Phenoxyphenylheterocyclyl derivatives as SSRIs

Details Phenoxyphenylheterocyclyl derivatives as SSRIs Phenoxyphenylheterocyclyl derivatives as SSRIs

2001-08-24

2003-10-07

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S429000, C548S531000, C548S540000, C548S565000, C548S577000

Reexamination Certificate

active

06630504

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
is H or C
1
-C
6
alkyl;
R
2
and R
3
, together with the interconnecting atoms form a 4 to 8-membered saturated ring containing one or two heteroatoms (includingthe nitrogen to which R
2
is attached) wherein a second heteroatom, if present, is selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent heteroatoms;
Z is CF
3
, OCF
3
, C
1
-C
6
alkylthio or C
1
-C
6
alkoxy;
Y is hydrogen, halogen, —OR
a
, R
a
or C
1
-C
6
alkylthio, and wherein R
a
is C
1
-C
4
alkyl optionally substituted with fluorine atoms;
or when Z and Y are attached para and meta to the ether linkage linking rings A and B, 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;
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 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.
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.
Halo means fluoro, chloro, bromo or iodo.
Preferably R
1
is hydrogen or methyl (more preferably hydrogen).
Preferably R
2
and R
3
, together with the interconnecting atoms, form a pyrrolidine ring.
Preferably at least one of Z or Y is para to the ether linkage linking ring A and ring B and is not hydrogen. More preferably the other Z or Y is meta to the ether linkage linking ring A and ring B.
Preferably Z is CF
3
, OCF
3
, SMe, SEt or OMe;
Y is hydrogen, F, Cl, Br, methyl, ethyl, OMe, SMe or SEt; or when Z and Y are attached para and meta to the ether linkage linking rings A and B, Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 or 6-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 (preferred linkages forming the fused ring are —(CH
2
)
3
—, —S(CH
2
)
2
—, —CH
2
S—CH
2
—, —SCH═N—, —(CH
2
)
4
—, —S(CH
2
)
2
O—, —N═CH═CH═CH—, —CH═N—CH═N— and —CH═CH—N═CH—, wherein either end of these linkages can be attached para to the ether linkage).
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.
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, trifluor

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