Compounds with high monoamine transporter affinity

Details Compounds with high monoamine transporter affinity Compounds with high monoamine transporter affinity

2000-10-17

2003-02-25

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06525206

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel compositions with affinity for a monoamine transporter, such as the dopamine, norepinephrine, or serotonin transporter, in brain and in peripheral tissues.
BACKGROUND
Monoamine transporters play a variety of roles, and compounds with affinity for the monoamine transporters have been proposed for therapy and/or diagnosis of medical indications that include (but are not limited to) attention deficit hyperactivity disorder (ADHD), Parkinson's disease, cocaine addiction, smoking cessation, weight reduction, obsessive-compulsive disorder, various forms of depression, traumatic brain injury, stroke, and narcolepsy.
The dopamine transporter (DAT) in particular is a primary mechanism for terminating the effects of synaptic dopamine and maintaining homeostatic levels of extracellular dopamine in brain. Giros et al.,
Nature
379: 696-612 (1996). The dopamine transporter is a principal target of therapeutic and psychostimulant drugs of abuse. For example, the dopamine transporter is an important target of drugs (including methylphenidate, pemoline, amphetamine and bupropion) used to treat ADHD. Seeman and Madras,
Mol. Psychiatry
3:386-396 (1998); Cyr and Brown,
Drugs
, 56:215-223 (1998); Biederman, J. Clin. Psychiatry 59: 4-16 (1998); Riggs et al.,
J. Am Acad. Child Adolesc. Psychiatry
37:1271-1278 (1999). The dopamine transporter is also a principal target of brain imaging agents used, for example, diagnostically.
It has been suggested that the therapeutic benefit of benztropin (Cogenting) for Parkinson's disease results in part from blocking dopamine transport thereby increasing synaptic dopamine. Coyle and Snyder,
J. Pharmacol. Exp. Ther
.,170:221-319 (1969).
The antidepressant bupropion apparently is also a monoamine transport inhibitor [Hirschfeld,
J. Clin. Psychiatry
17:32-35 (1999)], and it has been suggested as a treatment to aid smoking cessation. Jorenby et al.,
N. Engl. J Med
., 340:685-691 (1999); McAfee et al.,
N. Engl. J. Med
., 338:619 (1998).
The dopamine transporter has been identified as an effective marker for dopamine terminals in Parkinson's disease. Kaufman and Madras,
Synapse
9: 43-49 (1991). Brain imaging of the transporter in humans with Parkinson's disease and in animals with experimentally produced Parkinsonism has confirmed the usefulness of the dopamine transporter in this application. Fischman et al., Synapse 29: 128-141, 1998, Seibyl et al.,
Ann. Neurol
. 38:589-598.
The serotonin transporter (SERT) regulates extracellular serotonin levels. It is a principal target of effective drugs (known as serotonin-selective reuptake inhibitors or SSRI's) used to treat melancholic depression, atypical depression, dysthymia and obsessive-compulsive disorder. It also is a conduit of entry into serotonin containing neurons of neurotoxic substituted amphetamines. Selective imaging agents that label the serotonin transporter would be useful to investigate the status of the transporter in depression [Malison et al.
Bio. Psychiatry
44:1090-1098 (1998)], alcoholism [Heinz et al.
Am. J. Psychiatry
155:1544-1549 (1998)], obsessive-compulsive disorder, and substituted amphetamine abusers [McCann et al.,
Lancet
352:1433-1437 (1998); Semple et al.,
Br., J. Psychiatry
175: 63-39 (1999)]. There are various reports generally dealing with individual serotonin transporter imaging agents. Acton et al.
Eur. J. Nucl. Med
. 26:1359-1362 (1999); Szabo et al.
J. Cereb. Blood Flow Metab
. 19:967-981 (1999); Oya et al.
J. Med Chem
. 42:333-335 (1999).
