Title of Invention

BENZAZEPINE DERIVATIVES

Abstract The present invention relates to certain 1-substituted-2,3,4,5-tetrahydro-3-benzazepine derivatives of Formula (I), that are modulators of the 5HT2C receptor. Accordingly, compounds of the present invention are useful for the prophylaxis or treatment of 5HT2C receptor associated diseases, conditions or disorders, such as, obesity and related disorders.
Full Text BENZAZEPINE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to certain substituted-2,3,4,5-tetrahydro-3-benzazepine
derivatives that are modulators of the 5HT2C receptor. Accordingly, compounds of the present
invention are useful for the prophylaxis or treatment of 5HT2C receptor associated diseases,
conditions or disorders, such as, obesity and related disorders.
BACKGROUND OF THE INVENTION
Obesity is a life-threatening disorder in which there is an increased risk of morbidity and
mortality arising from concomitant diseases such as, but not limited to, type II diabetes,
hypertension, stroke, certain forms of cancers and gallbladder disease.
Obesity has become a major healthcare issue in the Western World and increasingly in
some third world countries. The increase in the number of obese people is due largely to the-
increasing preference for high fat content foods but also, and this can be a more important factor,
the decrease in activity in most people's lives. In the last 10 years there has been a 30% increase in
the incidence of obesity in the USA and that about 30% of the population of the USA is now
considered obese. In spite of the growing awareness of the health concerns linked to obesity the
percentage of individuals that are overweight or obese continue to increase. In fact, the percentage
of children and adolescents who are defined as overweight has more than doubled since the early
1970s and about 13 percent of children and adolescents are now seriously overweight. The most
significant concern, from a public health perspective, is that children who are overweight grow up
to be overweight or obese adults, and accordingly are at greater risk for major health problems.
Therefore, it appears that the number of individuals that are overweight or obese will continue to
increase.
Whether someone is classified as overweight or obese is generally determined on the basis
of his or her body mass index (BMI) which is calculated by dividing their body weight (kilograms -
Kg) by their height squared (meters squared - m2). Thus, the units for BMI are Kg/m2. The BMI is
more highly correlated with body fat than any other indicator of height and weight. A person is
considered overweight when they have a BMI in the range of 25-30 kg/m2. Whereas a person with
a BMI over 30 kg/m2 is classified as obese and obesity is further divided into three classes, Class I
(BMI of about 30 to about 34.9 kg/m2), Class H (BMI of about 35 to 39.9 kg/m2) and Class HI
(about 40 kg/m2 or greater); see TABLE 1 below for complete classifications.


As the BMI increases for an individual there is an increased risk of morbidity and mortality relative
to an individual with normal BMI. Accordingly, overweight and obese individuals (BMI of about
25 kg/m" and above) are at increased risk for physical ailments such as, but not limited to, high
blood pressure, cardiovascular disease (particularly hypertension), high blood cholesterol,
dyslipidemia, type II (non-insulin dependent) diabetes, insulin resistance, glucose intolerance,
hyperinsulinemia, coronary heart disease, angina pectoris, congestive heart failure, stroke,
gallstones, cholescystitis and cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and
respiratory problems, some types of cancer (such as endometrial, breast, prostate, and colon),
complications of pregnancy, poor female reproductive health (such as menstrual irregularities,
infertility, irregular ovulation), diseases of reproduction (such as sexual dysfunction, both male and
female, including male erectile dysfunction), bladder control problems (such as stress incontinence),
uric acid nephrolithiasis, psychological disorders (such as depression, eating disorders, distorted
body image, and low self esteem). Research has shown that even a modest reduction in body
weight can correspond to a significant reduction in the risk of developing other ailments, such as,
but not limited to, coronary heart disease.
As mentioned above, obesity increases the risk of developing cardiovascular diseases.
Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront of the
cardiovascular complications induced by obesity. The incidence of coronary diseases is doubled in
subjects less than 50 years of age who are 30% overweight. The diabetes patient faces a 30% reduced
lifespan. After age 45, people with diabetes are about three times more likely than people without
diabetes to have significant heart disease and up to five times more likely to have a stroke. These
findings emphasize the inter-relations between risks factors for NIDDM and coronary heart disease
and the potential value of an integrated approach to the prevention of these conditions based on the

population had an ideal weight, the risk of coronary insufficiency would decrease by 25%
of cardiac insufficiency and of cerebral vascular accidents by 35%.
Diabetes has also been implicated in the development of kidney disease, eye diseases
nervous-system problems. Kidney disease, also called nephropathy, occurs when the kidney's'
mechanism" is damaged and protein leaks into urine in excessive amounts and eventually the kio.
fails. Diabetes is also a leading cause of damage to the retina and increases the risk of cataracts an>
glaucoma. Finally, diabetes is associated with nerve damage, especially in the legs and feet, which
interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes
complications are one of the nation's leading causes of death.
The first line of treatment for individuals that are overweight or obese is to offer diet and
life style advice, such as, reducing the fat content of their diet and increasing their physical activity.
However many patients find these difficult to maintain and need additional help from drug therapy
to sustain results from these efforts.
Most currently marketed products have been unsuccessful as treatments for obesity'owing
to a lack of efficacy or unacceptable side-effect profiles. The most successful drug so far was the
indirectly acting 5-hydroxytryptarnine (5-HT) agonist d-fenfluramine (Redux™) but reports of
cardiac valve defects in up to one third of the patient population led to its withdrawal by the FDA in
1998.
In addition, two drugs have recently been launched in the USA and Europe: Orlistat
(Xenical™), a drug that prevents absorption of fat by the inhibition of pancreatic lipase, and
Sibulramine (Reductil™), a 5-HT/noradrenaline re-uptake inhibitor. However, side effects
associated with these products may limit their long-term utility. Treatment with Xenical™ is
reported to induce gastrointestinal distress in some patients, while Sibutramine has been associated
with raised blood pressure in some patients.
Serotonin (5-HT) neurotransmission plays an important role in numerous physiological
processes both in health and in psychiatric disorders. 5-HT has been implicated in the regulation of
feeding behavior for some time. 5-HT works by inducing a feeling of fullness or satiety so eating
stops earlier and fewer calories are consumed. It has been shown that a stimulatory action of 5-HT
on the 5HT2C receptor plays an important role in the control of eating and in the anti-obesity effect
of d-fenfluramine. As the 5HT2C receptor is expressed in high density in the brain (notably in the
limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e. PW and DMH, and
predominantly in the choroid plexus) and is expressed in low density or is absent in peripheral
tissues, a selective 5HT2C receptor agonist can be an effective and safe anti-obesity agent. Also,
5HT2C knockout mice are overweight with cognitive impairment and susceptibility to seizure thus

establishing the clear use for a 5HT2C receptor agonist in 5HT2C receptor associated diseases or
disorders.
The 5HT2c receptor plays a role in obsessive compulsive disorder, some forms of
depression, and epilepsy. Accordingly, 5HT2c receptor agonists can have anti-panic properties, and
properties useful for the treatment of sexual dysfunction. In addition, 5HT2c receptor agonists are
useful for the treatment of psychiatric symptoms and behaviors in individuals with eating disorders
such as, but not limited to, anorexia nervosa and bulimia nervosa. Individuals with anorexia
nervosa often demonstrate social isolation. Anorexic individuals often present symptoms of being
depressed, anxious, obsession, perfectionistic traits, and rigid cognitive styles as well as sexual
disinterest. Other eating disorders include, anorexia nervosa, bulimia nervosa, binge eating disorder
(compulsive eating) and ED-NOS (i.e., eating disorders not otherwise specified - an official
diagnosis). An individual diagnosed with ED-NOS possess atypical eating disorders including
situations in which the individual meets all but a few of the criteria for a particular diagnosis. What
the individual is doing with regard to food and weight is neither normal nor healthy.
In addition, the 5HT2C receptor is also involved in other diseases, conditions and disorders;
such as Alzheimer Disease (AD). Therapeutic agents currently prescribed for Alzheimer's disease
(AD) are cholmornimetic agents that act by inhibiting the enzyme acetylcholinesterase. The
resulting effect is increased levels of acetylcholine, which modestly improves neuronal function and
cognition in patients with AD. Although, dysfunction of cholinergic brain neurons is an early
manifestation of AD, attempts to slow the progression of the disease with these agents have had
only modest success, perhaps because the doses that can be administered are limited by peripheral
cholinergic side effects, such as tremors, nausea, vomiting, and dry mouth. In addition, as AD
progresses, these agents tend to lose their effectiveness due to continued cholinergic neuronal loss.
Therefore, there is a need for agents that have beneficial effects in AD, particularly in
alleviating symptoms by improving cognition and slowing or inhibiting disease progression, without
the side effects observed with current therapies. Therefore, serotonin 5HT2c receptors, which are
exclusively expressed in brain, are attractive targets.
A major feature of AD is the formation of senile plaques made of amyloid deposits in a
selected area of the brain. New therapies should focus on prevention of the production of these
senile plaques. An amyloid deposit composed mainly of beta-amyloid peptide (A(3) occupies the
plaque center. Ap is a peptide of 40 to 43 residues derived from a larger amyloid precursor protein,
APP [Selkoe DJ, et al. Ann Rev Neurosci, 1994,17:489-517]. APP is a ubiquitous transmembrane
glycoprotein that is present at high levels in brain cells. APP also exists as secreted forms. By
cleavage in the Ap region of APP, the long N-terrninal fragment (secreted APP, APPs) is secreted

into the extracellular space. The rate of Ap production appears to be inversely coupled to rate APPs
secretion. In several cell cultures, APPs secretion was accompanied by reductions in secreted AP
[Buxbaum JD, et al. Proc Nat Acad Sci, 1993, 90:9195-9198; GabuzdaD, et al. JNeurochem,
1993, 61:2326-2329; Hung AY, et al. J Biol Chem, 1993, 268:22959-22962; and Wolf BA, et al. J
Biol Chem, 1995,270:4916-4922], suggesting that stimulated secretory processing of APP into
secreted APPs is associated with reduced formation of potentially amyloidogenic derivatives, or
plaques.
APPs is found in plasma and cerebrospinal fluid [Ghiso J, et al. Biochem Biophys Res
Comm, 1989, 163:430-437; and Podlisny MB, et al. Biochem Biophys Res Comimm, 1990,
167:1094-1101]. Considering the abundance of both membrane-bound APP and APPs, they are
likely to have significant biological functions. Current knowledge about APP functions indicates
APP is critically required for the maintenance of neuronal and synaptic structure and function.
Membrane-bound APP has been suggested to have a receptor-like structure [Kang J, et al. Nature,
1987, 325:733-736], with the cytoplasmic domain capable of complexing with a GTP-binding
protein [Nishimoto L, et al. Nature, 1993, 362:75-79]. Membrane-embedded full-length APP might
also have a cell adhesion function [Qiu W., et al. JNeurosci, 1995,15:2157-2167].
APPs has been shown to be neurotrophic and neuroprotective in vitro [Mattson MP, et al.
Neuron, 1993,10:243-254; and Qiu W., et al. JNeurosci, 1995,15:2157-2167]. Other proposed
functions for APPs include the regulation of blood coagulation [Cole GM, et al. Biochem Biophys
Res Commun, 1990, 170:288-295; Smith RP, et al. Science, 1990,248:1126-1128; and Van
Nostrand et al. Science, 1990, 248:745-748], wound-healing [Cunningham JM, et al.
Histochemistiy, 1991, 95:513-517], extracellular protease activity [Oltersdorf T, et al. Nature
(London), 1989, 341:144-147; and Van Nostrand WE, et al. Nature, 1989, 341:546-548], neurite
extension [Jin L., et al. JNeurosci, 1994, 14:5461-5470; and Robakis NK, et al. in Molecular
Biology of Alzheimer's Disease. (T. Miyatake, D J. Selkoe and Y. Ihara, ed.), 1990, pp. 179-188,
Elsevier Science Publishers B.V., Amsterdam], cell adhesiveness [Schubert D, et al. Neuron, 1989,
3:689-694], cell growth, [BhasinR., et al. Proc Natl Acad Sci USA, 1991, 88:10307-10311; and
Saitoh T., Cell, 1989, 58:615-622], and differentiation [Araki W., et al. Biochem Biophys Res
Commun,l99\, 181:265-271; Milward EA, et al. Neuron, 1991, 9:129-137; and Yamamoto K, et al.
JNeurobiol, 1994, 25:585-594].
The non-selective serotonin 5HT2c agonist dexnorfenfluramine (DEXNOR) stimulated
amyloid precursor protein (APPs) secretion in guinea pigs while reducing levels of Ap production •
in vivo following repeat administration [Arjona A, et al. "Effect of a 5HT2c serotonin agonist,
dexnorfenfluramine, on amyloid precursor protein metabolism in guinea pigs," Brain Res, 2002,

951:135-140]. Guinea pigs were chosen because guinea pig and human APP exhibit 98% sequence
homology [Beck M, et al. Biochem Biophys Acta, 1997, 1351:17-21], the proteins are processed
similarly [Beck M., et al. Neiiroscience, 1999,95:243-254], and the A(3 peptide sequences are
identical [Johnstone EM, et al. Brain Res Mol Brain Res, 1991,10:299-305]. Although DEXNOR
is non-selective, the observed effects were attenuated by a selective serotonin 5HT2c antagonist,
while a selective serotonin HT2A antagonist did not reverse the DEXNOR effects, indicating the
serotonin 5HT2c receptors are the most relevant target for this effect.
In addition, 5-HT stimulates APPs ectodomain secretion via the serotonin 5HT2A and
5HT2C receptors [Nitsch RM, et al. J Biol Chem, 1996, 271(8):4188-4194]. In this study,
researchers stimulated 3T3 fibroblasts with serotonin (5-HT), which were stably expressing
serotonin 5HT2A or 5HT2C receptors. 5-HT increased APPs secretion in a dose-dependent manner
in both cell lines. Maximal stimulation of APPs secretion peaked at about 4-fold. Selective
serotonin 5HT2A and 5HT2c antagonists blocked the effects in each cell line.
A serotonin 5HT2C receptor agonist can be effective for treating AD and preventing senile
plaques. Support for this claim comes from the fact that A|3 is known to be neurotoxic and a key
component in senile plaques involved in AD, APPs secretion and Ap levels seem to be inversely
related, and serotonin 5HT2c agonists increase levels of APPs in vitro in cell lines stably expressing
serotonin 5HT2C receptors while in vivo serotonin 5HT2C agonists increase levels of APPs and
decrease levels of A(3 as measured in cerebral spinal fluid of guinea pigs.
Evidence exists supporting the use of a compound of the present invention with agonist
activity at the serotonin 5HT2c receptor for the treatment of AD. The compound of the invention
can be used alone or in combination with another agent or agents (such as but not limited to AChE
inhibitors) that are typically prescribed for AD.
Another disease, disorder or condition that can is associated with the function of the 5HT2c
receptor is erectile dysfunction (ED). Erectile dysfunction is the inability to achieve or maintain an
erection sufficiently rigid for intercourse, ejaculation, or both. An estimated 20-30 million men in
the United States have this condition at some time in their lives. The prevalence of the condition
increases with age. Five percent of men 40 years of age report ED. This rate increases to between
15% and 25% by the age of 65, and to 55% in men over the age of 75 years.
Erectile dysfunction can result from a number of distinct problems. These include loss of
desire or libido, the inability to maintain an erection, premature ejaculation, lack of emission, and
inability to achieve an orgasm. Frequently, more than one of these problems presents themselves
simultaneously. The conditions maybe secondary to other disease states (typically chronic
conditions), the result of specific disorders of the urogenital system or endocrine system, secondary

