Benzazepine derivatives useful for the treatment of 5ht2c receptor associated diseases

(Field of invention) The present invention is 5HT_2cIt relates to a specific substitution-2,3,4,5-tetrahydro-3-benzazepine derivative which is a regulatory factor of the receptor. Therefore, the compound of the present invention is 5HT._2CIt is useful for the prevention or treatment of receptor-related diseases, conditions or disorders (eg, obesity and related disorders).

(Background of invention) Obesity is life-threatening, increasing the risk of morbidity and mortality resulting from complications such as, but not limited to, type II diabetes, hypertension, stroke, certain forms of cancer and gallbladder disease. It is an obstacle.

Obesity has become a major medical problem in the Western world and is becoming an increasingly problematic issue in some Third World countries. The increase in the number of obese people is largely due to the increased preference for high-fat foods, which can be a more important factor. However, it is also largely due to the reduced activity of most people's lives. Over the last decade, the incidence of obesity in the USA has increased by 30%, and it is now believed that about 30% of the US population is obese. Despite growing awareness of obesity-related health concerns, the proportion of overweight or obese individuals continues to increase. In fact, the proportion of children and adolescents determined to be overweight has more than doubled since the early 1970s, and currently about 13% of children and adolescents are severely overweight. The most important concern from a public health perspective is that overweight children grow into overweight or obese adults and therefore carry great risk for major health problems. Therefore, the number of individuals who are overweight or obese seems to continue to increase.

Whether a person is classified as overweight or obese is generally determined based on the person's body mass index (BMI). This body mass index (BMI) is the person's weight (kilograms, Kg) squared to the person's height (meters squared, m).²) To calculate. Therefore, the unit of BMI is Kg / m.²Is. This BMI is more closely associated with body fat than any other measure of height or weight. 25 ~ 30kg / m for people²Those people are considered overweight if they have a BMI in the range of. 30kg / m²People with a BMI above are classified as obese and obese, with three additional classes (Class I (about 30 to about 34.9 kg / m)).²BMI), Class II (about 35 ~ about 39.9kg / m)²BMI), and Class III (approx. 40 kg / m)²Above). See Table 1 below for the complete classification.

(table 1) (Classification of body weight by body mass index (BMI))

<tables num="1"><img file="JP4782003B2_D0001.tif" /></tables> 。

When BMI for an individual is increased, the risk of morbidity and mortality is increased relative to individuals with normal BMI. Therefore, overweight and obese individuals (about 25 kg / m)²The above BMI) increases the risk of physical illness. Physical illnesses include, but are not limited to; hypertension, cardiovascular disease (particularly hypertension), hypertensive cholesterol, hyperlipidemia, type II (non-insulin dependent) diabetes, insulin. Tolerance, glucose intolerance, hypertension, coronary heart disease, angina, congestive heart failure, stroke, gallstones, cholescystitis and cholelithiasis, ventilation, osteoarthritis, obstructive sleep apnea And respiratory problems, some types of cancer (eg endometrial cancer, breast cancer, prostate cancer, and colon cancer), complications of pregnancy, poor female sexual and reproductive health (eg) , Menstrual irregularities, infertility, ovulation disorders), reproductive disorders (eg, sexual dysfunction in both men and women (including erectile dysfunction in men)), bladder control problems (eg, stress incontinence), gallstones Illness, psychological disorders (eg, depression, eating disorders, distorted body) image), and low self-esteem). Studies have shown that even a modest loss of body weight can correspond to a significant reduction in the risk of developing other illnesses, such as, but not limited to, coronary heart disease.

As mentioned above, obesity increases the risk of developing cardiovascular disease. Coronary artery failure, atheroma disease, and heart failure are central to obesity-induced cardiovascular complications. The incidence of coronary disease is doubled in subjects under 50 years of age who are 30% overweight. Diabetics face a 30% reduction in lifespan. After the age of 45, people with diabetes are about three times more likely to have significant heart disease and five times more likely to have a stroke than people without diabetes. These findings underscore the internal relationship between risk factors for NIDDM and coronary heart disease and the potential value of approaches incorporated to prevent these conditions based on the prevention of obesity [Perry, IJ et al., BMJ 310,560-564 (1995)]. If the entire population has an ideal weight, the risk of coronary failure is estimated to be reduced by 25%, and the risk of heart failure and cerebrovascular accident is estimated to be reduced by 35%.

Diabetes is also involved in the development of kidney disease, eye disease and nervous system problems. Kidney disease, also called nephropathy, occurs when the "filtering function" of the kidneys is damaged and excess protein leaks into the urine, eventually causing the kidneys to fail. Diabetes is also a major cause of damage to the retina and increases the risk of cataracts and glaucoma. Ultimately, diabetes is associated with nerve damage, especially nerve damage in the legs and feet. This impairs the ability to feel pain and causes serious infections. In summary, diabetic complications are one of the leading causes of death in the nation.

The primary course of treatment for individuals who are overweight or obese provides dietary advice and lifestyle advice (eg, reducing dietary fat content and increasing physical activity). That is. However, many patients find it difficult to sustain these and need further help with medication to sustain the results of these efforts.

Most recent commercial products have not been successful treatments for obesity due to their lack of efficacy or the characteristics of unacceptable side effects. The most successful drug to date is the indirectly acting 5-hydroxytryptamine (5-HT) agonist d-fenfluramine (Redux).^TM), But was revoked by the FDA in 1998 due to reports of heart valve defects in up to one-third of the patient population.

In addition, the following two drugs have recently been marketed in the USA and Europe: Orlistant (Xenical)^TM) (A drug that interferes with fat absorption by inhibiting pancreatic lipase), and Sibutramine (Reductil)^TM) (5-HT / noradrenaline reuptake inhibitor). However, side effects associated with these products can limit their long-term efficacy. Xenical^TMTreatment with Sibutramine has been reported to induce gastrointestinal distress in some patients, while Sibutramine is associated with elevated blood pressure in some patients.

Serotonin (5-HT) neurotransmission plays an important role in neurophysiological processes in both health and psychiatric disorders. 5-HT has been associated with regulation of feeding behavior for some time. 5-HT works to stop eating faster and burn less calories by inducing a sensation of fullness or satiety. 5HT_2CThe stimulatory effect of 5-HT on the receptor has been shown to play an important role in the regulation of feeding and the anti-obesity effect of d-fenfluramine. This 5HT_2CReceptors are densely expressed in the brain (particularly marginal structures, extrapyramidal pathways, thalamus and hypothalamus (ie, PVN and DMH), and predominantly the choroid plexus) and in peripheral tissues at low densities. Or selective 5HT as it does not exist_2CReceptor agonists can be effective and can be safe anti-obesity agents. 5HT_2CKnockout mice are also overweight with cognitive dysfunction and susceptible to seizures, thus 5HT_2C5HT in receptor-related diseases or disorders_2CEstablish a clear use of receptor agonists.

This 5HT_2CReceptors play a role in obsessive-compulsive disorder, some forms of depression, and epilepsy. Therefore, 5HT_2CReceptor agonists may have anti-panic properties and properties useful in the treatment of sexual dysfunction. In addition, 5HT_2CReceptor agonists are useful in the treatment of psychiatric symptoms and psychiatric behavior in individuals with eating disorders such as, but not limited to, anorexia nervosa and bulimia nervosa. Individuals with anorexia nervosa often exhibit social isolation. Individuals with anorexia often exhibit symptoms of depression, anxiety, obsessive-compulsive disorder, perfectionism, and rigid cognitive style and sexual indifference. Other eating disorders include anorexia nervosa, bulimia nervosa, eating disorders (compulsive eating) and ED-NOS (ie, unspecified eating disorders-formal). The diagnosis is not specified). Individuals diagnosed with ED-NOS have atypical eating disorders, including situations in which an individual meets certain diagnoses, except for some criteria. What the individual does with respect to food and weight is neither normal nor healthy.

In addition, 5HT_2CReceptors are also associated with other diseases, conditions and disorders (eg, Alzheimer's disease (AD)). Currently, the therapeutic agents prescribed for Alzheimer's disease (AD) are choline-like agents that act by inhibiting the enzyme acetylcholinesterase. The resulting effect is an elevated level of acetylcholine, which moderately improves neuronal function and neuronal recognition in patients with AD. Despite the early onset of symptoms of AD, the dysfunction of cholinergic brain neurons, attempts to slow the progression of the disease with these agents have been modestly successful. This is probably because the doses that can be administered are limited by peripheral cholinergic side effects (eg, tremors, nausea, vomiting, and thirst). Moreover, with the progression of AD, these drugs tend to lose their effectiveness due to the persistent loss of cholinergic neurons.

Thus, especially in alleviating symptoms by improving cognition without the side effects observed with current treatments and by slowing or inhibiting the progression of the disease. There is a need for drugs that have beneficial effects in AD. Therefore, serotonin 5HT, which is expressed only in the brain_2CReceptors are attractive targets.

A major feature of AD is the formation of senile spots composed of amyloid deposits in selected areas of the brain. New treatments should focus on preventing the formation of these senile spots. Amyloid deposits, composed primarily of β-amyloid peptide (Aβ), occupy the plaque center. Aβ is a 40-43 residue peptide derived from the 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 a secretory form. Cleavage of the Aβ region of APP secretes long N-terminal fragments (secretory APPs, APPs) into the extracellular space. The rate of Aβ production appears to be inversely related to the rate of APP secretion. In some cell cultures, APP secretion was caused by a decrease in secretory Aβ ([Buxbaum JD et al., Proc Nat Acad Sci, 1993, 90: 9195-9198; Gabuzda D et al., J. Neurochem, 1993, 61: 2326-2329; Hung AY et al., J Biol Chem, 1993, 268: 22959-22962; and Wolf BA et al., 1995, 270: 4916-4922]). This suggests that stimulated secretory processing of AAP to secretory APP is associated with reduced formation of potential amyloidogenic derivatives or plaques.

APPs are 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 Commun, 1990, 167: 1094-1101]. Given the abundance ratio of both membrane-bound APPs and APPs, membrane-bound APPs and APPs may have important biological functions. Recent findings on APP function indicate that APP is critically required to maintain neuronal structure and function as well as synaptic structure and function. Membrane-bound APPs have been suggested to have a receptor-like structure [Kang J et al., Nature, 1987, 325: 733-736], suggesting that they have a cytoplasmic domain that can complex with GTP-binding proteins. [Nishimoto I. et al., Nature, 1993, 362: 75-79]. Membrane-embedded full-length APPs may also have cell adhesion function [Qiu W. et al., J. Neurosci, 1995, 15: 2157-2167].

APPs have been shown to be neurotrophic and neuroprotective in vitro [Mattson MP et al., Neuron, 1993, 10: 243-254; and Qiu W. et al., J Neurosci, 1995, 15: 2157-2167]. .. Other proposed features of APPs include 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 Treatment [Cunningham JM et al., Histochemistry, 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], Neuroprotease Elongation [Jin L. et al., J. Neurosci, 1994, 14: 5461-5470; and Robakis NK et al., In Molecular Biology of Alzheimer's Disease. ], Cell Adhesion [Schubert D et al., Neuron, 1989, 3: 689-694], Cell Proliferation, [Bhasin R. 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, 1991, 181: 265-271; Milward EA et al., Neuron, 1991, 9: 129-137; and Yamamoto K et al., J Neurobiol, 1994, 25: 585-594].

The above non-selective serotonin 5HT_2CThe agonist dexnorfenfluramine (DEXNOR) stimulates amyloid precursor protein (APPs) secretion in guinea pigs while reducing levels of Aβ products in vivo upon repeated doses [Arjona A et al., "Effect of" a 5HT_2C serotonin agonist, dexnorfenfluramine, on amyloid precursor protein metabolism in guinea pigs, "Brain Res, 2002, 951: 135-140]. Guinea pig APP and human APP showed 98% sequence homology [Beck M et al., Biochem Biophys Acta, 1997, 1351: 17-21] and the protein was processed as well [Beck M. et al., Neuroscience, 1999. , 95: 243-254], and because of the identical Aβ peptide sequence [Johnstone EM et al., Brain Res Mol Brain Res, 1991, 10: 299-305], guinea pigs were selected. Despite the non-selective DEXNOR, the observed effect is selective serotonin 5HT_2CSelective serotonin HT while attenuated by antagonists_2AAntagonists do not reverse the DEXNOR effect. This means that the above serotonin 5HT_2CReceptors have been shown to be the most relevant targets for this effect.

In addition, 5-HT is serotonin 5HT_2AReceptor and 5HT_2CStimulates receptor-mediated APPs ectodomain secretion [Nitsch RM et al., J Biol Chem, 1996, 271 (8): 4188-4194]. In this study, researchers found serotonin 5HT._2AReceptor or 5HT_2C3T3 fibroblasts that stably express the receptor were stimulated with serotonin (5-HT). 5-HT increased APPs secretion in a dose-dependent manner in both cell lines. The maximum stimulation of APPs secretion reached a maximum of about 4 times. Selective serotonin 5HT_2AAntagonists and 5HT_2CThe antagonist blocked the effect in each cell line.

Serotonin 5HT_2CReceptor agonists can be effective in treating AD and in preventing senile spots. Support for the appended claims derives from the fact that Aβ is known to be neurotoxic and an important component in AD-related senile plaques, resulting in APPs secretion and Aβ levels. , Seems to be inversely related, and serotonin 5HT_2CAgonist is serotonin 5HT_2CIn vitro serotonin 5HT, while increasing in vitro APPs levels in cell lines that stably express the receptor_2CAgonists derive from the fact that when measured in guinea pig cerebrospinal fluid, they increase the levels of APPs and decrease the levels of Aβ.

