Diphenyl ether compounds useful in therapy

Details Diphenyl ether compounds useful in therapy Diphenyl ether compounds useful in therapy

2001-03-16

2002-09-10

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S603000, C514S655000, C548S255000, C548S267200, C548S375100, C558S422000, C564S085000, C564S086000, C564S162000, C564S390000

Reexamination Certificate

active

06448293

ABSTRACT:

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.
According to a first aspect, the invention provides a compound of general formula (I), or pharmaceutically acceptable salts, solvates or polymorphs thereof;
wherein;
R
1
and R
2
, which may be the same or different, are hydrogen, C
1
-C
6
alkyl, (CH
2
)
m
(C
3
-C
6
cycloalkyl) wherein m=0, 1, 2 or 3, or R
1
and R
2
together with the nitrogen to which they are attached form an azetidine ring;
each R
3
is independently CF
3
, OCF
3
, C
1-4
alkylthio or C
1
-C
4
alkoxy;
n is 1, 2 or 3; and
R
4
and R
5
, which may be the same or different, are:
A—X, wherein A=—CH═CH— or —(CH
2
)
p
— where p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I, CONR
6
R
7
, SO
2
NR
6
R
7
, SO
2
NHC(═O)R
6
, OH, C
1-4
alkoxy, NR
8
SO
2
R
9
, NO
2
, NR
6
R
11
, CN, CO
2
R
10
, CHO, SR
10
, S(O)R
9
or SO
2
R
10
; R
6
, R
7
, R
8
and R
10
which may be the same or different, are hydrogen or C
1-6
alkyl optionally substituted independently by one or more R
12
; R
9
is C
1-6
alkyl optionally substituted independently by one or more R
12
; R
11
is hydrogen, C
1-6
alkyl optionally substituted independently by one or more R
12
, C(O)R
6
, CO
2
R
9
, C(O)NHR
6
or SO
2
NR
6
R
7
; R
12
is F (preferably up to 3), OH, CO
2
H, C
3-6
cycloalkyl, NH
2
, CONH
2
, C
1-6
alkoxy, C
1-6
alkoxycarbonyl 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
13
; or R
6
and R
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
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
13
;
wherein R
13
is hydroxy, C
1
-C
4
alkoxy, F, C
1
-C
6
alkyl, haloalkyl, haloalkoxy, —NH
2
, —NH(C
1
-C
6
alkyl) or —N(C
1
-C
6
alkyl)
2
; and wherein when R
1
and R
2
are methyl, R
4
and R
5
are hydrogen and n is 1, R
3
is not a —SMe group para to the ether linkage linking rings A and B.
Unless otherwise indicated, any alkyl group may be straight or branched and is of 1 to 6 carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.
Unless otherwise indicated, any 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.
Preferably R
1
and R
2
, which may be the same or different, are hydrogen or C
1
-C
6
alkyl. More preferably hydrogen or methyl.
Preferably each R
3
is independently —CF
3
, —OCF
3
, methylthio, ethylthio or methoxy.
Preferably at least one R
3
is para to the ether linkage linking ring A and B.
Preferably at least one R
3
is methylthio.
Preferably R
4
and R
5
, which may be the same or different, are —(CH
2
)
p
—X, where p is 0, 1 or 2 (preferably 0 or 1); X is hydrogen, hydroxy, CONR
6
R
7
, SO
2
NR
6
R
7
, NR
8
SO
2
R
9
, SR
10
, SOR
9
or SO
2
R
10
wherein R
6
, R
7
, R
8
, R
9
and R
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).
More preferably R
4
and R
5
, which may be the same or different, are: —(CH
2
)
p
—X, where p is 0 or 1; X is hydrogen, hydroxy, CONR
6
R
7
, SO
2
NR
6
R
7
or NR
8
SO
2
R
9
; wherein R
6
and R
7
, which may be the same or different, are hydrogen or C
1
,-C
3
alkyl optionally substituted by hydroxy, —CONH
2
or C
1
-C
3
alkoxy (preferably methoxy); R
8
is hydrogen, hydroxyethyl or methyl; or R
9
is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or pyrazolyl.
More preferably still R
4
and R
5
are not both hydrogen. More preferably still R
4
is hydrogen.
Preferably R
6
and R
7
, which may be the same or different, are hydrogen, C
1
-C
3
alkyl optionally substituted by hydroxy, —CONH
2
or C
1
-C
3
alkoxy (preferably methoxy). More preferably R
6
and R
7
, which may be the same or different, are hydrogen or methyl, more preferably still hydrogen.
When present, R
12
is preferably oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl. More preferably triazolyl, imidazolyl or pyrazolyl.
In the case where R
6
and R
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
2
or a morpholine ring which may be substituted by CONH
2
.
Preferably R
11
is hydrogen or C
1-6
alkyl.
Preferably R
8
is hydrogen, hydroxyethyl or methyl. More preferably hydrogen.
Preferably R
9
is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl. More preferably methyl or ethyl (preferably methyl).
Preferably R
10
is methyl or ethyl.
Preferably p is 1 or 0, more preferably 0.
Preferably
R
1
and R
2
, which may be the same or different, are hydrogen or methyl; at least one R
3
is para to the ether linkage and is CF
3
, OCF
3
, methylthio, ethylthio or methoxy; and
R
4
and R
5
, which may be the same or different, are (CH
2
)
p
—X, where p is 0 or 1; X is hydrogen, hydroxy, CONR
6
R
7
, SO
2
NR
6
R
7
, NR
8
SO
2
R
9
, SR
10
, SOR
9
or SO
2
R
10
and wherein R
6
and R
7
, which may be the same or different, are hydrogen, C
1
-C
3
alkyl optionally substituted by hydroxy, —CONH
2
or C
1
-C
3
alkoxy (preferably methoxy); or R
6
and R
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
2
; R
8
is hydrogen, hydroxyethyl or methyl (preferably hydrogen); R
9
is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; and R
10
is methyl or ethyl; or an oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl group.
More preferably R
1
and R
2
, which may be the same or different, are hydrogen or methyl; at least one R
3
is para to the ether linkage and is CF
3
, OCF
3
, methylthio, ethylthio or methoxy, and at least one R
3
is methylthio or ethylthio; and
R
4
and R
5
, which may be the same or different, are —(CH
2
)
p
—X, where p is 0 or 1; X is hydrogen, hydroxy, CONR
6
R
7
, SO
2
NR
6
R
7
or NR
8
SO
2
R
9
; wherein R
6
and R
7
, which may be the same or different, are hydrogen, C
1
-C
3
alkyl optionally substituted by hydroxy, —CONH

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