to treatment with pharmacological agents (e.g. antihypertensive drugs, antidepressant drugs,
antipsychotic drugs, etc.) or the result of psychiatric problems. Erectile dysfunction, when organic,
is primarily due to vascular irregularities associated with atherosclerosis, diabetes, and hypertension.
There is evidence for use of a serotonin 5HT2C agonist for the treatment of sexual
dysfunction in males and females. The serotonin 5HT2c receptor is involved with the processing
and integration of sensory information, regulation of central monoaminergic systems, and
modulation of neuroendocrine responses, anxiety, feeding behavior, and cerebrospinal fluid
production [Tecott, L.H., et.al. Nature 374: 542-546 (1995)]. In addition, the serotonin 5HT2C
receptor has been implicated in the mediation of penile erections in rats, monkeys, and humans.
The exact mechanism by which 5HT2c receptors mediate penile erections remains
unknown. However, there is good evidence, indirect and direct, supporting the role of serotonin
5HT2C receptors in the mediation of penile erections. Anatomical studies have shown that the penis
receives autonomic innervation from sympathetic and parasympathetic nuclei located in the spinal
cord [Pescatori ES, et al. J Urol 1993; 149: 627-32]. In agreement, experimental and clinical data
support that penile erections are controlled by a spinal reflex. A closer analysis showed that
activation of 5HT2 spinal receptors facilitated pudendal reflex in anesthetized cats [Danuser H and
ThorKB, Br J Pharmacol 1996; 118: 150-4]. Accordingly, stimulation of 5HT2C receptors has
been shown to be proerectile [Millan MJ, et al. European Journal of Pharmacology 1997; 325], and
5HT2c receptors have been described on proerectile spinal parasympathetic neurons [Bancila M et
al. Neuroscience 1999; 92: 1523-37].
Indirect evidence comes from the research and reports of the side effects induced by the use
of selective serotonin reuptake inhibitors (SSRIs). SSRIs have demonstrated antagonist action at
the serotonin 5HT2c receptors [Jenck et al. European Journal of Phannacology 231: 223-229
(1993); Lightlowler et al. European Journal of Phannacology 296: 137-43 (1996); and Palvimaki,
E., et al. Psychophaimacology 126: 234-240 (1996)]. Among the most derogatory side effects of
SSRIs noted in humans is increased difficulty in attaining penile erection. Although SSRIs have a
rich pharmacological profile, it is believed that the antagonist effects of SSRIs at the 5HT2c
receptors could be implicated in the inhibition of penile erections [Palvimaki, E., et al.
Psycliopharmacology 126: 234-240 (1996)].
Further evidence comes from studies with a variety compounds with known agonist activity
for the serotonin 5HT2C receptor. Pharmacologic studies with rats and rhesus monkeys provide
direct evidence of the proerectile properties of agonist of the serotonin 5-HT2C receptor [Millan MJ,
et al. European Journal of Phannacology 1997; 325; and Pomerantz, et al. European Journal of
Phannacology 243:227-34 (1993)]. These pro-erectile effects were unaffected by antagonists for

the serotonin 5HT2A and 5HT2B receptors, respectively. Antagonists of the serotonin 5HT2c
receptors attenuated the proerectile effects of the 5-HT2c agonists. The inhibition action
corresponded to each antagonist's affinity for the 5-HT2c receptors. In addition, agonists of the
serotonin 5HT2A and 5HT2B receptors did not elicit penile erections.
In summary, the 5HT2C receptor is a validated and well-accepted receptor target for the
prophylaxis and/or treatment of 5HT2c mediated receptor diseases and disorders, such as, obesity,
eating disorders, psychiatric disorders, Alzheimer Disease, sexual dysfunction and disorders related
thereto. It can be seen that there exists a need for selective 5HT2C receptor agonists that can safely
address these needs. The present invention is directed to these, as well as other, important ends. ,
SUMMARY OF THE INVENTION
The present invention is drawn to compounds which bind to and modulate the activity of
the 5HT2c receptor, and uses thereof. The term 5HT2c receptor as used herein includes the human
sequences found in GeneBank accession number AF498983, naturally-occurring allelicvariants,
mammalian orthologs, and recombinant mutants thereof.
One aspect of the present invention pertains to certain substituted-2,3,4,5-tetrahydro-3-
benzazepine derivatives as represented by Formula (I):

wherein:
R.! is H or Ci-8 alkyl;
R2 is CM alkyl, -CH2-0-Cw alkyl, CM haloalkyl or CH2OH; and
R3, R4, R5 and Re are each independently H, CM alkyl, amino, cyano,
halogen, CM haloalkyl, nitro or OH; or
a pharmaceutically acceptable salt, hydrate and solvate thereof;
provided that when R2 is CiA alkyl, -CH2-0-CM alkyl, and CH2OH then R3
and R6 are not both hydrogen.
Some embodiments of the present invention are compounds of Formula (I) wherein the
compounds are the R enantiomers.
Some embodiments of the present invention are compounds of Formula (I) wherein the
compounds are the S enantiomers.

Another aspect of the present invention also pertains to pharmaceutical compositions
comprising one or more compounds of the invention, and one or more pharmaceutically acceptable
carriers.
Another aspect of the present invention pertains to methods of modulating a 5HT2c receptor
comprising contacting said receptor with a therapeutically effective amount or dose of a compound
as described herein. Preferably, compounds of the present invention are agonists of the 5HT2c
receptor.
Another aspect of the present invention pertains to methods of prophylaxis or treatment of
disorders of the central nervous system; damage to the central nervous system; cardiovascular
disorders; gastrointestinal disorders; diabetes insipidus or sleep apnea comprising administering to
an individual in need of such prophylaxis or treatment a therapeutically effective amount or dose of
a compound of the present invention or a pharmaceutical composition thereof.
Another aspect of the present invention pertains to methods of decreasing food intake of.an
individual comprising administering to said individual a therapeutically effective amount or dose of
a compound of the present invention or a pharmaceutical composition thereof.
Another aspect of the present invention pertains to methods of inducing satiety in an
individual comprising adrninistering to said individual a therapeutically effective amount or dose of
a compound of the present invention or a pharmaceutical composition thereof.
Another aspect of the present invention pertains to methods of controlling weight gain of an
individual comprising administering to said individual suffering from weight control a
therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical
composition thereof.
Another aspect of the present invention pertains to methods of producing a pharmaceutical
composition comprising admixing at least one compound of the present invention and at least one
pharmaceutically acceptable carrier.
Another aspect of the present invention pertains to compounds, as described herein, for use
in a method of treatment of the human or animal body by therapy.
Another aspect of the present invention pertains to compounds, as described herein, for use
in a method of prophylaxis or treatment of disorders of the central nervous system; damage to the
central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus or
sleep apnea of the human or animal body by therapy.
Another aspect of the present invention pertains to use of compounds, as described herein,
for the manufacture of a medicament for use in the treatment or prophylaxis of disorders of the
central nervous system; damage to the central nervous system; cardiovascular disorders;

gastrointestinal disorders; diabetes insipidus or sleep apnea.
In some embodiments, the disorders of the central nervous system are selected the group
consisting of depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-
compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses,
schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised
intracranial pressure, epilepsy, personality disorders, Alzheimer disease, age-related behavioral
disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders
in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and
alcohol addiction, obesity, bulimia, anorexia nervosa and premenstrual tension. In further
embodiments, the disorder of the central nervous system is obesity. In further embodiments, the
disorder of the central nervous system is Alzheimer disease. In further embodiments, the sexual
dysfunction is Male erectile dysfunction.
In some embodiments, the damage to the central nervous system is by trauma, stroke,
neurodegenerative diseases, toxic CNS diseases or infective CNS diseases. In further embodiments,
the damage to the central nervous system is by encephalitis or meningitis.
In some embodiments, the cardiovascular disorder is thrombosis.
In some embodiments, the gastrointestinal disorder is dysfunction of gastrointestinal
motility.
In some embodiments, the invention pertains to methods for alleviation of a symptom of
any of the diseases, conditions or disorders mentioned herein.
In some embodiments, the individual is a mammal.
In some embodiments, the individual is a mammal and preferably, the mammal is a human.
In further embodiments, the human has a body mass index of about 18.5 to about 45.
In further embodiments, the human has a body mass index of about 25 to about 45.
In further embodiments, the human has a body mass index of about 30 to about 45.
In further embodiments, the human has abodymass index of about 35 to about 45.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
For clarity and consistency, the following definitions will be used throughout this patent
document.
AGONISTS shall mean moieties that interact and activate the receptor, such as the 5HT2c
receptor and initiates a physiological or pharmacological response characteristic of that receptor. For
example, when moieties activate the intracellular response upon binding to the receptor, or enhance GTP

binding to membranes.
The term ANTAGONISTS is intended to mean moieties that competitively bind to the receptor
at the same site as agonists (for example, the endogenous ligand), but which do not activate the
intracellular response initiated by the active form of the receptor, and can thereby inhibit the
intracellular responses by agonists or partial agonists. Antagonists do not diminish the baseline
intracellular response in the absence of an agonist or partial agonist.
CHEMICAL GROUP, MOIETY OR RADICAL:
As used herein, the term "alkyl" is intended to denote hydrocarbon compounds
including straight chain, branched and cyclic hydrocarbons, including for example but not
limited to methyl, ethyl, n-propyl, isopropyl, cj'clopropyl, n-butyl, sec-butyl, tert-butyl,
cyclobutyl, cyclopropylmethyl, n-pentyl, isopentyl, tert-pentyl, cyclopentyl,
cyclopentylmethyl, n-hexyl, cyclohexyl, and the like. The term "C^ alkyl" refers to an
alkyl group containing 1 to 8 carbon atoms. Likewise, the term "Cw alkyl" refers to an
alkyl group containing 1 to 4 carbon atoms. Throughout this specification, it should be
understood that the term alkyl is intended to encompass both non-cyclic hydrocarbon
compounds and cyclic hydrocarbon compounds. In some embodiments of the compounds
of the invention, alkyl groups are non-cyclic. In further embodiments, alkyl groups are
cyclic, and in further embodiments, alkyl groups are both cyclic and noncyclic. Where no
preference is specified, the term "alkyl" is intended to denote groups are both, cyclic and
non-cyclic.
The term "amino" denotes the group -NH2-
The term "cyano" denotes the group -CN.
The term "Cw haloalkyl" denotes an alkyl group, defined herein, wherein the alkyl
is substituted with one halogen up to fully substituted and a fully substituted Cw haloalkyl
can therefore be represented by the formula C„L2n+i wherein L is a halogen; when more
than one halogen is present then they may be the same or different and selected from the
group consisting of F, CI, Br or I. Examples of C^ haloalkyl groups include: fluoromethyl,
difluoromethyl, trifluoromethyL chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl
and the like.
The term "halogen" or "halo" denotes to a fluoro, chloro, bromo or iodo group.
The term "nitro" refers to the group -N02-
COMPOSITION shall mean a material comprising at least two compounds or two
components; for example, and not limitation, a Pharmaceutical Composition is a Composition.
CONTACT or CONTACTING shall mean bringing the indicated moieties together,

whether in an in vitro system or an in vivo system. Thus, "contacting" a 5HT2c receptor with a
compound of the invention includes the administration of a compound of the present invention to an
individual, preferably a human, having a 5HT2c receptor, as well as, for example, introducing a
compound of the invention into a sample containing a cellular or more purified preparation
containing a 5HT2c receptor.
IN NEED OF PROPHYLAXIS OR TREATMENT as used herein refers to a judgment
made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans;
veterinarian in the case of animals, including non-human mammals) that an individual or animal
requires or will benefit from prophylaxis or treatment. This judgment is made based on a variety of
factors that are in the realm of a caregiver'sexpertise, but that includes the knowledge that the
individual or animal is ill, or will be ill, as the result of a disease, condition or disorder that is
treatable by the compounds of the invention. In general, "in need of prophylaxis" refers to the
judgment made by the caregiver that the individual will become ill. In this context, the compounds
of the invention are used in a protective or preventive manner. However, "in need of treatment"
refers to the judgment of the caregiver that the individual is already ill, therefore, the compounds of
the present invention are used to alleviate, inhibit or ameliorate the disease, condition or disorder.
INDIVIDUAL as used herein refers to any animal, including mammals, preferably mice,
rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably
humans.
PHARMACEUTICAL COMPOSITION shall mean a composition comprising at least one
active ingredient, whereby the composition is amenable to investigation for a specified, efficacious
outcome in a mammal (for example, and not limitation, a human). Those of ordinary skill in the art
will understand and appreciate the techniques appropriate for determining whether an active ingredient
has a desired efficacious outcome based upon the needs of the artisan.
THERAPEUTICALLY EFFECTIVE AMOUNT as used herein refers to the amount of
active compound or pharmaceutical agent that elicits the biological or medicinal response in a
tissue, system, animal, individual or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes one or more of the following:
(1) Preventing the disease; for example, preventing a disease, condition or disorder in an
individual that may be predisposed to the disease, condition or disorder but does not yet experience
or display the pathology or symptomatology of the disease,
(2) Inhibiting the disease; for example, inhibiting a disease, condition or disorder in an
individual that is experiencing or displaying the pathology or symptomatology of the disease,
condition or disorder (i.e., arresting further development of the pathology and/or symptomatology),

and
(3) Ameliorating the disease; for example, ameliorating a disease, condition or disorder in
an individual that is experiencing or displajong the pathology or symptomatology of the disease,
condition or disorder (i.e., reversing the pathology and/or symptomatology).
Compounds of the Present Invention
One aspect of the present invention pertains to certain substituted-2,3,4,5-tetrahydro-3-
benzazepine derivatives as represented by Formula (I):

wherein:
Ri is H or Ci„8 alkyl;'
R2 is Cw alkyl, -CH2-0-CM alkyl, CM haloalkyl or CH2OH; and
R3, R4, R5 and R^ are each independent^ H, Cj^ alkyl, amino, cyano,
halogen, CM haloalkyl, nitro or OH; or
a pharmaceutically acceptable salt, hydrate and solvate thereof;
provided that when R2 is CM alkyl, -CH2-0-Cw alkyl, and CH2OH then R3
and R6 are not both hydrogen.
In some embodiments, when Rj is.H and R2 is CH3 then R3, R4 and R§ can not all be
hydrogens and R5 can not be hydrogen or iso-propyl.
It is appreciated that certain features of the invention, which are, for clarity, described in the
context of separate embodiments, may also be provided in combination in a single embodiment.
Conversely, various features of the invention which are, for brevity, described in the context of a
single embodiment, may also be provided separately or in any suitable subcombination.
It is understood and appreciated that compounds of Formula (I) may have one or more
chiral centers, and therefore can exist as enantiomers and/or diastereomers. The invention is
understood to extend to and embrace all such enantiomers, diastereomers and mixtures thereof,
including but not limited to racemates. Accordingly, one embodiment of the present invention
pertains to compounds of Formula (I) and formulae used throughout this disclosure that are R
enantiomers. Further, one embodiment of the present invention pertains to compounds of Formula
(I) and formulae used throughout this disclosure that are S enantiomers. It is understood that

compounds of Formula (I) and formulae used throughout this disclosure are intended to represent
all individual enantiomers and mixtures thereof, unless stated or shown otherwise.
In some embodiments of the present invention are compounds of Formula (I) wherein R, is
H. In some embodiments, compounds can be represented by Formula (la) as illustrated below:

wherein each variable in Formula (la) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention are. compounds of Formula (I) wherein R[ is
Ci_8 alkyl. In some embodiments Ri is methyl. In some embodiments, compounds can be
represented by Formula (lb) as illustrated below:

wherein each variable in Formula (lb) has the same meaning as described herein, supra and infra.
In some embodiments R) is ethyl. In some embodiments Rx is n-propyl. In some
embodiments R] is iyopropyl. In some embodiments Ri is 72-butyl.
Some embodiments of the present invention are compounds of Formula (T) wherein R2 is
CM alkyl. In some embodiments R2 is methyl. In some embodiments, compounds can be
represented by Formula (Ic) as illustrated below:

wherein each variable in Formula (Ic) has the same meaning as described herein, supra and infra.
In further embodiments R2 is ethyl. In some embodiments R2 is fro-propyl. In some
embodiments R2 is zz-butyl.

