Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-08-27
2003-08-26
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S086000, C564S099000, C564S162000, C564S336000, C562S432000, C560S017000, C560S024000, C560S025000, C560S027000, C560S157000, C514S478000, C514S544000, C514S568000, C514S605000, C514S617000
Reexamination Certificate
active
06610747
ABSTRACT:
This invention relates to novel diphenyl ether compounds which inhibit monoamine re-uptake. In particular compounds of the present invention exhibit activity as selective serotonin re-uptake inhibitors (SSRIs) and have utility therefore in a variety of therapeutic areas. Notably the compounds of the present invention are useful in the treatment or prevention of a variety of disorders, including those in which the regulation of monoamine transporter function is implicated, such as depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders and sexual dysfunction including premature ejaculation, and to pharmaceutical formulations containing such compounds.
According to a first aspect, the invention provides a compound of general formula (I), pharmaceutically acceptable salts, solvates or polymorphs thereof;
wherein;
R
1
and R
2
, which may be the same or different, are H, C
1
-C
6
alkyl or (CH
2
)
d
(C
3
-C
6
cycloalkyl) wherein d=0, 1, 2 or 3; or R
1
and R
2
together with the nitrogen to which they are attached form an azetidine ring;
Z or Y is —SR
3
and the other Z or Y is halogen or —R
3
; wherein R
3
is independently C
1
-C
4
alkyl optionally substituted with fluorine; except that R
3
is not CF
3
;
or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; with the proviso that when R
5
is fluorine and R
2
is methyl then the fused ring is not 1,3-dioxolane and Z and Y together do not form a fused phenyl ring;
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
.
Unless otherwise indicated, any alkyl group may be straight or branched and is of 1 to 6 carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.
Unless otherwise indicated, any carbocyclyl group contains 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic. Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclyl groups contain up to 3 double bonds. A preferred aromatic carbocyclyl group is phenyl. The term carbocylic should be similarly construed. In addition, the term carbocyclyl includes any fused combination of carbocyclyl groups, for example naphthyl, phenanthryl, indanyl and indenyl.
Unless otherwise indicated, any heterocyclyl group contains 5 to 7 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic. Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl. In addition, the term heterocyclyl includes fused heterocyclyl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl. The term heterocyclic should be similarly construed.
Halo means fluoro, chloro, bromo or iodo.
Preferably R
1
and R
2
, which may be the same or different, are hydrogen or C
1
-C
6
alkyl. More preferably hydrogen or methyl.
When Z or Y is —SR
3
, R
3
is preferably methyl or ethyl.
When Z and Y form a fused ring, the ring is preferably a heterocyclic ring. More preferably, the linkage contains one or two sulfur atoms.
Preferably R
4
and R
5
are not both hydrogen.
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
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;
when present, R
3
is methyl or ethyl; or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; and
R
4
and R
5
, which may be the same o
Adam Mavis Diane
Andrews Mark David
Elliott Mark Leonard
Gymer Geoffrey Edward
Hepworth David
Aulakh C. S.
Benson Gregg C.
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
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