29 (2 H, d), 7.76 (1 H, d), 7.97 (2 H, d),
8.80 (1 H, s), MS m/z (TS.sup.+) 341 (MH.sup.+).
EXAMPLE 185
[0369] N-[2-[4-(Methylsulfanyl)phenoxy]-5-(1
H-imidazol-1-yl)benzyl]-N-met- hylamine 148
[0370] The aryl bromid e d erivative from Example 23 (2 g, 6 mmol)
was combined with imidazole (5 g, 73.5 mmol), copper powder (381
mg, 6 mmol) and potassium carbonate (828 mg, 6 mmol) and the
mixture heated at 160.degree. C. for 3 hours. After cooling to room
temperature the mixture was partitioned between aqueous sodium
hydroxide (3 M) and ethyl acetate. The 1 5 organic layer was
separated, washed with aqueous sodium hydroxide (3 M) (3 times),
water (3 times), brine and then dried (MgSO.sub.4) and evaporated.
The residue was purified by flash chromatography [SiO.sub.2; DCM/
MeOH/ 880 NH.sub.3 (95:5:0.5)] to provide the title compound which
was isolated as its bis HCI salt by the standard method (57 mg,
2%); bis HCI salt: .delta..sub.H(d.sub.6-DMSO, 400 MHz) 2.49 (3 H,
s), 2.61 (3 H, s), 4.26 (2 H, s), 6.96 (1 H, d), 7.14 (2 H, d),
7.36 (1 H, 20 dd), 7.84 (1 H, s), 8.21 (1 H, s), 8.28 (1 H, s),
9.56 (3 H, brs); MS mz (TS.sup.+) 326 (MH.sup.+)
EXAMPLE 186
[0371] N-[2-[4-(Methylsulfanyl)phenoxy]-5-(1 H-imidazol-1
-yl)benzyl]-N,N-dimethylamine 149
[0372] The title compound was prepared from the aryl bromide of
example 9 using the procedure described for Example 185; bis HCI
salt: .delta..sub.H(CD.sub.3OD, 400 MHz) 2.51 (3 H, s), 3.00 (6 H,
s), 4.60 (2 H, s), 7.06 (1 H, d), 7.17 (2 H, d), 7.41 (2 H, d),
7.77 (3 H, m), 8.11 (2 H, d), 9.47 (1 H, s); MS m/z (TS.sup.+) 340
(MH.sup.+)
EXAMPLE 187
[0373] N-Methyl-N-[2-[4-(methylsulfanyl)phenoxy]-5-(1
H-1,2,4-triazol-1 -yl)benzyl]amine 150
[0374] The title compound was prepared from the aryl bromide of
example 23 using the procedure described for Examples 181/ 182, bis
HCI salt: .delta..sub.H(d.sub.6-DMSO, 400 MHz) 2.50 (3 H, s), 2.62
(3 H, s), 4.27 (2 H, s), 6.95 (1 H, d), 7.14 (2 H, d), 7.36 (2 H,
d), 7.85 (1 H, d), 8.21 (1 H, s), 8.27 (1 H, s), 9.26 (3 H, brs);
MS m/z (TS.sup.+) 327 (MH.sup.+)
EXAMPLE 188
[0375] N,N-dimethyl-N-[2-[4-(methylsulfanyl)phenoxy]-5-(1
H-1,2,4-triazol-1 -yl)benzyl]-amine 151
[0376] The title compound was prepared from the secondary amine of
example 187 using the reductive methylation procedure described for
Example 183; Free base: .delta..sub.H(CDC.sub.3, 400 MHz) 2.30 (6
H, s), 2.48 (3 H, s), 3.54 (2 H, s), 6.91 (2 H, d), 6.97 (1 H, d),
7.27 (2 H, d), 7.52 (1 H, dd), 7.82 (IH, d), 8.10 (1 H, s), 8.54 (1
H, s); MS m/z (TS.sup.+) 341 (MH.sup.+)
EXAMPLE 189
[0377] N-[2-[4-(Methylsulfanyl)phenoxy]-5-(4H-
1,2,4-triazol-4-yl)benzyl]-- N,N-dimethylamine 152
[0378] Th aniline of example 109 (500 mg, 1.7 mol),
N'-[(dimethylamino)methylidene]-N,N-dimethylhydrazonoformamide (590
mg, 4.15 mmol) [prepared according to Bartlett et al. J. Chem. Soc.
(C), 1967, 1664], and p-toluenesulfonic acid (394 mg, 2 mmol) were
mixed in toluene (10 mL) and heated at reflux for 2 days. The
mixture was cooled to room temperature and treated with saturated
aqueous sodium bicarbonate solution and diluted with ethyl acetate.
The organic layer was separated, washed with brine, dried
(MgSO.sub.4) and evaporated. The residue was purified by flash
chromatography [SiO.sub.2; DCM/ MeOH/ 880 NH.sub.3 (90:10:1)] to
afford the desired triazole derivative (100 mg, 17%);
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.29 (6 H, s), 2.48 (3 H, s),
3.54 (2 H, s), 6.92 (2 H, d), 6.95 (1 H, d), 7.19 (IH, dd), 7.29 (2
H, d), 7.46 (2 H, s); MS m/z (TS.sup.+) 341 (MH.sup.+)
EXAMPLE 190
[0379] 153
[0380] Copper powder (1.53 g, 24 mmol), potassium carbonate (6.08
g, mmol) and 3-aminopyrazole were mixed and heated to 50.degree. C.
to form a melt. Iodine (51 mg, 0.2 mmol) was added and the mixture
stirred for 20 minutes before the addition of the aryl bromide from
preparation 39 (8.77 g, 20 mmol). After a further 10 minutes the
reaction mixture was heated to 140.degree. C. for 9 hours, After
cooling to room temperature the mixture was partitioned between
saturated aqueous ethylenediaminetetraace- tic acid (EDTA) and
ethyl acetate (70 mL each) and the mixture stirred for 4 hours. The
mixture was further diluted with satuated aqueous EDTA and ethyl
acetate (1000 mL each). The ethyl acetate layer was separated,
washed with brine, dried and evaporated. The residue was purified
by flash chromatography {SiO.sub.2; [MeOH 880 NH.sub.3 (1:9)] in
DCM (1.fwdarw.10%) to provide the title compound as a brown oil
which solidified on standing under vacuum (1.52 g, 22 %);
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.44 (3 H, s), 2.52 (3 H, s),
3.77 (4 H, brs), 5.80 (1 H, s), 6.86 (3 H, m), 7.25 (2 H, d), 7.39
(1 H, dd), 7.58 (1 H, d), 7.63 (1 H, s).
EXAMPLE 191
[0381] N-{5-(3-Amino- 1 H-pyrazol- 1
-yl)-2-[4-(methylsulfanyl)phenoxy]ben- zyl}-N, N-dimethylamine
154
[0382] (i) Preparation of the Formamide
[0383] Formic acid (145 .mu.L, 3.84 mmol) was added to a solution
of pentafluorophenoi (642 mg, 3.49 mmol) in ether (5 mL) at
0.degree. C. followed by dicyclohexylcarbodiimide (722 mg, 3.49
mmol). The mixture was stirred at 0.degree. C. for 15 min and at
room temperature for 1 h before being filtered, the residue being
washed with ether. The ethereal solution of pentafluorophenyl
formate was evaporated to dryness, redissolved in DCM (8 mL) added
to a solution of the aminopyrazole from example 190 (1.08 g, 3.17
mmol) in DCM (8 mL) and the reaction mixture stirred at room
temperature for 1.5 hours. The reaction mixture was then diluted
with DCM and aqueous potassium carbonate (10%; 50 mL each). The
organic layer was separated and dried (MgSO.sub.4) before being
evaporated to dryness. The residue was purified by flash
chromatography {SiO.sub.2; [MeOH/ 880 NH.sub.3 (9:1)] in DCM
(1.fwdarw.1.5 %)} to provide the intermediate formamide (770 mg,
66%); .delta..sub.H(CDCI.sub.- 3, 400 MHz, 2 rotomers visible) 2.47
(3 H, s), 2.80 (3 H, s), 2.88 [3 H, s (minor rotomer)], 4.41 (2 H,
s), 4.56 [2 H, s (minor rotomer)], 5.79 [1 H, d (minor rotomer)],
5.81 (1 H, d), 6.83-6.92 (4 H, m), 7.36-7.46 (1 H, m), 7.46 (1 H,
s), 7.59 (1 H, d), 8.11 [1 H, s (minor rotomer)], 8.22 (1 H, s); MS
m/z (TS+) 369 (MH+).
[0384] (ii) Reduction to the Tertiary Amine
[0385] The formamide from stage (i) (770 mg, 2.09 mmol) was
dissolved in THF (21 mL) and treated with borane-tetrahydrofuran
complex (1 M in THF, 6.27 mL, 6.27 mmol) at room temperature. The
reaction mixture was heated at reflux for 2 hours before being
cooled to room temperature and quenched by the cautious addition of
hydrochloric acid (6 M; 15 mL). The mixture was then reheated to
80.degree. C. for 30 minutes before being recooled to room
temperature. The mixture was made basic by the addition of
sodiumhydroxide (2 M; 50 mL) and then extracted with DCM (70 mL).
the organic layer was separated, dried (MgSO.sub.4) and evaporated.