Some embodiments of the present invention are compounds of Formula (I) wherein R2 is
CM haloalkyl. Examples of a CM haloalkyl group include, but are not limited to, CH2F, CHF2,
CF3, CH2CHF2, CH2CH2F, CH2CF3 and CF2CF3. In some embodiments R2 is -CF3.
Some embodiments of the present invention are compounds of Formula (I) wherein R3 is H.
In some embodiments R3 is CM alkyl. In some embodiments R3 is methyl (i.e.,
-CH3).
Some embodiments of the present invention are compounds of Formula (I) wherein R3 is
amino.
Some embodiments of the present invention are compounds of Formula (I) wherein R3 is
cyano.
Some embodiments of the present invention are compounds of Formula (I) wherein R3 is
halogen. In some embodiments R3 is a fluorine atom. In some embodiments, compounds can be
represented by Formula (Ie) as illustrated below:

wherein each variable in Formula (Ie) has the same meaning as described herein, supra and infra.
In some embodiments, compounds of the present invention are of Formula (Ie) and R2 is Cw alkyl;
in further embodiments, R2 is CH3.
In some embodiments, R3 is a chlorine atom. In some embodiments, compounds can.be
represented by Formula (Ig) as illustrated below:

wherein each variable in Formula (Ig) has the same meaning as described herein, supra and infra.
In some embodiments, compounds of the present invention are of Formula (Ig) and R2 is d_4 alkyl;
in further embodiments, R2 is CH3.
In some embodiments R3 is a bromine atom.
In some embodiments R3 is an iodine atom.

Some embodiments of the present invention are compounds of Formula (I) wherein R3 is
CM haloalkyl. In some embodiments R3 is CF3.
Some embodiments of the present invention are compounds of Formula (I) wherein R3 is
nitro.
Some embodiments of the present invention are compounds of Formula (I) wherein R3 is
-OH.
Some embodiments of the present invention are compounds of Formula (I) wherein R4 is H.
Some embodiments of the present invention are compounds of Formula (I) wherein R4 is
CM allcyl. In some embodiments, R4 is methyl (i.e., -CH3).
Some embodiments of the present invention are compounds of Formula (I) wherein R4 is
amino.
Some embodiments of the present invention are compounds of Formula (I) wherein R4 is
cyano.
Some embodiments of the present invention are compounds of Formula (I) wherein R4 is
halogen. In some embodiments R4 is a fluorine atom. In some embodiments, compounds can be
represented by Formula (Ii) as illustrated below:

wherein each variable in Formula (Ii) has the same meaning as described herein, supra and infra.
In some embodiments, compounds of the present invention are of Formula (Ii) and R2 is CM alkyl;
in further embodiments, R2 is CH3.
In some embodiments R4 is a chlorine atom. In some embodiments, compounds can be
represented by Formula (Ik) as illustrated below:


wherein each variable in Formula (Ik) has the same meaning as described herein, supra and infra.
In some embodiments, some embodiments of the present are of Formula (Ik) and R2 is Cj_4 alkyl; in
further embodiments, R2 is CH3.
In some embodiments R4 is a bromine atom.
In some embodiments R4 is an iodine atom.
Some embodiments of the present invention are compounds of Formula (I) wherein R4 is
CM haloalkyl. In some embodiments R4 is CF3.
Some embodiments of the present invention are compounds of Formula (I) wherein R, is
nitro.
Some embodiments of the present invention are compounds of Formula (I) wherein R4 is
-OH.
Some embodiments of the present invention are compounds of Formula (I) wherein R5 is H.
Some embodiments of the present invention are compounds of Formula (I) wherein R5 is
Cj.4 alkyl. In some embodiments R5 is methyl (i.e., -CH3).
Some embodiments of the present invention are compounds of Formula (I) wherein R5 is
amino.
Some embodiments of the present invention are compounds of Formula (I) wherein R5 is
cyano.
Some embodiments of the present invention are compounds of Formula (I) wherein R5 is
halogen. In some embodiments R5 is a fluorine atom. In some embodiments, compounds can be
represented by Formula (Im) as illustrated below:

wherein each variable in Formula (Im) has the same meaning as described herein, supra and infra.
In some embodiments, compounds of the present invention are of Formula (Im) and R2 is CM alkyl;
in further embodiments, R2 is CH3.
Some embodiments of the present invention are compounds of Formula (I) wherein R5 is
halogen. In some embodiments R5 is a chlorine atom. In some embodiments, compounds can be
represented by Formula (Io) as illustrated below:


wherein each variable in Formula (Io) has the same meaning as described herein, supra and infra.
In some embodiments, compounds of the present invention are of Formula (Io) and R2 is CM alkyl;
in further embodiments R2 is CFI3.
In some embodiments R5 is a bromine atom. In some embodiments R5 is an iodine atom.
Some embodiments of the present invention are compounds of Formula (I) wherein R5 is
C1-4 haloalkyl. In some embodiments R5 is CF3.
Some embodiments of the present invention are compounds of Formula (I) wherein R5 is
nitro.
Some embodiments of the present invention are compounds of Formula (I) wherein R5 is
-OH
Some embodiments of the present invention are compounds of Formula (I) wherein R6 is H.
Some embodiments of the present invention are compounds of Formula (I) wherein Rs is
CM alkyl. In some embodiments R5 is -CH3.
Some embodiments of the present invention are compounds of Formula (I) wherein R6 is
amino.
Some embodiments of the present invention are compounds of Formula (I) wherein Rg is
cyano.
Some embodiments of the present invention are compounds of Formula (I) wherein Re is
halogen. In some embodiments Rg is a fluorine atom. In some embodiments, compounds can be
represented by Formula (Iq) as illustrated below:

wherein each variable in Formula (Iq) has the same meaning as described herein, supra and infra.
In some embodiments, compounds of the present invention are of Formula (Iq) and R2 is CM alkyl;
in further embodiments R2 is CH3.

In some embodiments R6 is a chlorine atom. In some embodiments, compounds can be
represented by Formula (Is) as illustrated below:

wherein each variable in Formula (Is) has the same meaning as described herein, supra and infra.
In some embodiments, compounds of the present invention are of Formula (Is) and RT is Cj_4 alkyl
in further embodiments, R2 is CH3.
In some embodiments R6 is a bromine atom. In some embodiments Re is an iodine atom.
Some embodiments of the present invention are compounds of Formula (I) wherein R6 is
C]^ haloalkyl. In some embodiments R5 is CF3.
Some embodiments of the present invention are compounds of Formula (I) wherein Rg is
nitro.
Some embodiments of the present invention are compounds of Formula (I) wherein Ro is
-OH.
In some embodiments, compounds of the present invention are of Formula (Ic) wherein Ri
is H or C^B alkyl, and R3, R4, R5, and Rg are each independently H or halogen.
In some embodiments, compounds of the present invention are of Formula (Ic) wherein Rj
is H or CH3, and R3, R4, R5, and R5 are each independently H, F, CI, or Br.
In some embodiments, compounds of the present invention are of Formula (Ic) wherein Rj
is H, and R3 is H, F, CI, or Br; R4 is H or CI; R5 is H; and R^ is H or CI.
In some embodiments, compounds of the present invention are of Formula (Ic) wherein Ri
is CH3, and R3 is H, F, CI, or Br; R, is H or CI; R5 is H; and Rg is H or CI.
This application is related to US Provisional Patent Application, Serial No. 60/479,280,
which is incorporated by reference in its entirety.
Still further embodiments of the present invention are compounds of Formula (I) as shown
in TABLE 2 below or a pharmaceutical^ acceptable salt, hydrate and solvate thereof:




Some embodiments of the present invention are compounds of Formula (I) selected from
the group consisting of: 638-DicMoro-l-methyl-2,334,5-tetrahydro-li7-3-benzazepine; 6-Chloro-l-
methyl-2)3,4,5-tetrahydro-lff-3-benzazepnie; 8-Chloro-9-fluoro-l-methyl-233,4,5-tetrahydro-lF-3-
benzazepine; and 8,9-Dichloro-l-methyl-2,3,4,5-tetrahydro-li?-3-benzazepine; or a
pharmaceutically acceptable salt, hydrate and solvate thereof.
Some embodiments of the present invention are compounds of Formula (I) selected from
the group consisting of: e^-Dichloro-l-methyl^^^.S-tetrahydro-lif-S-benzazepine; 6-Chloro-l-
me%l-2,3;4,54e1rahydro-li?-3-benzazepme;8-Chloro-9-fluoro4-memyl-2,3)4,5-tetrahydro-l5'-3-
benzazepine; 8,9-Dichloro-l-methyl-2,3,4,5-tetrahydro-li?-3-benzazepine; and 9-bromo-8-chloro-l-
methyl-2,3,4,54etrahydro-lH-3-benzazepine; or a pharmaceutically acceptable salt, hydrate and
solvate thereof.
Some embodiments of the present invention are compounds of Formula (I) selected from
the group consisting of: N-methyl-6,8-Dichloro-l-methyl-2,3,4,5-tetrahydro-li?-3-benzazepine; N-
methyl-6-CWoro4-memyl-2,3,4,54e1xahydro-li7-3-beri2azepme;N-methyl-8-Chloro-9-fluoro-l-

methyl-2,3,4,5-tetrahydro-lif-3-benzazepine;N-methyl-8,9-Dichloro-l-methyl-2,3,4,5-tetrahydro-
l.tf-3-benzazepine; andN-methyl-9-bromo-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine;
or a pharmaceutically acceptable salt, hydrate and solvate thereof.
Some embodiments of the present invention are compounds of Formula (I) selected from
the group consisting of: (R)-6,8-Dichloro-l-methyl-2,3,4,5-tetrahydro-li1/-3-benzazepine; (R)-6-
Chloro-l-methyl^^^^-tetrahydro-li/^-benzazepinej^-S-Chloro^-fluoro-l-methyl^^^.S-
tetrahydro-lZf-3-benzazepine; (R)-8,9-Dichloro-l-methyl-2,3,4,5-te1iahydro-l#-3-benzazepine; and
(R)-9-bromo-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine; or a pharmaceutically .
acceptable salt, hydrate and solvate thereof.
Some embodiments of the present invention are compounds of Formula (I) selected from
the group consisting of: (S)-6,8-Dichloro-l-methyl-2,3,4,5-tetrahydro-li?-3-benzazepine; (S)-6-
Chloro-l-methyl-2,3,4,5-tetrahydro-lif-3-benzazepine;(S)-8-Chloro-9-fluoro-l-methyl-2,3,4,5-
tetrahydro-IH-3-benzazepine; (S)-8,9-Dichloro-1 -methyl-2,3,4,5-tetrahydro- IH-3-benzazepine; and
(S)-9-bromo-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine; or a pharmaceutically
acceptable salt, hydrate and solvate thereof.
Some embodiments of the present invention are compounds of Formula (I) selected from
the group consisting of: (R)-N-methyl-6,8-Dichloro-l-methyl-2,3,4,5-tetrahydro-17f-3-benzazepine;
(R)-N-memyl-6-Chloro4-methyl-2,3,4,54etrahydro4i?-3-benzazepine;(R)-N-methyl-8-Chloro-9-
fluoro-1 -methyl-2,3,4,5-tetrahydro-li^-3-benzazepine; (R)-N-methyl-8,9-Dichloro-1 -methyl-
2,3,4,5-tetrahydro-l/f-3-benzazepine; and (R)-N-methyl-9-bromo-8-chloro-l-methyl-2,3,4,5-
tetrahydro-lH-3-benzazepine; or a pharmaceutically acceptable salt, hydrate and solvate thereof.
Some embodiments of the present invention are compounds of Formula (I) selected from
the group consisting of: (S)-N-memyl-6,8-Dichloro-l-methyl-2,3,4,5-tetrahydro-li?-3-benzazepme;
(S)-N-me%l-6-Chloro-l-memyl-2,3,4,5-tetrahydro-liJ-3-benzazepme;(S)-N-memyl-8-Chloro-9-
fluoro-l-me&yl-2,3,4,5-tetrahydro-liJ-3-benzazepme;(S)-N-memyl-8,9-Dichloro-l-methyl-2,3,4,5-
tetrahydro-lif-3-benzazepine;and(S)-N-memyl-9-bromo-8-cMoro-l-methyl-2,3,4,5-tetrahydro-lH-
3-benzazepine; or a pharmaceutically acceptable salt, hydrate and solvate thereof.
At various places in the present specification substituents of compounds of the invention
are disclosed in groups or in ranges. It is specifically intended that the invention include each and
every individual subcombination of the members of such groups and ranges. For example, the term
"CM alkyl" is specifically intended to individually and separately disclose methyl, ethyl, C3 alkyl
and C4 alkyl.