Serotonin 5HT to treat AD_2CThere is evidence to support the use of compounds of the invention with agonistic activity at the receptor. The compounds of the present invention may be used alone or in combination with other agents typically formulated for AD, such as, but not limited to, AChE inhibitors.

5HT_2CAnother disease, disorder or condition that may be associated with receptor function is erectile dysfunction (ED). Erectile dysfunction is unable to achieve or maintain an erection that is hard enough for sexual intercourse, ejaculation, or both. An estimated 20-30 million men in the United States have this condition at some point in their lives. The prevalence of this condition increases with age. 5% of 40-year-old men report ED. This ratio increases between 15% and 25% by age 65 and increases to 55% in men age 75 and older.

Erectile dysfunction can result from many individual problems. These problems include decreased desire or libido, inability to sustain an erection, premature ejaculation, lack of injection, and inability to reach orgasm. More than one of these problems frequently appears at the same time. This condition is a secondary condition of another disease condition (typically a chronic condition), a specific disorder of the genitourinary system or endocrine system, resulting in pharmacological agents (eg, antidepressants, antihypertensive agents, anti). It can be a secondary condition of treatment with depressants, antipsychotics, etc., or the result of psychiatric problems. Erectile dysfunction, when organistically, is primarily due to vascular irregularities associated with atherosclerosis, diabetes, and hypertension.

Serotonin 5HT for the treatment of male and female sexual dysfunction_2CThere is evidence for the use of agonists. This serotonin 5HT_2CReceptors are involved in sensory information, regulation of the central monoaminergic system, and regulation of neuroendocrine responses, anxiety, feeding behavior, and processing and integration of cerebrospinal fluid products [Tecott, LH et al., Nature 374: 542-546 (1995)]. In addition, this serotonin 5HT_2CReceptors are involved in mediating penile erections in rats, monkeys, and humans.

5HT_2CThe exact mechanism that mediates receptor penile erection remains unknown. However, serotonin 5HT in the mediation of penile erection_2CThere is good indirect and direct evidence to support the role of the receptor. Anatomical studies have shown that the penis is subject to autonomic innervation from the sympathetic and parasympathetic nuclei located in the spinal cord [Pescatori ES et al., J Urol 1993; 149: 627-32]. Synchronized, experimental and clinical data support that penile erection is controlled by the spinal reflex. A more detailed analysis is on 5HT in anesthetized cats.₂Activation of spinal cord receptors has been shown to promote vulvar reflexes [Danuser H and Thor KB, Br J Pharmacol 1996; 118: 150-4]. Therefore, 5HT_2CReceptor stimulation has been shown to be proerectile [Millan MJ et al., European Journal of Pharmacology 1997; 325], and 5HT._2CReceptors have been described for parasympathetic neurons of the pre-erected spinal cord [Bancila M et al., Neuroscience 1999; 92: 1523-37].

Indirect evidence comes from studies and reports of side effects induced by the use of selective serotonin reuptake inhibitors (SSRIs). SSRI is serotonin 5HT_2CShows antagonistic activity at the receptor [Jenck et al., European Journal of Pharmacology 231: 223-229 (1993); Lightlowler et al., European Journal of Pharmacology 296: 137-43 (1996); and Palvimaki, E. et al., Psychopharmacology 126: 234-240 (1996)]. Many of the adverse side effects of SSRIs noted in humans may increase the difficulty of achieving a penile erection. 5HT despite the many pharmacological properties of SSRIs_2CIt is believed that the antagonistic effect of SSRIs on the receptor may be associated with inhibition of penile erection [Palvimaki, E. et al., Psychopharmacology 126: 234-240 (1996)].

Further evidence is serotonin 5HT_2CIt results from studies with various compounds having known agonistic activity on the receptor. Pharmacological studies in rats and rhesus monkeys show serotonin-5HT_2CIt provides direct evidence of the pre-erection properties of receptor agonists [Millan MJ et al., European Journal of Pharmacology 1997; 325; and Pomerantz et al., European Journal of Pharmacology 243: 227-34 (1993)]. Each of these pre-erection effects is serotonin 5HT_2AReceptor and serotonin 5HT_2BNot affected by antagonists to the receptor. Serotonin 5HT_2CReceptor antagonists are 5-HT_2CIt weakens the pre-erection effect of the agonist. This inhibitory effect is 5-HT_2CCorresponds to the affinity of each antagonist for the receptor. In addition, serotonin 5HT_2AReceptor and serotonin 5HT_2BReceptor agonists do not induce penile erection.

<p> In summary, 5HT_2CReceptor is 5HT_2CConfirmed and well-recognized receptors for the prevention and / or treatment of diseases and disorders of mediated receptors (eg, obesity, eating disorders, psychiatric disorders, Alzheimer's disease, sexual dysfunction, and related disorders) It is a target. Selective 5HT_2CSelective 5HT that can safely address the needs of receptor agonists_2CIt can be understood that there is a need for receptor agonists. The present invention relates to these important objectives, as well as other important objectives.</p>