The residue was purified by flash chromatography {SiO.sub.2; [MeOH/
880 NH.sub.3 (9:1)] in DCM (1.fwdarw.5 %)} to provide the title
compound as a solid (100 mg, yield 13%); .delta..sub.H(CDCI.sub.3,
400 MHz) 2.22 (6 H, s), 2.42 (3 H, s), 2.42 (2 H, s), 3.76 (2 H,
brs), 5.80 (1 H, d), 6.82 (2 H, d), 6.91 (IH, d), 7.21 (2 H, d),
7.41 (1 H, dd), 7.63 (1 H, d); MS m/z (TS.sup.+) 355
(MH.sup.+).
EXAMPLE 192
[0386] 5-Chloro-2-[4-(methylsulfanyl)phenoxy]benzylamine 155
[0387] To a suspension of lithium aluminium hydride (745 mg, 19.6
mmol) in diethyl ether (30 mL) was added aluminium chloride (872
mg, 6.54 mmol) in diethyl ether (10 mL). Following complete
addition the mixture was stirred for 15 minutes at room
temperature, then the nitrile from preparation 58 (2.44 g, 8.7
mmol) in diethyl ether (10 mL) was added dropwise. The mixture was
then stirred for 2 hours at room temperature, after which time it
was quenched by the addition of sodium hydroxide (1 M; 5 mL) and
then diluted with diethyl ether (20 mL). After stirring for 5
minutes the liquid phase was decanted off and the residue washed
twice more with diethyl ether (2.times.20 mL). The combined organic
layers were washed with saturated aqueous sodium bicarbonate (20
mL), brine (20 mL), dried (MgSO.sub.4) and evaporated to a yellow
oil (2.35 g, 96%); .delta..sub.H(CDCI.sub.3, 400 MHz) 2.47 (3 H,
s), 3.84 (2 H, s), 6.75-6.79 (2 H, m), 6.87-6.90 (2 H, m),
7.15-7.29 (2 H, m), 7.38-7.41 (1 H, m); MS m/z (TS.sup.+) 280, 282
(MH.sup.+).
PREPARATIONS
PREPARATION 1
[0388] 2-[4-(Methylsulfanyl)phenoxy]benzaldehyde 156
[0389] 2-Fluorobenzaldehyde (31.6 mL, 300 mmol) and
4-(methylmercapto)phenol (46.27 g, 330 mmol) were dissolved in DMF
(500 mL) and potassium carbonate (62.2 g, 450 mmol) was then added.
The mixture was heated at 100.degree. C. for 12 h under a nitrogen
atmosphere. After cooling to room temperature the mixture was
evaporated to dryness, co-evaporated with toluene and then
partitioned between ethyl acetate and water. The organic layer was
separated, washed with water, dried (MgSO.sub.4) and evaporated to
a brown oil of the desired aldehyde material (84.4 g) which was
contaminated with ca 15% of starting phenol, but sufficiently pure
to use directly in the next stage; .delta..sub.H(CDCI.sub.3, 400
MHz) 2.47 (3 H, s), 6.87 (1 H, d), 6.99 (2 H, m), 7.17 (1 H, m),
7.29 (2 H, m), 7.49 (1 H, m), 7.92 (1 H, d), 10.49 (1 H, s). If
required the crude mixture can be purified by flash chromatography
[SiO.sub.2; ethyl acetate/ hexanes (2.fwdarw.10%)] to obtain a pure
sample of the desired aldehyde compound.
[0390] Alternatively the title compound can be prepared as
follows:
[0391] Potassium carbonate (538.7 g, 3.89 mol) and
4-(methylmercapto)pheno- l (400 g, 2.85 mol) were added
successively to DMF (3 L). 2-Fluorobenzaldehyde (322 g, 2.59 mol)
was then added to the slurry and the mixture heated in the range 92
to 100.degree. C. After 19 h the reaction mixture was allowed to
cool to room temperature and water (2L) added. The solution was
cooled to below 10.degree. C. and the pH adjusted to 2 with 2.5 M
HCI (1.5 L), keeping the temperature below 10.degree. C. Water (2.6
L) was added and the slurry stirred at below 5.degree. C. for 2 h.
The slurry was filtered and the cake washed with water (4.times.1
L). The crude product was dissolved in dichloromethane and the
solvent 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 (634 g, 100%).
PREPARATIONS 2-18
[0392] The reaction of preparation 1 was repeated under similar
conditions using a range of commercially available phenols and
2-fluorobenzaldehydes to provide the compounds of preparations 2 to
18. Each reaction was monitored carefully by thin layer
chromatography and was run until deemed complete. The data for
these compounds are given in the table below.
32 157 Preparation R.sup.4 R.sup.5 (R.sup.3).sub.n Data 2 H Br
3-CF.sub.3 .delta..sub.H(CDCl.sub.3, 300MHz)6.82(1H, d), 7.23(1H,
d), 7.34 (1H, s), 7.48(1H, d), 7.52(1H, dd), 7.65(1H, d), 8.09(1H,
s), 10.40(1H, s) 3 H Br 4-CF.sub.3 .delta..sub.H(CDCl.sub.3,
300MHz)6.87(1H, d), 7.16(2H, d), 7.61-7.72(3H, m), 8.08(1H, s),
10.36(1H, s); MS m/z (TS.sup.+)344,346(MH.sup.+). 4 H H 4-CF.sub.3
.delta..sub.H(CDCl.sub.3, 300MHz)7.00(1H, d), 7.16(2H, d), 7.28
(3H, m), 7.62(3H, m), 7.98(1H, d), 10.49(1H, s) 5 Br H 4-CF.sub.3
.delta..sub.H(CDCl.sub.3, 300MHz)7.11(1H, s), 7.18(2H, d), 7.42
(1H, d), 7.69(2H, d), 7.84(1H, d), 10.40(1H, s) 6 H H 4-OCF.sub.3
.delta..sub.H(CDCl.sub.3, 300MHz)6.92(1H, d), 7.08(2H, m), 7.23(3H,
m), 7.55(1H, m), 7.96(1H, dd), 10.50 (1H, s);
MSm/z(TS.sup.+)300(MNH.sub.4.su- p.+). 7 H Br 4-OCF.sub.3
.delta..sub.H(CDCl.sub.3, 300MHz)6.81(1H, d), 7.08(2H, m), 7.26(2H,
m), 7.62(1H, dd), 8.04(1H, d), 10.40(1H, s) 8 Br H 4-OCF.sub.3
.delta..sub.H(CDCl.sub.3- , 300MHz)7.05(1H, d), 7.10(2H, d),
7.30(2H, d), 7.35(1H, dd), 7.80(1H, d), 10.45(1H, s) 9 H Br 4-SMe
.delta..sub.H(CDCl.sub.3, 300MHz)2.49(3H, s), 6.78(1H, d), 6.98(2H,
m), 7.29(2H, m), 7.48(1H, dd), 8.02(1H, d), 10.44(1H, s);
MSm/z(TS.sup.+)340(MNH.sub.4.sup.+) 10 H F 4-SMe
.delta..sub.H(CDCl.sub.3, 300MHz)2.49(3H, s), 6.86-6.99(3H, m),
7.19-7.30(3H, m), 7.58(1H, m), 10.40(1H, d) 11 H H 4-SMe
.delta..sub.H(CDCl.sub.3, 400MHz)2.47(3H, s), 6.87(1H, d), 6.99(2H,
m), 7.17(1H, m), 7.29(2H, m), 7.49(1H, m), 7.92(1H, d), 10.49(1H,
s) 12 H H 3-OCF.sub.3 .delta..sub.H(CDCl.sub.3, 400MHz)6.97(3H, m),
7.03(1H, d), 7.26(1H, m), 7.40(1H, m), 7.57(1H, m), 7.98(1H, m),
10.45(1H, s); MSm/z(TS.sup.+)300(MNH.sub.4.sup.+). 13 H MeO 4-SMe
.delta..sub.H(CDCl.sub.3, 300MHz)2.48(3H, s), 3.86(3H, s), 6.90
(3H, m), 7.10(1H, dd), 7.26(2H, d), 7.40(1H, d), 10.39(1H, s) 14 Br
H 4-SMe .delta..sub.H(CDCl.sub.3, 300MHz)2.50(3H, s), 7.00-7.06(3H,
m), 7.29-7.34(3H, m), 7.88(2H, d), 10.46(1H, s) 15 H H 4-Br
.delta..sub.H(CDCl.sub.3, 300MHz)6.90(1H, d), 6.94(2H, d), 7.22(1H,
t), 7.48(2H, d), 7.52(1H, m), 7.94(1H, d), 10.46(1H, s) 16.sup.a H
Br 3-OMe 4-SMe .delta..sub.H(CDCl.sub.3, 300MHz)2.46(3H, s),
3.89(3H, s), 6.65 (2H, m), 6.83(1H, d), 7.20(1H, d), 7.40(1H, dd),
8.04(1H, d), 10.46(1H, s); MSm/z(TS.sup.+)370/372 (MNH.sub.4.sup.+)
17.sup.b H Br 3-CF.sub.34-SMe .delta..sub.H(CDCl.sub.3,
300MHz)2.55(3H, s), 6.81(1H, d), 7.20(1H, d), 7.40(1H, s), 7.46(1H,
d), 7.66(1H, d), 8.08(1H, s), 10.43(1H, s) 18 MeO MeO 4-SMe
.delta..sub.H(CDCl.sub.3, 400MHz)2.48(3H, s), 3.82(3H, s), 3.93
(3H, s), 6.43(1H, s), 6.95(2H, d), 7.28(2H, d), 7.38 (1H, s),
10.25(1H, 5), MSm/z(TS.sup.+)305(MH.sup.+). .sup.aThe phenol of
preparation 35 was used. .sup.bThe phenol of preparation 34 was
used.