Methods and Use
One aspect of the present invention pertains to methods of modulating a 5HT2c receptor
comprising contacting said receptor with a therapeutically effective amount or dose of a compound
as described herein. Preferably, compounds of the present invention are agonists of the 5HT2c
receptor.
Another aspect of the present invention pertains to methods of prophylaxis or treatment of a
5HT2c receptor associated disease in an individual comprising administering to the individual in
need of such prophylaxis or treatment a therapeutically effective amount or dose of a compound of
the present invention or a pharmaceutical composition thereof. In some embodiments, the 5HT2c
receptor associated disease is selected from the group consisting of disorders of the central nervous
system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders;
diabetes insipidus and sleep apnea. In some embodiments, the individual is a mammal. Preferably,
the mammal is a human.
In some embodiments, the 5HT2c receptor associated related disease is selected from the
group consisting of depression, atypical depression, bipolar disorders, anxiety, anxiety disorders,
obsessive-compulsive disorders, social phobias, panic states, attention deficit hyperactivity disorder,
disruptive behavior disorders, impulse control disorders, borderline personality disorder, sleep
disorders (e.g., sleep apnea), autism, seizure disorders, mutism, selective mutism, childhood anxiety
disorders, sexual dysfunction in males (e.g., premature ejaculation and erectile difficulty or
dysfunction), sexual dysfunction in females, psychoses, schizophrenia, migraine and other
conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy,
personality disorders, Alzheimer disease, age-related behavioral disorders, behavioral disorders
associated with dementia, dementia of aging, organic mental disorders, mental disorders in
childhood, aggressivity, age-related memory disorders, memory loss, chronic fatigue syndrome,
drug and alcohol addiction, alcoholism, tobacco abuse, weight loss, obesity, bulimia, bulimia
nervosa, anorexia nervosa, binge eating disorder, premenstrual tension, premenstrual syndrome
(PMS or late luteal phase dysphoric disorder), post-traumatic syndrome, spinal cord injury, damage
of the central nervous system (e.g., trauma, stroke, neurodegenerative diseases or toxic or infective
disorders (e.g., thrombosis), gastrointestinal disorders (e.g., dysfunction of gastrointestinal motility),
diabetes insipidus, and type II diabetes.
In some embodiments, the 5HT2c receptor associated disease is selected from the group
consisting of high blood pressure, hypertension, high blood cholesterol, dyslipidemia, type II (non-
insulin dependent) diabetes, insulin resistance, glucose intolerance, hypermsulinemia, coronary
heart disease, angina pectoris, congestive heart failure, stroke, gallstones, cholescystitis and

cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and respiratory problems, some types of
cancer (such as endometrial, breast, prostate, and colon), complications of pregnancy, poor female
reproductive health (such as menstrual irregularities, infertility, irregular ovulation), bladder control
problems (such as stress incontinence), uric acid nephrolithiasis, psychological disorders (such as
depression, eating disorders, distorted body image, and low self esteem).
In some embodiments, the 5HT2c receptor associated disease is selected from the group
consisting of psychiatric symptoms and behaviors in individuals with eating disorders such as, but
not limited to, anorexia nervosa and bulimia nervosa. Individuals with eating disorders often
demonstrate social isolation. For example, anorexic individuals often present symptoms of being
depressed, anxious, obsession, perfectionistic traits, and rigid cognitive styles as well as sexual
disinterest. In addition to anorexia nervosa and bulimia nervosa, other eating disorders include,
binge eating disorder (compulsive eating) and ED-NOS (i.e., eating disorders not otherwise
specified - an official diagnosis). An individual diagnosed with ED-NOS possess atypical eating
disorders including situations in which the individual meets all but a few of the criteria for a
particular diagnosis. In essence, what the individual is doing with regard to food and weight is
neither normal nor healthy.
In some embodiments, the 5HT2C receptor associated disease is selected from the group
consisting of anorexia athletica (compulsive exercising), body dysmorphic disorder (bigorexia),
infection-triggered auto immune subtype of anorexia in children, orthorexia nervosa, night-eating
syndrome, nocturnal sleep-related eating disorder, rumination syndrome, gourmand syndrome,
Prader-Willi syndrome, pica, and cyclic vomiting syndrome.
Another aspect of the present invention pertains to methods of decreasing food intake of an
individual comprising administering to the individual a therapeutically effective amount or dose of a
compound of the present invention or a pharmaceutical composition thereof. In some embodiments,
the individual is a mammal. Preferably, the mammal is a human. In further embodiments, the
human has a body mass index of about 18.5 to about 45. In further embodiments, the human has a
body mass index of about 25 to about 45. In further embodiments, the human has a body mass
index of about 30 to about 45. In further embodiments, the human has a body mass index of about
35 to about 45.
Another aspect of the present invention pertains to methods of inducing satiety in an
individual comprising administering to said individual a therapeutically effective amount or dose of
a compound of the present invention or a pharmaceutical composition thereof. In some
embodiments, the individual is a mammal. Preferably, the mammal is a human. In further
embodiments, the human has a body mass index of about 18.5 to about 45. In further embodiments,

the'human has a body mass index of about 25 to about 45. In further embodiments, the human has
a body mass index of about 30 to about 45. In further embodiments, the human has a body mass
index of about 35 to about 45.
Another aspect of the present invention pertains to methods of controlling weight gain of an
individual comprising administering to said individual suffering from weight control a
therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical
composition thereof. In some embodiments, the individual is a mammal. Preferably, the mammal
is ahuman. In further embodiments, the human has abody mass index of about 18.5 to about 45.
In further embodiments, the human has a body mass index of about 25 to about 45. In further
embodiments, the human has a body mass index of about 30 to about 45. In further embodiments,
the human has a body mass index of about 35 to about 45.
Another aspect of the present invention pertains to methods of producing a pharmaceutical
composition comprising admixing at least one compound of the present invention and at least one
pharmaceutically acceptable carrier.
Another aspect of the present invention pertains to compounds, as described herein, for use
in a method of prophylaxis or treatment of disorders of the central nervous system; damage to the
central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus or
sleep apnea of the human or animal body by therapy.
Another aspect of the present invention pertains to use of compounds, as described herein,
for the manufacture of a medicament for use in the treatment or prophylaxis of disorders of the
central nervous system; damage to the central nervous system; cardiovascular disorders;
gastrointestinal disorders; diabetes insipidus or sleep apnea.
In some embodiments, the disorders of the central nervous system are selected the group
consisting of depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-
compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses,
schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised
intracranial pressure, epilepsy, personality disorders, Alzheimer disease, age-related behavioral
disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders
in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and
alcohol addiction, obesity, bulimia, anorexia nervosa and premenstrual tension. In further
embodiments, the disorder of the central nervous system is obesity, ha further embodiments, the
disorder of the central nervous system is Alzheimer disease. In further embodiments, the sexual
dysfunction is Male erectile dysfunction.
In some embodiments, the damage to the central nervous system is by trauma, stroke,

neurodegenerative diseases, toxic CNS diseases or infective CNS diseases. In further embodiments,
the damage to the central nervous system is by encephalitis or meningitis.
In some embodiments, the cardiovascular disorder is thrombosis.
In some embodiments, the gastrointestinal disorder is dysfunction of gastrointestinal
motility.
Another aspect of the present invention pertains to methods of producing a pharmaceutical
composition comprising admixing at least one compound of the present invention and at least one
pharmaceutically acceptable carrier.
Another aspect of the present invention pertains to compounds, as described herein, for use
in a method of treatment of the human or animal body by therapy.
Another aspect of the present invention pertains to compounds, as described herein, for use
in a method of prophylaxis or treatment of disorders of the central nervous system; damage to the
central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus or
sleep apnea of the human or animal body by therapy.
Another aspect of the present invention pertains to use of compounds, as described herein,
for the manufacture of a medicament for use in the treatment or prophylaxis of disorders of the
central nervous system; damage to the central nervous system; cardiovascular disorders;
gastrointestinal disorders; diabetes insipidus or sleep apnea.
Another aspect of the present invention pertains to the use of a compound of the present
invention with agonist activity at the serotonin 5HT2c receptor for the treatment and/or prophylaxis
of AD and AD related disorders. The compounds of the present invention can be used alone or in
combination with another agent or agents (such as but not limited to AChE inhibitors) that are
typically prescribed for AD.
Combination Therapy - Prophylaxis and Treatment
In the context of the present invention, a compound of Formula (I) or pharmaceutical
composition thereof can be utilized for modulating the activity of the 5HT2c receptor associated
diseases, conditions and/or disorders as described herein. Examples of modulating the activity of
5HT2c receptor associated diseases include the prophylaxis or treatment of obesity and/or
overweight by decreasing food intake, inducing satiation (i.e., the feeling of fullness), controlling
weight gain, decreasing body weight and/or affecting metabolism such that the recipient loses
weight and/or maintains weight. Such compounds and pharmaceutical compositions can therefore
be used in the context of disorders and/or diseases where weight gain is a component of a disease
and/or disorder such as those listed herein. Furthermore, compounds and composition of the

present invention can be used for the prophylaxis and/or treatment of Alzheimer Disease, erectile
dysfunction and other 5HT2c receptor associated diseases and/or disorders described herein.
While the compounds of the invention can be administered as the sole active
pharmaceutical agent (i.e., mono-therap)'), they can also be used in combination with other
pharmaceutical agents (i.e., combination-therapy) for the treatment of the
diseases/conditions/disorders described herein. Therefore, another aspect of the present invention
includes methods of prophylaxis and/or treatment comprising administering to an individual in need
of prophylaxis and/or treatment a therapeutically effective amount of a compound of the present
invention, for example Formul (I), in combination with one or more additional pharmaceutical
agent as described herein.
Suitable pharmaceutical agents that can be used in combination with the compounds of the
present invention include anti-obesity agents such as apolipoprotein-B secretion/microsomal
triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholescystoltinin-A (CCK-A)
agonists, serotonin and norepinephrine reuptake inhibitors (for example, sibutramine),
sympamornimetic agensts, p3 adrenergic receptor agonists, dopamine agonists (for example,
bromocriptine), melanocyte-stimulating hormone receptor analogs, cannabinoid 1 receptor
antagonists [for example, SR141716:7V-(piperidin-l-yl)-5-(4-chlorophenyl)-l-(2,4-dicMorophenyl)-
4-methyl-lff-pvrazole-3-carboxamide], melanin concentrating hormone antagonists, leptons (the
OB protein), leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (such
as tetrahydrolipstatin, i.e., Orlistat), anorectic agents (such as a bombesin agonist), Neuropeptide-Y
antagonists, thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid
receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists,
glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (such as Axokine™ available
from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company,
Cincinnati, OH), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3
receptor antagonists or reverse agonists, neuromedin U receptor agonists, noradrenergic anorectic
agents (for example, phentermine, mazindol and the like) and appetite suppressants (for example,
bupropion).
Other anti-obesity agents, including the agents set forth infra, are well known, or will be
readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
In some embodiments, the anti-obesity agents are selected from the group consisting of
orlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine. In a further
embodiment, compounds of the present invention and combination therapies are administered in
conjunction with exercise and/or a sensible diet.

It will be understood that the scope of combination-therapy of the compounds of the present
invention with other anti-obesity agents, anorectic agents, appetite suppressant and related agents is
not limited to those listed above, but includes in principle any combination with any pharmaceutical
agent or pharmaceutical composition useful for the treatment of overweight and obese individuals.
Other suitable pharmaceutical agents, in addition to anti-obesity agents, that can be used in
combination with the compounds of the present invention include agents useful in the treatment of
concomitant diseases. For example, individuals that are over weight or obese increase their risk of
morbidity and mortality arising from concomitant diseases, such as, but not limited to, congestive
heart failure, type II diabetes, atherosclerosis, dyslipidemia, hyperinsulinemia, hypertension, insulin
resistance, hyperglycemia, retinopathy, nephropathy and neuropathy. Treatment for one or more of
the diseases cited herein include the use of one or more pharmaceutical agents known in the art
belonging to the classes of drugs referred to, but not limited to, the following: sulfonylureas,
meglitinides, biguanides, a-glucosidase inhibitors, peroxisome proliferators-activated receptor-y
(i.e., PPAR-y) agonists, insulin, insulin analogues, HMG-CoA reductase inhibitors, cholesterol-
lowering drugs (for example, fibrates that include: fenofibrate, bezafibrate, gemfibrozil, clofibrate
and the like; bile acid sequestrants which include: cholestyramine, colestipol and the like; and
niacin), antiplatelet agents (for example, aspirin and adenosine diphosphate receptor antagonists that
include: clopidogrel, ticlopidine and the like), angiotensin-converting enzyme inhibitors,
angiotensin II receptor antagonists and adiponectin. In accordance to one aspect of the present
invention, a compound of the present can be used in combination with a pharmaceutical agent or
agents belonging to one or more of the classes of drugs cited herein.
It will be understood that the scope of combination-therapy of the compounds of the present
invention with other pharmaceutical agents isnot limited to those listed herein, supra or infra, but
includes in principle any combination with any pharmaceutical agent or pharmaceutical composition
useful for the treatment diseases, conditions or disorders that are linked to overweight and obese
individuals.
Some embodiments of the present invention include methods of prophylaxis or treatment of
a disease, disorder or condition as described herein comprising administering to an individual in
need of such prophylaxis or treatment a therapeutically effect amount or dose of a compound of the
present invention in combination with at least one pharmaceutical agent selected from the group
consisting of: sulfonylureas, meglitinides, biguanides, a-glucosidase inhibitors, peroxisome
proliferators-activated receptor-y (i.e., PPAR-y) agonists, insulin, insulin analogues, HMG-CoA
reductase inhibitors, cholesterol-lowering drugs (for example, fibrates that include: fenofibrate,
bezafibrate, gemfibrozil, clofibrate and the like; bile acid sequestrants which include:

cholestyramine, colestipol and the like; and niacin), antiplatelet agents (for example, aspirin and
adenosine diphosphate receptor antagonists that include: clopidogrel, ticlopidine and the like),
angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists and adiponectin. In
some embodiments, methods of the present invention include compounds of the present invention
and the pharmaceutical agents are administered separately. In further embodiments, compounds of
the present invention and the pharmaceutical agents are administered together.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the
present invention include a-glucosidase inhibitors. a-Glucosidase inhibitors belong to the class of
drugs which competitively inhibit digestive enzymes such as a-amylase, maltase, a-dextrinase,
sucrase, etc. in the pancreas and or small intesting. The reversible inhibition by a-glucosidase
inhibitors retard, diminish or otherwise reduce blood glucose levels by delaying the digestion of
starch and sugars. Some representative examples of a-glucosidase inhibitors include acarbose, N-
(l,3-dihydroxy-2-propyl)valiolamine (generic name; voglibose), miglitol, and a-glucosidase
inhibitors known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the
present invention include sulfonylureas. The sulfonylureas (SU) are drugs which promote secretion
of insulin from pancreatic p cells by transmitting signals of insulin secretion via SU receptors in the
cell membranes. Examples of the sulfonylureas include glyburide , glipizide, glimepiride and other
sulfonylureas known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the
present invention include the meglitinides. The meghtmides are benzoic acid derivatives represent
a novel class of insulin secretagogues. These agents target postprandial hyperglycemia and show
comparable efficacy to sulfonylureas in reducing HbAic. Examples of meglitinides include
repaglinide, nateglinide and other meglitinides known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the
present invention include the biguanides. The biguanides represent a class of drugs that stimulate
anaerobic glycolysis, increase the sensitivity to insulin in the peripheral tissues, inhibit glucose
absorption from the intestine, suppress of hepatic gluconeogenesis, and inhibit fatty acid oxidation.
Examples of biguanides include phenformin, metformin, buformin, and biguanides known in the
art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the
present invention include the a-glucosidase inhibitors. The a-glucosidase inhibitors competitively
inhibit digestive enzymes such as a-amylase, maltase, a-dextrinase, sucrase, etc. in the pancreas
and or small intestine. The reversible inhibition by a-glucosidase inhibitors retard, diminish or

otherwise reduce blood glucose levels by delaying the digestion of starch and sugars. Examples of
a-glucosidase inhibitors include acarbose, N-(l,3-dihydroxy-2-propyl)valiolamine (generic name;
voglibose), miglitol, and a-glucosidase inhibitors known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the
present invention include the peroxisome proliferators-activated receptor-y (i.e., PPAR-y) agonists.
The peroxisome proliferators-activated receptor-y agonists represent a class of compounds that
activates the nuclear receptor PPAR-y and therefore regulate the transcription of insulin-responsive
genes involved in the control of glucose production, transport and utilization. Agents in the class
also facilitate the regulation of fatty acid metabolism. Examples of PPAR-y agonists include
rosiglitazone, pioglitazone, tesaglitazar, netoglitazone, GW-409544, GW-501516 and PPAR-y
agonists known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the
present invention include the HMG-CoA reductase inhibitors. The HMG-CoA reductase inhibitors
are agents also referred to as Statin compounds that belong to a class of drugs that lower blood
cholesterol levels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA) reductase. HMG-CoA
reductase is the rate-limiting enzyme in cholesterol biosynthesis. The statins lower serum LDL
concentrations by upregulating the activity of LDL receptors and are responsible for clearing LDL
from the blood. Some representative examples the statin compounds include rosuvastatin,
pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin,
rosuvastatin, pitavastatin, BMS's "superstatin", and HMG-CoA reductase inhibitors known in the
art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the
present invention include the angiotensin converting enzyme (ACE) inhibitors. The angiotensin
converting enzyme inhibitors belong to the class of drugs that partially lower blood glucose levels as
well as lowering blood pressure by inhibiting angiotensin converting enzymes. Examples of the
angiotensin converting enzyme inhibitors include captopril, enalapril, alacepril, delapril; ramipril,
lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril, moveltopril,
perindopril, quinapril, spirapril, temocapril, trandolapril, and angiotensin converting enzyme
inhibitors known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the
present invention include the angiotensin II receptor antagonists. Angiotensin II receptor
antagonists target the angiotensin II receptor subtype 1 (i.e., ATI) and demonstrate a beneficial
effect on hypertension. Examples of angiotensin II receptor antagonists include losartan (and the
potassium salt form), and angiotensin II receptor antagonists known in the art.

