Serotonin transport inhibitors

Details Serotonin transport inhibitors Serotonin transport inhibitors

2002-02-28

2004-01-13

Solola, Taofiq A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S320000, C514S432000, C514S456000, C544S173000, C544S111000, C546S192000, C546S200000, C549S023000, C549S283000, C549S285000, C549S397000

Reexamination Certificate

active

06677338

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds that inhibit 5-hydroxytryptamine reuptake and the use of those compounds on diseases mediated by 5HT receptors. Compounds that provide such inhibition can be useful, for example, as therapeutic anti-depressants.
BACKGROUND OF THE INVENTION
Serotonin (5-hydroxytryptamine) neurotransmission is regulated and terminated by active transport via the serotonin transporter (SERT). The SERT is member of a large superfamily of sodium/chloride dependent transporters that carry biogenic amines and other biologically active substrates to the interior of cells (Amara S G, Kuhar M J. 1993. 16:73-93; Blakely R D, et al., 1994. J Exp Biol 196:263-281). Structurally related to dopamine and norepinephrine transporters (Nelson N. 1998. J Neurochem 71:1785-1803), the SERT is the primary site of action of diverse antidepressant drugs, ranging from tricyclics such as imipramine and amitriptyline, to serotonin selective reuptake inhibitors (SSRI's) such as citalopram, fluoxetine and sertraline.
Antidepressant drugs delay the removal of extracellular serotonin from the synapse by blocking serotonin transport, thereby prolonging the duration of serotonin receptor activity. The increased availability of serotonin triggers a cascade of neuroadaptive processes, which produces symptom relief after two to four weeks. Presently known antidepressants also produce certain side effects and may selectively alleviate specific symptoms of depression (Nestler E J. 1998. Biol Psychiatry 44:526-533). Thus, it is desirable to develop novel antidepressants. The majority of clinically approved drugs to treat depression or obsessive-compulsive disorder are high affinity inhibitors of serotonin and/or norepinephrine transport. Of these transporter inhibitors, none are tropane analogs, they display low affinity for the dopamine transporter (DAT), and all contain an amine nitrogen in their structure.
Over the past decade, a wide array of tropane analogs with high affinity for the monoamine transporters have been synthesized in a program to develop cocaine medications (Madras B K, et al., 1990. Pharmacol Biochem Behav 35:949-953; Madras B K, et al., 1996. Synapse 24:340-348; Carroll F I, et al., 1992. J Med Chem 35:2497-2500; Meltzer P C, et al., 1994. J Med Chem 37:2001-2010; Kozikowski A P, et al., 1995. J Med Chem 38:3086-3093; Lomenzo S A, et al., 1997. J Med Chem 40:4406-4414; Davies H M, et al., 1994. J Med Chem 37:1262-1268). The majority of these compounds target the dopamine transporter and have not been considered candidate medications for depression because of stimulant or abuse liability concerns (Reith M E, et al., 1986. Biochem Pharmacol 35:1123-1129; Ritz M C, et al., 1987. Science 237:1219-1223; Madras B K, et al., 1989. J Pharmacol Exp Ther 251:131-141; Bergman J, et al., 1989. J Pharmacol Exp Ther 251:150-155). Tropane analogs selective for the serotonin over the dopamine transporter have been reported. (Blough B E, et al., 1996. J Med Chem 39:4027-4035; Blough B E, et al., 1997. J Med Chem 40:3861-3864; Smith M P, et al., 1998. J Am Chem Soc 1201:9072-9075; Davies, H M, et al., 1996. J Med Chem 39:2554-2558.
Psychotherapeutics drugs, including antidepressants, all incorporate an amine nitrogen into the structure. In fact, antidepressants presently used have an aromatic ring(s) and an amine nitrogen. Although the aromatic ring is an indispensable component of most drugs acting on biogenic amine receptors or transporters, we previously demonstrated that an amine nitrogen is not necessary for compounds to bind to or block the dopamine transporter (Madras B K, et al., 1996. Synapse 24:340-348; Meltzer P C, et al., 1997. J Med Chem 40:2661-2673; Meltzer P C, et al., 1999. Bioorg Med Chem Lett 9:857-862; Meltzer P C, 2000. J Med Chem 43:2982-2991). Biological activity of these compounds was retained if the amine nitrogen was replaced either by an oxygen (oxa) atom or a carbon (carba) atom (Madras B K, et al., 1996. Synapse 24:340-348; Madras B K, et al., 1998. Soc for Neurosci Abst 24:113.11, 278p; Madras B K, et al., Addiction Biology 5:351-359, 2000; Meltzer P C, 2000. J Med Chem 43:2982-2991).