PREPARATIONS 19-20
[0393] The following diphenylethers were prepared in an analogous
fashion to the reaction described for preparation 1 using
2-chloro-5-nitrobenzald- ehyde with the appropriate commercially
available phenol. Shorter reaction times (ca. 3 h) were sufficient
to achieve good conversions in these cases.
33 158 Preparation R.sup.3 data 19 --SMe .delta..sub.H(CDCl.sub.3,
400MHz)2.53(3H, s), 6.90(1H, d), 7.10(2H, m), 7.37 (2H, m),
8.30(1H, dd), 8.79(1H, d), 10.58(1H, s); MSm/z(TS.sup.+)
307(MNH.sub.4.sup.+). 20 --CF.sub.3 .delta..sub.H(CDCl.sub.3,
400MHz)6.98(1H, d), 7.27(2H, d), 8.36(1H, dd), 8.83 (1H, d),
10.55(1H, s); MSm/z(TS.sup.+)311(MH.sup.+)
PREPARATION 21
[0394] N,N-Dimethyl-N-{2-[4-(methylsulfanyl)phenoxy]benzyl}amine
159
[0395] The aldehyde of preparation 1 (21.23 g, 87 mmol) was
dissolved in a 1:1 mixure of THF and DCM (180 mL each) together
with dimethylamine hydrochloride (7.81 g, 95.8 mmol) and
triethylamine (36.4 mL, 261 mmol). Sodium triacetoxyborohydride
(27.7 g, 130.7 mmol) was then added to the reaction mixture stirred
at room temperature under a nitrogen atmosphere overnight. The
reaction mixture was evaporated, and then partitioned between DCM
and water (1000 mL each). The organic layer was separated, dried
(MgSO.sub.4) and then evaporated to a brown oil. The residue could
be purified by flash chromatography [SiO.sub.2; {(MeOH/ 880
NH.sub.3) (9:1)} (0.fwdarw.5%) in DCM] to afford the desired amine
free base compound as a brown oil; .delta..sub.H(CDCI.sub.3, 400
MHz) 2.26 (6 H, s), 2.46 (6 H, s), 3.45 (2 H, s), 6.84-6.90 (3 H,
m), 7.13 (1 H, t), 7.20-7.26 (3 H, m), 7.46 (1 H, d); MS m/z
(TS.sup.+) 274 (MH.sup.+). Alternatively, the crude reaction
product could be purified by formation and crystallisation of the
hydrochloride salt by dissolution in diethyl ether (150 mL)
followed by addition of hydrochloric acid (1 M) in diethyl ether
(150 mL) to the stirred solution. The hydrochloride salt of the
desired dimethylamine compound was collected as a white solid
(22.58 g, 84%); .delta..sub.H(CDCI.sub.3, 400 MHz) 2.43 (3 H, s),
2.80 (6 H, d), 4.32 (2 H, s), 6.86 (1 H, d), 6.93 (2 H, d), 7.20 (1
H, t), 7.25 (2 H, m), 7.36 (1 H, dt) 7.85 (1 H, dd), 12.47 (1 H,
br).
[0396] Alternatively, the hydrochloride salt of the title compound
can be prepared as follows.
[0397] A solution of the product from preparation 1 (390 g, 1.59
mol) in DCM (2.73 L) was added to THF (2.73 L). To that was added
dimethylamine hydrochloride (143 g, 1.75 mol) and triethylamine
(485 g, 4.80 mol) successively. The temperature was adjusted to
20.degree. C. and after 1 h sodium triacetoxyborohydride (508 g,
2.93 mol) was added. After 20 h, dichloromethane (3.9 L) was added
and a solution of 8% sodium bicarbonate (3.9 L) was added over 0.5
h. The layers were separated and the organic layer washed with
water (2.5 L). The layers were again separated and the organic
layer was concentrated to a volume of 1.65 L. Ethyl acetate (2.89
L) was added and the solvent removed replacing with fresh ethyl
acetate to give a final volume of 2.92 L. The solution was then
cooled to below 5.degree. C. and 6.75 M hydrochloric acid in
isopropanol (0.25 L, 1.69 mol) added maintaining the temperature
below 10.degree. C. After stirring for 1 h at below 5.degree. C.,
the slurry was filtered, washed with ethyl acetate (2.times.0.39 L)
and dried in a vacuum oven at 50.degree. C. overnight to give the
desired product as a powdery solid (308.3 g, 63%).
PREPARATIONS 22-25
[0398] The amines of Preparations 22 to 25 were prepared according
to the process 5 described in preparation 21.
34 160 Starting Preparation Material R.sup.3 Data 22 (HCl salt)
Prep. 4 4-CF.sub.3 .delta..sub.H(CDCl.sub.3, 300MHZ)2.79(6H, s),
4.28(2H, s), 6.96(1H, d), 7.06(2H, d), 7.29(1H, t), 7.42(1H, t),
7.63(2H, d), 7.95(1H, d); MSm/z(TS.sup.+)296 (MH.sup.+). 23 Prep. 6
4-OCF.sub.3 .delta..sub.H(CDCl.sub.3, 300MHz)2.25(6H, s), 3.44(2H,
s), 6.92(3H, m), 7.17(3H, m), 7.23(1H, m), 7.49 (1H, d);
MSm/z(TS.sup.+)312(MH.sup.+). 24 Prep. 12 3-OCF.sub.3
.delta..sub.H(CDCl.sub.3, 400MHz)2.23(6H, s), 3.41(2H, s), 6.78(1H,
s), 6.83(1H, d), 6.90(1H, d), 6.97(1H, d), 7.18(1H, m), 7.28(2H,
m), 7.49(1H, d); MS m/z(TS.sup.+)312(MH.sup.+). 25 Prep 15 4-Br HCl
salt: .delta..sub.H(d.sub.6-DMSO, 400MHz)2.71(6H, s), 4.30(2H, s),
6.87(1H, d), 7.07(2H, d), 7.22(1H, t), 7.42(1H, t), 7.60(2H, d),
7.78(1H, d)
PREPARATION 26
[0399] N-Methyl-N-{2-[4-(trifluoromethoxy)phenoxy]benzyl}amine
161
[0400] The aldehyde compound of preparation 6 (2.5 g, 8.86 mmol)
was dissolved in a solution of monomethylamine in ethanol (ca. 8 M)
(11 mL, 88 mmol), and the mixture stirred at room temperature
overnight. THF/ ethanol (1:1) was added to the mixture to aid
dissolution and sodium borohydride (3.35 g, 88.6 mmol) was added.
Stirring was continued for 4 h before the reaction was quenched by
cautious addition of hydrochloric acid (1 M) (until gas evolution
ceased). The mixture was basified with aqueous sodium hydroxide (2
M), and then extracted with ethyl acetate (3 times). The combined
organic fractions were dried (MgSO.sub.4) and evaporated to an oil
which was purified by flash chromatography [SiO.sub.2; DCM/ MeOH/
880 NH.sub.3 (93:7:1)] to afford the desired amine compound as a
colourless oil (2.23 g, 84%); 8H (CDCI.sub.3, 300 MHz) 1.72 (1 H,
br), 2.42 (3 H, s), 3.77 (2 H, s), 6.92 (3 H, m), 7.16 (3 H, m),
7.23 (1 H, m), 7.41 (1 H, d); MS m/z (TS.sup.+) 298 (MH.sup.+).
PREPARATION 27
[0401] N-Methyl-N-{2-[4-(trifluoromethyl)phenoxy]benzyl}amine
162
[0402] The title amine was synthesised using the conditions
described for preparation 26 starting from the aldehyde compound of
Preparation 4; .delta..sub.H(CDCI.sub.3, 300 MHz) 2.57 (3 H, s),
4.14 (2 H, s), 5.50 (2 H, brs), 6.88 (1 H, d), 7.18 (3 H, m), 7.34
(1 H, t), 7.61 (2 H, d), 7.70 (1 H, d); MS m/z (TS.sup.+) 282
(MH.sup.+).
PREPARATION 28
[0403] N-Methyl-N-{2-[4-(methylsulfanyl)phenoxy]benzyl}amine
163
[0404] The title amine was prepared from the aldehyde of
preparation 1 according to the method described for preparation 26;
.delta..sub.H(CD.sub.3OD, 300 MHz) 2.41 (3 H, s), 2.45 (3 H, s),
3.80 (2 H, s), 6.84 (1 H, d), 6.94 (2 H, d), 7.15 (1 H, m), 7.28 (3
H, m), 7.43 (1 H, d); MS m/z (TS.sup.+) 260 (MH.sup.+).
