Therapeutic compounds

Details Therapeutic compounds Therapeutic compounds

2002-06-25

2004-07-13

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...

C546S089000, C546S080000, C544S126000, C544S361000, C514S232800, C514S254080

Reexamination Certificate

active

06762191

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides aryl or heteroaryl substituted benzofuran derivatives, and more specifically, provides compounds of formula (I) as described hereinbelow. These compounds are 5-HT ligands, and are useful for treating diseases wherein modulation of 5-HT activity is desired.
BACKGROUND OF THE INVENTION
Serotonin has been implicated in a number of diseases and conditions that originate in the central nervous system. These include diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia, and other bodily states. R. W. Fuller, Biology of Serotonergic Transmission, ed. Neville V. Osborne, John Wiley and Sons (1982), p 221; D. J. Boullin, Serotonin in Mental Abnormalities 1, John Wiley and Sons (1978), p. 316; J. Barchas, et al., Serotonin and Behavior, Academic Press, New York, N.Y. (1973). Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.
As a result of the broad distribution of serotonin within the body, there is a tremendous interest in drugs that affect serotonergic systems. In particular, receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinsonism, and Huntington's chorea), and chemotherapy-induced vomiting. M. D. Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15:Supplement 7 (1990).
The major classes of serotonin receptors (5-HT
1-7
) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al.,
Neuroscience and Behavioral Reviews,
1990, 14, 35; and D. Hoyer, et al.
Pharmacol. Rev.
1994, 46, 157-203. Recently discovered information regarding subtype identity, distribution, structure, and function suggests that it is possible to identify novel, subtype specific agents, having improved therapeutic profiles (e.g. fewer side effects).
For example, the 5-HT
2
family of receptors is comprised of 5-HT
2A
, 5-HT
2B
, and 5-HT
2C
subtypes, which have been grouped together on the basis of primary structure, secondary messenger system, and operational profile. All three subtypes are G-protein coupled, activate phospholipase C as a principal transduction mechanism, and contain a seven-transmembrane domain structure. There are distinct differences in the distribution of the three 5-HT
2
subtypes. The 5-HT
2B
and 5-HT
2A
receptors are widely distributed in the periphery, while the 5-HT
2C
receptor has been found only in the central nervous system, being highly expressed in many regions of the human brain. See G. Baxter, et al.
Trends in Pharmacol. Sci.
1995, 16, 105-110.
Subtype 5-HT
2A
has been associated with effects including vasoconstriction, platelet aggregation, and bronchoconstriction, while subtype 5-HT
2C
has been associated with diseases that include depression, anxiety, obsessive compulsive disorder, panic disorders, phobias, psychiatric syndromes, and obesity. Very little is known about the pharmacologic role of the 5-HT
2B
receptor. See F. Jenck, et al.,
Exp. Opin. Invest. Drugs,
1998, 7, 1587-1599; M. Bos, et al.,
J. Med. Chem.,
1997, 40, 2762-2769; J. R. Martin, et al.,
The Journal of Pharmacology and Experimental Therapeutics,
1998, 286, 913-924; S. M. Bromidge, et al.,
J. Med. Chem.,
1998, 41,1598-1612; G. A. Kennett,
Drugs,
1998, 1, 4, 456-470; and A. Dekeyne, et al.,
Neuropharmacology,
1999, 38, 415-423.
Japanese Patent Application S63-149645 discusses a vast genus of compounds that are reported to be useful to prevent photochemical browning of organic pigments. The compounds specifically prepared in the application differ considerably in structure from the compounds of the invention. For example, they lack a benzofuran type ring system.
U.S. Pat. No. 5,616,575 relates to tricyclic ibogaine analogs of the following formula.
The compounds are reported to be useful to treat cocaine addiction and the use of other addictive substances. The compounds differ from the compounds of the invention at the groups R
2
and R
3
in the above formula.
There is currently a need for pharmaceutical agents that are useful to treat diseases and conditions associated with 5-HT receptors.
SUMMARY OF THE INVENTION
In accordance with the present invention, novel compounds that demonstrate useful biological activity, and particularly activity as 5-HT receptor ligands, are provided. Thus, the present invention provides a compound of formula (I):
wherein:
R
1
, R
2
, R
3
, and R
4
are independently hydrogen, halo, —CF
3
, —OCF
3
, —CN, —NO
2
, —C
1-8
alkyl, —C
3-8
cycloalkyl, —OR
8
, —NR
8
R
9
, —SR
8
, —C(═O)aryl, aryl, —C
1-8
alkylene(aryl), —C(═O)heteroaryl, heteroaryl, or —C
1-8
alkylene(heteroaryl);
R
5
is hydrogen, C
1-8
alkyl, haloC
1-8
alkyl, C
3-8
cycloalkyl, C
1-8
alkanoyl, haloC
1-8
alkanoyl, —C(═O)OR
8
, —C(═O)aryl, aryl, —C
1-8
alkylene(aryl), —C(═O)heteroaryl, heteroaryl, or —C
1-8
alkylene(heteroaryl);
R
6
is hydrogen or C
1-4
alkyl;
each R
8
and R
9
is independently hydrogen, C
1-8
alkyl, haloC
1-8
alkyl, C
3-8
cycloalkyl, —C(═O)aryl, aryl, —C
1-8
alkylene(aryl), —C(═O)heteroaryl, heteroaryl, —C
1-8
alkylene(heteroaryl) or R
8
and R
9
together with the nitrogen to which they are attached form a pyrrolidino, piperidino, azepano, piperazino, morpholino, or thiomorpholino ring;
m is 0, 1, or 2;
n is 1 or 2;
X is oxy (—O—), thio (—S—) —S(═O)— or —SO
2
—;
the bond represented by — is absent or present; and
wherein any C
1-8
alkyl, C
1-8
alkylene, C
1-8
alkoxy or C
3-8
cycloalkyl of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
8
and R
9
is optionally partially unsaturated; and
wherein any aryl or heteroaryl of R
1
, R
2
, R
3
, R
4
, R
5
, R
8
or R
9
is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from halo, —CN, —NO
2
, —CF
3
, —OCF
3
, C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkynyl, C
3-8
cycloalkyl, C
3-8
cycloalkenyl, aryl, heteroaryl, —OR
c
, —SR
c
, —C(═O)R
c
, —CO
2
R
c
, —C(═O)NR
c
R
d
, —NR
c
C(═O)R
d
, —NR
c
R
d
, —NR
c
C(═O)NR
c
R
d
, —SO
2
—NR
c
R
d
or —SO
2
R
c
;
wherein each R
c
and R
d
is independently hydrogen, C
1-8
alkyl, C
1-8
alkanoyl, C
1-8
alkoxycarbonyl, aryl, —C
1-8
alkylene(aryl), —C(═O)aryl, —C(═O)oaryl, heteroaryl, —C
1-8
alkylene(heteroaryl), —C(═O)heteroaryl, —C(═O)oheteroaryl or R
c
and R
d
together with the nitrogen to which they are attached form a pyrrolidino, piperidino, azepano, piperazino, morpholino, or thiomorpholino ring;
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises a therapeutically effective amount of the compound or salt),
a method for treating a disease or condition in a mammal (e.g. a human) wherein a 5-HT receptor is implicated and modulation of a 5-HT function is desired comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof to the mammal,
a method for treating or preventing a disease or disorder of the central nervous system in a mammal comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof to the mammal,
a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical diagnosis or therapy (e.g. the treatment or prevention of 5-HT related disease such as anxiety, obesity, depression, or a stres

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