<p> (Gist of the invention) The present invention is 5HT_2CBinds to the receptor and 5HT_2CCompounds that regulate receptor activity and their uses will be described. As used herein, term 5HT_2CReceptors include the human sequence found in GeneBank Accession No. AF498983, naturally occurring allelic variants, mammalian orthologs, and recombinant variants thereof.</p><p> One aspect of the present invention is the equation (I) :.</p><p><chemistry num="2"><img file="JP4782003B2_D0002.tif" /></chemistry>With respect to the specific substitutions represented by -2,3,4,5-tetrahydro-3-benzazepine derivatives: here, R₁Is H or C_1~8Alkyl; R₂Is C_1~4Alkyl, -CH₂-OC_1~4Alkyl, C_1~4Haloalkyl, or CH₂OH; and R₃, R₄, R₅, And R₆Are independently H and C, respectively._1~4Alkyl, amino, cyano, halogen, C_1~4Haloalkyl, nitro or OH; or These pharmaceutically acceptable salts, hydrates, and solvates; However, R₂But C_1~4Alkyl, -CH₂-OC_1~4Alkyl, and CH₂If OH, R₃And R₆Are neither hydrogen.</p><p> In some embodiments of the present invention, the compound is a compound of formula (I) in which the compound is an R enantiomer.</p><p> In some embodiments of the present invention, the compound is a compound of formula (I) in which the compound is an S enantiomer.</p><p> Another aspect of the invention also relates to a pharmaceutical composition comprising one or more compounds of the invention and one or more pharmaceutically acceptable carriers.</p><p> Another aspect of the present invention is 5HT._2CThe present invention relates to a method for regulating a receptor, which comprises contacting the receptor with a pharmaceutically effective amount or a pharmaceutically effective dose of a compound described herein. Preferably, the compounds of the invention are 5HT._2CIt is an agonist of the receptor.</p><p> Another aspect of the invention is the following methods of preventing or treating the central nervous system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; urinary disorders or sleep apnea disorders, as such. The present invention relates to a method comprising a step of administering a pharmaceutically effective amount or a pharmaceutically effective dose of a compound of the present invention or a pharmaceutically acceptable composition thereof to an individual in need of such prevention or treatment.</p><p> Another aspect of the present invention is a method of reducing food intake of an individual, which comprises the step of administering to the individual a pharmaceutically effective amount or a pharmaceutically effective dose of a compound of the present invention or a pharmaceutical composition thereof. Regarding the method.</p><p> Another aspect of the present invention is a method of inducing satiety in an individual, which comprises the step of administering to the individual a pharmaceutically effective amount or a pharmaceutically effective dose of a compound of the present invention or a pharmaceutical composition thereof. Regarding the method.</p><p> Another aspect of the present invention is a method of controlling the weight gain of an individual, wherein a pharmaceutically effective amount or a pharmaceutically effective dose of the compound of the present invention or a pharmaceutical composition thereof is administered to an individual suffering from weight control. The present invention relates to a method including the steps to be performed.</p><p> Another aspect of the invention relates to a method of producing a pharmaceutical composition, comprising the step of mixing at least one compound of the invention with at least one pharmaceutically acceptable carrier. ..</p><p> Another aspect of the invention relates to the compounds described herein for use in methods of treating a human or animal body therapeutically.</p><p> Another aspect of the invention is that treatment prevents or prevents the central nervous system of the human or animal body; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus or sleep apnea disorders. With respect to the compounds described herein for use in the method of treatment.</p><p> Another aspect of the invention is the manufacture of pharmaceuticals for use in treating or preventing central nervous system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus or sleep apnea disorders. With respect to the use of the compounds described herein for.</p><p> In some embodiments, the disorder of the central nervous system is selected from the group consisting of: depression, atypical depression, bipolar disorder, anxiety disorder, compulsive disorder, social phobia or panic, sleep disorder, Sexual dysfunction, mental illness, schizophrenia, migraine and other conditions associated with headache or other pain, increased intracranial pressure, epilepsy, personality disorder, Alzheimer's disease, age-related behavioral disorders, dementia-related behavioral disorders , Organic psychiatric disorders, childhood psychiatric disorders, aggression, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addictions, obesity, hyperphagia, nervous loss of appetite and premenstrual tension. In a further embodiment, the disorder of the central nervous system is obesity. In a further embodiment, the disorder of the central nervous system is Alzheimer's disease. In a further embodiment, the sexual dysfunction is erectile dysfunction in men.</p><p> In some embodiments, damage to the central nervous system is due to trauma, stroke, neurodegenerative disorders, toxic CNS disease or infectious CNS disease. In a further embodiment, the damage to the central nervous system is due to encephalitis or meningitis.</p><p> In some embodiments, the cardiovascular disorder is thrombosis.</p><p> In some embodiments, the gastrointestinal disorder is a dysfunction of gastrointestinal motility.</p><p> In some embodiments, the present invention relates to methods for alleviating the symptoms of any disease, condition, or disorder referred to herein.</p><p> In some embodiments, the individual is a mammal.</p><p> In some embodiments, the individual is a mammal, preferably the mammal is a human.</p><p> In a further embodiment, the human has an obesity index of about 18.5 to about 45.</p><p> In a further embodiment, the human has an obesity index of about 25-about 45.</p><p> In a further embodiment, the human has an obesity index of about 30-about 45.</p><p> In a further embodiment, the human has an obesity index of about 35 to about 45.</p><p> (Detailed description of the invention) (Definition) For clarity and consistency, the following definitions are used throughout this patent document.</p><p> An "agonist" is a receptor (eg, 5HT)_2cReceptor) means the part that interacts with and activates it and initiates the physiological or pharmacological response properties of that receptor. For example, when the moiety activates an intracellular response during binding to its receptor, or when it enhances GTP binding to the membrane.</p><p> The term "antagonist" is at the same site as an agonist (eg, an endogenous ligand) and competitively binds to its receptor, but does not activate the intracellular response initiated by the active form of that receptor, thereby the agonist. Alternatively, it is intended to mean a portion that can inhibit the intracellular response by a partial agonist. Antagonists do not reduce the baseline intracellular response in the absence of agonists or partial agonists.</p><p> Chemical groups, partials or radicals: As used herein, the term "alkyl" is intended to mean hydrocarbon compounds including linear hydrocarbons, branched hydrocarbons and cyclic hydrocarbons, eg, methyl, ethyl, n-. Examples include propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, n-pentyl, isopentyl, tert-pentyl, cyclopentyl, cyclopentylmethyl, n-hyxyl, cyclohexyl and the like. , Not limited to these. Terminology "C_1~8"Alkyl" means an alkyl group containing 1 to 8 carbon atoms. Similarly, the term "C_1~4"Alkyl" means an alkyl group containing 1 to 4 carbon atoms. Throughout the specification, it is understood that the term alkyl is intended to include both acyclic hydrocarbon compounds and cyclic hydrocarbon compounds. In some embodiments of the compounds of the invention, the alkyl group is acyclic. In a further embodiment, the alkyl group is cyclic, and in a further embodiment, the alkyl group is both cyclic and acyclic. Here, no priority is specified and the term "alkyl" is intended to mean a group that is both cyclic and acyclic.</p><p> The term "amino" is the group-NH₂Means.</p><p> The term "cyano" means group-CN.</p><p> Terminology "C_1~4"Haloalkyl", as defined herein, means an alkyl group, where this alkyl group is substituted with at least one halogen and formula C._nI_{2n + 2}Completely substituted as represented by, where L is a halogen; if one or more halogens are present, they may be the same or different, F, Cl, Br, Or it can be selected from I. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like.</p><p> The term "halogen" or "halo" means a fluoro group, a chloro group, a bromo group or an iodine group.</p><p> The term "nitro" is the group-NO₂To say.</p><p> "Composition" means a substance comprising at least two compounds or two components; for example, without limitation, a pharmaceutical composition is a composition.</p><p> "Contacting" or "contacting" means bringing together the indicated portions, either in vitro or in vivo. Therefore, 5HT_2C"Contacting" a receptor with a compound of the invention refers to 5HT of the compound of the invention._2CAdministration to individuals having the receptor (preferably humans) and, for example, a sample containing cells or a more purified 5HT of the compounds of the invention._2CIncludes introduction into a preparation containing the receptor.</p><p> "Needs prevention or treatment" as used herein means a caregiver (eg, in the case of humans, a doctor, a nurse, a nurse practitioner, etc .; animals (including non-human mammals). In the case of), it means the judgment made by the veterinarian) that the individual or animal needs or benefits from the prevention or treatment. This determination is made on the basis of various factors in the area of caregiver expertise, but the individual or animal is ill or ill as a result of a disease, condition or disorder that can be treated by the compounds of the invention. Includes the finding that it will be. In general, "needing prevention" 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 protective or preventative modes. However, "needing treatment" is the caregiver's judgment that the individual is already ill, and therefore the compounds of the invention are intended to reduce, suppress or ameliorate the disease, condition or disorder. used.</p><p> "Individual" as used herein is any animal (including mammals), preferably rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, Or primates, and most preferably humans.</p><p> A "pharmaceutical composition" comprises a composition that comprises at least one active ingredient, thereby accepting a study for a particular effective result in a mammal (eg, human, but not limited to). means. One of ordinary skill in the art will understand and recognize suitable techniques for determining whether an active ingredient has the desired effective result based on the needs of the expert.</p><p> A "therapeutically effective amount" as used herein is a biological response in a tissue, organ system, animal, individual or human being sought by a researcher, veterinarian, physician or other clinician. Alternatively, it refers to the amount of an active compound or pharmaceutical drug that induces a drug response. These include one or more of the following: (1) Preventing a disease; for example, in an individual who may be susceptible to a disease, condition or disorder, but has not yet had or indicated a medical condition or general symptom of the disease. Preventing disability, (2) Suppressing the disease; for example, suppressing the disease, condition or disorder (ie, pathology and / or overall) in an individual who has or exhibits a condition or general symptom of the disease, condition or disorder. To prevent further development of symptoms) and (3) To improve the disease; for example, to improve the disease, condition or disorder (ie, condition and / or overall) in an individual who has or exhibits a condition or general symptom of the disease, condition or disorder. To reverse the symptom) (Compound of the present invention) One aspect of the present invention is equation (I) :.</p><p><chemistry num="3"><img file="JP4782003B2_D0003.tif" /></chemistry>With respect to specific substitutions as represented by -2,3,4,5-tetrahydro-3-benzazepine derivatives or pharmaceutically acceptable salts, hydrates and solvates thereof. here: R₁Is H or C_1~8Alkyl; R₂Is C_1~4Alkyl, -CH₂-OC_1~4Alkyl, C_1~4Haloalkyl or CH₂OH; and R₃, R₄, R₅And R₆Are independently H and C_1~4Alkyl, amino, cyano, halogen, C_1~4Haloalkyl, nitro or OH; However, R2 is C_1~4Alkyl, -CH₂-OC_1~4Alkyl and CH₂For OH, R₃And R₆Are neither hydrogen.</p><p> In some embodiments, R₁Is H and R₂Is CH₃If, then R₃, R₄And R₆Cannot be all hydrogen, R₅Can neither be hydrogen nor isopropyl.</p><p> It is recognized that certain features of the invention described in the context of separate embodiments for clarity can also be provided in combination in a single embodiment. Conversely, the various features of the invention described in a single embodiment for brevity are also provided separately or in any suitable small combination.</p><p> It is understood and recognized that compounds of formula (I) can have one or more chiral centers and therefore can exist as enantiomers and / or diastereomers. It is understood that the present invention extends and includes all such enantiomers, diastereomers and mixtures thereof, including but not limited to racemates. Accordingly, one embodiment of the present invention relates to a compound of formula (I) and a compound of formula R enantiomer used throughout the disclosure. In addition, one embodiment of the invention relates to a compound of formula (I) and a compound of formula S enantiomer used throughout the disclosure. It is understood that the compounds of formula (I) and the compounds of formula used throughout this disclosure are intended to represent all of the individual enantiomers and mixtures thereof, unless otherwise stated or indicated. ..</p><p> In some embodiments of the invention, the compound of formula (I) is R.₁Is H. In some embodiments, the compounds are of formula (Ia) :, as shown below.</p><p><chemistry num="4"><img file="JP4782003B2_D0004.tif" /></chemistry>Can be represented by, where each variable in formula (Ia) has the same meaning as described herein (above and below).</p><p> Some embodiments of the present invention have R in formula (I).₁Is C_1~8It is a compound that is alkyl. In some embodiments, R₁Is methyl. In some embodiments, the compounds are of formula (Ib) :, as shown below.</p><p><chemistry num="5"><img file="JP4782003B2_D0005.tif" /></chemistry>Can be represented by, where each variable in formula (Ib) has the same meaning as described herein (above and below).</p><p> In some embodiments, R₁Is ethyl. In some embodiments, R₁Is n-propyl. In some embodiments, R₁Is isopropyl. In some embodiments, R₁Is n-butyl.</p><p> Some embodiments of the present invention have R in formula (I).₂Is C_1~4It is a compound that is alkyl. In some embodiments, R₂Is methyl. In some embodiments, the compounds are of formula (Ic) :, as shown below.</p><p><chemistry num="6"><img file="JP4782003B2_D0006.tif" /></chemistry>Can be represented by, where each variable in formula (Ic) has the same meaning as described herein (above and below).</p><p> In a further embodiment, R₂Is ethyl. In some embodiments, R₂Is isopropyl. In some embodiments, R₂Is n-butyl.</p><p> Some embodiments of the present invention have R in formula (I).₂Is C_1~4It is a compound that is haloalkyl. C_1~4An example of a haloalkyl group is CH₂F, CHF₂, CF₃, CH₂CHF₂, CH₂CH₂F, CH₂CF₃And CF₂CF₃However, the present invention is not limited to these. In some embodiments, R₂Is -CF₃Is.</p><p> Some embodiments of the present invention have R in formula (I).₃Is a compound in which is H. In some embodiments, R₃Is C_1~4It is alkyl. In some embodiments, R₃Is methyl (ie-CH₃).</p><p> Some embodiments of the present invention have R in formula (I).₃Is an amino compound.</p><p> Some embodiments of the present invention have R in formula (I).₃Is a compound in which is cyano.</p><p> Some embodiments of the present invention have R in formula (I).₃Is a compound that is a halogen. In some embodiments, R₃Is a fluorine atom. In some embodiments, the compounds are of formula (Ie) :, as shown below.</p><p><chemistry num="7"><img file="JP4782003B2_D0007.tif" /></chemistry>Can be represented by, where each variable in formula (Ie) has the same meaning as described herein (above and below). In some embodiments, the compounds of the invention are compounds of formula (Ie), R.₂Is C_1~4Is. In a further embodiment, R₂Is CH₃Is.</p><p> In some embodiments, R₃Is a chlorine atom. In some embodiments, the compounds are of formula (Ig) :, as shown below.</p><p><chemistry num="8"><img file="JP4782003B2_D0008.tif" /></chemistry>Can be represented by, where each variable in formula (Ig) has the same meaning as described herein (above and below). In some embodiments, the compounds of the invention are compounds of formula (Ig), R.₂Is C_1~4Is. In a further embodiment, R₂Is CH₃Is.</p><p> In some embodiments, R₃Is a bromine atom.</p><p> In some embodiments, R₃Is an iodine atom.</p><p> Some embodiments of the present invention include R in the compounds of formula (I).₃Is C_1~4It is a compound that is haloalkyl. In some embodiments, R₃Is CF₃Is.</p><p> Some embodiments of the present invention include R in the compounds of formula (I).₃Is a compound in which is nitro.</p><p> Some embodiments of the present invention include R in the compounds of formula (I).₃Is a compound in which is -OH.</p><p> Some embodiments of the present invention include R in the compounds of formula (I).₄Is a compound in which is H.</p><p> Some embodiments of the present invention include R in the compounds of formula (I).₄Is C_1~4It is a compound that is alkyl. In some embodiments, R₄Is methyl (ie-CH₃).</p><p> Some embodiments of the present invention include R in the compounds of formula (I).₄Is an amino compound.</p><p> Some embodiments of the present invention include R in the compounds of formula (I).₄Is a compound in which is cyano.</p><p> Some embodiments of the present invention include R in the compounds of formula (I).₄Is a compound that is a halogen. In some embodiments, R₄Is a fluorine atom. In some embodiments, the compounds are of formula (Ii) :, as shown below.</p><p><chemistry num="9"><img file="JP4782003B2_D0009.tif" /></chemistry>Can be represented by, where each variable in formula (Ii) has the same meaning as described herein (above and below). In some embodiments, the compounds of the invention are compounds of formula (Ii) and are R.₂Is C_1~4It is alkyl. In a further embodiment, R₂Is CH₃Is.</p><p> In some embodiments, R₄Is a chlorine atom. In some embodiments, the compounds have the formula (Ik) :, as shown below.</p><p><chemistry num="10"><img file="JP4782003B2_D0010.tif" /></chemistry>Can be represented by, where each variable in formula (Ik) has the same meaning as described herein (above and below). In some embodiments, some embodiments of the invention are R with a compound of formula (Ik).₂Is C_1~4It is alkyl. In a further embodiment, R₂Is CH₃Is.</p><p> In some embodiments, R₄Is a bromine atom.</p><p> In some embodiments, R₄Is an iodine atom.</p><p> Some embodiments of the present invention have R in formula (I).₄Is C_1~4It is a compound that is haloalkyl. In some embodiments, R₄Is CF₃Is.</p><p> Some embodiments of the present invention have R in formula (I).₄Is a compound in which is nitro.</p><p> Some embodiments of the present invention have R in formula (I).₄Is a compound in which is -OH.</p><p> Some embodiments of the present invention have R in formula (I).₅Is a compound in which is H.</p><p> Some embodiments of the present invention have R in formula (I).₅Is C_1~4It is a compound that is alkyl. In some embodiments, R₅Is methyl (ie-CH₃).</p><p> Some embodiments of the present invention have R in formula (I).₅Is an amino compound.</p><p> Some embodiments of the present invention have R in formula (I).₅Is a compound in which is cyano.</p><p> Some embodiments of the present invention have R in formula (I).₅Is a compound that is a halogen. In some embodiments, R₅Is a fluorine atom. In some embodiments, the compounds are of formula (Im) :, as shown below.</p><p><chemistry num="11"><img file="JP4782003B2_D0011.tif" /></chemistry>Can be represented by, where each variable in formula (Im) has the same meaning as described herein (above and below). In some embodiments, the compounds of the invention are compounds of formula (Im) and are R.₂Is C_1~4It is alkyl. In a further embodiment, R₂Is CH₃Is.</p><p> Some embodiments of the present invention have R in formula (I).₅Is a compound that is a halogen. In some embodiments, R₅Is a chlorine atom. In some embodiments, the compounds are of formula (Io) :, as shown below.</p><p><chemistry num="12"><img file="JP4782003B2_D0012.tif" /></chemistry>Can be represented by, where each variable in formula (Io) has the same meaning as described herein (above and below). In some embodiments, the compounds of the invention are compounds of formula (Io) and are R.₂Is C_1~4It is alkyl. In a further embodiment, R₂Is CH₃Is.</p><p> In some embodiments, R₅Is a bromine atom. In some embodiments, R₅Is an iodine atom.</p><p> Some embodiments of the present invention have R in formula (I).₅Is C_1~4It is a compound that is haloalkyl. In some embodiments, R₅Is CF₃Is.</p><p> Some embodiments of the present invention have R in formula (I).₅Is a compound in which is nitro.</p><p> Some embodiments of the present invention have R in formula (I).₅Is a compound in which is -OH.</p><p> Some embodiments of the present invention have R in formula (I).₆Is a compound in which is H.</p><p> Some embodiments of the present invention have R in formula (I).₆Is C_1~4It is a compound that is alkyl. In some embodiments, R₆Is -CH₃Is.</p><p> Some embodiments of the present invention have R in formula (I).₆Is an amino compound.</p><p> Some embodiments of the present invention have R in formula (I).₆Is a compound in which is cyano.