PREPARATION 29
[0405] N-{2-[4-(Ethylsulfanyl)phenoxy]benzyl}-N,N-dimethylamine
164
[0406] The product from preparation 25 (1.09 g, 3.18 mmol) was
dissolved in DMSO (3.2 mL) and treated with sodium ethanethiolate
(535 mg, 6.36 mmol) and palladium tetrakis(triphenylphosphine) (367
mg, 1155.57). The mixture was stirred and heated to 100.degree. C.
overnight. After cooling to room temperature, the mixture was
partitioned between water and diethyl ether (100 mL each). The
organic layer was separated and the aqueous layer re-extracted with
diethyl ether (100 mL). The combined ether layers were washed with
brine (100 mL), dried (MgSO.sub.4) and evaporated to a bright red
oil. Purification by flash chromatography [SiO.sub.2; DCM/ MeOHI
880 NH.sub.3 (93:7:1)] afforded an orange oil which was dissolved
in ethyl acetate (10 mL) and treated with hydrochloric acid (1 M)
in diethyl ether (5 mL). The solvents were evaporated to afford a
beige solid which was recrystallised from boiling ethyl acetate to
give a cream powder (491 mg, 54%); 1.30 (3 H, t), 2.80 (6 H, d),
2.92 (2 H, q), 4.31 (2 H, d), 6.88 (1 H, d), 6.94 (2 H, d), 7.23 (1
H, t), 7.38 (2 H, d), 7.87 (1 H, d); MS mlz (ES.sup.+) 288
(MH.sup.+)
PREPARATION 30
[0407]
5-(Aminosulfonyl)-2-[3-methoxy-4-(methylsulfanyl)phenoxy]-N-methylb-
enzamide 165
[0408] The sulfonamide from preparation 67 (405 mg, 1.7 mmol) was
combined with the 5 phenol of preparation 35 (297 mg, 1.7 mmol),
potassium carbonate (362 mg, 2.6 mmol) and DMF (10 mL), and the
mixture was then heated at 110.degree. C. for 18 hours. After
cooling to room temperature the reaction mixture was diluted with
water, acidified to pH 3 with hydrochloric acid (2 M) and extracted
with ethyl acetate (2.times.75 mL). The organic layers were
combined, dried (MgSO.sub.4) and evaporated to dryness. The residue
was purified by flash chromatography [SiO.sub.2; DCM/ MeOH/ 880
NH.sub.3 (93:7:1.fwdarw.90:10:1)] to afford the title amide as a
brown oil (600 mg, 90%); .delta..sub.H(DMSO-d.sub.6, 400 MHz) 2.33
(3 H, s), 2.75 (3 H, d), 3.75 (3 H, s), 6.69 (1 H, d), 6.82 (1 H,
s), 6.86 (1 H, d), 7.16 (1 H, d), 7.30 (2 H, s), 7.75 (1 H, d),
8.07 (1 H, s), 8.25 (1 H, m); MS m/z (TS.sup.+) 383 (MH.sup.+).
PREPARATIONS 31-33
[0409] The amides below were prepared by the procedure described
for preparation 30 using the sulfonamide of preparation 67 and the
appropriate phenol as indicated.
35 166 Starting Preparation Material (R.sup.3).sub.n .sup.1H NMR
Data 31 -- 4-SMe .delta..sub.H(CDCl.sub.3, 400MHz)2.46(3H, s),
3.46(3H, s), 4.27 (2H, d), 7.64(1H, d), 11.60(1H, br);
MSm/z(TS.sup.+)363 (MH.sup.+). 32 Prep 36 4-OMe
.delta..sub.H(CD.sub.3OD, 400MHz)2.36(3H, s), 2.96(3H, s), 3.87
3-SMe (3H, s), 6.87(2H, m), 6.99(2H, m), 7.86(1H, d), 8.34 (1H, s);
MSm/z(ES.sup.-)381(MH.sup.+). 33 Prep 34 3-CF.sub.3
.delta..sub.H(CDCl.sub.3, 400 MHz)2.56(3H, s), 3.52(3H, s), 4.39
4-SMe (2H, s), 7.04(1H, d), 7.12(1H, s), 7.31(2H, d), 7.40 (1H, d),
7.71(1H, d)
PREPARATION 34
[0410] 4-(Methylsulfanyl)-3-(trifluoromethyl)phenol 167
[0411] (i) Sulfide formation:
1-(methylsulfanyl)-4-nitro-2-(trifluoromethy- l)benzene
[0412] 2-Fluoro-5-nitrobenzotrifluoride (30 mL, 218.4 mmol) was
dissolved in DMF (218 mL) and treated with
4,4'-thiobis-(6-tert-butyl-meta-cresol) (150 mg, 0.4 mmol) then
sodium methanethiolate (15 g, 214 mmol). The reaction mixture was
stirred at room temperature overnight, after which time it was
evaporated to a low volume. The residue was partitioned between
diethyl ether and water (1000 mL each). The organic fraction washed
sequentially with water and brine (750 ml each), dried (MgSO.sub.4)
and evaporated to a yellow oil. Purification by flash
chromatography [SiO.sub.2; ethyl acetate/ pentane
(5:95.fwdarw.10:90)] afforded a mixture of two compounds which was
further purified by flash chromatography [SiO.sub.2; DCM/ pentane
(10:90.fwdarw.40:60)] to afford the title sulfide (7.96 g, 15%);
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.58 (3 H, s), 7.39 (1 h, d),
8.28 (1 H, dd), 8.46 (1 H, d)
[0413] (ii) Nitro reduction:
4-(methylsulfanyl)-3-(trifluoromethyl)aniline
[0414] A suspension of the sulfide from stage (i) in acetic acid
(168 mL) and water (25 mL) was treated with iron powder (11.25 g,
201 mmol). The mixture was stirred at room temperature for 2 hours
before being evaporated to a small volume. The residue was
partitioned between saturated NaHCO.sub.3(aq), ethyl acetate (200
mL each) then filtered through a plug of arbocel.RTM.. The organic
layer was separated and the aqueous layer re-extracted with ethyl
acetate (2.times.100 mL). The combined organic layers were dried
(MgSO.sub.4) and evaporated to a brown oil of the title aniline
slighly contaminated with acetic acid (8 g ca. 100%); .delta..sub.H
(CDCI.sub.3, 400 MHz) 2.40 (3 H, s), 6.77 (1 H, dd), 6.95 (1 H, d),
7.32 (1 H, d).
[0415] (iii) Diazonium salt formation/ hydrolysis:
4-(methylsulfanyl)-3-(t- rifluoromethyl)phenol
[0416] A suspension of the aniline from stage (ii) (8.00 g, 38.2
mmol) in water was treated with concentrated sulfuric acid (20 mL)
and cooled to 0.degree. C. with vigorous stirring. Solution of
sodium nitrite (2.9 g, 42.1 mmol) in water (15 mL) was added
dropwise, and upon completion of the addition the mixture was
stirred at this temperature for a further 30 minutes by which time
dissolution had occurred. A solution of copper(ll) nitrate
hemipentahydrate (120 g, 516 mmol) in water (900 mL) was added
followed by solid copper(l) oxide (4.9 g, 34.4 mmol). Vigorous
stirring was continued until nitrogen evolution subsided (10-15
minutes). The reaction mixture was extracted with diethyl ether
(2.times.400 mL) and these combined organics were extracted with
aqueous sodium hydroxide (1M) (3 x 100 mL). The combined NaOH
fractions were acidified to pH 2 with concentrated hydrochloric
acid, and extracted with diethyl ether (2.times.150 mL). The
combined organic fractions were washed with brine, dried
(MgSO.sub.4) and evaporated to a brown oil (3.5 g, 44%):
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.44 (3 H, s), 5.50 (1 H, brs),
6.97 (1 H, dd), 7.16 (I H, d), 7.38 (1 H, d); MS m/z (ES.sup.+) 207
(M-H.sup.+)
PREPARATION 35
[0417] 3-Methoxy4-(methylsulfanyl)phenol 168
[0418] (i) Formation of benzylether:
6-(benzyloxy)-1,3-benzoxathiol-2-one
6-Hydroxy-1,3-benzoxathiol-2-one (50 g, 297 mmol) was dissolved in
DMF (500 mL), and treated with benzyl bromide (53 mL, 446 mmol) and
potassium carbonate (82 g, 595 mmol). The mixture was heated at
60.degree. C. under a nitrogen atmosphere overnight before being
evaporated to dryness. The residue was partitioned between diethyl
ether (700 mL) and water (400 mL) and the organic layer separated.
The aqueous layer was re-extracted with diethyl ether (2.times.800
mL) and the combined organic fractions washed with water
(2.times.500 mL), dried (MgSO.sub.4), and evaporated to a yellow
oil. Purification by flash chromatography [SiO.sub.2; ethyl
acetate/ pentane (1:19.fwdarw.1:9)] gave a gummy white solid which
was triturated with Et.sub.2O/ pentane to give a white solid of the
desired benzylether (17.65 g, 23%); .delta..sub.H(CDCI.sub.3, 300
MHz) 5.10 (2 H, s), 6.92 (IH, d), 6.98 (1 H, s), 7.28 (1 H, d),
7.35-7.45 (5 H, m); MS m/z (TS.sup.+) 276 (MNH.sub.4.sup.+).
[0419] (ii) Hydrolysis of the thioxolone ring:
5-(benzyloxy)-2-sulfanylphe- nol
[0420] The benzylether from step (i) (17.55 g, 67.9 mmol) was
dissolved in THF (125 mL) and treated with aqueous sodium hydroxide
(2 M; 125 mL). After stirring at room temperature for 2 hours the
mixture was evaporated to remove THF and the remaining aqueous
solution was washed with diethyl ether (3.times.10 mL). The aqueous
layer was then acidified with concentrated hydrochloric acid to pH
1 causing the mixture to effervesce. The mixture was then extracted
with diethyl ether (3.times.100 mL) and the combined extracts were
washed with brine (100 mL), dried (MgSO.sub.4) and evaporated to a
yellow oil (13.65 g, 86 %); .delta..sub.H(CDCI.sub.3, 300 MHz) 5.08
(2 H, s), 6.40 (1 H, s), 6.55 (IH, d), 6.63 (1 H, s), 7.30-7.45 (5
H, m); MS m/z (TS.sup.+) 250 (MNH.sub.4.sup.+).