Other treatments for one or more of the diseases cited herein include the use of
pharmaceutical agents known in the art belonging to the classes of drugs referred to, but not limited
to, the following: amylin agonists (for example, pramlintide), insulin secretagogues (for example,
GLP-1 agonists; exendin-4; insulinotropin (NN2211); dipeptyl peptidase inhibitors (for example,
NVP-DPP-728), acyl CoA cholesterol acetyltransferase inhibitors (for example, Ezetimibe,
eflucimibe, and like compounds), cholesterol absorption inhibitors (for example, ezetimibe,
pamaqueside and like compounds), cholesterol ester transfer protein inhibitors (for example, CP-
529414, JTT-705, CETi-1, and like compounds), microsomal triglyceride transfer protein inhibitors
(for example, implitapide, and like compounds), cholesterol modulators (for example, NO-1886,
and like compounds), bile acid modulators (for example, GT103-279 and like compounds) and
squalene synthase inhibitors.
Squalene synthesis inhibitors belong to a class of drugs that lower blood cholesterol levels
by inhibiting synthesis of squalene. Examples of the squalene synthesis inhibitors include (S)-ot-
[Bis[2,2-dimethyl-l -oxopropoxy)methoxy] phosphinyl]-3-phenoxybenzenebutanesulfonic acid,
mono potassium salt (BMS-188494) and squalene synthesis inhibitors known in the art.
Compositions of the Present Invention
According to a further aspect, the present invention also pertains to pharmaceutical
compositions comprising one or more compounds of Formula (I) or any formulae disclosed herein,
and one or more pharmaceutically acceptable carriers.
Some embodiments of the present invention include a method of producing a
pharmaceutical composition comprising admixing at least one compound according to any of the
compound embodiments disclosed herein and a pharmaceutically acceptable carrier.
Formulations may be prepared by any suitable method, typically by uniformly rnixing the
active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions,
and then, if necessary, forming the resulting mixture into a desired shape.
Conventional excipients, such as binding agents, fillers, acceptable wetting agents,
tabletting lubricants, and disintegrants may be used in tablets and capsules for oral administration.
Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or
oily suspensions, and syrups. Alternatively, the oral preparations may be in the form of dry powder
that can be reconstituted with water or another suitable liquid vehicle before use. Additional
additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils),
preservatives, and flavorings and colorants may be added to the liquid preparations. Parenteral
dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid

vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampoule.
These are just a few examples of the many appropriate methods well known in the art for preparing
dosage forms.
A compound of the present invention can be formulated into pharmaceutical compositions
using techniques well known to those in the art. Suitable pharmaceutically-acceptable carriers,
outside those mentioned herein, are known in the art; for example, see Remington, The Science and
Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro, A. R.,
et al.).
While it is possible that, for use in the prophylaxis or treatment, a compound of the
invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable
however to present the compound or active ingredient as a pharmaceutical formulation or
composition further comprising a pharmaceutically acceptable carrier.
The invention thus further provides pharmaceutical formulations comprising a compound of
the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more
pharmaceutically acceptable carriers thereof and/or prophylactic ingredients. The carrier(s) must be
"acceptable" in the sense of being compatible with the other ingredients of the formulation and not
overly deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including
buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and
intravenous) administration or in a form suitable for administration by inhalation, insufflation or by
a transdermal patch. Transdermal patches dispense a drug at a controlled Tate by presenting the
drug for absorption in an efficient manner with a minimum of degradation of the drug. Typically,
transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive
and a removable protective layer with a release liner. One of ordinary skill in the art will
understand and appreciate the techniques appropriate for manufacturing a desired efficacious
transdermal patch based upon the needs of the artisan.
The compounds of the invention, together with a conventional adjuvant, carrier, or diluent,
may thus be placed into the form of pharmaceutical formulations and unit dosages thereof, and in
such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions,
suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of
suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral
(including subcutaneous) use. Such, pharmaceutical compositions and unit dosage forms thereof
may comprise conventional ingredients in conventional proportions, with or without additional
active compounds or principles, and such unit dosage forms may contain any suitable effective

amount of the active ingredient commensurate with the intended daily dosage range to be employed.
For oral administration, the pharmaceutical composition may be in the form of, for
example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably
made in the form of a dosage unit containing a particular amount of the active ingredient. Examples
of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional
additives such as lactose, mannitol, com starch or potato starch; with binders such as crystalline
cellulose, cellulose derivatives, acacia, com starch or gelatins; with disintegrators such as corn
starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or
magnesium stearate. The active ingredient may also be administered by injection as a composition
wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically
acceptable carrier.
Compounds of the present invention or a solvate or physiologically functional derivative
thereof can be used as active ingredients in pharmaceutical compositions, specifically as 5HT2c
receptor agonists. By the term "active ingredient" is defined in the context of a "pharmaceutical
composition" and shall mean a component of a pharmaceutical composition that provides the
primary pharmacological effect, as opposed to an "inactive ingredient" which would generally be
recognized as providing no pharmaceutical benefit.
The dose when using the compounds of the present invention can vary within wide limits,
and as is customary and is known to the physician, it is to be tailored to the individual conditions in
each individual case. It depends, for example, on the nature and severity of the illness to be treated,
on the condition of the patient, on the compound employed or on whether an acute or chronic
disease state is treated or prophylaxis is conducted or on whether further active compounds are
administered in addition to the compounds of the present invention. Representative doses of the
present invention include, but not limited to, about 0.001 mg to about 5000 mg, about 0.001 to
about 2500 mg, about 0.001 to about 1000 mg, 0.001 to about 500 mg, 0,001 mg to about 250 mg,
about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg.
Multiple doses may be administered during the day, especially when relatively large amounts are
deemed to be needed, for example 2, 3 or 4, doses. Depending on the individual and as deemed
appropriate from the patient's physician or care-giver it may be necessary to deviate upward or
downward from the doses described herein.
The amount of active ingredient, active salt or hydrate thereof, required for use in treatment
will vary not only with the particular salt selected but also with the route of administration, the
nature of the condition being treated and the age and condition of the patient and will ultimately be
at the discretion of the attendant physician or clinician.

In general, one skilled in the art understands how to extrapolate in vivo data obtained in a
model system, typically an animal model, to another, such as a human. Typically, animal models
include, but are not limited to, rodent models. In some circumstances, these extrapolations may
merely be based on the weight of the animal model in comparison to another, such as a mammal,
preferably a human, however, more often, these extrapolations are not simply based on weights, but
rather incorporate a variety of factors. Representative factors include, but are not limited to, the
type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route
of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic
and toxicology profiles of the particular compound employed, whether a drug delivery system is
utilized, on whether an acute or chronic disease state is being treated or prophylaxis is conducted or
on whether further active compounds are administered in addition to the compounds of the Formula
(I) as part of combination-therapy. The dosage regimen for treating a disease condition with the
compounds and/or compositions of the present invention is selected in accordance with a variety
factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore
may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage
and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used
in the methods of this invention.
The desired dose may conveniently be presented in a single dose or as divided doses
administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
The sub-dose itself maybe further divided, e.g., into a number of discrete loosely spaced
administrations. The daily dose can be divided, especially when relatively large amounts are
administered as deemed appropriate, into several, for example 2, 3 or 4, part administrations. If
appropriate, depending on individual behavior, it may be necessary to deviate upward or downward
from the daily dose indicated.
The compounds of the present invention can be administrated in a wide variety of oral and
parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage
forms may comprise, as the active component, either a compound of the invention or a
pharmaceutically acceptable salt of a compound of the invention.
For preparing pharmaceutical compositions from the compounds of the present invention,
the selection of a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture
of both. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories,
and dispersible granules. A solid carrier can be one or more substances which may also act as
diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet
disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided
active component.
In tablets, the active component is mixed with the carrier having the necessary binding
capacity in suitable proportions and compacted to the desire shape and size.
The powders and tablets may contain varying percentage amounts of the active compound.
A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the
active compound; however, an artisan would know when amounts outside of this range are
necessary. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate,
talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is
intended to include the formulation of the active compound with encapsulating material as carrier
providing a capsule in which the active component, with or without carriers, is surrounded by a
carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets,
powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral
administration.
For preparing suppositories, a low melting wax, such as an admixture of fatty acid
glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds,
allowed to cool, and thereby to solidify.
Formulations suitable for vaginal administration may be presented as pessaries, tampons,
creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as
are known in the art to be appropriate.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water
or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be
formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for
example, sterile injectable aqueous or oleaginous suspensions maybe formulated according to the
known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable
preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally
acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of
injectables.

The compounds according to the present invention may thus be formulated for parenteral
administration (e.g. by injection, for example bolus injection or continuous infusion) and may be
presented in unit dose form in ampoules, pre-fiiled syringes, small volume infusion or in multi-dose
containers with an added preservative. The pharmaceutical compositions may take such forms as
suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory
agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient
may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from
solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component
in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided
active component in water with viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly
before use, to liquid form preparations for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in addition to the active component,
colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners,
solubilizing agents, and the like.
For topical administration to the epidermis the compounds according to the invention may
be formulated as ointments, creams or lotions, or as a transdermal patch.
Ointments and creams may, for example, be formulated with an aqueous or oily base with
the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an
aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing
agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
Formulations suitable for topical administration in the mouth include lozenges comprising
active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the
active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and
mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for
example with a dropper, pipette or spray. The formulations may be provided in single or multi-dose
form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an
appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be
achieved for example by means of a metering atomizing spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol

formulation in which the active ingredient is provided in a pressurized pack with a suitable
propellant. If the compounds of the Formula (I) or pharmaceutical compositions comprising them
are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out,
for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler
or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the Formula
(I) as an aerosol can be prepared by processes well-known to the person skilled in the art. For their
preparation, for example, solutions or dispersions of the compounds of the Formula (I) in water,
water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for
example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the
bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for
example include carbon dioxide, CFC's, such as, dichlorodifluoromethane, trichlorofluoromethane,
or dichlorotetrafluoroethane; and the like. The aerosol may conveniently also contain a surfactant
such as lecithin. The dose of drug may be controlled by provision of a metered valve.
In formulations intended for administration to the respiratory tract, including intranasal
formulations, the compound will generally have a small particle size for example of the order of 10
microns or less. Such a particle size may be obtained by means known in the art, for example by
micronization. When desired, formulations adapted to give sustained release of the active
ingredient may be employed.
Alternatively the active ingredients may be provided in the form of a dry powder, for
example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch
derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently
the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in
unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the
powder may be administered by means of an inhaler.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the
preparation is subdivided into unit doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package containing discrete quantities of
preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of
any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration are
preferred compositions.
The compounds according to the invention may optionally exist as pharmaceutically
acceptable salts including pharmaceutically acceptable acid addition salts prepared from

pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Representative
acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic,
pamoic, pantothenic, phosphoric, succinic, sulfrric, tartaric, oxalic, p-toluenesulfonic and the like,
such as those pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2
(1977); incorporated herein by reference in its entirety.
The acid addition salts may be obtained as the direct products of compound synthesis. In
the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid,
and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The
compounds of this invention may form solvates with standard low molecular weight solvents using
methods known to the skilled artisan.
Compounds of the present invention can be converted to. "pro-drugs." The term "pro-
drugs" refers to compounds that have been modified with specific chemical groups known in the art
and when administered into an individual these groups undergo biotransformation to give the parent
compound. Pro-drugs can thus be viewed as compounds of the invention containing one or more
specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property
of the compound. In general, the "pro-drug" approach is utilized to facilitate oral absorption. A
thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery
Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,
ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of
which are hereby incorporated by reference in their entirety.
Some embodiments of the present invention include a method of producing a
pharmaceutical composition for "combination-therapy" comprising admixing at least one compound
according to any of the compound embodiments disclosed herein, at least one pharmaceutical agent
as described herein and a pharmaceutically acceptable carrier.
In some embodiments the pharmaceutical agents is selected from the group consisting of:
apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4
agonists, cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors
(for example, sibutramine), sympathomimetic agensts, p3 adrenergic receptor agonists, dopamine
agonists (for example, bromocriptine), melanocyte-stimulating hormone receptor analogs,
cannabinoid 1 receptor antagonists [for example, SR141716: iV-(piperidrn-l-yl)-5-(4-chlorophenyl)-
l-(2,4-dichlorophenyl)-4-methyl-li7-pyrazole-3-carboxamide], melanin concentrating hormone
antagonists, leptons (the OB protein), leptin analogues, leptin receptor agonists, galanin antagonists,

lipase inhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorectic agents (such as a bombesin
agonist), Neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone or an analogue
thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin
binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neutrotrophic factors
(such as Axokine™), human agouti-related proteins (AGRP), ghrelin receptor antagonists,
histamine 3 receptor antagonists or reverse agonists, neuromedin U receptor agonists, noradrenergic
anorectic agents (for example, phentermine, mazindol and the like) and appetite suppressants (for
example, bupropion). In further embodiments, the pharmaceutical agent is selected from the group
consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine.
In some embodiments the pharmaceutical agents is selected from the group consisting of:
sulfonylureas, meglitinides, biguanides, a-glucosidase inhibitors, peroxisome proliferators-activated
receptor-y (i.e., PPAR-y) agonists, insulin, insulin analogues, HMG-CoA reductase inhibitors,
cholesterol-lowering drugs (for example, fibrates that include: fenofibrate, bezafibrate, gemfibrozil,
clofibrate and the like; bile acid sequestrants which include: cholestyramine, colestipol and the like;
and niacin), antiplatelet agents (for example, aspirin and adenosine diphosphate receptor antagonists
that include: clopidogrel, ticlopidine and the like), angiotensin-converting enzyme inhibitors,
angiotensin II receptor antagonists and adiponectin.
It is noted that when the 5HT2c receptor agonists are utilized as active ingredients in a
pharmaceutical composition, these are not intended for use only in humans, but in other non-human
mammals as well. Indeed, recent advances in the area of animal health-care mandate that
consideration be given for the use of 5HT2c receptor agonists for the treatment of obesity in
domestic animals {e.g., cats and dogs), and 5HT2c receptor agonists in other domestic animals
where no disease or disorder is evident (e.g., food-oriented animals such as cows, chickens, fish,
etc.). Those of ordinary skill in the art are readily credited with understanding the utility of such
compounds in such settings.
Preparation of Compounds of the Invention
In the illustrated syntheses outlined below, the labeled substituents have the same
identifications as set out in the definitions of the compounds of the present invention of Formula (I)
and the Formulae of the subgenera as described herein.
Those of skill in the art will appreciate the wide variety of compounds of the present
invention can be prepared according to Schemes I through V, Infra. One representative synthesis is
set forth below in Scheme I, for when R2 is methyl:


By utilizing, for example, an appropriately substituted 2-phenyl ethylamino Compound A
having any of a wide variety of substituents R3, R4, R5 and R6 the corresponding substituted 1-
methyl-2,3,4,5-tetrahydro-li?-3-benzazepine (Compound H) can be prepared. In a subsequent step,
Compound H can be readily alkylated by, for example, treatment with excess formaldehyde or
formaldehyde equivalent such as paraformaldehyde (for methylation) or a higher order aldehyde,
followed by reduction with NaBH3CN or similar reducing agent according to methodologies known
in the art.
In addition, numerous synthetic transformations can be performed at different stages in the
pathway illustrated in Scheme I to prepare additional compounds of Formula (I). For example,
Compound E can be converted into a number of compounds of the invention including, R2 =
-CH2OH. hi this case, the double bond of Compound E can be hydroborated using methods known
in the art, such as diborane, disiamylborane and the like, to give a primary alcohol after oxidative
workup (i.e., H2O2). Either the N-protection can be removed to give desired compounds of the
invention or the primary alcohol can be subsequently converted to an ether using methods known in
the art such as, for example, the Williamson ether procedure, using an alkyl halide in the presence

of a base. In this example, the N-protection can be removed to give compounds of Formula (I)
wherein R2 is the group CH20-CM alkyl. Alternatively, the primary alcohol can be fluorinated
using reagents known in the art, such as dialkylaminosulfur trifluorides and the like. Certain
dialkylaminosulfur trifluorides include, but not limited to, bis(2-memoxyemyl)amino-sulfur
trifluoride, (diethylamino)sulfur trifluoride, (dimemylamino)sulfur trifluoride, morpholinosulfur
trifluoride and the like. Treatment with a fiuorinating agent can give monofluoroalkyl compounds
of Formula (I), wherein R2 is -CH2F. In addition, the primary alcohol prepared from Compound E
can be further oxidized to give the corresponding aldehyde and in a similar manner subsequently
converted to difluoroalkyl compounds of Formula (I), wherein R2 is -CHF2.
Reaction Scheme II is provided below showing these illustrative transformations and is not
intended to be limiting:


By utilizing, for example, an appropriately substituted 2-phenyl ethylamino Compound A
having any of a wide variety of substituents R3, R4, R5 and R« the corresponding 1-substituted-
2,3,4,5-terrahydro-l.ff-3-benzazepine [i.e., a compound of Formula (la)] can be prepared. Scheme
HI illustrates one general pathway for the introduction of R2 groups into the compounds of the
present invention. Compound A is acylated with a carboxylic acid derivative using one of the many
methods, such as one of the commonly known coupling agents, available to the artisan. A
particularly useful method uses an acid chloride as described in the Examples, Infra. The
carboxylic acid derivative is selected to possess a leaving group or a moiety that can be converted
into a leaving group (i.e., Lg). The resulting Compound K is cyclized in the presence of a Lewis
Acid, such as, for example, aluminum chloride. After reduction, compounds of the invention are
obtained wherein Ri is H [i.e., a compound of Formula (la)].
One alternate synthetic approach that can be used to prepare compounds of the present
invention utilizes Compound L (i.e., R2 is H). In this method, the amide nitrogen is first alkylated
(providing the Ri group, Compound N) or protected (i.e., Compound O) using any number of the
methods known in the art. The R2 group is subsequently introduced via an alkylation reaction to
provide Compounds P and Q respectively. Alkylation reactions can be conducted under basic
conditions, for example, using DMF/NaH, and an alkylating agent of the formula R2-Lg (wherein:
R2 has the same meaning as described herein and Lg is a leaving group known in the art, such as,
CI, Br, I, OMs, OTs and the like). Examples of the alkylating agent include, but are not limited to,
CH3I, CH3OMs, CH3OTs, CH3CH2I, CF3CH2I, CF3I, CH30CH2C1 and the like. A representative
alkylation example has been reported by Orito, K. and Matsuzaki, T. in Tetrahedron, 1980, 36, 81,
1017-1021 and is incorporated herein by reference in its entirety. In the example when the nitrogen
is protected (i.e., Compound provide compounds of the invention wherein Ri is H. In the example where the nitrogen is
alkylated (i.e., Compound P), then the amide is merely reduced to provide compounds wherein Ri is
alkyl. This method is illustrated in Schemes IV and V below:



Those of skill in the art will appreciate that a wide variety of compounds of the present
invention can be prepared according to Schemes I through V.
Protecting groups may be required for various functionality or functionalities during the
synthesis of some of the compounds of the invention. Accordingly, representative protecting groups
that are suitable for a wide variety of synthetic transformations are disclosed in Greene and Wuts,
Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, 1999, the
disclosure of which is incorporated herein by reference in its entirety.
As described herein, compounds of the present invention can exist in various forms, for
example, enantiomers and racemates. In is understood that the optically active forms can be
obtained by resolution of the racemates, separated by chiral chromatography or by asymmetric
synthesis using methods known in the art to obtain enantiomers.
Other Utilities
Another object of the present invention relates to radio-labeled compounds of Formula (I)
that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for
localizing and quantitating the 5HT2c receptor in tissue samples, including human, and for
identifying 5HT2c receptor ligands by inhibition binding of a radio-labeled compound. It is a
further object of this invention to develop novel 5HT2c receptor assays of which comprise such
radio-labeled compounds.
The present invention embraces isotopically-labeled compounds of Formula (I) and any
subgenera herein, such as but not limited to, Formula (la) through Formula (Is). An "isotopically"
or "radio-labeled" compounds are those which are identical to compounds disclosed herein, but for
the fact that one or more atoms are replaced or substituted by an atom having an atomic mass or
mass number different from the atomic mass or mass number typically found in nature (i.e.,
naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present
invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T
for tritium), nC, 13C, ,4C, 13N, 15N, 150, nO, 180,18F, 35S, 36C1,82Br, 75Br, 76Br, 77Br, 123I,124I,125I
and I31I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend

on the specific application of that radio-labeled compound. For example, for in vitro 5HT2c
receptor labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 125I, 131I, 35S or
will generally be most useful. For radio-imaging applications UC, 18F, 1251,1231,1241,131I, 75Br, 76Br
or ^Br will generally be most useful.
It is understood that a "radio-labeled " or "labeled compound" is a compound of Formula
(I) that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected
from the group consisting of 3H, ,4C, 1251,35S and S2Br.
Certain isotopically-labeled compounds of the present invention are useful in compound
and/or substrate tissue distribution assays. In some embodiments the radionuclide 3H and/or MC
isotopes are useful in these studies. Further, substitution with heavier isotopes such as deuterium
(i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g.,
increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some
circumstances. Isotopically labeled compounds of the present invention can generally be prepared
by following procedures analogous to those disclosed in the Schemes supra and Examples infra, by
substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Other synthetic
methods that are useful are discussed infra. Moreover, it should be understood that all of the atoms
represented in the compounds of the invention can be either the most commonly occurring isotope
of such atoms or the more scarce radio-isotope or nonradio-active isotope.
Synthetic methods for incorporating radio-isotopes into organic compounds are applicable
to compounds of the invention and are well known in the art. These synthetic methods, for
example, incorporating activity levels of tritium into target molecules, are as follows:
A. Catalytic Reduction with Tritium Gas - This procedure normally yields high specific
activity products and requires halogenated or unsaturated precursors.
B. Reduction with Sodium Borohydride [3H] - This procedure is rather inexpensive and
requires precursors containing reducible functional groups such as aldehydes, ketones, lactones,
esters, and the like.
C. Reduction with Lithium Aluminum Hydride [3H ] - This procedure offers products at
almost theoretical specific activities. It also requires precursors containing reducible functional
groups such as aldehydes, ketones, lactones, esters, and the like.
D. Tritium Gas Exposure Labeling - This procedure involves exposing precursors
containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
E. N-Methylation using Methyl Iodide [3H] - This procedure is usually employed to
prepare O-methyl or N-methyl (3H) products by treating appropriate precursors with high specific
activity methyl iodide (3H). This method in general allows for higher specific activity, such as for

example, about 70-90 Ci/mmol.
Synthetic methods for incorporating activity levels of 125I into target molecules include:
A. Sandmeyer and like reactions - This procedure transforms an aryl or heteroaryl amine
into a diazonium salt, such as a tetrafluoroborate salt, and subsequently to I25I labeled compound
using Na12iI. A represented procedure was reported by Zhu, D.-G. and co-workers in J. Org. Chan.
2002, 67, 943-948.
B. Ortho 125Iodination of phenols - This procedure allows for the incorporation of I25I at
the ortho position of a phenol as reported by Collier, T. L. and co-workers in J. Labeled Compd
Radiopharm. 1999, 42, S264-S266.
C. Aryl and heteroaryl bromide exchange with I25I - This method is generally a two step
process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri-
alkyltin intermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph3P)4] or through an aryl
or heteroaryl hthium, in the presence of a tri-alkyltinhalide or hexaallcylditin [e.g.,
(GH3)3SnSn(CH3)3]. A represented procedure was reported by Bas, M.-D. and co-workers in J.
Labeled Compd Radiopharm. 2001, 44, S280-S282.
A radio-labeled 5HT2c receptor compound of Formula (I) can be used in a screening assay
to identify/evaluate compounds, fn general terms, a newly synthesized or identified compound (i.e.,
test compound) can be evaluated for its ability to reduce binding of the "radio-labeled compound of
Formula (I)" to the 5HT2C receptor. Accordingly, the ability of a test compound to compete with
the "radio-labeled compound of Formula (I)" for the binding to the 5HT2c receptor directly
correlates to its binding affinity.
The labeled compounds of the present invention bind to the 5HT2c receptor. In one
embodiment the labeled compound has an IC50 less than about 500 pM, in another embodiment the
labeled compound has an IC50 less than about 100 uM, in yet another embodiment the labeled
compound has an IC50 less than about 10 uM, in yet another embodiment the labeled compound has
an IC50 less than about 1 pM, and in still yet another embodiment the labeled inhibitor has an IC50
less than about 0.1 |jM.
Other uses of the disclosed receptors and methods will become apparent to those in the art
based upon, inter alia, a review of this disclosure.
As will be recognized, the steps of the methods of the present invention need not be
performed any particular number of times or in any particular sequence. Additional objects,
advantages, and novel features of this invention will become apparent to those skilled in the art
upon examination of the following examples thereof, which are intended to be illustrative and not
intended to be limiting.

EXAMPLES
Example 1
Intracellular IP3 Accumulation Assay:
HEK293 cells were transfected in 15cm sterile dishes with or without (control) 16ug of
human 5HT2C receptor cDNA [for example see, Saltzman, A. G., et al. Biochem. Biophys. Res.
Commim. 181,1469-1478 (1991)] using 25ul of lipofectamine. Cells were then incubated for 3-4
hours at 37°C/5%C02 and then transfection media was removed and replaced with lOOul of
DMEM. Cells were then plated onto 100cm sterile dishes. The next day cells were plated into 96
well PDL microliter plates at a density of 55K/0.2ml. Six hours latter, media was exchanged with
[3H]inositol (0.25 uCi/well) in inositol free DMEM and plates were incubated at 37°C/5%C02
overnight. The next day, wells were aspirated and 200ul of DMEM containing test compound,
lOuM pargyline, and lOmM LiCl was added to appropriate wells. Plates were then incubated at
37°C/5%C02 for three hours followed aspiration and by addition of fresh ice cold stop solution (1M
KOH, 19mM Na-borate, 3.8 mM EDTA) to each well. Plates were kept on ice for 5-10 min and the
wells were neutralized by addition of 200ul of fresh ice cold neutralization solution (7.5% HC1).
Plates were then frozen until further processing is desired. The lysate was then transferred into 1.5
ml Eppendorf tubes and 1 ml of chloroform/methanol (1:2) was added/tube. The solution was
vortexed for 15 seconds and the upper phase was applied to a Biorad AG1-X8™ anion exchange
resin (100-200 mesh). First, the resin was washed with water at 1:1.25 W/V and 0.9 ml of upper
phase was loaded onto the column. The column was then washed with 10 ml of 5 mM myo-inositol
and 10 ml of 5 mM Na-borate/60mM Na-formate. The inositol tris phosphates were eluted into
scintillation vials containing 10 ml of scintillation cocktail with 2 ml of 0.1 M formic acid/ 1 M
ammonium formate. The columns were regenerated by washing with 10 ml of 0.1 M formic
acid/3M ammonium formate and rinsed twice with dd H20 and stored at 4°C in water.
The biological activities in the IP Accumulation Assay for several representative
compounds are shown in Table 3 below:


Example 2
Inhibition of food intake in food-deprived rats
Male Sprague-Dawley rats (250-350g) are deprived of food overnight prior to testing. Prior
to food deprivation, the animals are weighed and separated into treatment groups in order to balance
groups according to body weight. On the test day, animals are placed into individual cages (no
bedding) at 9:00am with free access to water. At 10:00am, animals are injected with test compound
(p.o., i.p., or s.c.) and then presented with a pre-weighed amount of food in a dish either 60 min
(p.o.) or 30 min (i.p. and s.c.) after drug administration. Food consumption over different time
points is determined by weighing the food cup at 1,2, 4, and 6 hr after the food is presented. Thus,
food consumption is measured at 2, 3, 5, and 7 hr post-injection in p.o. studies, and at 1.5; 2.5, 4.5,
and 6.5 hr post-injection in i.p. and s.c. studies.
Example 3
Syntheses of Selected Compounds of the Invention
Example 3.1: Preparation of (R,S) 6,8-Dichloro-l-methyl-2,3,4,S-tetrahydro-lfl-3-
benzazepine (Also referred to herein as Compound 1).

Step 1: Preparation of 2-chloro-N-[2-(2,4-dichlorophenyl)ethyl]propionamide.
A solution of 2,4-dichlorophenethylamine (1.0 g, 5.3 mmol) in dichloromethane (20 mL)
was treated with diisopropylethylamine (0.82 g, 6.3 mmol) and 2-chloropropionylchloride (0.67
mL, 5.3 mmol) sequentially, and stirred at 20°C for 4 hours. The mixture was diluted with
dichloromethane (50 mL), washed with 10% aqueous HC1, brine (20 mL), dried with Na2S04 and
concentrated, resulting in 1.5 g of the desired product as a brown oil. MS calculated for
C11H12CI3NO+H: 280, observed: 280.
Step 2: Preparation of 6,8-dichloro-l-methyl-2-oxo-2,3,5-trihydro-lH-3-benzazepine.
Neat2-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]propionamide (2.5 g, 9.1 mmol) and A1C13
(3.6 g, 27 mmol) were heated at 150CC for 18 hours while stirring. The product mixture was
quenched with water (10 mL), diluted with dichloromethane (100 mL), the organic phase separated,
washed with brine (5 0 mL), dried with Na2S04 and concentrated, resulting in 1.9 g of a brown oil.
MS calculated for CnHnCl2NO+H: 244, observed: 244.