</p><p> Some embodiments of the present invention have R in formula (I).₆Is a compound that is a halogen. In some embodiments, R₆Is a fluorine atom. In some embodiments, the compounds have the formula (Iq) :, as shown below.</p><p><chemistry num="13"><img file="JP4782003B2_D0013.tif" /></chemistry>Can be represented by, where each variable in equation (Iq) has the same meaning as described herein (above and below). In some embodiments, the compounds of the invention are compounds of formula (Iq) and are R.₂Is C_1~4It is alkyl. In a further embodiment, R₂Is CH₃Is.</p><p> In some embodiments, R₆Is a chlorine atom. In some embodiments, the compounds are of formula (Is) :, as shown below.</p><p><chemistry num="14"><img file="JP4782003B2_D0014.tif" /></chemistry>Can be represented by, where each variable in formula (Is) has the same meaning as described herein (above and below). In some embodiments, the compounds of the invention are compounds of formula (Is) and are R.₂Is C_1~4It is alkyl. In a further embodiment, R₂Is CH₃Is. In some embodiments, R₆Is a bromine atom. In some embodiments, R₆Is an iodine atom.</p><p> Some embodiments of the present invention have R in formula (I).₆Is C_1~4It is a compound that is haloalkyl. In some embodiments, R₆Is CF₃Is.</p><p> Some embodiments of the present invention have R in formula (I).₆Is a compound in which is nitro.</p><p> Some embodiments of the present invention have R in formula (I).₆Is a compound in which is -OH.</p><p> In some embodiments, the compounds of the invention are compounds of formula (Ic), R.₁Is H or C_1~8Alkyl and R₃, R₄, R₅And R₆Are independently H or halogen.</p><p> In some embodiments, the compounds of the invention are compounds of formula (Ic), R.₁Is H or CH₃And R₃, R₄, R₅And R₆Are independently H, F, Cl, or Br, respectively.</p><p> In some embodiments, the compounds of the invention are compounds of formula (Ic), R.₁Is H, and R₃Is H, F, Cl or Br; R₄Is H or Cl ;; R₅Is H; and R₆Is H or Cl.</p><p> In some embodiments, the compounds of the invention are compounds of formula (Ic), R.₁Is CH₃And R₃Is H, F, Cl or Br; R₄Is H or Cl ;; R₅Is H; and R₆Is H or Cl.</p><p> This application relates to US Provisional Patent Application No. 60 / 479,280, which is hereby incorporated by reference in its entirety.</p><p> Still further embodiments of the invention are compounds of formula (I) as shown in Table 2, or pharmaceutically acceptable salts, hydrates and solvates thereof:</p><p><tables num="2-1"><img file="JP4782003B2_D0015.tif" /></tables></p><p><tables num="2-2"><img file="JP4782003B2_D0016.tif" /></tables> 。 </p><p> Some embodiments of the invention include: 6,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 6-chloro-1-methyl-2,3, 4,5-Tetrahydro-1H-3-benzacepine; 8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and 8,9-dichloro-1-methyl A compound of formula (I) selected from the group consisting of -2,3,4,5-tetrahydro-1H-3-benzazepine, or a pharmaceutically acceptable salt, hydrate and solvate thereof.</p><p> Some embodiments of the invention include: 6,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 6-chloro-1-methyl-2,3, 4,5-Tetrahydro-1H-3-benzacepine; 8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8,9-dichloro-1-methyl- Selected from the group consisting of 2,3,4,5-tetrahydro-1H-3-benzazepine; and 9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine A compound of formula (I), or a pharmaceutically acceptable salt, hydrate and solvate thereof.</p><p> Some embodiments of the invention include: N-methyl-6,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-6-chloro- 1-Methyl-2,3,4,5-tetrahydro-1H-3-benzacepine; N-methyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3- Benz Azepine; N-Methyl-8,9-Dichloro-1-methyl-2,3,4,5-Tetrahydro-1H-3-Benz Azepine; and N-Methyl-9-Bromo-8-Chloro-1-methyl-2 , 3,4,5-Tetrahydro-1H-3-A compound of formula (I) selected from the group consisting of benzazepine, or a pharmaceutically acceptable salt, hydrate and solvate thereof.</p><p> Some embodiments of the invention include: (R) -6,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (R) -6-chloro- 1-Methyl-2,3,4,5-Tetrahydro-1H-3-benzacepine; (R)-8-Chloro-9-Fluoro-1-methyl-2,3,4,5-Tetrahydro-1H-3- Benz azepine; (R) -8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benz azepine; and (R) -9-bromo-8-chloro-1-methyl-2 , 3,4,5-Tetrahydro-1H-3-A compound of formula (I) selected from the group consisting of benzazepine, or a pharmaceutically acceptable salt, hydrate and solvate thereof.</p><p> Some embodiments of the invention include: (S) -6,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (S) -6-chloro- 1-Methyl-2,3,4,5-Tetrahydro-1H-3-benzacepine; (S)-8-Chloro-9-Fluoro-1-methyl-2,3,4,5-Tetrahydro-1H-3- Benz azepine; (S) -8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benz azepine; and (S) -9-bromo-8-chloro-1-methyl-2 , 3,4,5-Tetrahydro-1H-3-A compound of formula (I) selected from the group consisting of benzazepine, or a pharmaceutically acceptable salt, hydrate and solvate thereof.</p><p> Some embodiments of the invention include: (R) -N-methyl-6,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (R)- N-Methyl-6-Chloro-1-Methyl-2,3,4,5-Tetrahydro-1H-3-benzacepine; (R) -N-Methyl-8-Chloro-9-Fluoro-1-Methyl-2, 3,4,5-Tetrahydro-1H-3-benzazepine; (R) -N-methyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and ( A compound of formula (I) selected from the group consisting of R) -N-methyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, or a compound thereof. Pharmaceutically acceptable salts, hydrates and solvates.</p><p> Some embodiments of the invention include: (S) -N-methyl-6,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (S)- N-Methyl-6-Chloro-1-Methyl-2,3,4,5-Tetrahydro-1H-3-benzacepine; (S)-N-Methyl-8-Chloro-9-Fluoro-1-methyl-2, 3,4,5-Tetrahydro-1H-3-benzazepine; (S)-N-methyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and ( A compound of formula (I) selected from the group consisting of S) -N-methyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, or a compound thereof. Pharmaceutically acceptable salts, hydrates and solvates.</p><p> Substitutions of the compounds of the invention are disclosed in groups or ranges at various locations herein. It is expressly intended that the present invention includes each small combination of members of such groups and ranges and any individual small combination. For example, the term "C_1~4"Alkyl" is methyl, ethyl, C₃Alkyl and C₄It is expressly intended that the alkyl will be disclosed independently and separately.</p><p> (Method and application) One aspect of the present invention is 5HT_2cWith respect to methods of modulating the receptor, the method comprises contacting the receptor with a therapeutically effective amount or therapeutically effective dose of a compound described herein. Preferably, the compounds of the invention are 5HT._2CIt is an agonist of the receptor.</p><p> Another aspect of the invention is 5HT in an individual._2cWith respect to a method of preventing or treating a receptor-related disease, the method comprises administering to an individual in need of such prevention or treatment a therapeutically effective amount or therapeutically effective dose of a compound of the invention or a pharmaceutical composition thereof. Including. In some embodiments, the 5HT_2cReceptor-related disorders are selected from the group consisting of central nervous system disorders; 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.</p><p> In some embodiments, the 5HT_2cReceptor-related disorders include depression, atypical depression, bipolar disorder, anxiety, anxiety disorder, compulsive disorder, social fear, panic, attention deficiency bulimia, mitotic behavior disorder, impulse dysregulation, borderline personality disorder. , Sleep disorders (eg, sleep aspiration), autism, seizure disorders, apathy, selective apathy, early childhood anxiety disorders, sexual dysfunction in men (eg, premature ejaculation and erectile difficulty or erectile disorders) , Sexual dysfunction in women, mental illness, schizophrenia, migraine and headache or other pain-related conditions, increased intracranial pressure, epilepsy, personality disorder, Alzheimer's disease, age-related behavioral disorders, dementia-related behavioral disorders , Aging dementia, organic mental disorders, mental disorders in early childhood, aggression, age-related memory disorders, memory loss, chronic fatigue syndrome, drug addiction and alcohol addiction, alcohol dependence, tobacco abuse, weight loss, obesity, Bulimia nervosa, bulimia nervosa, bulimia nervosa, eating disorders, premenstrual tension, premenstrual syndrome (PMS or late luteal psychiatric symptoms), posttraumatic syndrome, spinal cord injury, damage to the central nervous system (eg,) Selected from the group consisting of trauma, stroke, bulimia nervosa or addictive and infectious diseases (eg, thrombosis), gastrointestinal disorders (eg, gastrointestinal motility dysfunction), urinary dysfunction, and type II diabetes. To.</p><p> In some embodiments, the 5HT_2cReceptor-related diseases include hypertension, hypertension, hypertension, dyslipidemia, type II (non-insulin-dependent) diabetes, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina, Congestive heart failure, stroke, gallstones, cholescystitis and cholelithiasis, gout, osteoarthritis, obstructive sleep aspiration and respiratory problems, some types of cancer (eg, uterine body cancer, breast cancer, prostate cancer) And colon cancer), pregnancy complications, female reproductive health disorders (eg, irregular menstruation, infertility, irregular ovulation), bladder control problems (eg, tension incontinence), uroacid nephropathy, psychological disorders (eg) , Depression, eating disorders, distorted body image, and low self-esteem).</p><p> In some embodiments, 5HT_2cReceptor-related disorders are selected from the group consisting of psychiatric symptoms and behaviors in individuals with eating disorders, such as, for example, anorexia nervosa and bulimia nervosa. Individuals with eating disorders often exhibit social isolation. For example, anorexic individuals exhibit oppression, anxiety, obsession, perfectionist qualities, and strong cognitive patterns and symptoms of sexual indifference. In addition to anorexia nervosa and bulimia nervosa, other eating disorders include binge eating disorders (compulsive eating) and ED-NOS (ie, binge eating disorders-official diagnostics). Be done. Individuals diagnosed with ED-NOS have atypical eating disorders, including situations in which the individual meets all but a few criteria for a particular diagnosis. In essence, what the individual does with respect to diet and weight is neither normal nor healthy.</p><p> In some embodiments, 5HT_2cReceptor-related disorders include anorexia athletica (compulsive exercise), body dysmorphic disorder (bigorexia), infection-induced autoimmune subtypes of anorexia in children, orthorexia nervosa ), Nocturnal sleep, nocturnal sleep-related feeding disorders, anorexia syndrome, gourmand syndrome, Prader-Willi syndrome, pica and periodic vomiting syndrome.</p><p> Another aspect of the invention relates to a method of reducing food intake in an individual, which method comprises administering a therapeutically effective amount or a therapeutically effective dose of a compound of the invention or a pharmaceutical composition thereof. In some embodiments, the individual is a mammal. Preferably, the mammal is a human. In a further embodiment, the human has an obesity index of about 18.5 to about 45. In a further embodiment, the human has an obesity index of about 25-about 45. In a further embodiment, the human has an obesity index of about 30-about 45. In a further embodiment, the human has an obesity index of about 35 to about 45.</p><p> Another aspect of the invention relates to a method of inducing satiety in an individual, which method comprises administering to the individual a therapeutically effective amount or a therapeutically effective dose of a compound of the invention or a pharmaceutical composition thereof. .. In some embodiments, the individual is a mammal. Preferably, the mammal is a human. In a further embodiment, it has an obesity index of about 18.5 to about 45. In a further embodiment, the human has an obesity index of about 25-about 45. In a further embodiment, the human has an obesity index of about 30-about 45. In a further embodiment, the human has an obesity index of about 35 to about 45.</p><p> Another aspect of the invention relates to a method of regulating weight gain in an individual, which is a therapeutically effective or therapeutically effective dose of a compound of the invention or a pharmaceutical composition thereof for an individual suffering from weight regulation. Includes the step of administering. In some embodiments, the individual is a mammal. Preferably, the mammal is a human. In a further embodiment, the human has an obesity index of about 18.5 to about 45. In a further embodiment, the human has an obesity index of about 25-about 45. In a further embodiment, the human has an obesity index of about 30-about 45. In a further embodiment, the human has an obesity index of about 35 to about 45.</p><p> Another aspect of the invention relates to a method of making a pharmaceutical composition, which method comprises mixing at least one compound of the invention and at least one pharmaceutically acceptable carrier.</p><p> Another aspect of the invention is the treatment of central nervous system disorders of the human or animal body; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; methods of preventing or treating diabetes insipidus or sleep apnea. With respect to the compounds described herein for use in.</p><p> Another aspect of the invention is for the manufacture of formulations for use in the treatment or prevention of central nervous system disorders; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus or sleep apnea. With respect to the use of the compounds described herein.</p><p> In some embodiments, the central nervous system disorder is depression, atypical depression, bipolar disorder, anxiety disorder, obsessive disorder, social fear or panic, sleep disorders, sexual dysfunction, psychiatric disorders, psychiatric disorders. , Migraine and other conditions associated with headache or other pain, increased intracranial pressure, epilepsy, personality disorder, Alzheimer's disease, age-related behavioral disorders, dementia-related behavioral disorders, organic psychiatric disorders, mental illness in early childhood It is selected from the group consisting of disorders, aggression, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addictions, obesity, hyperphagia, nervous loss of appetite and premenstrual tension. In a further embodiment, the disorder of the central nervous system is obesity. In a further embodiment, the disorder of the central nervous system is Alzheimer's disease. In a further embodiment, the sexual dysfunction is a male erectile disorder.</p><p> In some embodiments, the disorder of the central nervous system is due to trauma, stroke, neurodegenerative disease, addictive CNS disease or infectious CNS disease. In a further embodiment, the disorder of the central nervous system is due to encephalitis or meningitis.</p><p> In some embodiments, the cardiovascular disorder is thrombosis.</p><p> In some embodiments, the gastrointestinal disorder is a gastrointestinal motility dysfunction.</p><p> Another aspect of the invention relates to a method of making a pharmaceutical composition, which method comprises mixing at least one compound of the invention and at least one pharmaceutically acceptable carrier.</p><p> Another aspect of the invention relates to the compounds described herein for use in methods of therapeutic treatment of the human or animal body.</p><p> Another aspect of the invention is in the method of treating central nervous system disorders of the human or animal body; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus or sleep apnea. With respect to the compounds described herein for use.</p><p> Another aspect of the invention is for the manufacture of formulations for use in the treatment or prevention of central nervous system disorders; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus or sleep apnea. With respect to the use of the compounds described herein.</p><p> Another aspect of the invention is serotonin 5HT for the treatment and / or prevention of AD and AD-related diseases._2CThe present invention relates to the use of a compound of the present invention having agonistic activity at a receptor. The compounds of the invention can be used alone or in combination with other agents typically formulated for AD, such as, but not limited to, AChE inhibitors.</p><p> (Combination Treatment-Prevention and Treatment) In the context of the present invention, compounds of formula (I) or pharmaceutical compositions thereof are described herein in 5HT._2CIt can be utilized to regulate the activity of receptor-related diseases, conditions and / or disorders. 5HT_2CExamples of regulation of activity of receptor-related disorders include prevention or treatment of obesity and / or overweight by reducing food intake, induction of satiety (ie, full sensation), regulation of weight gain, weight loss and / Or the recipient may affect metabolism to lose weight and / or maintain weight. Thus, such compounds and pharmaceutical compositions can be used in disorders and / or disease situations in which weight gain is a component of the diseases and / or disorders listed herein. In addition, the compounds and compositions of the invention are Alzheimer's disease, erectile disorders and other 5HTs described herein._2CIt can be used for the prevention and / or treatment of receptor-related diseases and / or disorders.</p><p> The compounds of the invention can be administered as single active agents (ie, monotherapy), but they are also combined with other agents for the treatment of the diseases / conditions / disorders described herein. It can also be used (ie, combination therapy). Accordingly, another aspect of the invention is to provide a therapeutically effective amount of a compound of the invention (eg, formula (I)) to an individual in need of prevention and / or treatment of one or more of the compounds described herein. Includes prophylactic and / or treatment methods that include the step of administration in combination with additional agents.</p><p> Suitable agents that can be used in combination with the compounds of the invention include anti-obesity agents such as apolipoprotein / microsome triglyceride transfer protein (apo-B / MTP) inhibitors, MCR-4 agonists, cholecystokinin-. A (CCK-A) agonists, serotonin and norpinephrine reuptake inhibitors (eg sibutramine), sympathetic agonists, β₃Adrenalinergic receptor agonists, dopamine agonists (eg bromocryptin), melanin cell stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists [eg SR141716: N- (piperidin-1-yl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxamide], melanin aggregation hormone antagonist, leptone (OB protein), leptin analog, leptin receptor agonist, galanin antagonist, lipase inhibitor (eg,) Tetrahydrolipstatin, or Orlistat, an appetite-lowering drug (eg, bombesin agonist), a neuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glycocorticoid receptor agonist or antagonist, olexin Receptor antagonists, urocortin-binding protein antagonists, glucagon-like peptide-1 receptor agonists, hairy neurotrophic factors (eg, Regeneron) Axokine available from Pharmaceuticals, Inc., Tarrytown, NY and Procter &amp; Gamble Company, Cincinnati, OH^TM), Human agouti-related protein (AGRP), grelin receptor antagonist, histamine 3 receptor antagonist or reverse agonist, neuromedin U receptor agonist, noradrenalinergic appetite-lowering drug (eg, fentermin, mazindole, etc.) and appetite suppressant (eg, bupropion) ).</p><p> Other anti-obesity agents, including the agents described below, are well known to those of skill in the art or are readily apparent at the time of disclosure of the present invention.</p><p> In some embodiments, the anti-obesity agent is selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin and pseudoephedrine. In a further embodiment, the compounds and combination therapies of the invention can be administered in conjunction with exercise and / or a sensible diet.</p><p> The scope of combination therapies of the compounds of the invention with other anti-obesity agents, appetite-suppressing agents, appetite-suppressing agents and related agents is not limited to those listed above, but in principle, overweight and obesity. Includes any combination with any pharmaceutical agent or composition useful for the treatment of an individual.</p><p> In addition to anti-obesity agents, other suitable pharmaceutical agents that may be used in combination with the compounds of the invention include agents useful in treating complications. For example, individuals who are overweight or obese have complications (eg, congestive heart failure, type II diabetes, atherosclerosis, dyslipidemia, hyperinsulinemia, hypertension, insulin resistance, hyperglycemia, etc. Increased risk of morbidity and mortality resulting from (but not limited to) retinopathy, nephropathy and neurological disease. Treatment for one or more of the diseases cited herein includes, but is not limited to, the use of one or more pharmaceutical agents known in the art belonging to the class of drugs for: Sulfonylurea, meglitinide, biguanide, α-glucosidase inhibitor, peroxysome growth factor activating receptor-γ (ie, PPAR-γ) agonist, insulin, insulin analog, HMG-CoA reductase inhibitor, cholesterol-lowering agent (eg, fibrate including: : Phenofibrate, bezafibrate, gemfibrozil, clopidogrel, etc .; metal bile acid ion blockers including: cholestiramine, cholestipole, etc.; and niacin), antiplatelet drugs (eg, aspirin and adenosine diphosphate receptor antagonists, including: : Clopidogrel, ticlopidine, etc.), angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist and adiponectin. According to one aspect of the invention, the compounds of the invention may be used in combination with pharmaceutical agents belonging to one or more of the classes of drugs referred to herein.