[0421] (iii) Methylation of the phenol and thiophenol:
4-(benzyloxy)-2-methoxy-1-(methylsulfanyl)benzene
[0422] A mixture of the thiophenol-phenol from stage (ii) (13.5 g,
58.1 mmol) and potassium carbonate (9.64 g, 69.7 mmol) in DMF (150
mL) at 0.degree. C. was treated with methyl iodide (7.97 mL, 128
mmol). The mixture was allowed to reach room temperature and
stirred for 3 days The reaction was evaporated to dryness and the
residue partitioned between water (150 mL) and diethyl ether (150
mL). The aqueous layer was removed and extracted further with
diethyl ether (2.times.75 mL). the combined organic layers were
washed with water (2.times.50 mL), brine (50 mL), dried
(MgSO.sub.4) and evaporated to a yellow oil. Purification by flash
chromatography [SiO.sub.2; ethyl acetate in pentane (2%
.fwdarw.4%)] afforded an oil which solidified to a white solid
after drying under vacuum (11.5 g, 65%); .delta..sub.H(CDCI.sub.3,
300 MHz) 2.40 (3 H, s), 3.90 (3 H, s), 5 08 (2 H, s), 6.57 (2 H,
s), 7.20 (1 H, dd), 7.35-7.45 (5 H, m); MS m/z (TS.sup.+) 261
(MH.sup.+).
[0423] (iv) Cleavage of the benzylether:
3-methoxy-4-(methylsulfanyl)pheno- l
[0424] The benzylether from stage (iii) (9.27 g, 39.5 mmol) was
dissolved in DCM (5 mL), ethanethiol (5 mL) and BF.sub.3.OEt.sub.2
(5 mL, 39.5 mol) were then added at room temperature under a
nitrogen atmosphere. The mixture was stirred overnight before the
reaction was quenched with hydrochloric acid (2 M) and stirred for
a further 30 mins. The mixture was then basified by the addition of
sodium hydroxide (2 M) until pH 10 was attained. The mixture was
then washed with ethyl acetate (3.times.50 mL). The aqueous layer
was reacidified by the addition of hydrochloric acid (2 M) to pH 1
and extracted with ethyl acetate (4.times.50 mL). The extracts were
combined, dried (MgSO.sub.4) and evaporated to an oil. Purification
by flash chromatography [SiO.sub.2; EtOAc/ pentane
(1:9.fwdarw.1:4)] afforded the desired phenol compound as a
colourless solid (1.73 g, 28%); .delta..sub.H(CDCI.sub.3, 400 MHz)
2.21 (3 H, s), 3.70 (3 H, s), 6.30 (1 H, d), 6.35 (IH, s), 6.96 (1
H, d), 9.39 (1 H, brs)
PREPARATION 36
[0425] 4-Methoxy-3-(methylsulfanyl)phenol 169
[0426] (i) Formation of allylether:
5-(allyloxy)-1,3-benzoxathiol-2-one
[0427] 5-Hydroxy-1,3-benzoxathiol-2-one (2g, 11.9 mmol) [prepared
according to J. Org. Chem. 1990, 55, 2736] was dissolved in acetone
(13 mL) and treated with potassium carbonate (3.29 g, 23.8 mmol)
followed by allyl bromide (1.13 mL, 13.1 mmol). The mixture was
then stirred under nitrogen atmosphere for 24 hours. The reaction
mixture was evaporated to dryness and the residue was partitioned
between water and diethyl ether (50 mL each). The organic fraction
was separated and the aqueous layer re-extracted with diethyl ether
(50 mL). The combined organic fractions were dried (MgSO.sub.4) and
evaporated to a brown oil. Purification by flash chromatography
[SiO.sub.2; pentane/ ethyl acetate (95:5.fwdarw.90:10)] afforded
the desired compound as a colourless oil (1.9 g, 77%);
.delta..sub.H(CDCI.sub.3, 400 MHz) 4.50 (2 H, d), 5.28 (1 H, d),
5.38 (1 H, d), 6.00 (1 H, ddt), 6.83 (I H, dd), 6.91 (1 H. d), 7.15
(I H, d)
[0428] (ii) Hydrolysis of the thiocarbonate:
4-(allyloxy)-2-sulfanylphenol
[0429] The allyl ether from stage (i) (834 mg) was dissolved in
degassed THF (5 mL) and treated with degassed aqueous sodium
hydroxide (2 M; 5 mL, 10 mmol). After stirring for 30 minutes the
solution was acidified with hydrochloric acid (2 M) to pH 1 causing
the mixture to effervesce. The mixture was extracted with diethyl
ether (2.times.30 mL) and the combined extracts were dried
(MgSO.sub.4) and evaporated to a clear oil which used directly in
the next stage; .delta..sub.H(CDCI.sub.3, 300 MHz) 3.13 (1 H, s),
4.49 (2 H, d), 5.30 (1 H, d), 5.44 (1 H, dt), 5.76 (1 H. s),
5.97-6.12 (1 H, m), 6.79-6.96 (2 H, m), 7.16-7.25 (1 H, m).
[0430] (iii) Methylation of the phenol and thiophenol:
4-(allyloxy)-1-methoxy-2-(methylsulfanyl)benzene
[0431] The thiophenol from stage (ii) was added as a solution in
acetone (4 mL) to a slurry of potassium carbonate (1.66 g, 12 mmol)
in acetone (4 mL) and methyl iodide (623 microlitres, 10 mmol). The
mixture was stirred at room temperature overnght and then
evaporated to a gummy solid. This residue was partitioned between
diethyl ether and water (50 mL each) and the organic layer
separated. The aqueous layer was re-extracted with diethyl ether
(50 mL) and the combined organic fractions were dried (MgSO.sub.4)
and evaporated to an oil. Purification by flash chromatography
[SiO.sub.2, pentanel ethyl acetate (19:1.fwdarw.10:1] afforded the
title ally ether as an oil (556 mg, 66%); .delta..sub.H(CDCI.sub.3,
400 MHz) 2.38 (3 H, s), 3.81 (3 H, s), 4.44 (2 H, d), 5.23 (1 H,
d), 5.36 (1 H, d), 6.00 (1 H, ddt), 6.61 (1 H, d), 6.69-6.72 (2 H,
m)
[0432] (iv) Deallylation of allylether:
4-methoxy-3-(methylsulfanyl)phenol
[0433] The allyl ether from stage (iii) (556 mg, 2.64 mmol) was
dissolved in dry THF (26 mL) together with palladium
tetrakis(triphenylphosphine) (153 mg, 0.13 mmol) and the mixture
was cooled to 0.degree. C. Sodium borohydride (600 mg, 15.9 mmol)
was added and the mixture was allowed to reach room temperature and
stirred overnight. The reaction had proceeded to ca. 50% conversion
as judged by TLC anlysis and so a further batch of palladium
tetrakis(triphenylphosphine) (153 mg, 0.13 mmol) was added and the
mixture warmed to 45 .degree. C. and stirred for a further 12
hours. The reaction was quenched by the cautious addition of sat.
NH.sub.4Cl.sub.(aq) (until effervescence ceased) and the resulting
mixure was extracted with ethyl acetate (3.times.50 mL). The
combined extracts were dried (MgSO.sub.4) and evaporated to a
yellow-orange oil. Purification by flash chromatography [SiO.sub.2;
DCM/ MeOHI 880 NH.sub.3 (93:7:1)] afforded the desired title phenol
as a colourless oil (425 mg, 90%); .delta..sub.H(CDCI.sub.3, 400
MHz) 2.39 (3 H, s), 3.83 (3 H, s), 4.97 (1 H, s), 6.57 (1 H, dd),
6.67 (1 H, S), 6.68 (1 H, d).
