Biaryl ether derivatives useful as monoamine reuptake...

Details Biaryl ether derivatives useful as monoamine reuptake... Biaryl ether derivatives useful as monoamine reuptake...

2002-05-22

2003-07-22

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S383000, C514S406000, C514S438000, C514S471000, C514S650000, C514S424000, C514S327000

Reexamination Certificate

active

06596741

ABSTRACT:

BACKGROUND OF THE INVENTION
Serotonin Selective Reuptake Inhibitors (SSRIs) currently provide efficacy in the treatment of major depressive disorder (MDD) and are generally perceived by psychiatrists and primary care physicians as effective, well-tolerated and easily administered. However, they are associated with undesirable features, such as reports of sexual dysfunction, delayed onset of action and a level of non-responsiveness estimated to be as high as 30% (see M. J. Gitlin,
Journal of Clinical Psychiatry,
1994, 55, 406-413 and R. T. Segraves,
Journal of Clinical Psychiatry,
1992, 10(2), 4-10). Preclinical and clinical evidence has indicated that the sexual dysfunction associated with SSRI therapy can be reduced through the use of dopamine reuptake inhibitors (DRIs), such as bupropion (see A. K. Ashton,
Journal of Clinical Psychiatry,
1998, 59(3), 112-115). Furthermore, the combination of SRI and DRI may hasten the onset of action as well as offering relief to refractory patients, possibly through a synergistic mechanism (see R. D. Marshall et al,
Journal of Psychopharmacology,
1995, 9(3), 284-286) and prove beneficial in the treatment of substance abuse and attention deficit hyperactivity disorder (ADHD) according to Barrickman et al,
Journal of the American Academy of Child and Adolescent Psychology,
1995, 34(5), 649 and Shekim et al,
Journal of Nervous and Mental Disease,
1989, 177(5), 296.
This invention relates to novel biaryl ether derivatives that exhibit activity as monoamine (e.g., dopamine, serotonin) reuptake inhibitors, to pharmaceutical compositions containing such compounds and to methods of using such compounds to treat central nervous system (CNS) and other disorders.
U.S. Pat. No. 4,018,830, issued Apr. 19, 1997, refers to phenylthioaralkylamines and 2-phenylthiobenzylamines which are active as antiarrhythmics
WO 97/17325, International Publication Date May 15, 1997, refers to derivatives of N,N-dimethyl-2-(arylthio)benzylamine which selectively influence serotonin transport in the central nervous system and are useful as antidepressants.
U.S. Pat. No. 5,190,965, issued Mar. 2, 1993, and U.S. Pat. No. 5,430,063, issued Jul. 4, 1995, refer to phenoxyphenyl derivatives which have utility in the treatment of depression.
U.S. Pat. No. 4,161,529, issued Jul. 17, 1979, refers to pyrrolidine derivatives that possess anticholesteremic and hypolipemic activity.
U.S. Provisional Application No. 60/121,313, filed Feb. 23, 1999, refers to biaryl ethers that have activity in inhibiting reuptake of both serotonin and dopamine.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula:
wherein phenyl ring A and phenyl ring B can each, independently, be replaced by a naphthyl group, and wherein when phenyl ring A is replaced by a naphthyl group, the ethereal oxygen of structure I and the carbon to which R
3
, R
4
and NR
1
R
2
are attached, are attached to adjacent ring carbon atoms of the naphthyl group and neither of said adjacent ring carbon atoms is also adjacent to a fused ring carbon atom of said naphthyl group;
n and m are selected, independently, from one, two and three;
R
1
and R
2
are selected, independently, from hydrogen, (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl, and (C
2
-C
4
)alkynyl, or R
1
and R
2
, together with the nitrogen to which they are attached, form a four to eight membered saturated ring containing one or two heteroatoms, including the nitrogen to which R
1
and R
2
are attached, wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C
1
-C
6
)alkyl;
R
3
and R
4
are selected, independently, from hydrogen and (C
1
-C
4
) alkyl optionally substituted with from one to three fluorine atoms, or R
3
and R
4
together with the carbon to which they are attached form a four to eight membered saturated carbocyclic ring, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C
1
-C
6
)alkyl;
or R
2
and R
3
, together with the nitrogen to which R
2
is attached and the carbon to which R
3
is attached, form a four to eight membered saturated ring containing one or two heteroatoms, including the nitrogen to which R
2
is attached, wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C
1
-C
6
)alkyl;
each X is selected, independently, from phenyl, heteroaryl (e.g., furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isoxazole, imidazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,4-triazole, 1,2,3,-triazole, tetrazole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzisothiazole and indole) or heterocycle (e.g., imidazolidine, oxazolidine, thiazolidine, pyrrolidine, piperidine, morpholine) groups as defined below and may be further substituted by hydrogen, halo (i.e., fluorine, chlorine, bromine, iodine), (C
1
-C
4
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
4
)alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, amino, hydroxy, carbonyl, (C
1
-C
4
)alkylamino, di-[(C
1
-C
4
)alkyl]amino, NR
5
(C═O)(C
1
-C
4
)alkyl, SO
2
NR
5
R
6
and SO
p
(C
1
-C
6
)alkyl, wherein R
5
and R
6
are selected, independently, from hydrogen and (C
1
-C
6
)alkyl, and p is zero, one or two;
each Y is selected, independently, from hydrogen, halo (i.e., chloro, fluoro, bromo or iodo), (C
1
-C
4
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
4
)alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, amino, (C
1
-C
4
)alkylamino, di-[(C
1
-C
4
)alkyl]amino, NR
5
(C═O)(C
1
-C
4
)alkyl, SO
2
NR
5
R
6
and SO
p
(C
1
-C
6
)alkyl, wherein R
5
and R
6
are selected, independently, from hydrogen and (C
1
-C
6
)alkyl, and p is zero, one or two; and
each Z is selected independently from hydrogen, halo (i.e., chloro, fluoro, bromo or iodo), (C
1
-C
4
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
4
)alkoxy;
and the pharmaceutically acceptable salts thereof. Compounds of formula I, and their pharmaceutically acceptable salts, have activity in inhibiting reuptake of serotonin, dopamine, and norepinephrine.
In one embodiment of the present invention, ring B is phenyl, not replaced with a naphthyl group. In another embodiment, phenyl ring B in the compounds of formula I is replaced with a naphthyl group.
In a preferred embodiment when ring B is phenyl, each Y is hydrogen or halo. In a more preferred embodiment, m is 1 or 2, and each Y is chlorine.
In another embodiment, the invention relates to compounds of formula I, or pharmaceutically acceptable salts, thereof as described above, but wherein X is selected from furan, thiophene, pyrrole, and 1,2,3-triazole, and wherein X may be further substituted as recited above.
In another embodiment, X is a lactam, for example 1-pyrrolidin-2-one or 1-piperidin-2-one, optionally substituted as recited above and attached to ring A through the lactam nitrogen.
In another embodiment, X is a tetrazole optionally substituted as recited above and attached to ring A through the tetrazole carbon.
In another embodiment, the invention relates to compounds of formula I or salts thereof as described above, but wherein each Z is selected from hydrogen and halo. Preferably, Z is hydrogen.
In a further embodiment, the invention relates to compounds of formula I or salts thereof as described above, wherein R
3
and R
4
are independently selected from hydrogen and unsubstituted (C
1
-C
4
) alkyl. Preferably, one or both of R
3
and R
4
are hydrogen.
In a further embodimen

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