</p><p> The scope of combination therapies of the compounds of the invention with other pharmaceutical agents is not limited to those listed above or below herein, but in principle, diseases associated with overweight and obese individuals. It is understood to include any pharmaceutical agent or combination with any pharmaceutical composition useful for treating a condition or disorder.</p><p> Some embodiments of the invention include methods for preventing or treating a disease, disorder or condition as described herein, which methods require such prevention or treatment. Including the step of administering a therapeutically effective amount of a compound of the present invention in combination with at least one pharmaceutical agent selected from the following group to an individual: sulfonylurea, meglycinide, biguanide, α-glucosidase. Inhibitors, peroxysome growth factor activating receptor-γ (ie, PPAR-γ) agonists, insulin, insulin analogs, HMG-CoA reductase inhibitors, cholesterol-lowering agents (eg, fenofibrate, bezafibrate, gemfibrozil, clopidogrel) Rate etc .; bile acid metal ion blockers including: cholestyramine, cholestipol etc .; and niacin), antiplatelet drugs (eg, aspirin and adenosine diphosphate receptor antagonists: clopidogrel, ticlopidine, etc.), angiotensin converting enzymes Inhibitors, angiotensin II receptor antagonists and adiponectin. In some embodiments, the methods of the invention include the compounds of the invention, the pharmaceutical agents being administered separately. In a further embodiment, the compounds and pharmaceutical agents of the invention are administered together.</p><p> Suitable pharmaceutical agents that can be used in conjunction with the compounds of the invention include α-glucosidase inhibitors. α-Glucosidase inhibitors belong to a class of drugs that competitively inhibit digestive enzymes (eg, α-amylase, maltase, α-dextrinase, sucrase, etc.) in the pancreas and / or small intestine. Reversible inhibition by α-glucosidase inhibitors slows, reduces, or otherwise lowers blood glucose levels by delaying the digestion of starch and sugar. Some typical examples of α-glucosidase inhibitors are acarbose, N- (1,3-dihydroxy-2-propyl) valiolamine (genus name; voglibose), miglitol, and Examples thereof include a-glucosidase inhibitors known in the art.</p><p> Suitable pharmaceutical agents that can be used in conjunction with the compounds of the invention include sulfonylureas. Sulfylurea (SU) is a drug that promotes insulin secretion from pancreatic β-cells by transmitting a signal of insulin secretion via the SU receptor on the cell membrane. Examples of this sulfonylurea include glybrid, glipizide, glimepiride and other sulfonylureas known in the art.</p><p> Suitable pharmaceutical agents that can be used in conjunction with the compounds of the invention include meglitinide. This meglitinide is a benzoic acid derivative that represents a novel class of insulin secretagogues. These drugs target postprandial hyperglycemia and HbA_1cIt is as effective as sulfonylurea in reducing. Examples of meglitinides include repaglinide, nateglinide and other meglitinides known in the art.</p><p> Suitable pharmaceutical agents that can be used in conjunction with the compounds of the invention include biguanides. This biguanide represents a class of drugs that stimulate anaerobic glycolysis, increase sensitivity to insulin in peripheral tissues, inhibit intestinal glucose absorption, suppress hepatic glucose formation, and inhibit fatty acid oxidation. To do. Examples of biguanides include phenformin, metformin, buformin, and biguanides known in the art.</p><p> Suitable pharmaceutical agents that can be used in conjunction with the compounds of the invention include α-glucosidase inhibitors. This α-glucosidase inhibitor competitively inhibits digestive enzymes in the pancreas and / or small intestine (eg, α-amylase, maltase, α-dextrinase, sucrase, etc.). Reversible inhibition by α-glucosidase inhibitors slows, reduces, or otherwise lowers blood glucose levels by delaying the digestion of starch and sugar. Examples of α-glucosidase inhibitors include acarbose, N- (1,3-dihydroxy-2-propyl) variolamine (genus name; voglibose), miglitol, and a-glucosidase inhibitors known in the art.</p><p> Suitable pharmaceutical agents that can be used in conjunction with the compounds of the invention include peroxisome growth factor activating receptor γ (ie, PPAR-γ) agonists. This peroxisome proliferator-activated receptor γ represents a class of compounds that activate the nuclear receptor PPAR-γ and, as a result, regulate the transcription of insulin-responsive genes involved in the regulation of glucose production, glucose transport and glucose utilization. To do. This class of drugs also promotes the regulation of fatty acid metabolism. Examples of PPAR-γ agonists include rosiglitazone, pioglitazone, tesaglitazone, netoglitazone, GW-409544, GW-501516 and PPAR-g agonists known in the art.</p><p> Suitable pharmaceutical agents that can be used in conjunction with the compounds of the invention include HMG-CoA reductase inhibitors. This HMG-CoA reductase inhibitor is also a drug called a statin compound that belongs to the class of drugs that lower blood cholesterol levels by inhibiting hydroxymethylglutaryl CoA (HMG-CoA) reductase. HMG-CoA reductase is a rate-determining enzyme in cholesterol biosynthesis. This statin lowers serum LDL levels by upregulating the activity of LDL receptors and is involved in the removal of LDL from the blood. Some representative examples of this statin compound are rosuvastatin, pravastatin and its sodium salts, simvastatin, lovastatin, atorvastatin, fulvastatin, serivastatin, rosuvastatin, pitabastatin, BMS "superstatin", and known in the art. HMG-CoA reductase inhibitors can be mentioned.</p><p> Suitable pharmaceutical agents that can be used in conjunction with the compounds of the invention include angiotensin converting enzyme (ACE) inhibitors. This angiotensin converting enzyme inhibitor belongs to a class of drugs that partially lower blood glucose levels and lower blood pressure by inhibiting angiotensin converting enzyme. Examples of this angiotensin-converting enzyme inhibitor include captopril, enalapril, alacepril, delapril; ramipril, lisinopril, imidapril, benazepril, seronapril, silazapril, enalapril, fosinopril, moveltopril, moveltopril, perintopril, perindopril. Examples include delapril and angiotensin converting enzyme inhibitors known in the art.</p><p> Suitable pharmaceutical agents that can be used in conjunction with the compounds of the invention include angiotensin II receptor antagonists. Angiotensin II receptor antagonists target the angiotensin II receptor antagonist subsipe 1 (ie, AT1) and show beneficial effects on hypertension. Examples of angiotensin II receptor antagonists include losartan (and its potassium salt form) and angiotensin II receptor antagonists known in the art.</p><p> Other treatments for one or more of the diseases referred to herein include the use of pharmaceutical agents known in the art that belong to the class of drugs referred to below (but not limited to these). Includes: Amylin agonists (eg, plumlintide), insulin secretagogues (eg, GLP-1 agonists); Exidin-4 (exendin-4); insulinotropin (NN2211); Dipeptyl peptidase inhibitors (eg, GLP-1) , NVP-DPP-728), acetyl CoA cholesterol acetyl transferase inhibitors (eg, ezetimibe, eflucimibe, and similar compounds), cholesterol absorption inhibitors (eg, ezetimibe, pamaqueside and similar compounds), cholesterol ester transfer proteins Inhibitors (eg CP-529414, JTT-705, CETi-1, and similar compounds), Microsomal triglyceride transfer protein inhibitors (eg, implitapide, and analogs), cholesterol regulators (eg, NO-1886, and analogs), bile acid regulators (eg, GT103-279 and analogs), and squalene synthase. Inhibitor.</p><p> Squalene synthesis inhibitors belong to the class of drugs that lower blood cholesterol levels by inhibiting squalene synthesis. Examples of this squalene synthesis inhibitor are (S) -α- [bis [2,2-dimethyl-1-oxopropoxy) methoxy] phosphinyl] -3-phenoxybenzenebutanesulfonic acid, monopotassium salt (BMS-188494). And squalene synthesis inhibitors known in the art.</p><p> (Composition of the present invention) According to a further aspect, the invention is also a pharmaceutical containing one or more compounds of formula (I) or any of the formulas disclosed herein, and one or more pharmaceutically acceptable carriers. Regarding the composition.</p><p> Some embodiments of the invention include a method for producing a pharmaceutical composition, wherein the method comprises at least one compound according to any of the compound embodiments disclosed herein. Includes the step of mixing with a pharmaceutically acceptable carrier.</p><p> The formulation is uniformly mixed with any suitable method (typically in the required proportions of the active compound and / or liquid and / or finely divided solid carriers, and then this is obtained if necessary. It can be prepared by the step of forming the mixture into a desired shape).</p><p> Conventional excipients (eg, binders, fillers, acceptable wetting agents, tablet lubricants and tablet degradants) can be used in tablets and capsules for oral administration. Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, the oral preparation can be in the form of a dry powder that can be reconstituted with pre-use water or another suitable liquid vehicle. As additional additives (eg, suspensions or emulsifiers), non-aqueous vehicles (including edible oils), preservatives, and flavors and colorants can be added to the liquid preparation. Parenteral dosage forms can be prepared by dissolving the compounds of the invention in a suitable solution and filtering the liquid before filling and sealing the appropriate vial or ampoule. These are just a few of the many suitable methods well known in the art for preparing dosage forms.</p><p> The compounds of the present invention can be formulated in pharmaceutical compositions using techniques well known to those of skill in the art. Suitable pharmaceutically acceptable carriers other than those described herein are known in the art; eg, Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams &amp; Wilkins, See (Editor: Gennaro, AR et al.).</p><p> It is conceivable that the compounds of the invention for prophylactic or therapeutic use may be administered as raw or pure chemicals in alternative use, but the compounds or active ingredients are pharmaceutically acceptable. It is preferred to present as a pharmaceutical formulation or composition that further comprises possible carriers.</p><p> Accordingly, the present invention further provides a pharmaceutical formulation, which, along with one or more of its pharmaceutically acceptable carriers and / or prophylactic ingredients, is a compound of the invention or pharmaceutically thereof. Contains an acceptable salt or derivative. The carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not overly harmful to its recipient.</p><p> Pharmaceutical formulations include oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (intramuscular, subcutaneous and intravenous). ), Or a pharmaceutical formulation in a form suitable for administration by inhalation, gas injection, or sublingual application. Transdermal application distributes the drug at a controlled rate by providing absorption to the drug in an efficient manner that minimizes the breakdown of the drug. Typically, the transdermal application includes a permeable backing layer, a removable protective layer with a single pressure sensitive adhesive and a release liner. Those skilled in the art will understand and recognize suitable techniques for producing the desired effective transdermal application based on the needs of those skilled in the art.</p><p> Thus, the compounds of the invention can be placed in the form of pharmaceutical formulations, and their unit dosages, along with conventional adjuvants, carriers, or diluents, in such form for all oral use. Can be used as solids (eg tablets or filled capsules) or liquids (eg solutions, suspensions, emulsions, elixirs, gels or capsules filled with identical) or for rectal administration Can be used in the form of suppositories; or can be used in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may include conventional ingredients in conventional proportions with or without additional active compounds or active ingredients, and such unit dosages. The dosage form may include any suitable effective amount of active ingredient, corresponding to the intended daily dosage range to be used.</p><p> Pharmaceutical compositions for oral administration can be, for example, in the form of tablets, capsules, suspensions or liquids. The pharmaceutical composition is preferably produced in the form of dosage units containing a particular amount of active ingredient. Examples of such dosage units are conventional additives (eg lactose, mannitol, corn starch or potato starch); binders (eg crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin); Capsules, tablets, powders, granules or suspensions with disintegrators (eg corn starch, potato starch or sodium carboxymethyl-cellulose); and lubricants (eg talc or magnesium stearate). The active ingredient can also be administered by injection as a composition, where, for example, saline, glucose or water can be used as a suitable pharmaceutically acceptable carrier.</p><p> The compound of the present invention or a solvate thereof or a physiologically functional derivative is an active ingredient in a pharmaceutical composition (particularly 5HT)._2CCan be used as a receptor agonist). The term "active ingredient" is defined in the context of "pharmaceutical composition" and has a major pharmacological effect, as opposed to "inactivating ingredient" which is generally recognized as not providing pharmaceutical benefits. Should mean the components of the pharmaceutical composition that provides.</p><p> When using the compounds of the invention, it is customary and well known to physicians that the doses can vary over a wide range and should be adjusted to the individual condition of each individual case. For example, the above doses may indicate the nature and severity of the disease being treated, the patient's condition, the compounds used, or whether an acute or chronic disease condition is treated or prophylaxis is performed. , Or whether additional active compounds are administered in addition to the compounds of the invention. Typical doses of the present invention are 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, but not limited to these. Multiple doses may be administered during the day, especially if it is determined that a relatively large dose (eg, 2-dose, 3-dose or 4-dose) is required. It may be necessary to deviate upwards or downwards from the doses described herein, depending on the individual and as deemed appropriate by the patient's physician or caregiver.</p><p> The amount of active ingredient, active salt or hydrate thereof required for use in the treatment is not only by the particular salt selected, but also the route of administration, the nature of the condition being treated and the age of the patient. And changes with condition, and ultimately at the discretion of the attending physician or clinician.</p><p> In general, one of ordinary skill in the art will understand how in vivo data obtained in a model system (typically an animal model) can be estimated for another system (eg, human). Typically, the animal model includes, but is not limited to, a rodent animal model. In some environments, these estimates may simply be based on the weight of the animal model compared to another (eg, mammal, preferably human), but in many cases these estimates are simply body weight. Incorporate various factors, not based on. Typical factors include the patient's type, age, weight, gender, eating habits and medical condition, disease severity, route of administration, and pharmacological considerations of the particular compound used (eg, activity, Efficacy, pharmacokinetic profile and toxicity profile), whether a drug delivery system is utilized, whether an acute or chronic disease condition is treated or whether prophylaxis is performed, or additional active compounds , Whether or not it is administered in addition to the compound of formula (I) as part of the combination therapy, but is not limited thereto. Dosage regimens for treating disease conditions with the compounds and / or compositions of the invention are selected according to the various factors described above. Thus, the dosing regimen actually used can vary widely and therefore can deviate from the preferred dosing regimen, and those skilled in the art will be tested with dosages and dosing regimens outside these typical ranges. Recognize that it can be used in the methods of the invention, where appropriate.</p><p> The desired dose can be routinely given in single doses or in divided doses administered at appropriate intervals (eg, 2 times, 3 times, 4 times or more sub-dose per day (sub) Can be given as -dose)). The sub-dose itself can be further divided, for example, into many, separately loosely divided doses. The daily dose can be divided into several (eg, 2, 3 or 4) partial doses, especially if a relatively large amount is administered as appropriate. Where appropriate, it may be necessary to deviate upwards or downwards from the indicated daily dose, depending on the nature of the individual.</p><p> The compounds of the invention can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain either the compounds of the invention or pharmaceutically acceptable salts of the compounds of the invention as active ingredients.</p><p> The selection of suitable pharmaceutically acceptable carriers for preparing pharmaceutical compositions from the compounds of the invention can be either solid, liquid or a mixture of both. Preparations in solid form include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. The solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants or encapsulating materials.</p><p> In the powder, the carrier is a finely powdered solid that is a mixture with the finely powdered active ingredient.</p><p> In tablets, the active ingredient is mixed with a carrier having the required binding capacity in appropriate proportions and miniaturized to the desired shape and size.</p><p> The powders and tablets may contain amounts of the active compound in various percentages. Typical amounts in powders and tablets may include 0.5% to about 90% of the active ingredient; those skilled in the art will recognize when amounts outside this range are required. Suitable carriers for powders and tablets include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacant gum, methylcellulose, sodium carboxymethylcellulose, low melting point brazing, cacao butter and the like. The term "preparation" is an encapsulating material as a carrier that provides a capsule, in which the active ingredient containing or not containing a carrier is surrounded by the carrier and thus associates with that carrier. It is intended to include a formulation of an active compound having. Similarly, cashiers and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used in solid forms suitable for oral administration.</p><p> A low melting point wax (eg, a mixture of fatty acid glycerides or cocoa butter) for preparing a suppository is first melted and its active ingredient is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into a mold of a convenient size, cooled and thereby solidified.</p><p> Suitable formulations for vaginal administration may be indicated as pessaries, tampons, creams, gels, pastes, foams or sprays, which include, in addition to the active ingredient, carriers known to those of skill in the art to be suitable.</p><p> Preparations in liquid form include solutions, suspensions, and emulsions (eg, water, or water-propylene glycol solutions). For example, parenteral injection liquid preparations can be formulated as a solution in an aqueous polyethylene glycol solution. Injectable preparations (eg, aqueous suspensions or oily suspensions for sterile injections) can be formulated according to known techniques using suitable dispersants or wetting and suspending agents. The sterile injectable preparation is also in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (eg, as a solution in 1,3-butanediol). possible. Water, Ringer solution, and isotonic sodium chloride solution are acceptable vehicles and solvents that can be used. In addition, sterile fixed oils are commonly used as solvents or suspension media. Any sterile fixed oil, including synthetic monoglycerides or diglycerides, can be used for this purpose. In addition, fatty acids (eg, oleic acid) find use in injectable preparations.</p><p> Thus, compounds according to the invention can be formulated for parenteral administration (eg, by injection (eg, bolus injection or continuous inhalation)), ampoules, prefilled syringes, with added preservatives, It can be present in small volume injections or in unit dose form in multiple dose containers. Pharmaceutical compositions take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, with prescription agents (eg, suspending agents, stabilizers, and / or dispersants). Can include. Alternatively, the active ingredient may be in powder form, which is by aseptic isolation of a sterile solid to be constructed with a suitable vehicle (eg, sterile pyrogen-free water) prior to use. Or obtained by lyophilization from the solution.</p><p> An aqueous solution suitable for oral use can be prepared by dissolving the active ingredient in water and, if desired, adding the appropriate colorants, flavors, stabilizers and thickeners.</p><p> Aqueous suspensions suitable for oral use are finely powdered active ingredients in water with viscous materials (eg, natural or synthetic rubber, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents). Can be made by the step of dispersing.</p><p> Also included are solid form preparations intended to be converted into liquid form formulations for oral administration immediately prior to use. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredients, these preparations may include colorants, flavors, stabilizers, buffers, artificial sweeteners and natural sweeteners, dispersants, thickeners, solubilizers and the like.</p><p> Compounds according to the invention for topical administration to the epidermis can be formulated as ointments, creams or lotions, or as transdermal patches.