Norepinephrine regulates mood, is involved in learning and memory, and controls endocrine and autonomic functions. Dysfunction of norepinephrine neurotransmission has been implicated in depression, cardiovascular and thermal pathophysiology. The norepinephrine transporter (NET) regulates extracellular levels of norepinephrine in brain, in heart, and in the sympathetic nervous system. Clinically, the norepinephrine transporter is a principal target of selective or non-selective anti-depressant drugs and stimulant drugs of abuse such as cocaine and amphetamines. Blockade of the norepinephine transporter is implicated in appetite suppression. Gehlert et al.
J. Pharmacol. Exp. Ther
. 287:122-127 (1998). Imaging of the norepinephrine transporter may also be useful for viewing the status of sympathetic innervation in the heart and in other adrenergic terminals, and for detecting neuroblastomas. Hadrich et al.
J. Med. Chem
. 42:3010-3018 (1999); Raffel et al.,
J. Nucl. Med
. 40:323-330 (1999).
It is desirable to avoid unwanted side effects of treatments targeting monoamine transporters, to the extent possible: It is also desirable to produce efficient and effective diagnostics for various conditions involving monoamine transporters.
SUMMARY
The invention features compounds of two general classes that have high and selective monoamine transport affinity. Featured compounds of the first class (which we term oxaindanes) generally have the following formula:
WHERE:
* indicates a chiral center, and each chiral center, independently, may be R, S, or R/S.
—X=—CH
2
R
1
; —CHR
1
R
5
; —CR
1
═O; —CR
6
═O; —O—R
1
; —SR
1
; —SOR
6
; —SO
2
R
6
; —SO
2
NHR
1
; or —CH═CR
1
R
5
and where:
a. —R
1
and —R
5
are independently selected from: —H; —CH
3
; —CH
2
CH
3
; or —CH
2
(CH
2
)
m
CH
3
, where m=0, 1, 2, or 3; PROVIDED THAT,
when X=—O—R
1
, then R
1
≠H; and
b. —R
6
is 'selected from: —OH; —OCH
3
; —NHR
1
; —O-alkyl; —O-alkenyl; —O-alkynyl; —O-allyl; —O-iodoallyl; -alkyl; -alkenyl; -alkynyl; -allyl; -isopropyl; and -isobutyl.
—Ar=either
a) phenyl substituted at any two positions with R
3a
and R
3b
, where R
3a
and R
3b
are as defined in options “I.” or “II.”, below; or
b) 1-napththyl or 2-naphthyl, substituted at any two positions with R
3a
, and R
3b
where R
3a
and R
3b
are as defined in option “I.”, below);
OPTION I for R
3a
, and R
3b
(phenyl or naphthyl substitutions)
—R
3a
and —R
3b
are independently selected from: —H; —Br; —Cl; —I; —F; —H; —OCH
3
; —CF
3
; —NO
2
; —NH
2
; —CN; —NHCOCH
3
, —C(CH
3
)
3
, —(CH
2
)
q
CH
3
where q=0-6; —COCH
3
; —F (at the 2, 3 or 4 position), —Cl (at the 2, 3 or 4 position); —I (at the 2, 3 or 4 position); alkyl; alkenyl; alkynyl; allyl; iospropyl; isobutyl; alkyl; -alkylN
2
S
2
chelator; -alkylN
2
S
2
Tc chelator, such that N
2
S
2
is part of a chelating moiety such as those known in the art which contain two nitrogens and two sulfur atoms, in addition to carbon and optionally other heteroatoms, see, for example, O'Neil et al.,
Bioconjugate Chem
. 5:182-193 (1994); O'Neil et al.,
Inorg. Chem
. 33:319-323 (1994); Kung et al.,
J. Nucl. Med
. 27:1051 (1986); Kung et al.,
J. Med. Chem
. 28: 1280-1284 (1985), hereby incorporated by reference; or COR
7
, where R
7
is defined below;
 OR
OPTION II. for R
3a
, and R
3b
(phenyl substitutions)
—R
3a
and —R
3b
as a pair are independently selected from the following pairs: 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; or 3-F,4-OH;
n=0 or 1;
—R
2
=—COOCH
3
; —COR
7
; -alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN
2
S
2
chelator, —O-alkylN
2
S
2
chelator. -alkylN
2
S
2
Tc chelator; —O-alkylN
2
S
2
Tc chelator; where,
—R
7
is —HR
8
; morpholinyl; piperidinyl; —CH
3
; —CH
2
CH
3
; —CH
2
(CH
2
)
r
CH
3
where r=0, 1, 2, or 3; alkyl; alkenyl; alkynyl; allyl; isopropyl; iodoallyl; O-iodoallyl; -isobutyl; —CH
2
SO
2
; -alkylN
2
S
2
chelator; -alkylN
2
S
2
Tc chelator; O-alkylN
2
S
2
chelator, or —O-alkylN
2
S
2
Tc chelator; and —R
8
is -alkyl; -alkenyl; -allyl; iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN
2
S
2
chelator; —O-alkylN
2
S
2
chelator, -alkylN
2
S
2
Tc chelator; —O-alkylN
2
S
2
Tc chelator.
Preferred substituents for the above general formula are as follows: n is preferably 0; X is preferably —O—R
1
, where R
1
is preferably —CH
3
; Ar

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