PREPARATION 37
[0434] tert-Butyl
5-bromo-2-[4-(methylsulfanyl)-3-(trifluoromethyl)phenoxy-
]benzyl-(methyl)carbamate 170
[0435] A solution of the amine from example 27 (822 mg, 2.02 mmol)
in DCM (10 mL) was treated with di(tert-butyl) dicarbonate (530 mg,
2.43 mmol) at room temperature. After stirring for 1 hour the
reaction mixture was washed with hydrochloric acid (2M) (5 mL),
saturated aqueous sodium bicarbonate (5 mL), dried (MgSO.sub.4) and
evaporated to a pale yellow oil (1.17 g, ca. 100%);
.delta..sub.H(CDCI.sub.3, 300 MHz) 1.57 (9H, brs), 2.50 (3 H, brd),
2.87 (3 H, brs), 4.43 (2 H, brs), 6.78 (1 H, brt), 7.04 (IH, brs),
7.27 (1 H, obs), 7.33-7.50 (3 H, brm); MS m/z (TS.sup.+) 508
(MH.sup.+)
PREPARATIONS 38-39
[0436]
36 171 The following Boc-protected aryl bromides were prepared by
the method described for Preparation 37 from the appropriate
secondary amine. Starting Preparation Material (R.sup.3).sub.n data
38 Example 26 3-OMe .delta..sub.H(CDCl.sub.3, 400MHz)1.48 (9H,
brm), 2.40(3H, s), 2.90 4-SMe (3H, brm), 3.85(3H, s)4.45(2H, brm),
6.45(1H, dd), 6.54(1H, d), 6.72(1H, d), 7.14(1H, d), 7.32(1H, dd),
7.39(1H, brs); MSm/z(TS.sup.+)470(MH.sup.+) 39 Example 23 4-SMe
.delta..sub.H(CDCl.sub.3, 400MHz)1.39(9H, s), 2.41(3H, s), 2.83
(3H, br), 4.39(2H, brs), 6.68(1H, d), 6.80(2H, d), 7.15- 7.30(3H,
m), 7.35(1H, s); MSm/z(TS.sup.+)440(MH.sup.+), 340
([M-Boc]H.sup.+)
PREPARATION 40
[0437] Methyl
3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-[4-(methyls-
ulfanyl)-3-(trifluoromethyl)phenoxy]benzoate 172
[0438] The arylbromide from preparation 37 (1.02 g, 2.02 mmol) was
dissolved in methanol (15 mL) and treated with triethylamine (0.85
mL, 6.60 mmol), palladium(II) acetate (45 mg, 0.202 mmol),
triphenylphosphine (106 mg, 0.404 mg) in a stainless steel vessel.
The mixture was placed under 100 psi of carbon monoxide and heated
to 100.degree. C. for 24 hours. The solution was then evaporated to
dryness and the residue purified by flash chromatography
[SiO.sub.2; ethyl 15 acetate/ pentane (1:9.fwdarw.1:3)] to afford
the title ester as a yellow oil (412 mg, 42%),
.delta..sub.H(CDCI.sub.3, 400 MHz) 1.41 (9 H, s), 2.46 (3 H, s),
2.85 (3 H, brs), 3.87 (3 H, s), 4.50 (2 H, brs), 6.79 (1 H, d),
7.07 (1 H. d), 7.28 (1 H, s), 7.38 (1 H, d), 7.87 (1 H, d), 7.97 (1
H, brs); MS m/z 397 [M--(OMe)--(t--Bu)]
PREPARATIONS 41-42
[0439] The following esters were prepared by the method described
in Preparation 40 from the requisite aryl bromide.
37 173 Starting Preparation Material (R.sup.3).sub.n data 41
Preparation 3-OMe .delta..sub.H(CDCl.sub.3, 400MHz)1.50(9H, s),
2.46(3H, s), 2.94 38 4-SMe (3H, brs), 3.87(3H, s), 3.92(3H, s),
4.57(2H, brm), 6.59(2H, m), 6.84(1H, d), 7.89(1H, d), 800(1H, brm);
MSm/z(TS.sup.+)448(MH.sup.+) 42 Preparation 4-SMe
.delta..sub.H(CDCl.sub.3, 400MHz)1.42(9H, s), 2.43(3H, s), 2.90 39
(3H, brs), 3.85(3H, s), 4.51(2H, brd), 6.76(1H, d), 6.91(2H, d),
7.28(2H, m), 7.83(1H, d), 7.95(1H, brd);
MSm/z(TS.sup.+)418(MH.sup.+)
PREPARATION 43
[0440] 3-{[(tert-Butoxycarbonyl)(methyl)amino]
methyl}-4-[4-(methylsulfany- l )-3-(trifluoromethyl)phenoxy]benzoic
acid 174
[0441] The ester from preparation 40 (400 mg, 0.82 mmol) was
dissolved in methanol (5 mL) and water (2 mL), and potassium
carbonate (114 mg, 0.82 mmol) was added. The reaction mixture was
then heated at reflux for 18 hours. After cooling to room
temperature the mixture was evaporated to dryness and the residue
diluted with ethyl acetate (10 mL) and water (5 mL) and acidified
with hydrochloric acid (2 M) (2-3 mL). The organic layer was
separated and the aqueous layer re-extracted with ethyl acetate (5
mL). The combined organic fractions were washed with brine (5 mL),
dried (MgSO.sub.4) and evaporated to a yellow oil (388 mg, 100%);
.delta..sub.H(CDCI.sub.3, 300 MHz) 1.47 (9H, s), 2.54 (3 H, s),
2.95 (3 H, brs), 4.57 (2 H, brs), 6.83 (1 H, d), 7.15 (1 H, dd),
7.35 (1 H, s), 7.42 (1 H, d), 7.99 (1 H, d), 8.07 (IH, brs); MS m/z
(TS.sup.+) 489 (MNH.sub.4.sup.+)
PREPARATION 44
[0442]
3-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-4-[4-(methylsulfanyl-
)phenoxy]benzoic acid 175
[0443] The ester from preparation 42 (2.31 g, 5.39 mmol) was
dissolved in THF, treated with aqueous lithiumhydroxide (1 M) and
the mixture heated at reflux for 16 hours. After cooling to room
temperature and evaporation of most of the THF, the mixture was
acidified with saturated aqueous ammonium choride and diluted with
DCM (50 mL). The mixture was filtered and the organic layer
separated. The aqueous layer was then re-extracted with DCM (50 mL)
and the combined organic extracts dried (MgSO.sub.4) and evaporated
to white foam (ca. 2.3 g, ca. 100%) which was not purified further;
.delta..sub.H(CDCI.sub.3, 300 MHz) 1.45 (9 H, s), 2.51 (3 H, s),
2.91 (3 H, brs), 4.55 (2 H, brd), 6.80 (1 H, d), 6.98 (2 H, d),
7.29 (2 H, d), 7.92 (1 H, d), 8.03 (1 H, brd); MS m/z (TS.sup.+)
404 (MH.sup.+)
PREPARATION 45
[0444] 3-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-4-[3-meth
oxy-4-(methylsulfanyl)phenoxy]benzoic acid 176
[0445] The title carboxylic acid was prepared from the ester of
preparation 41 using the method described above for preparation 44.
.delta..sub.H(CDCI.sub.3, 400 MHz) 1.43 (9 H, s), 2.39 (3 H, s),
2.87 (3 H, brs), 3.81 (3 H, s), 4.52 (2 H, brm), 6.54 (2 H, m),
6.79 (2 H, d), 7.13 (1 H, d), 7.90 (1 H, d), 8.00 (1 H, brm); MS
m/z (ES.sup.+) 432 (M-H.sup.+)
PREPARATION 46
[0446] tert-Butyl 5-(aminocarbonyl)-2-[4-(methylsulfanyl
)-3-(trifluoromethyl)phenoxy]-benzyl(methyl)carbamate 177
[0447] The carboxylic acid from example 43 (388 mg, 0.82 mmol) was
dissolved in DCM (10 mL) and treated with triethylamine (287 .mu.L,
2.06 mmol), 1-hydroxybenzotriazole (139 mg, 1.03 mmol) and WSCDI
(205 mg, 1.07 mmol). The solution was stirred at room temperature
for 1 hour before the addition of saturated ammonia in THF (2 mL,
excess), and then left to stir overnight. The mixture was acidified
with hydrochloric acid (2 M; 5 mL) and the organic layer separated
. The aqueous layer was re-extracted with DCM (10 mL with trace of
methanol added) and the combined extracts were washed with brine
(10 mL), dried (MgSO.sub.4) and evaporated to a white solid (396
mg, 100%); 8H (CD.sub.3OD, 300 MHz) 1.41 (9 H, s), 2.54 (3 H, s),
2.90 (3 H, s), 4.58 (2 H, s), 6.95 (1 H, d), 7.21 (1 H, d), 7.30 (1
H, s), 7.60 (1 H, d), 7.83 (1 H, d), 7.91 (1 H, s); MS mlz (TS+)
488 (MNH.sub.4).
PREPARATIONS 47-54
[0448] The series of amides below was prepared from the appropriate
carboxylic acid using the method described in preparation 46.