</p><p> Ointments and creams can be formulated with an aqueous or oily base, for example, with the addition of appropriate thickeners and / or gelling agents. Lotions can be formulated with an aqueous or oily base and may generally include one or more emulsions, stabilizers, dispersants, suspensions, thickeners, or colorants.</p><p> Suitable formulations for topical oral administration include rosenge with an active agent in a flavored base (usually sucrose and gum arabic or tragacanto gum); inactive bases (eg gelatin and glycerin or sucrose and). Glycerol containing the active ingredient in gum arabic; as well as mouthwashes containing the active ingredient in a suitable liquid carrier.</p><p> The solution or suspension is applied directly to the nasal cavity, for example, by conventional means using a dropper, pipette or spray. The formulations may be provided in single dose form or multiple dose form. In the latter case of droppers or pipettes, this can be achieved by a patient who administers an appropriate predetermined volume of the above solution or suspension. In the case of spray, this can be achieved, for example, with a metering sprayer spray pump.</p><p> Administration to the respiratory tract can be achieved by an aerosol formulation, where the active ingredient is provided in a pressurized pack with a suitable spray. If the compound of formula (I) or a pharmaceutical composition containing them is administered as an aerosol (eg, nasal aerosol) or by inhalation, this may be, for example, a spray, atomizer, pumped atomizer, inhaler. Can be performed using a metered dose inhaler or a dry powder inhaler. Pharmaceutical forms for administration of compounds of formula (I) as aerosols can be prepared by processes well known to those of skill in the art. For these preparations, for example, a solution or dispersion of a compound of formula (I) in water, a water / alcohol mixture or a suitable physiological saline, is a conventional additive (eg, benzyl alcohol or other suitable). Preservatives, absorption enhancers (enhancers), solubilizers, dispersants, and others to increase bioavailability and, where appropriate, customary sprays (eg carbon dioxide, CFCs (eg carbon dioxide, CFC)). , Dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoromethane)) and the like. The aerosol may also routinely contain a surfactant (eg, lecithin). The dose of drug can be controlled by providing a metering valve.</p><p> In formulations intended for administration into the respiratory tract, including intranasal formulations, the compounds generally have a particulate size (eg, on the order of 10 microns or less). Such particle sizes can be obtained by means known in the art (eg, by pulverization). If desired, formulations adapted to provide sustained release of the active ingredient can be used.</p><p> Alternatively, the active ingredient may be in the form of a dry powder (eg, a mixed powder of the above compounds in a suitable powder base (eg, lactose, starch, starch derivative (eg, hydroxypropylmethylcellulose) and polyvinylpyrrolidone (PVP))). Can be provided at. Conveniently, the powder carrier forms a gel in the nasal cavity. The powder composition may be present in unit dose form, eg, in gelatin, or blister packaging, eg, in capsules or cartridges, from which the powder can be administered by inhalation.</p><p> Pharmaceutical preparations are preferably in unit dosage form. In such a form, the preparation is subdivided into unit doses containing the appropriate amount of active ingredient. The unit dosage form may be a packaged preparation, a package containing a dispersed amount of preparation (eg, packaged tablets, capsules, and powder in vials or ampoules).</p><p> Also, the unit dosage form may be a capsule, tablet, cachet, or rosenge itself, or the unit dosage form may be an appropriate number of capsules, tablets, cachet, or capsule. It can be either of the rosenge itself.</p><p> Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.</p><p> Compounds according to the invention are optionally as pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Can exist. Typical acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamate, horseuric acid, hydrobromic acid. , Hydrochloride, isetionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage acid, nitrate, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfiric acid, tartrate acid Acids, p-toluene sulfonic acids, etc. (eg, their pharmaceutically acceptable salts listed in the Journal of Pharmaceutical Sciences, 66, 2 (1977); the entire of which is incorporated herein by reference. ), But is not limited to these.</p><p> The acid addition salt can be obtained as a direct product of the synthesis of the compound. In an alternative method, the free base can be dissolved in a suitable solvent containing the appropriate acid, and the salt can be isolated by evaporating the solvent or otherwise separating the salt and solvent. .. The compounds of the present invention can be solvated with standard low molecular weight solvents using methods known to those of skill in the art.</p><p> The compounds of the invention can be converted to "prodrugs". The term "prodrug" refers to a compound that has been modified with a particular chemical group known in the art, and when administered to an individual, these groups undergo in vivo conversion to give the parent compound. Therefore, a prodrug is considered to be a compound of the invention containing one or more specialized non-toxic protecting groups, which are used in a transient manner to alter or eliminate the properties of the compound. Can be done. In general, the "prodrug" approach is utilized to facilitate oral absorption. A thorough discussion of T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," the ACS Symposium Series Vol. 14, and Bioreversible Carriers in Drug Design, Edward B. Roche (eds.), American Pharmaceutical Association and Pergamon Provided to Press, 1987, both of which are incorporated herein by reference in their entirety.</p><p> Some embodiments of the invention include methods for producing pharmaceutical compositions for "combination therapy", which methods follow embodiments of any compound disclosed herein. Includes the step of mixing at least one compound, at least one pharmaceutical agent described herein, and a pharmaceutically acceptable carrier.</p><p> In some embodiments, the pharmaceutical agent is selected from the group consisting of: apolipoprotein-B secretion / microsomal triglyceride transfer protein (apo-B / MTP) inhibitor, MCR-4 agonist, cholecystokinin ( cholescystokinin) -A (CCK-A) agonist, serotonin and norepinephrine reuptake inhibitor (eg sibutramine), sympathomimetic agenst, β₃Adrenaline-acting receptor agonists, dopamine agonists (eg bromocryptin), melanin cell stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists [eg SR141716: N- (piperidin-1-yl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxamide], melanin aggregation hormone antagonist, leptin (OB protein), leptin analog, leptin receptor agonist, galanin antagonist, lipase inhibitor (eg, tetrahydrolipstatin) (tetrahydrolipstatin), ie orlistat, appetite suppressant (eg, bombesin agonist), neuropeptide-Y antagonist, thyromimetic agent), dehydroepiandrosterone or analogs thereof, glycocorticoid receptor agonist or glycocorticoid receptor antagonist, olexin receptor antagonist, urocortin-binding protein antagonist, glucagon-like peptide-1 receptor agonist, hairy neuronutrient factor (For example, AxokineO), human agouti-related protein (AGRP), grelin receptor antagonist, histamine 3 receptor antagonist or histamine 3 receptor reverse agonist, neuromedin U receptor agonist, noradrenalinergic appetite suppressant (eg, fentermin, matindole, etc.) And appetite suppressants (eg, bupropion). In a further embodiment, the pharmaceutical agent is selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine.</p><p> In some embodiments, the pharmaceutical agent is selected from the group consisting of: sulfonylurea, meglitinide, biguanide, α-glucosidase inhibitor, peroxysome growth factor activating receptor-γ (ie, PPAR-γ) agonist. , Insulin, insulin analogs, HMG-CoA reductase inhibitors, cholesterol-lowering agents (eg, fibrates including: phenofibrate, bezafibrates, gemfibrozil, clopidogrel, etc .; including bile acid metal ion blockers: cholestyramine, cholestyramine, etc. And niacin), antiplatelet agents (eg, aspirin and adenosine diphosphate receptor antagonists including: clopidogrel, ticropidine, etc.), angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists and adiponectin.</p><p> 5HT_2CNote that when a receptor agonist is utilized as an active ingredient in a pharmaceutical composition, it is intended for use not only in humans, but also in other non-human mammals as well. In fact, recent advances in the area of animal health care have been 5HT for the treatment of obesity in livestock (eg cats and dogs)._2C5HT in receptor agonists and other livestock of unknown disease or disorder (eg, edible animals (eg, cattle, chickens, fish, etc.))_2CIt is required to consider the use of receptor agonists. Those skilled in the art will readily appreciate the usefulness of such compounds in such settings.</p><p> (Preparation of the compound of the present invention) In the illustrated synthesis outlined below, the labeled substituents are set forth in the definition of compounds of the invention in formula (I) and in the subgenus formulas as described herein. It is the same thing.</p><p> Those skilled in the art will recognize that a wide variety of compounds of the invention can be prepared according to Schemes I-V described below. One representative composition is shown in Scheme I below, which is R₂Is methyl:</p><p><chemistry num="15"><img file="JP4782003B2_D0017.tif" /></chemistry> For example, any wide variety of substituents R₃, R₄, R₅And R₆By utilizing an appropriately substituted 2-phenylethylamino compound A having the corresponding substituted 1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound H) Can be prepared. In subsequent steps, compound H is treated, for example, with excess formaldehyde or a formaldehyde equivalent (eg, paraformaldehyde (for methylation) or higher aldehydes) and then NaBH according to methods known in the art.₃It can be easily alkylated by reduction with CN or a similar reducing agent.</p><p> In addition, a number of synthetic conversions can be performed at various stages of the pathway exemplified in Scheme I to prepare additional compounds of formula (I). For example, compound E is a number of compounds of the invention (R).₂=-CH₂Can be converted to (including OH). In this case, the double bond of compound E is hydroborated using methods known in the art (eg, diborane, disiamylborane, etc.) to oxidative workup (ie, H).₂O₂), A primary alcohol can be obtained. N-protection can be removed to obtain the desired compound of the invention, or by using a method known in the art using alkyl halides in the presence of bases (eg, Williamson ether procedure). Either that the primary alcohol can then be converted to ether is done. In this example, the N protection is given by Equation (I) (where R₂Is CH₂OC_1-4It can be removed to give rise to a compound (which is an alkyl group). Alternatively, the primary alcohol can be fluorinated using reagents known in the art (eg, dialkylaminosulfur trifluoride, etc.). Specific dialkylaminoio trifluoride includes bis (2-methoxyethyl) amino-sio trifluoride, (diethylamino) sulfur trifluoride, (dimethylamino) sulfur trifluoride, and morpholinosulfur trifluoride. ), But not limited to these. Treatment with a fluorinating agent is described in formula (I) (where R).₂Is -CH₂F) monofluoroalkyl compounds can be produced. In addition, the primary alcohol prepared from compound E can be further oxidized to produce the corresponding aldehyde, and in a similar fashion, then formulas (I) (R).₂Is -CHF₂Can be converted to a difluoroalkyl compound.</p><p> Reaction Scheme II is provided below and this Reaction Scheme II shows and is not intended to limit these exemplary transformations:</p><p><chemistry num="16"><img file="JP4782003B2_D0018.tif" /></chemistry> Another representative synthetic pathway for the preparation of compounds of formula (I) is shown in Reaction Scheme III below:</p><p><chemistry num="17"><img file="JP4782003B2_D0019.tif" /></chemistry> For example, any wide variety of substituents R₃, R₄, R₅And R₆By utilizing an appropriately substituted 2-phenylethylamino compound A having the corresponding 1-substituted-2,3,4,5-tetrahydro-1H-3-benzazepine [ie, the compound of formula (Ia)). ] Can be prepared. Scheme III to the compounds of the invention R₂Illustrates one common route for introducing groups. Compound A is acylated with a carboxylic acid derivative using one of many methods (eg, one of the commonly known coupling agents available to those of skill in the art). .. A particularly useful method uses acid chlorides as described in Examples below. The carboxylic acid derivative is selected to have a leaving group or moiety that can be converted to a leaving group (ie, Lg). The resulting compound K is cyclized in the presence of Lewis acid (eg, aluminum chloride). After the reaction, the compounds of the invention (where R₁Is H [ie, the compound of formula (Ia)].</p><p> One alternative synthetic approach that can be used to prepare the compounds of the invention is compound L (ie, R).₂Is H). In this method, the amide nitrogen is first alkylated using any number of methods known in the art (R).₁The group provides, compound N), or is protected (ie, compound O). Then R₂Are introduced via an alkylation reaction to provide compound P and compound Q, respectively. Alkylation reactions include, for example, DMF / NaH, and formula R.₂-Lg (here: R₂Have the same meaning as described herein, and Lg is an alkyl of a leaving group known in the art (eg, Cl, Br, I, OMs, OTs, etc.). It can be performed under basic conditions using agents. An example of this alkylating agent is CH₃I, CH₃OMs, CH₃OTs, CH₃CH₂I, CF₃CH₂I, CF₃I, CH₃OCH₂Cl and the like can be mentioned, but are not limited to these. Representative alkylation examples have been reported by Orito, K. and Matsuzaki, T. Tetrahedron, 1980,36,81,1017-1021, which are incorporated herein by reference in their entirety. In the case where nitrogen is protected (ie, compound Q), the protecting group is first removed and the amide is reduced to reduce the compound of the invention (where R).₁Is H) is provided. In the example where the nitrogen is alkylated (ie, compound P), then the amide is simply reduced to R.₁Compounds are provided in which is alkyl. This method is illustrated in Scheme IV and Scheme V below:</p><p><chemistry num="18"><img file="JP4782003B2_D0020.tif" /></chemistry></p><p><chemistry num="19"><img file="JP4782003B2_D0021.tif" /></chemistry> Those skilled in the art will recognize that a wide variety of compounds of the invention can be prepared according to Schemes I-V.</p><p> Protecting groups may require a variety of functionality during the synthesis of some of the compounds of the invention. Therefore, representative protecting groups suitable for a wide variety of synthetic conversions are Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley &amp; Sons, New York, 1999 (the entire disclosure of which is described herein. (Used as a reference in the document).</p><p> As described herein, the compounds of the invention can be present in various forms (eg, enantiomers and racemates). It is understood that optically active forms can be obtained by conversion of racemates and can be separated by chiral chromatography or asymmetric synthesis using methods known in the art to obtain enantiomers.</p><p> (Other usefulness) Another object of the present invention relates to a radiolabeled compound of formula (I), which is not only useful in radioimaging, but also 5HT in tissue samples (including humans)._2C5HT for localization and quantification of receptors and by inhibiting the binding of radiolabeled compounds_2CIt is also useful in both in vitro and in vivo assays to identify receptor ligands. New 5HT containing such radiolabeled compounds_2CIt is a further object of the present invention to develop a receptor assay.</p><p> The present invention includes isotope-labeled compounds of formula (I) and any subgenus herein, such as, but not limited to, formulas (Ia) to (Is). An "isotope" or "radiolabeled" compound is a compound that is identical to the compounds disclosed herein, provided that one or more atoms are typically found naturally (ie, that is). Excludes the fact that it is replaced or replaced by an atom having an atomic mass or mass number that is different from the (naturally occurring) atomic mass or mass number. Suitable radionuclides that can be incorporated into the compounds of the present invention include²H (also referred to as D for Juuterium),³H (also referred to as T for tritium),¹¹C,¹³C,¹⁴C,¹³N,¹⁵N,¹⁵O,¹⁷O,¹⁸O,¹⁸F,³⁵S,³⁶Cl,⁸²Br,⁷⁵Br,⁷⁶Br,⁷⁷Br,¹²³I,¹²⁴I,¹²⁵I and¹³¹I, but not limited to these. The radionuclide incorporated into the complete radiolabeled compound depends on the particular application of the radiolabeled compound. For example, in vitro 5HT_2CFor receptor labeling and competitive assays³H,¹⁴C,⁸²Br,¹²⁵I,¹³¹I, or³⁵Compounds that incorporate S are generally the most useful. For application of radioimaging,¹¹C,¹⁸F,¹²⁵I,¹²³I,¹²⁴I,¹³¹I,⁷⁵Br,⁷⁶Br or⁷⁷Br is generally the most useful.</p><p> It is understood that the "radioactive label" or "labeled compound" is a compound of formula (I) incorporating at least one radionuclide: in some embodiments, the radionuclide is³H,¹⁴C,¹²⁵I,³⁵S and⁸²Selected from the group consisting of Br.</p><p> The particular isotope-labeled compounds of the invention are useful in compound and / or substrate tissue distribution assays. In some embodiments, radionuclides³H isotope and / or¹⁴C isotopes are useful in these studies. In addition, heavier isotopes (eg, deuterium (ie, ie)²Substitution in H)) may provide certain therapeutic benefits resulting from greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances. The isotope-labeled compounds of the present invention are generally prepared by substituting the non-isotope-labeled reagent with an isotope-labeled reagent according to a procedure similar to the procedure described in the above scheme and the examples below. obtain. Other useful synthetic methods are discussed below. Moreover, all of the atoms represented by the compounds of the invention can be either the most commonly present isotopes of such atoms, or the rarer radioisotopes or non-radioactive active isotopes. It is understood that it is.</p><p> Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds of the present invention and are well known in the art. Synthetic methods for these (eg, incorporating active levels of tritium into the target molecule) are as follows: A. Catalytic reduction with tritium gas-This procedure usually produces high specific activity products and requires halogenated or unsaturated precursors.</p><p> B. Sodium borohydride [³Reduction at H]-This procedure is fairly inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like.</p><p> C. Lithium aluminum hydride [³H]-This procedure provides the product with the most theoretical specific activity. This also requires precursors containing reducing functional groups such as aldehydes, ketones, lactones, esters and the like.</p><p> D. Tritium Gas Exposure Labeling-This procedure involves exposing a precursor containing exchangeable protons to tritium gas in the presence of a suitable catalyst.</p><p> E. Methyl iodide [³N-Methylation Using H]-This procedure usually uses a suitable precursor of high specific activity methyl iodide (H).³By treating with H), O-methyl product or N-methyl product (³Used to prepare H). This method generally allows for high specific activity, for example about 70-90 Ci / mmol.</p><p> Of activity level¹²⁵Synthetic methods for incorporating I into the target molecule include: A. Sandmeier and similar reactions-This procedure converts arylamines or heteroarylamines to diazonium salts (eg, tetrafluoroborate), followed by Na.¹²⁵Using I,¹²⁵Convert to I-labeled compound. Representative procedures are reported by Zhu, D.-G. and co-workers, J.Org.Chem.2002,67,943-948.</p><p> B. Phenol ortho¹²⁵Iodination-This procedure is at the ortho position of phenol¹²⁵Allows incorporation of I, reported by Collier, TLand co-workers, J.Labeled Compd Radiopharm. 1999,42, S264-S266.</p><p> C.¹²⁵Aryl Bromide and Heteroaryl Bromide Exchange at I-This method is generally a two-step process. The first step is trialkyltin halide or hexaalkyltin [eg, (CH).₃)₃SnSn (CH₃)₃] In the presence of, for example, using a Pd-catalyzed reaction [ie, Pd (Ph3P) 4], or by aryllithium or heteroaryllithium, to the aryl bromide or heteroaryl bromide to the corresponding trialkyltin intermediate. This is the process of conversion. Representative procedures are reported by Bas, M.-D. and co-workers, J. Labeled Compd Radiopharm. 2001,44, S280-S282.</p><p> Radioactive label of formula (I) 5HT_2CReceptor compounds can be used in screening assays to identify / evaluate compounds. In general, newly synthesized or identified compounds (ie, test compounds) are 5HT._2CThe ability to reduce the binding of the "radiolabeled compound of formula (I)" to the receptor can be evaluated. Therefore, 5HT_2CThe ability of the test compound to compete with the "radiolabeled compound of formula (I)" for binding to the receptor directly correlates with its binding affinity.</p><p> The labeled compound of the present invention is 5HT._2CIt binds to the receptor. In one embodiment, the labeled compound is an IC less than about 500 μM.₅₀In another embodiment, the labeled compound has an IC of less than about 100 μM.₅₀In yet another embodiment, the labeled compound is an IC of less than about 10 μM.₅₀In yet another embodiment, the labeled compound is an IC of less than about 1 μM.₅₀In yet another embodiment, the labeled compound is an IC of less than about 0.1 μM.₅₀Have.</p><p> Other uses of the disclosed receptors and methods will become apparent to those of skill in the art, among others, based on the detailed reading of this disclosure.</p><p> As will be appreciated, the steps of the methods of the invention need not be performed any particular number of times or any particular order. Further objects, advantages and novel features of the present invention will be apparent to those skilled in the art by reading the following examples.</p>