Step 3: Preparation oi'6,8-dichIoro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine.
A solution of 6,8-Dichloro-l-methyl-2-oxo-2,3,5-trihydro-lH-3-benzazepine (1.9 g, 7.8
mmol) in tetrahydrofuran (50 mL) was treated with 1.0 M borane in THF (20.0 mL, 20.0 mmol).,
and stirred at 20°C for 5 hours. The mixture was quenched with metiianol (10 mL), acidified with
concentrated HC1 (0.2 mL), azeotroped with methanol (3 x 100 mL) and concentrated. Flash
chromatography (5% methanol in dichloromethane) resulted in 1.0 g of a clear oil. :H NMR (400
MHz, CDC13) 6 7.20 (s, 1 H), 6.90 (s, 1 H), 4.30 (bs, 1 H), 3.92 (m, 1 H), 3.51 (m, 1 H), 3.37 (m, 2
H), 3.03 (m, 1 H), 2.77 (m, 2 H), 1.31 (d, J=8 Hz, 3 H). MS calculated forCnH13Cl2N+H: 230,
observed: 230.
Example 3.2: Preparation of (R,S) 6-Chloro-l-methyl-2,3,4,5-tetrahydro-l.Hr-3-benzazepine
(Compound 2).
Compound 2 was prepared utilizing a similar procedure as described for the preparation of
Compound 1. (R,S) 6-chloro-l-methyl-2,3,4,5-tetxahydro-lF-3-benzazepine was obtained from 2-
chlorophenethylamine as a colorless oil. *H NMR (400 MHz, CDC13) 6 7.17 (d, J=8 Hz, 1 H), 6.93
(m, 2 H), 3.97 (bs, 1 H), 3.79 (m, 1 H), 3.3-3.1 (m, 3 H), 2.95 (d, J=ll Hz, 1 H), 2.8-2.6 (m, 2 H),
1.3 (d, J=8 Hz, 3 H). MS calculated for CnHMClN+H: 196, observed: 196.
Example 3.3: Preparation of (R,S) 8-Chloro-9-fluoro-l-methyl-2,3,4,5-tetrahydro-liJ-3-
benzazepine (Compound 3).

Step 1: Preparation of N-Trifluoroacetyl-8-chloro-9-fluoro-l-methyl-2,3,4,5-
tetrahydro-lH-3-benzazepine.
A solution of N-trifluoroacetyl-8-chloro-l-methyl-2,3,4,5-tetrahydro-lif-3-benzazepine (2.5
g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol),
trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75°C. The product mixture
was poured into water (200 mL), extracted with EtOAc (200 ml.), the organic phase washed with
saturated aqueous NaHC03 (2 x 100 mL), brine (100 mL), dried with Na2S04 and concentrated.

The crude product was purified by flash chromatography (6 % EtOAc in hexane, silica) resulting in
0.6 g of a white solid. MS calculated for C13H12C1F4N0+H: 310, observed: 310.
Step 2: Preparation of 8-Chloro-9-fluoro-l-methyI-2,3,4,5-tetrahydro-lH-3-
benzazepine.
A solution of N-trifluoroacetyl-8-chloro-9-fluoro-l-methyl-2,3,4,5-tetrahydro-IH-3-
benzazepine (160 mg, 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH (2
mL), and stirred for 3.5 hours at 25°C. The product mixture was concentrated, extracted 3 times
with CH2C12 (5 mL), dried with Na2S04 and concentrated to give 93 mg of a clear oil. *H NMR
(400 MHz, CDC13) 5 7.06 (dd, J=8, 8 Hz, 1 H), 6.75 (d, J=8 Hz, 1 H), 3.58 (m, 1 H), 3.25-3.15 (m,
3 H), 2.93 (d, J=13 Hz, 1 H) 2.75-2.60 (m, 3H), 1.96 (bs, 1 H), 1.33 (d, J=8 Hz, 3 H). MS
calculated for CnH13ClFN+H: 214, observed: 214.
Example 3.4: Preparation of (R,S) S^-Dichloro-l-methyl^AS-tetrahydro-lir-S-
benzazepine (Compound 4).

Compound 4 was prepared utilizing a similar procedure as described herein for the
preparation of Compound 1. (R,S) 8,9-dichloro-l-methyl-2,3,4,5-tetrahydro-li?-3-benzazepine was
obtained from 3,4-dichlorophenethylamine as a colorless oil. :H NMR (400 MHz, CDC13) 5 7.40
(d, J=8 Hz, 1 H), 7.16 (d, J=8 Hz, 1 H), 4.17 (m, 1 H), 3.55 (m, 2 H), 3.5-3.3 (m, 2 H), 3.2-3.0 (m,
2 H), 1.43 (d, J=7 Hz, 3 H). MS calculated for CnH13Cl2N+H: 230, observed: 230.
Example 3.5: Preparation of (S)-8,9-dichloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine
(Compound 5).

Step 1: Preparation of (S)-N-Trifluoroacetyl-8-chloro-l-methyl-2,3,4,5-tetrahydro-
lH-3-benzazepine.
(S)-N-Trifluoroacetyl-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine was prepared
from (S)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine utilizing a similar procedure as
described herein for the preparation of Compound 7 (one exception is that the resolution step was
performed using D-tartaric acid). JH NMR (400 MHz, CDC13, mixture of rotamers) 6 7.27 (m, 1H),

6.96 (m, 1H), 4.26 (bin, 0.6H), 4.19-4.03 (m, 1.7H), 3.92-3.87 (m, 0.8H) 3.75-3.69 (m, 0.8H),
3.47-3.22 (m, 2H), 2.91 (m, 1H), 1.28-1.25 (m, 3H). MS calculated for CoHnClFjNO+H: 292,
observed: 292.
Step 2: Preparation of (S)-N-Trifluoroacetyl-S,9-dichloro-l-niethyl-2,3,4,5-
tetrahydro-lH-3-benzazepine.
A solution of (S)-N-Trifluoroacetyl-8-cliloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine
(0.62g, 2.1 mmol) in dichloromethane (10 mL) was treated with N-chlorosuccinimide (0.284 g, 2.1
mmol) and trifluoromemansulfonic acid (0.639 g, 4.2 mmol). The reaction was stirred for 16h at
20°C, diluted with water (20 mL) and extracted with dichloromethane (25 mL). The organics were
dried with MgS04, filtered and concentrated. HPLC purification was done to provide 0.078 g of a
white solid. 'H NMR (400 MHz, CDC13, mixture of rotamers) 5 7.32-7.25 (m, 1H), 6.97-6.93 (m,
1H), 4.27-4.24 (m, 0.6H), 4.19-4.13 (m, 1H), 4.0S-4.01 (m, 1H), 3.91-3.86 (0.8H, m), 3.74-3.69
(m, 0.8H), 3.45-3.37 (m, 1H), 3.31-3.21 (m, 1H), 2.96-2.80 (m, 1H), 1.28-1.22 (m, 3H). MS
calculated for CnHnC^FsNO+H: 326, observed: 326.
Step 3: Preparation of (S)-8,9-dichloro-l-methyl-23,4,5-tetrahydro-lH-3-
benzazepine.
A solution of (S)-N-trifluoroacetyl-8,9-dichloro-l-methyl-2,3,4,5-tetrahydro-liZ-3-
benzazepine (0.270 g, 1.2 mmol) in methanol (10 mL) was treated with 15% aqueous NaOH (10
mL), and stirred for 3.5 hours at 25°C. The product mixture was concentrated, extracted 3 times
with CH2C12 (25 mL), dried with Na2S04 and concentrated to give 0.270 g of a clear oil. *H 1S1MR
(400 MHz, CDC13) 5 7.40 (d, J=8 Hz, 1 H), 7.16 (d, J=8 Hz, 1 H), 4.17 (m, 1H), 3.55 (m, 2 H),
3.5-3.3 (m, 2 H), 3.2-3.0 (m, 2 H), 1.43 (d, J=7 Hz, 3 H). MS calculated for CUH13C12N+H: 230,
observed: 230.
Example 3.6: Preparation of (S)-8-chloro-9-fluoro-l-methyI-2,3,4,5-tetrahydro-l-H-3-
benzazepine (Compound 6).

Step 1: Preparation of (S)-N-Trifluoroacetyl-8-chloro-9-fluoro-l-methyl-2,3,4,5-
tetrahydro-lH-3-benzazepine.
A solution of (S)-N-trifluoroacetyl-8-chloro-l-methyl-2,3,4,5-tetrahydro-li?-3-benzazeprne
(2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol),
trifiuoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75°C. The product mixture

was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with
saturated aqueous NaHC03 (2 x 100 mL), brine (100 mL), dried with Na2S04 and concentrated.
The crude product was purified by flash chromatography (6 % EtOAc in hexane, silica) resulting in
0.6 g of a white solid. MS calculated for C13H12C1F4N0+H: 310, observed: 310.
Step 2: Preparation of (S)-8-chloro-9-fluoro-l-metb.yI-2,3,4,5-tetrahydro-lH-3-
benzazepine.
A solution of (S)-N-trifluoroacetyl-8-chloro-9-fluoro-l-methyl-233,4,5-tetrahydro-li?-3-
benzazepine (160 mg3 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH (2
mL), and stirred for 3.5 hours at 25°C. The product mixture was concentrated, extracted 3 times
with CH2C12 (5 mL), dried with Na2S04 and concentrated to give 93 mg of a clear oil. JH NMR
(400 MHz, CDC13) 5 7.06 (dd, J=8, 8 Hz, 1 H), 6.75 (d, J=8 Hz, 1 H), 3.58 (m, 1 H), 3.25-3.15 (m,
3 H), 2.93 (d, J=13 Hz, 1 H) 2.75-2.60 (m, 3H), 1.96 (bs, 1 H), 1.33 (d, J=8 Hz, 3 H). MS
calculated for CnH13ClFN+H: 214, observed: 214.
Example 3.7: Preparation of (R)-8,9-dichloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine
(Compound 7).

Step 1: Preparation of 2-(4-chlorophenyl)ethyl-N-2-chloropropionamide
To a 1-liter, 3-necked round bottom flask under argon balloon equipped with reflux
condenser and addition funnel, were added sequentially 2-(4-chlorophenyl) ethylamine (30 g, 193
mmol), 400 mL acetonitrile, triethylamine (19.5 g, 193 mmol) and 80 mL acetonitrile. The clear
colorless solution was stirred and cooled to 0°C. 2-Chloropropionyl chloride (24.5 g, 193 mmol,
distilled) in 5 mL acetonitrile was slowly added over 20 minutes to evolution of white gas,
formation of white precipitate, and color change of reaction mixture to slight yellow. An additional
10 mL of acetonitrile was used to rinse the addition funnel. The mixture was stirred at 0°C for 30
minutes and then warmed to room temperature and stirred vigorously for an additional one hour.
The yellow reaction mixture was concentrated on the rotary evaporator to a solid containing
triethylamine hydrochloride (7636 grams). This material was taken up in 100 mL ethylacetate and
200 mL water, and stirred vigorously. The layers were separated and the aqueous layer was
extracted with an additional 100 mL ethylacetate. The combined organic layers were washed twice
with 25 mL of saturated brine, dried over magnesium sulfate, filtered, and concentrated to a light
tan solid (41.6 grams, 88 %). TLC in ethylacetate-hexane, 8:2 showed a major spot two-thirds of

the way up the plate and a small spot at the baseline. Baseline spot was removed as follows: This
material was taken up in 40 mL of ethylacetate and hexane was added until the solution became
cloudy. Cooling to 0°C produced a white crystalline solid (40.2 grams,, 85 % yield). The product is
a known compound (Hasan et al., Indian J. Chan., 1971, 9(9), 1022) with CAS Registry No.
34164-14-2. LC/MS gave product 2.45 minute; 246.1 M++H+. 'H NMR (CDC13): 5 7.2 (dd, 4H,
Ar), 6.7 (br S, 1H, NH), 4.38 (q, 1H, CHCH3), 3.5 (q, 2H, ArCH.CILNH), 2.8 (t, 2H, ArCH2), 1.7
(d, 3H, CH3). I3C NMR (CDC13): 169 (1C, C=0), 136 (1C, Ar-Cl), 132 (1C, Ar), 130 (2C, Ar),
128 (2C, Ar), 56 (1C, CHC1), 40 (1C, CHN), 34 (1C, CHAr), 22 (1C, CH3).
Step2: Preparation of 8-chloro-l-methyl-2,3»4,5-tetrahydro-lH-3-benzazepin-2-one.
2-(4-Chlorophenyl)ethyl-N-2-chloropropionamide (10 g, 40.6 mmol) and aluminum
chloride (16 g, 119.9 mmol) were added to a clean dry 100 mL round bottom flask equipped with
an argon balloon, stirring apparatus, and heating apparatus. The white solid melted to a tan oil with
bubbling at 91 °C. (Note: if impure starting materials are used, a black tar can result but clean
product can still be isolated). The mixture was heated and stirred at 150°C for 12 hours. The
reaction can be followed by LC/MS with the starting material at 2.45 minutes (246.1 M^+H*), the
product at 2.24 minutes (209.6 M++H+) on a 5 minute reaction time from 5-95% w/ 0.01 % TFA in
water/MeCN(50:50). After cooling to room temperature, the reaction mixture was quenched with
slow addition of 10 mL of MeOH followed by 5 mL of 5 % HC1 in water and 5 mL of ethyl acetate.
After separation of the resulting layers, the aqueous layer was extracted a second time with 10 mL
of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and
concentrated to a tan solid (6.78 grams, 80 % yield). LC/MS showed one peak, at 2.2 min and
209.6 MI. This material was taken up in ethyl acetate, filtered through celite and Kieselgel 60 (0.5
inch plug on a 60 mL Buchner funnel) and the filtrate was recrystallized from hexane/ethyl acetate
to give final product (4.61 grams, 54 % yield). 'HNMR (CDC13): 8 7.3-7.1 (m, 3H, Ar), 5.6 (br s,
1H, NH), 4.23 (q, 1H, CHCH3), 3.8 (m, 1H, ArCHzCILNH), 3.49 (m, 1H, ArCHzCHjNH), 3.48
(m, lH,ArCH2CH2NH), 3.05 (m,lH,ArCH2CH2NH), 1.6 (d,3H,CH2). 13C NMR (CDC13): 178
(1C, CO), 139 (1C, Ar), 135 (1C, Ar), 130,129 (2C, Ar), 126 (2C, Ar), 42 (1C, C), 40 (1C,
CHN), 33 (1C, CHAr), 14 (1C, CH3).
Step 3: Preparation of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine.
8-Chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazapin-2-one (150 mg, 0,716 mmol,
purified by HPLC or recrystallization) was added to a 50 mL round bottom flask with 2M borane-
tetrahydrofuran solution (2 mL, 2.15 mmol). The mixture was stirred 10 hours at room temperature
under an argon balloon. LC/MS showed the desired product as the major peak with approximately
5 % of starting material still present. The reaction mixture was quenched with 5 mL methanol and

the solvents were removed on the rotary evaporator. This procedure was repeated with methanol
addition and evaporation. The mixture was evaporated on the rotary evaporator followed by 2 hours
in vacuo to give the product as a white solid (117 mg, 70 % yield). ]H NMR (CDC13): 5 10.2 (br s,
1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J = 2, 8 Hz), 7.11 (d, 1H, J = 2 Hz), 7.03 (d, 1H, J = 8 Hz), 3.6 ■ •
(m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J = 7 Hz). LC/MS: 1.41 minute, 196.1 M + H*
and 139 major fragment.
Step 4: Preparation of L-(+)-tartaric acid salt of (R)-8-chloro-l-methyl-2,3,4,5-
tetrahydro-lH-3-benzazepine.
To a clean, dry 50 mL round bottom flask were added 11.5 g (0.06 mol) of 8-chloro-l-
methyl-2,3,4,5-tetrahydro-lH-3-benzazepme to 2.23 g (0.015 mol) of L-(+)-tartaric acid. The
suspension was diluted with 56 g of tert-butanol and 6.5 mL of H20. The mixture was heated to
reflux (75-78°C) and stirred for 10 min to obtain a colorless solution. The solution was slowly
cooled down to room temperature (during lh) and stirred for 3h at room temperature. The
suspension was filtered and the residue was washed twice with acetone (10 mL). The product was
dried under reduced pressure (50 mbar) at 60 °C to yield 6.3 g of the tartrate salt (ee = 80). This
tartrate salt was added to 56 g of tert-butanol and 6.5 mL of H20. The resulting suspension was
heated to reflux and 1 to 2g of H20 was added to obtain a colorless solution. The solution was
slowly cooled down to room temperature (over the course of lh) and stirred for 3h at room
temperature. The suspension was filtered and the residue was washed twice with acetone (10 mL).
The product was dried under reduced pressure (50 mbar) at 60°C to produce 4.9 g (48 % yield) of
product (ee >98.9). ,
Step 5: Conversion of Salt to Free Amine - (R)-S-ckloro-l-methyl-2,3,4,5-tetrahydro-
lH-3-benzazepine.
The L-tartaric acid salt of 8-cWoro-l-memyl-2,3,4,5-tetrahy&o-lH-3-berizazepme (300 mg,
0.87 mmol) was added to a 25 mL round bottom flask with 50% sodium hydroxide solution (114
pL, 2.17 mmol) with an added 2 mL of water. The mixture was stirred 3 minutes at room
temperature. The solution was extracted with methylene chloride (5 mL) twice. The combined
organic extracts were washed with water (5 mL) and evaporated to dryness on the pump to afford
free amine (220 mg crude weight). LC/MS 196 (M+H).
Step 6: Preparation of (R)-N-Trifluoroacetyl-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-
benzazepine.
A solution of (R)-8-cnloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride
salt (1.0 g, 4.31mmol) in dichloromethane (50 mL) at 0°C was treated with pyridine (1.0 mL) and
trifluoroacetic anhydride (1.35 g, 6.46 mmole). This was warmed to 20°C, stirred for 3h and