38 178 Starting Preparation Material R.sup.5 (R.sup.3).sub.n data
47 Prep 44 179 4-SMe .delta..sub.H(CDCl.sub.3, 300MHz)1.48(9H, s),
2.50(3H, s), 2.89(3H, s), 3.39(3H, s), 3.57(2H, m), 3.66(2H, m),
4.54(2H, brs), 6.45(1H, brs), 6.83(1H, d), 6.92(2H, d), 7.28(2H,
d), 7.49 (1H, m), 7.72(1H, s); MSm/z(TS.sup.+)461 (MH.sup.+) 48
Prep 44 180 4-SMe .delta..sub.H(CDCl.sub.3, 300MHz)1.40(9H, s),
2.45(3H, s), 2.84(3H, s), 3.53(2H, m), 3.76(2H, m), 4.46(2H, s),
6.74(1H, d), 6.87(2H, d), 7.23 (2H, d), 7.61(1H, d), 7.71(1H, s);
MSm/z (TS.sup.+)447(MH.sup.+) 49 Prep 44 181 4-SMe
.delta..sub.H(CDCl.sub.3, 400MHz)1.22(2H, s), 1.42(9H, s), 2.45(3H,
s), 2.86(3H, brs), 4.10(2H, s), 4.51(2H, brs), 6.78(2H, d),
6.89(2H, d), 7.24(1H, m), 7.62(1H, d), 7.74(1H, s); MS
m/z(TS.sup.+)378(MNH.sub.4.sup.+) 50 Prep 44 182 4-SMe
.delta..sub.H(CDCl.sub.3, 400MHz)1.25(3H, d), 1.43(9H, s), 2.46(3H,
s), 2.85(3H, s), 3.61(1H, m), 3.84(1H, m), 4.23(1H, m), 4.50(2H,
brs), 6.80(1H, m), 6.89(2H, d), 7.25(2H, d), 7.60 (1H, d), 7.68(1H,
s); MSm/z(TS.sup.+)361(([M- Boc]H.sup.+) 51 Prep 44 183 4-SMe
.delta..sub.H(CDCl.sub.3, 400MHz)1.24(3H, d), 1.42(9H, s), 2.45(3H,
s), 2.85(3H, s), 3.81(1H, m), 3.95(1H, m), 4.23(1H, brs), 4.49(2H,
brs), 6.18(1H, brs), 6.79(1H, d), 6.88(2H, d), 7.24(2H, d),
7.60(1H, d), 7.67(1H, s); MS m/z(TS.sup.+)361([M-Boc]H.sup.+) 52
Prep 44 184 4-SMe .delta..sub.H(CDCl.sub.3, 300MHz)1.44(9H, s),
2.46(3H, s), 2.87(3H, brs), 2.97(3H, d), 4.51(2H, s), 6.32(1H,
brs), 6.79(1H, d), 6.90(2H, d), 7.27(2H, d), 7.46(1H, d), 7.70(1H,
s); MS m/z(TS.sup.+)418(MH.sup.+) 53 Prep 45 185 3-OMe 4-SMe
.delta..sub.H(CDCl.sub.3, 400MHz)1.42(9H, brs), 239 (3H, s),
2.88(3H, brs), 3.82(3H, s), 4.51(2H, brs), 6.51(2H, m), 6.82(1H,
d), 7.12(1H, d), 7.64(1H, dd), 7.71(1H, d); MSm/z(TS.sup.+)450
(MNH.sub.4.sup.+) 54 Prep 45 186 3-OMe 4-SMe
.delta..sub.H(CDCl.sub.3, 400MHz)1.43(9H, brs), 2.39 (3H, s),
2.86(3H, brs), 2.97(3H, d), 3.80(3H, s), 4.50(2H, brs), 6.06(1H,
brm), 6.46(2H, m), 6.82(1H, d), 7.12(1H, d), 7.60(1H, dd), 7.65(1H,
d); MSm/z(TS.sup.+)464(MH.sub.4.sup.+)
PREPARATION 55
[0449] 2-[4-(Methylsulfanyl)phenoxy]-5-nitrobenzonitrile 187
[0450] A mixture of 2-chloro-5-nitrobenzonitrile (3.75 g, 20.5
mmol), 4-(methylsulfanyl)phenol (3 g, 21.4 mmol) and potassium
carbonate (3.4 g, 24.6 mmol) in DMF (50 mL) was heated at
100.degree. C. for 2.5 h. After cooling to room temperature the
solvent was removed in vacuo and the residue was partitioned
between DCM (200 mL) and water (200 mL). The organic layer was
washed with water (100 mL), dried (MgSO.sub.4) and evaporated to
give the product contaminated with traces of
4-(methylsulfanyl)phenol and DMF (6.08 g, quantitative yield);
.delta..sub.H(CDCI.sub.3, 400 MHz) 2.53 (3 H, s), 6.90 (1 H, d),
7.08 (2 H, d), 7.36 (2 H, d), 8.30 (1 H, dd), 8.57 (1 H, d); MS m/z
(TS.sup.+) 304 (MNH.sub.4.sup.+).
PREPARATIONS 56-58
[0451] 188
[0452] The diphenylethers below were prepared in an analogous
fashion to that in preparation 55 from the appropriate
ortho-chlorobenzonitrile (commercially available) and 5 phenol
components as indicated.
39 Starting Preparation Material R.sup.5 (R.sup.3).sub.n data 56
Prep 35 NO.sub.2 3-OMe, .delta..sub.H (CDCl.sub.3, 400 MHz) 2.40
(3H, s), 3.85 4-SMe (3H, s), 6.60 (1H, d), 6.70 (1H, d), 6.88 (1H,
d), 7.17 (1H, d), 8.26 (1H, d), 8.50 (1H, s); MS m/z (TS.sup.+) 334
(MNH.sub.4.sup.+) 57 Prep 34 NO.sub.2 3-CF.sub.3, .delta..sub.H
(CDCl.sub.3, 400 MHz) 2.58 (3H, s), 6.90 (1H, 4-SMe d), 7.30 (1H,
dd), 7.49 (2H, m), 8.37 (1H, dd), 8.60 (1H, d); MS m/z (TS.sup.+)
372 (MNH.sub.4.sup.+) 58 -- Cl 4-SMe Material used crude MS m/z
(TS.sup.+) 293 (MH.sup.+).
PREPARATION 59
[0453] 5-Amino-2-[4-(methylsulfanyl)phenoxy]benzonitrile 189
[0454] Iron powder (8.0 g, 143 mmol) was added portionwise over 10
min to a suspension of the nitrile of preparation 55 (20.5 mmol) in
acetic acid (100 mL) and water (15 mL) and the resulting mixture
was stirred at room temperature for 2 h. The solvent was removed in
vacuo and the residue was partitioned between DCM (250 mL) and
aqueous potassium carbonate (10%; 300 mL). The aqueous layer was
extracted with DCM (100 mL) and the combined organic layers were
dried (MgSO.sub.4) and evaporated to give a pale brown solid (5.01
g, 95%); .delta..sub.H(CDCI.sub.3, 400 MHz) 2.47 (3 H, s), 3.71 (2
H, br), 6.81 (2 H, s), 6.92 (3 H, m), 7.25 (2 H, m); MS m/z
(TS.sup.+) 274 (MNH.sub.4.sup.+).
PREPARATIONS 60-61
[0455] The anilines below were prepared in an analogous fashion to
that in preparation 59 from the appropriate nitro compound.
40 190 Starting Preparation Material (R.sup.3).sub.n data 60 Prep
56 3-OMe .delta..sub.H(CDCl.sub.3, 400MHz)2.49(3H, s), 3.91(2H,
brs), 6.88 4-SMe (2H, s), 6.92(1H, d), 7.19(1H, d), 7.23(1H, d),
7.40(1H, d); MSm/z(TS.sup.+)342(MNH.sub.4.sup.+) 61 Prep 57
3-CF.sub.3 .delta..sub.H(CDCl.sub.3, 400MHz)2.49(3H, s), 3.91(2H,
brs), 6.88 4-SMe (2H, s), 6.92(1H, d), 7.19(1H, d), 7.23(1H, d),
7.40(1H, d); MSm/z(TS.sup.+)342(MNH.sub.4.sup.+)
PREPARATION 62
[0456]
N-{3-Cyano-4-[4-(methylsulfanyl)phenoxy]phenyl}methanesulfonamide
191
[0457] Methanesulfonyl chloride (3 mL, 38.8 mmol) was added to a
solution of the nitrile of preparation 59 (5 g, 19.5 mmol) and
triethylamine (5.6 mmol) in DCM (50 mL) and the mixture was stirred
at room temperature for 2 h. The solvent was removed in vacuo and
the residue was partitioned between DCM (50 mL) and hydrochloric
acid (2 M; 50 mL). The aqueous layer was extracted with DCM (50 mL)
and the combined organic extracts were concentrated in vacuo. The
residue was taken up in THF (15 mL), sodium hydroxide (2 M; 50 mL)
was added and the mixture was stirred for 3 h. The reaction was
acidified with hydrochloric acid (2 M; 55 mL) and extracted with
DCM (2.times.100 mL), the combined organic extracts being dried
(MgSO.sub.4) and evaporated to give a pale yellow crystalline solid
(6.45 g, 99%); .delta..sub.H(CDCI.sub.3, 400 MHz) 2.50 (3 H, s),
3.03 (3 H, s), 6.47 (1 H, br), 6.86 (1 H, d), 7.02 (2 H, d), 7.32
(2 H, d), 7.37 (1 H, dd), 7.54 (1 H, d); MS m/z (ES.sup.+) 357
(MNa.sup.+).
PREPARATIONS 63-64
[0458] The methane sulfonamides below were prepared from the
requisite aniline by the method described in preparation 62.
41 192 Starting Preparation Material (R.sup.3).sub.n data 63 Prep
60 3-OMe .delta..sub.H (CDCl.sub.3, 400MHz) 2.47 (3H, s), 3.06 (3H,
s), 3.90 (3H, 4-SMe s), 6.66 (2H, m), 6.90 (1H, d), 7.20 (1H, d),
7.40 (1H, dd), 7.55 (1H, d) 64 Prep 61 3-CF.sub.3 .delta..sub.H
(CDCl.sub.3, 400 MHz) 2.52 (3H, s), 3.08 (3H, s), 6.89 (1H, 4-SMe
d), 7.21 (1H, d), 7.32-7.47 (3H, m), 7.58 (1H, s)
PREPARATION 65
[0459]
N-{3-Cyano-4-[4-(methylsulfanyl)phenoxy]phenyl)-N-methylmethanesulf-
onamide 193
[0460] Methyl iodide (2.5 mL, 40.2 mmol) and potassium carbonate
(1.25 g, 9.04 mmol) were added to a solution of the sulfonamide of
preparation 62 (2.7 g, 8.07 mmol) in acetonitrile (40 mL) and the
mixture was stirred at room temperature for 68 h. The reaction
mixture was poured into sodium hydroxide (2 M; 50 mL) and extracted
with ethyl acetate (50 mL). The organic layer was washed with
brine, dried (MgSO.sub.4) and evaporated to give the title compound
(2.75 g, 98%); .delta..sub.H(CDCI.sub.3, 300 MHz) 2.50 (3 H, s),
2.87 (3 H, s), 3.30 (3 H, s), 6.82 (1 H, d), 7.03 (2 H, d), 7.32 (2
H, d), 7.49 (1 H, dd), 7.62 (1 H, d); MS m/z (TS.sup.+) 366
(MNH.sub.4.sup.+).