(Example 1) Intracellular IP₃Accumulation assay): HEK293 cells, 16 μg human 5HT using 25 μl lipofectamine_2CTransfected in a 15 cm sterile dish with or without receptor cDNA [see, eg, Saltzman, AG, et al. Biochem.Biophys.Res.Commun.181,1469-1478 (1991)]. The cells are then placed at 37 ° C / 5% CO₂Incubated in 3-4 hours, then the transfection medium was removed and replaced with 100 μl DMEM. The cells were then plated on a 100 cm sterile dish. The next day, cells were plated on 96-well PDL microtiter-well plates at a density of 55 K / 0.2 ml. After 6 hours, the medium was placed in DMEM without inositol, [³Replace with H] inositol (0.25uCi / well) and replace the plate with 37 ° C 5% CO₂Incubated overnight. The next day, the wells were aspirated and 200 μl DMEM, 10 μM pargyline, and 10 mM LiCl containing the test compound were added to the appropriate wells. Then plate the plate at 37 ° C / 5% CO₂Incubate for 3 hours in, followed by aspiration and fresh ice-cooled stop solution (1M KOH, 19 mM Na borate, 3.8 mM EDTA) was added to each well. The plate was maintained on ice for 5-10 minutes and the wells were neutralized by the addition of 200 μl of fresh ice-cold neutralizing solution (7.5% HCl). The plate was then frozen until further treatment was desired. The lysate was then transferred into a 1.5 ml Eppendorf tube and 1 ml chloroform / methanol (1: 2) / tube was added. Vortex this solution for 15 seconds and biorad AG1-X8 on top phase^TMApplied to anion exchange resin (100-200 mesh). First, the resin was washed with 1: 1.25 W / V water and 0.9 ml of top phase was filled into the column. The column was then washed with 10 ml 5 mM myo-inositol and 10 ml 5 mM Na borate / 60 mM Na formate. Inositol trisphosphate was eluted in a scintillation vial containing 10 ml of scintillation cocktail with 2 ml of 0.1 M formic acid / 1 M ammonium formate. This column was regenerated by washing with 10 ml of 0.1 M formic acid and 3 M ammonium formate, and ddH.₂Rinse twice with O and store in water at 4 ° C.

