Diaryl compounds

Details Diaryl compounds Diaryl compounds

2003-07-31

2004-10-05

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S307000, C514S311000, C514S351000, C514S256000, C546S139000, C546S152000, C546S300000, C546S329000, C544S242000

Reexamination Certificate

active

06800652

ABSTRACT:

This invention relates to novel 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.
U.S. Pat. Nos. 5,190,965 and 5,430,063 disclose a class of phenoxyphenyl compounds, which are a class of dopamine antagonists. WO 93/12080, WO 97/17325 and EP 0,402,097 disclose substituted diphenylsulfides, which are serotonin uptake inhibitors. WO 01/72687, WO 00/50380 and WO 01/27068 describe diphenyl ether derivatives, which are selective serotonin re-uptake inhibitors. J. Med. Chem 2002, 45(6), 1253-1258, discloses diphenyl sulfides as selective serotonin transporter ligands.
According to a first aspect the invention provides a compound of general formula (I) or pharmaceutically acceptable salts, solvates or polymorphs thereof;
wherein;
X is S or CH
2
;
L and U, which may be the same or different, are —N—, —N
+
(—O
−
)— or —C(H)—;
M and Q, which may be the same or different, are —N—, —N
+
(—O
−
)— or —C(R
4
)—;
wherein ring A contains 1 or 2 nitrogen atoms, and wherein when L, U, M or Q is —N
+
(—O
−
)—, ring A contains no other nitrogen atom;
R
1
and R
2
, which may be the same or different, are hydrogen, C
1
-C
8
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;
W, Y and Z, which may be the same or different, are hydrogen, halogen, C
1-
C
6
alkyl, CF
3
, OCF
3
, C
1-
C
4
alkylthio or C
1-
C
4
alkoxy; or Y and Z are linked so that, together with the interconnecting atoms, Y and Z form a fused 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein when Y and Z form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; and wherein W, Y and Z are not all hydrogen;
and
each R
4
is independently:
—(CH
2
)
p
—R
5
;
where p is 0, 1 or 2;
R
5
is hydrogen, CONR
6
R
7
, SO
2
NR
6
R
7
, SO
2
NHC(═O)R
6
, hydroxy, C
1-
C
4
alkoxy, NR
8
SO
2
R
9
, NO
2
, NR
6
R
11
, CN, CO
2
R
10
, 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-
C
6
alkyl optionally substituted independently by one or more R
12
; R
9
is C
1-
C
6
alkyl optionally substituted independently by one or more R
12
; R
11
is hydrogen, C
1-
C
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 fluoro, hydroxy, CO
2
H, C
3-
C
6
cycloalkyl, NH
2
, CONH
2
, C
1-
C
6
alkoxy, C
1-
C
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, fluoro, C
1
-C
6
alkyl, haloalkyl, haloalkoxy, —NH
2
, —NH(C
1
-C
6
alkyl) or —N(C
1
-C
6
alkyl)
2
; or
when both M and Q are CR
4
, the R
4
groups are linked so that together with the interconnecting atoms, the R
4
groups form a fused 5- to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic.
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.
Preferably, L and U are —CH—.
Preferably, W, Y and Z are each independently selected from hydrogen, methyl, ethyl, CF
3
, OCF
3
, C
1
-C
4
alkylthio, methoxy, ethoxy, chloro, fluoro and bromo.
Preferably, W and Z are hydrogen.
Preferably, Y is methylthio.
Preferably, M and Q are each independently selected from —N— and —CH—.
More preferably, one of M and Q is —N— and the other is —CH—.
More preferably, L and U are —CH—, one of M and Q is —N— and the other is —CH—.
Preferably, R
1
and R
2
are each independently selected from hydrogen and C
1
-C
6
alkyl.
More preferably, R
1
is methyl and R
2
is hydrogen or methyl.
Preferred compounds are:
N-methyl-N-[(4-{[4-(methylsulfanyl)phenyl]sulfanyl}-3-pyridinyl)methyl]amine,
N,N-dimethyl-N-[(4-{[4-(methylsulfanyl)phenyl]sulfanyl}-3-pyridinyl)methyl]amine,
N-methyl-N-[(3-{[4-(methylsulfanyl)phenyl]sulfanyl}-4-pyridinyl)methyl]amine,
N,N-dimethyl-N-[(3-{[4-(methylsulfanyl)phenyl]sulfanyl}-4-pyridinyl)methyl]amine,
N-methyl-N-({3-[4-(methylsulfanyl)benzyl]-4-pyridinyl}methyl)amine,
N,N-dimethyl-({3-[4-(methylsulfanyl)benzyl]-4-pyridinyl}methyl)amine,
N-methyl-N-({4-[4-(methylsulfanyl)benzyl]-3-pyridinyl}methyl)amine, and
N,N-dimethyl-N-({4-[4-(methylsulfanyl)benzyl]-3-pyridinyl}methyl)amine.
For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternatives groups, the selected groups may be the same or different.
For the avoidance of doubt, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
The pharmaceutically or veterinarily acceptable salts of the compounds of formula I which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulf

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