PREPARATION 66
[0461]
N-{3-cyano-4-[4-(methylsulfanyl)phenoxy]phenyl}-N-(2-hydroxyethyl)m-
ethane-sulfonamide 194
[0462] 2-Bromoethanol (2.5 mL, 35.3 mmol) and potassium carbonate
(4.9 g, 35.5 mmol) were added to a solution of the sulfonamide of
preparation 62 (2.7 g, 8.07 mmol) in acetonitrile (40 mL) and the
mixture was stirred at room temperature for 68 h. TLC analysis
indicated starting material remaining so the mixture was then
heated at reflux for 20 hrs. After cooling, the reaction mixture
was poured into sodiumhydroxide (2 M; 50 mL) and extracted with
ethyl acetate (50 mL). The organic layer was washed with brine,
dried (MgSO.sub.4) and evaporated. Purification of the residue by
multiple column chromatography (SiO.sub.2) gave the title compound
(1.90 g, 62%); .delta..sub.H(CDCI.sub.3, 300 MHz) 2.50 (3 H, s),
3.00 (3 H, s), 3.77 (2 H, m), 3.80 (2 H, m), 6.83 (1 H, d), 7.04 (2
H, d), 7.33 (2 H, d), 7.50 (1 H, dd), 7.67 (1 H, d); MS m/z
(TS.sup.+) 396 (MNH.sub.4.sup.+).
PREPARATION 67
[0463] 5-(Aminosulfonyl)-2-fluoro-N-methylbenzamide 195
[0464] To a suspension of 5-(aminosulfonyl)-2-fluorobenzoic acid
[prepared according to Chem. Pharm. Bull. 1995, 43(4), 582-7]
(3.0g, 13.7mmol) in dichloromethane (100 mL) at room temperature
under nitrogen was added
1-(3-dimethylaminopropyl)-3-ethylcarbodlimide hydrochloride (WSCDI)
(2.89 g, 15.06 mmol) followed by a solution of methylamine in
tetrahydrofuran (2 M, 8.21 mL, 16.42 mmol), dropwise and the
reaction allowed to stir for 16 hours. The crude reaction mixture
was then evaporated to dryness and the residue chromatographed on
silica gel, eluting with dichloromethane:methanol:ammonia (84:14:2)
as solvent to give the amide (732mg, 23%) as a white powder. H NMR
(300 MHz, d.sub.4-MeOH): .delta.=2.97 (3 H, s), 7.40 (1 H, t), 8.05
(1 H, m), 8.29 (1 H, d). MS m/z 250 (MNH.sub.4).sup.+
PREPARATION 68
[0465]
N'-(3-{3-[(Dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]pheny-
l}propanoyl)-4-methylbenzenesulfonohydrazide 196
[0466] Treating the unsaturated amide formed in example 68 to the
reduction conditions used for example 71 afforded the title
compound; Free base: .delta..sub.H(CDCI.sub.3, 400 MHz) 2.28 (6 H,
s), 2.36 (2 H, t), 2.41 (3 H, s), 2.46 (3 H, s), 2.48-2.67 (2 H,
brm), 2.77 (2 H, t), 3.48 (2 H, s), 6.74 (1 H, d), 6.84 (2 H, d),
6.91 (1 H, dd), 7.23-7.30 (5 H, m), 7.75 (2 H, d); MS m/z
(TS.sup.+) 514,516 (MH.sup.+)
PREPARATION 69
[0467]
N'-(3-{4-[(Dimethylamino)methyl]-3-[4-(methylsulfanyl)phenoxy]pheny-
l}propanoy)4-methylbenzenesulfonohydrazide 197
[0468] Treating the unsaturated amide formed in example 69 to the
reduction conditions used for example 71 afforded the title
compound; Free base: .delta..sub.H(CDCI.sub.3, 300 MHz) 2.23 (2 H,
t), 2.38 (3 H, s), 2.48 (3 H, s), 2.62 (2 H, t), 4.27 (2 H, s),
6.68 (1 H, s), 6.97 (1 H. d), 7.04 (2 H, d), 7.30-7.34 (4 H, m),
7.58 (1 H, d), 7.62 (1 H, d), 9.64 (1 H, s), 9.91 (1 H, s), 10.34
(1 H, brs); MS m/z (ES.sup.+) 514 (MH.sup.+)
Biological Activity
[0469] A number of compounds were tested for biological activity by
their ability to inhibit the uptake of serotonin by human serotonin
transporters as follows.
[0470] (i) Cell Culture
[0471] 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.degree. C and 5% CO.sub.2 in DMEM-culture media (supplemented
with 10% dialysed foetal calf serum (FCS), 2 mM 1-glutamine and 250
.mu.g/ml geneticin)). Cells were harvested for the assay to yield a
cell suspension of 750,000 cells/ml.
[0472] (i) Determination of inhibitor potency
[0473] 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 .sup.3H-Serotonin, .sup.3H-Noradrenaline or
.sup.3H-Dopamine substrates. All reactions were 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 .sup.3H-substrate incorporated into the
cells was then quantified.
[0474] Assay plates were dried in a microwave oven, scintillation
fluid added, and radioactivity measured. Potency of test compounds
was quantified as IC.sub.50 values (concentration of test compound
required to inhibit the specific uptake of radiolabelled substrate
into the cells by 50%).
[0475] (iii) Standard Assay Buffer Composition:
[0476] Trizma hydrochloride (26 mM)
[0477] NaCI (124 mM)
[0478] KCI (4.5 mM)
[0479] KH.sub.2PO.sub.4 (1.2 mM)
[0480] MgCI.sub.2.6H.sub.2) (1.3 mM)
[0481] Ascorbic acid (1.136 mM)
[0482] Glucose (5.55 mM)
[0483] pH 7.40
[0484] CaCI.sub.2 (2.8 mM)
[0485] Pargyline (100 .mu.M)
[0486] Note: The pH of the buffer was adjusted to 7.40 with 1 M
NaOH before addition of CaCI.sub.2 and pargyline.
[0487] (iv) Summary of Assay Parameters
42 hSERT hDAT hNET Assay Assay Assay Cell concentration per 75,000
75,000 75,000 assay well. Substrate Concentration. .sup.3H-5HT
.sup.3H-Dopamine .sup.3H-Noradrenaline (50 nM) (200 nM) (200 nM)
Incubation time 5 5 15 (minutes)
[0488] Compounds having a serotonin re-uptake inhibition (SRI)
IC.sub.50 value of less than or equal to 1OOnM are the title
compounds of Examples 1-4, 6, 9-12, 14, 23, 25, 28-33, 35-53,
55-62, 64, 65, 71-80, 84, 85, 87, 90-92, 94-99, 101-106, 110, 112,
114-122, 125, 128-142, 145-149 and 154-191.
[0489] Compounds having an serotonin re-uptake inhibition (SRI)
IC.sub.50 value of less than or equal to 100 nM 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 are the title compounds of Examples 3, 4, 6, 9-12, 14,
23, 25, 28-33, 35-40, 45-53, 55, 56, 58, 62, 64, 65, 71, 73-76, 84,
85, 87, 90-92, 94-98, 101-104, 106, 110, 112, 114-122, 128-131,
134-141, 145-148, 155-159, 161, 162,165, 167-179 and 181-191.
[0490] Compounds having an serotonin re-uptake inhibition (SRI)
IC.sub.50 value of less than or equal to 100 nM 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 are the title compounds of Examples 3, 4, 6, 9-12, 14,
23, 25, 28-32, 35-40, 46-51, 53, 55, 58, 62, 64, 71, 73-76, 84, 85,
87, 90, 91, 94-98, 101-104, 106, 110, 112, 114, 116-118, 120, 121,
128-131, 135,137,139-141, 145-148,155-159, 161, 162,169-179 and
181-190.
[0491] Compounds having an serotonin re-uptake inhibition (SRI)
IC.sub.50 value of less than or equal to 100 nM 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 are the title compounds of Examples 3, 4, 9, 14, 23, 25,
28-30, 35, 36, 38-40, 46, 53, 58, 74, 84, 85, 87, 90, 91, 94-98,
101, 104, 110, 114, 116, 117, 120, 121, 128, 130, 135, 140, 141,
145-148, 156, 157, 169, 170, 174-176, 181-185 and 187-190.
[0492] Compounds having an serotonin re-uptake inhibition (SRI)
IC.sub.50 value of less than or equal to 50 nM 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 are the title compounds of Examples 3, 4, 9, 14, 23, 25,
28, 30, 36, 38-40, 46, 53, 58, 74, 84, 85, 87, 90, 91, 94-98, 101,
104, 110, 114, 116, 117, 120, 121, 128, 130, 135, 140, 141, 145,
147, 148, 156, 157, 169, 170, 174-176, 181-185 and 187-190.
* * * * *