It would be desirable to have high affinity non-amines with selectivity for the serotonin transporter and compounds that inhibit the transport of serotonin.
SUMMARY OF THE INVENTION
The present invention relates to the discovery that tropane compounds lacking an amine group show surprisingly effective results in treating certain neuropsychiatric disorders related to serotonin transport.
Compounds that are useful as therapeutic agents in the methods of the present invention include non-amine tropane compounds represented by the following general structural formula:
wherein:
R
1
=COOCH
3
, COR
3
, lower alkyl, lower alkenyl, lower alkynyl, CONHR
4
, or COR
6
;
R
2
=is a 6&agr;, 6&bgr;, 7&agr; or 7&bgr; substituent, which can be selected from H, OH, OR
3
, F, Cl, Br, and NHR
3
;
X=CH
2
, CHY, CYY
1
, CO, O, S; SO, SO
2
, or C═CX
1
Y with the C, O or S atom being a member of the ring;
X
1
=NR
3
, CH
2
, CHY, CYY
1
CO, O, S; SO, SO
2
, or NSO
2
R
3
;
R
3
=H, (CH
2
)
n
C
6
H
4
Y, C
6
H
4
Y, CHCH
2
, lower alkyl, lower alkenyl or lower alkynyl;
Y and Y
1
=H, Br, Cl, I, F, OH, OCH
3
, CF
3
, NO
2
, NH
2
, CN, NHCOCH
3
, N(CH
3
)
2
, (CH
2
)
n
CH
3
, COCH
3
, or C(CH
3
)
3
;
R
4
=CH
3
, CH
2
CH
3
, or CH
3
SO
2
;
R
6
=morpholinyl or piperidinyl;
Ar=phenyl-R
5
, naphthyl-R
5
, anthracenyl-R
5
, phenanthrenyl-R
5
, or diphenylmethoxy-R
5
;
R
5
=Br, Cl, I, F, OH, OCH
3
, CF
3
, NO
2
, NH
2
, CN, NHCOCH
3
, N(CH
3
)
2
, (CH
2
)
n
CH
3
, COCH
3
, C(CH
3
)
3
where n=0-6, 4-F, 4-Cl, 4-I, 2-F, 2-Cl 2-I, 3-F, 3-Cl 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc, 3,4-diOCH
3
, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
m=0 or 1; and
n=0, 1, 2, 3, 4 or 5.
Preferred compounds have a SERT/DAT selectivity ratio of at least about 3. Other embodiments have a SERT/DAT selectivity ratio of at least about 8 and other preferably at least about 50.
The invention also relates to compounds shown above that have a potency (K
i
), or IC
50
, at the SERT of less than about 500 nM, preferably less than about 100 nM. In certain preferred embodiments the compounds have a K
i
at the SERT less than about 50 nM, preferably less than about 25 nM and more preferably less than about 15 nM.
Especially preferred compounds have a SERT/DAT selectivity ratio of at least about 3 and an IC
50
at the SERT of less than about 500 nM.
The substituents at the 2 and 3 position of the ring can be &agr;- or &bgr;-. Thus, the compounds include compounds in the boat and chair conformation. Although R
1
is illustrated in the 2-position, it should be recognized that substitution at the 4-position is also included and the position is dependent on the numbering of the tropane ring. The compounds of the present invention can be racemic, pure R-enantiomers, or pure S-enantiomers. Thus, the structural formulas illustrated herein are intended to represent each enantiomer and diastereomer of the illustrated compound.
The term “lower alkyl” when used herein designates aliphatic saturated branched or straight chain hydrocarbon monovalent substituents containing from 1 to about 8 carbon atoms such as methyl, ethyl, isopropyl, n-propyl, n-butyl, (CH
2
)
n
CH
3
, C(CH
3
)
3
; etc., more preferably 1 to 4 carbons. The term “lower alkoxy” designates lower alkoxy substituents containing from 1 to about 8 carbon atoms such as methoxy, ethoxy, isopropoxy, etc., more preferably 1 to 4 carbon atoms.
The term “lower alkenyl” when used herein designates aliphatic unsaturated branched or straight chain vinyl hydrocarbon substituents containing from 2 to about 8 carbon atoms such as allyl, etc., more preferably 2 to 4 carbons. The term “lower alkynyl” designates lower alkynyl substituents containing from 2 to about 8 carbon atoms, more preferably 2 to 4

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