diluted with 1M HC1 (25 mL). This was extracted with dichloromethane (2 x 50 mL) and the
organics dried with MgS04j filtered and concentrated to give 1.17 g as an off-white solid. 'H NMR
(400 MHz, CDC13, mixture of rotamers) 5 7.27 (m, 1H), 6.96 (m, 1H), 4.26 (bm, 0.6H), 4.19-4.03
(m, 1.7H), 3.92-3.87 (m, 0.8H), 3.75-3.69 (m, 0.8H), 3.47-3.22 (m, 2H), 2.91 (m, 1H), 1.28-1.25
(m, 3H). MS calculated for Ci3H13ClF3NO+H: 292, observed: 292.
Step 7: (R)-8,9-dichloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine
Compound 7 was prepared from (R)-N-trifluoroacetyl-8-chloro-l-methyl-2,3,4,5-
tetrahydro-lH-3-benzazepine utilizing a similar two step procedure as described herein for the
preparation of Compound 5. *H NMR (400 MHz, CDC13) 5 7:40 (d, J=8 Hz, 1 H), 7.16 (d, J=8 Hz,
1 H), 4.17 (m, 1 H), 3.55 (m, 2 H), 3.5-3.3 (m, 2 H), 3.2-3.0 (m, 2 H), 1.43 (d, J=7 Hz, 3 H). MS
calculated for CuHi3Cl2N+H: 230, observed: 230.
Example 3.8: Preparation of (S)-9-bromo-S-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-
benzazepine (Compound 8).

Step 1: -Preparation of (S)-N-Trifluoroacetyl-9-bromo-8-cMoro-l-methyl-2,3,4,5-
tetrahydro-lH-3-benzazepine.
A solution of (S)-N-Trifluoroacetyl-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine
(0.875g, 3.0 mmol) in dichloroethane (7 mL) was treated with N-bromosuccinimide (0.284 g, 2.1
mmol) and trifluoromethansulfonic acid (0.639 g, 4.2 mmol). The reaction was stirred for 16h at
75°C, diluted with ethyl acetate (20 mL) and extracted with water (2x10 mL). The organics were
dried with MgS04, filtered and concentrated. Flash chromatography (5 % EtOAc in hexanes, silica)
resulted in 0.13 g of a clear oil. MS calculated for Ci3H12BrClF3NO+H: 370, observed: 370.
Step 2: Preparation of (S)-9-bromo-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-
benzazepine.
Compound 8 was prepared from (S)-N-trifluoroacetyl-9-bromo-8-chloro-l-methyl-2,3,4,5-
tetrahydro-l.ff-3-benzazepine utilizing a similar procedure as described herein for the preparation of
Compound 5. (S)-9-bromo-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine was obtained
from(S)-N-1rifluoroacetyl-9-bromo-8-chloro-l-memyl-2,3,4,5-terrahydro-lF-3-benzazepine. *H
NMR (400 MHz, CDC13) 5 7.17 (d, J = 8 Hz, 1H), 6.92 (d, J = 8 Hz, 1H), 3.92-3.87 (m, 1H), 3.29-
3.20 (m, 2H), 3.11 (dd, J = 14, 5 Hz, 1H), 2.99 (dd, J = 14, 2 Hz, 1H), 2.74-2.65 (m, 2H), 1.32 (d,
J = 7 Hz, 3H). MS calculated for CnH13BrClN+H: 274, observed: 274.

Example 3.9: Preparation of (R>N-methyl-8,9-dichloro-l-methyl-2,3,4,5-tetrahydro-lH-3-
benzazepine (Compound 9).

A solution of 0El)-8,9-dichloro-l-meihyl-2,3,4,5-tetrahydro-lH-3-benzazepine (0.05g, 0.20
mmol) in dichloroethane (3mL) was treated with sodium triacetoxyborohydride (0.073g, 0.35
mmol) and formaldehyde (0.017 mL, 37% solution in water). This was stirred at 20°C for 2h. The
reaction was diluted with 15% NaOH and extracted with ethyl acetate (2x10 mL). The organics
were dried with MgS04, filtered and concentrated to give 0.042 g as an oil. JH NMR (400 MHz,
CDC13) 5 7.19 (d, J = 8 Hz, 1H), 6.89 (d, J = 8 Hz, 1H), 3.91-3.S8 (m, 1H), 3.28 (ddd, J = 15, 12, 2
Hz, 1H), 2.99-2.88 (m, 2H), 2.68 (ddd, J = 15, 5, 1 Hz, 1H), 2.36-2.32 (m, 4H), 2.13 (t, J = 11Hz,
1H), 1.27 (d, J = 7 Hz, 3H). MS calculated for C12H15C12N+H: 243, observed: 243.
Example 3.10: Preparation of (S)-N-methyl-8,9-dicMoro-l-methyl-2,3,4,5-tetrahydro-lH-3-
benzazepine (Compound 10).

Step 1: Preparation of (S)-N-methyl-8,9-dichloro-l-methyl-2,3,4,5-tetrahydro-lH-3-
benzazepine.
Compound 10 was prepared from (S)-8,9-dichloro-l-methyl-2,3,4,5-tetrahydro-lif-3-
benzazepine utilizing a similar procedure as described herein for the preparation of Compound 9.
!H NMR (400 MHz, CDC13) 6 7.19 (d, J = 8 Hz, 1H), 6.89 (d, J = 8 Hz, 1H), 3.91-3.88 (m, 1H),
3.28 (ddd, J = 15,12,2 Hz, 1H), 2.99-2.88 (m, 2H), 2.68 (ddd, J = 15, 5, 1 Hz, 1H), 2.36-2.32 (m,
4H), 2.13 (t, J = 11 Hz, 1H), 1.27 (d, J = 7 Hz, 3H). MS calculated for O3H15CI2N+H: 243,
observed: 243. ■
Example 3.11: Preparation of (S)-N-methyl-9-bromo-8-chloro-l-methyl-2,354,5-tetrahydro-
lH-3-benzazepine (Compound 11).


Compound 11 was prepared from (S)-9-bromo-8-chloro-l-memyl-2,3,4,5-tetrahydro-1H-3-
benzazepine utilizing a similar procedure as described herein for the preparation of Compound 9.
1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8 Hz, 1H), 6.92 (d, J = 8 Hz, 1H), 3.94-3.88 (m, 1H),
3.29 (ddd, J = 15,12,2 Hz, 1H), 2.98-2.93 (m, 1H), 2.90 (ddd, J = 15, 6 ,1 Hz, 1H), 2.36-2.32 (m,
4H) 2.13 (t, J = 11 Hz, 1H), 1.33 (d, J = 7 Hz, 3H). MS calculated for C12H15Cl2N+H: 288,
observed: 288.
Example 4 Separation of enantiomers for selected compounds of the invention
Compounds of the present invention can be separated into their respective enantiomers
using a Varian ProStar HPLC system with a 20 mm x 250 mm Chiralcel OD chiral column, eluting
with 0.2 % diethylamdne in various concentrations of isopropanol (IPA) in hexanes, for example,
5% IPA in hexanes, 1% IPA in hexanes and like concentrations.
It is intended that each of the patents, applications, printed publications, and other
published documents mentioned or referred to in this specification be herein incorporated by
reference in their entirety.
Those skilled in the art will appreciate that numerous changes and modifications may be
made to the preferred embodiments of the invention and that such changes and modifications may
be made without departing from the spirit of the invention. It is therefore intended that the
appended claims cover all such equivalent variations as fall within the true spirit and scope of the
invention.

We claim:
1. A benzazepine compound of Formula (I)
wherein:
R1 is H or C1-8 alkyl;
R2 is C1-4 alkyl, -CH2-O-C1-4 alkyl, C1-4 haloalkyl or CH2OH; and
R3, R4, R5 and R6 are each independently H, C1-4 alkyl, amino, cyano, halogen, C1-4
haloalkyl, nitro or OH; or
a pharmaceutically acceptable salt;
provided that when R2 is C1-4 alkyl, -CH2-O-C1-4 alkyl, or CH2OH then R3 and R6 are not both
hydrogen.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1
is H.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1
is C1-8 alkyl.
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2
is C1-4 alkyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2
is methyl.
6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2
is C1-4 haloalkyl.
7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3
is H.
8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3
is C1-4 alkyl.
9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3
is halogen.
10. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R3 is C1-4 haloalkyl.
11. The compound as claimed claim 1, or a pharmaceutically acceptable salt thereof, wherein R4
is H.
12. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R4 is C1-4 alkyl.

13. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R4 is halogen.
14. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R4 isC1-4 haloalkyl.
15. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R5 is H.
16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R5 is C1-4 alkyl.
17. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R5 is halogen.
18. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R5 is C1-4 haloalkyl.
19. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R6 is H.
20. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R6 is C1-4 alkyl.

21. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R6 is halogen.
22. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R6 is C1-4 haloalkyl.
23. The compound as claimed in claim 1 selected from:
6,8-Dichloro-1 -methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;
6-Chloro-1 -methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;
8-Chloro-9-fluoro-1 -methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and
8,9-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or
a pharmaceutically acceptable salt thereof.
24. The compound as claimed in claim 1 that is 9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-
1H-3-benzazepine; or a pharmaceutically acceptable salt thereof.
25. The compound as claimed in claim 1 selected from:
N-methyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and
N-methyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;or
a pharmaceutically acceptable salt thereof.
26. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
said compound is an R enantiomer.

27. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
said compound is an S enantiomer.
28. A pharmaceutical composition comprising a compound as claimed in claim 1, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
29. A compound as claimed in any one of the claims 1 to 27 for use in modulating a 5HT2C
receptor.
30. A method of producing a pharmaceutical composition comprising admixing at least one
compound as claimed in any one of claims 1 to 27 and a pharmaceutically acceptable carrier.
31. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R1 is H, methyl, ethyl, n-propyl, iso-propyl or n-butyl;
R2 is methyl, ethyl, iso-propyl, n-butyl or-CF3;
R3 is H, -CH3, amino, cyano, fluorine atom, chlorine atom, bromine atom, iodine atom,
CF3, nitro or -OH;
R4 is H, -CH3, amino, cyano, fluorine atom, chlorine atom, bromine atom, iodine atom,
CF3, nitro or -OH;
R5 is H, -CH3, amino, cyano, fluorine atom, chlorine atom, bromine atom, iodine atom,
CF3, nitro or -OH; and
R6 is H, -CH3, amino, cyano, fluorine atom, chlorine atom, bromine atom, iodine atom,
CF3, nitro or -OH.


The present invention relates to certain 1-substituted-2,3,4,5-tetrahydro-3-benzazepine
derivatives of Formula (I), that are modulators of the 5HT2C receptor.

Accordingly, compounds of the present invention are useful for the prophylaxis or treatment of
5HT2C receptor associated diseases, conditions or disorders, such as, obesity and related
disorders.

Documents:

00117-kolnp-2006-abstract.pdf

00117-kolnp-2006-claims.pdf

00117-kolnp-2006-description complete.pdf

00117-kolnp-2006-form 1.pdf

00117-kolnp-2006-form 13.pdf

00117-kolnp-2006-form 3.pdf

00117-kolnp-2006-form 5.pdf

00117-kolnp-2006-gpa.pdf

00117-kolnp-2006-international publication.pdf

00117-kolnp-2006-international search authority.pdf

00117-kolnp-2006-pct forms.pdf

00117-kolnp-2006-priority document.pdf

117-KOLNP-2006-ABSTRACT.pdf

117-KOLNP-2006-AMANDED CLAIMS.pdf

117-kolnp-2006-assignment.pdf

117-KOLNP-2006-CORRESPONDENCE 1.1.pdf

117-KOLNP-2006-CORRESPONDENCE 1.2.pdf

117-KOLNP-2006-CORRESPONDENCE 1.3.pdf

117-KOLNP-2006-CORRESPONDENCE-1.4.pdf

117-KOLNP-2006-CORRESPONDENCE-1.5.pdf

117-KOLNP-2006-CORRESPONDENCE.pdf

117-kolnp-2006-correspondence1.6.pdf

117-kolnp-2006-examination report.pdf

117-KOLNP-2006-FORM 1.pdf

117-KOLNP-2006-FORM 13.1.1.pdf

117-kolnp-2006-form 13.pdf

117-kolnp-2006-form 18.pdf

117-kolnp-2006-form 3.1.pdf

117-KOLNP-2006-FORM 3.pdf

117-kolnp-2006-form 5.1.pdf

117-KOLNP-2006-FORM 5.pdf

117-KOLNP-2006-FORM-27.pdf

117-kolnp-2006-gpa.pdf

117-kolnp-2006-granted-abstract.pdf

117-kolnp-2006-granted-claims.pdf

117-kolnp-2006-granted-description (complete).pdf

117-kolnp-2006-granted-form 1.pdf

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117-KOLNP-2006-OTHERS 1.1.pdf

117-KOLNP-2006-OTHERS-1.2.pdf

117-kolnp-2006-others.pdf

117-KOLNP-2006-PA-1.1.pdf

117-KOLNP-2006-PA.pdf

117-kolnp-2006-reply to examination report.pdf


Patent Number 247906
Indian Patent Application Number 117/KOLNP/2006
PG Journal Number 22/2011
Publication Date 03-Jun-2011
Grant Date 01-Jun-2011
Date of Filing 13-Jan-2006
Name of Patentee ARENA PHARMACEUTICALS, INC.
Applicant Address 6166, NANCY RIDGE DRIVE, SAN DIEGO, CA
Inventors:
# Inventor's Name Inventor's Address
1 SMITH, BRIAN 13182 MESA CREST PLACE, SAN DIEGO, CA 92129
2 SCHULTZ, JEFFREY 10156 PRAIRIE FAWN DRIVE, SAN DIEGO, CAL 92127
3 SMITH, JEFFREY 10547 CAMINITO BASSWOOD, SAN DIEGO, CA 92131
4 GILSON CHARLES, III 7176 SALIZAR STREET, SAN DIEGO, CA 92111
PCT International Classification Number C07D 223/16
PCT International Application Number PCT/US2004/019670
PCT International Filing date 2004-06-16
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/479,280 2003-06-17 U.S.A.