The biological activity in the IP accumulation assay for some representative compounds is shown in Table 3 below.

<tables num="3"><img file="JP4782003B2_D0022.tif" /></tables> Most of the compounds in the examples showed activity in the range between about 11 nM and about 5 μM in the IP accumulation assay.

(Example 2) (Inhibition of food intake in food-deprived rats) Male Sprague 0 Dawley rats (250-350 g) are not fed overnight prior to the test. Before feeding, the animals were weighed and divided into treatment groups according to their weight to balance the groups. On the day of the test, animals are placed in individual cages (without straw) at 9:00 am with free access to water. At 10:00 am, animals were injected with the test compound (po, ip, or sc) and pre-weighed into dishes either 60 minutes (po) or 30 minutes (ip and sc) after drug administration. Give a quantity of food. Food consumption over different time points is determined by weighing the food cup 1 hour, 2 hours, 4 hours, and 6 hours after feeding. Therefore, food consumption was measured in po studies 2 hours, 3 hours, 5 hours and 7 hours after injection, and in ip studies and sc studies 1.5 hours, 2.5 hours and 4.5 hours after injection. And measure after 6.5 hours.

(Example 3) (Synthesis of selected compounds of the present invention) (Example 3.1: Preparation of (R, S) 6,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzacepine (also referred to herein as compound 1))

<chemistry num="20"><img file="JP4782003B2_D0023.tif" /></chemistry> (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 continuously treated with diisopropylethylamine (0.82 g, 6.3 mmol) and 2-chloropropionyl (0.67 mL, 5.3 mmol). , And stirred at 20 ° C for 4 hours. The mixture is diluted with dichloromethane (50 mL), washed with 10% aqueous HCl, brine (20 mL) and Na.₂SO₄It was dried in and concentrated to give 1.5 g of the desired product as a brown oil. MS C₁₁H₁₂Cl₃Calculated for NO + H: 280 Observed: 280.

(Step 2: Preparation of 6,8-dichloro-1-methyl-2-oxo-2,3,5-trihydro-1H-3-benzazepine) Neat 2-chloro-N- [2- (2,4-dichlorophenyl) ethyl] propionamide (2.5 g, 9.1 mmol) and AlCl₃(3.6 g, 27 mmol) was heated at 150 ° C. for 18 hours with stirring. The product mixture is quenched with water (10 ml), diluted with dichloromethane (100 mL), the organic phase is separated, washed with brine (50 mL) and Na.₂SO₄It was dried in and concentrated to give 1.9 g of a brown oil. MS C₁₁H₁₁Cl₂Calculated value for NO + H: 244, observed value: 244.

(Step 3: Preparation of 6,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) A solution of 6,8-dichloro-1-methyl-2-oxo-2,3,5-trihydro-1H-3-benzazepine (1.9 g, 7.8 mmol) in tetrahydrofuran (50 mL) was added to THF (20.0 ml, 20.0 mmol). ) Was treated with 1M borane and stirred at 20 ° C for 5 hours. The mixture was quenched with methanol (10 mL), acidified with concentrated HCl (0.2 mL), azeotroped with methanol (3 x 100 mlL) and concentrated. Flash chromatography (5% methanol in dichloromethane) yielded 1.0 g of clear oil.¹1 H NMR (400 MHz, CDCl₃) δ7.20 (s, 1H), 6.90 (s, 1H), 4.30 (bs, 1H), 3.92 (m, 1H), 3.51 (m, 1H), 3.37 (m, 2H), 3.03 (m, 1H) ), 2.77 (m, 2H), 1.31 (d, J = 8 Hz, 3H). MS C₁₁H₁₃Cl₂Calculated value for N + H: 230, observed value: 230.

(Preparation of Example 3.2 (R, S) 6-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 2))

<chemistry num="21"><img file="JP4782003B2_D0024.tif" /></chemistry> Compound 2 was prepared using a procedure similar to that described for the preparation of compound 1. (R, S) 6-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtained from 2-chlorophenethylamine as a colorless oil.¹1 H NMR (400 MHz, CDCl₃) δ7.17 (d, J = 8 Hz, 1H), 6.93 (m, 2H), 3.97 (bs, 1H), 3.79 (m, 1H), 3.3-3.1 (m, 3H), 2.95 (d, J) = 11Hz, 1H), 2.8-2.6 (m, 2H), 1.3 (d, J = 8Hz, 3H). MS C₁₁H₁₄Calculated value for ClN + H: 196, observed value: 196.

(Example 3.3; Preparation of (R, S) 8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 3))

<chemistry num="22"><img file="JP4782003B2_D0025.tif" /></chemistry> (Step 1: Preparation of N-trifluoroacetyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) A solution of N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL), It was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred for 60 hours at 75 ° C. The mixture of products is poured into water (200 mL), extracted with EtOAc (200 mL) and the organic phase is saturated with aqueous LVDS.₃Wash with (2 x 100 mL), brine (100 mL) and Na₂SO₄Dried and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexanes, silica) to give 0.6 g of a white solid. C₁₃H₁₂ClF₄Calculated value for NO + H: 310, observed value: 310.

(Step 2: Preparation of 8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) A solution of N-trifluoroacetyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (160 mg, 0.22 mmol) in methanol (3 mL), 15 Treated with% aqueous NaOH (2 mL) and stirred at 25 ° C for 3.5 hours. Concentrate the product mixture, 3 times, CH₂Cl₂Extract with (5 mL) and Na₂SO₄It was dried in and concentrated to give 93 mg of a clear oil.¹1 H NMR (400MHz, CDCl₃) δ7.06 (dd, J = 8,8Hz, 1H), 6.75 (d, J = 8Hz, 1H), 3.58 (m, 1H), 3.25-3.15 (m, 3H), 2.93 (d, J = 13Hz) , 1H) 2.75-2.60 (m, 3H), 1.96 (bs, 1H), 1.33 (d, J = 8Hz, 3H). MS C₁₁H₁₃Calculated value: 214, observed value: 214 for ClFN + H.

(Preparation of Example 3.4 (R, S) 8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 4))

<chemistry num="23"><img file="JP4782003B2_D0026.tif" /></chemistry> Compound 4 was prepared using a procedure similar to that described herein for the preparation of compound 1. (R, S) 8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtained from 3,4-dichlorophenethylamine as a colorless oil.¹1 H NMR (400 MHz, CDCl₃) δ7.40 (d, J = 8Hz, 1H), 7.16 (d, J = 8Hz, 1H), 4.17 (m, 1H), 3.55 (m, 2H), 3.5-3.3 (m, 2H), 3.2- 3.0 (m, 2H), 1.43 (d, J = 7Hz, 3H). MS C₁₁H₁₃Cl₂Calculated value for N + H: 230, observed value: 230.

(Example 3.5 (S) -8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-preparation of benzazepine (Compound 5))

<chemistry num="24"><img file="JP4782003B2_D0027.tif" /></chemistry> (Step 1: Preparation of (S) -N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (S) -N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is similar to the procedure described herein for the preparation of compound 7. Prepared from (S) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine using the procedure of (with one exception, using D-tartaric acid). , The division process was performed).¹1 H NMR (400MHz, CDCl₃, Mixture of rotational isomers) δ7.27 (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 C₁₃H₁₃ClF₃Calculated value for NO + H: 292, observed value: 292.

(Step 2: Preparation of (S) -N-trifluoroacetyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) A solution of (S) -N-trifluoroacetyl-9-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.62 g, 2.1 mmol) in dichloromethane (10 mL), Treated with N-chlorosucciimide (0.284 g, 2.1 mmol) and trifluoromethanesulfonic acid (0.639 g, 4.2 mmol). The reaction was stirred for 16 hours at 20 ° C., diluted with water (20 mL) and extracted with dichloromethane (25 mL). Debug organic matter₄It was dried in, filtered, and concentrated. HPLC production was performed to obtain 0.078 g of a white solid.¹1 H NMR (400MHz, CDCl₃, Mixture of rotational isomers) δ7.32-7.25 (m, 1H), 6.97-6.93 (m, 1H), 4.27-4.24 (m, 0.6H), 4.19-4.13 (m, 1H), 4.08-4.01 ( 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 C₁₃H₁₂C_l2F₃Calculated value for NO + H: 326, observed value: 326.

(Step 3: Preparation of (S) -8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) Solution of (S) -N-trifluoroacetyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.270 g, 1.2 mmol) in methanol (10 mL) Was treated with 15% aqueous NaOH (10 mL) and stirred at 25 ° C for 3.5 hours. Concentrate the product mixture, 3 times, CH₂Cl₂Extract with (25 mL) and Na₂SO₄It was dried in and concentrated to give 0.270 g of a clear oil.¹1 H NMR (400MHz, CDCl₃) δ7.40 (d, J = 8Hz, 1H), 7.16 (d, J = 8Hz, 1H), 4.17 (m, 1H), 3.55 (m, 2H), 3.5-3.3 (m, 2H), 3.2- 3.0 (m, 2H), 1.43 (d, J = 7Hz, 3H). MS C₁₁H₁₃Cl₂Calculated value for N + H: 230, observed value: 230.

(Example 3.6 (S) Preparation of -8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 6))

<chemistry num="25"><img file="JP4782003B2_D0028.tif" /></chemistry> (Step 1: Preparation of (S) -N-trifluoroacetyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (S) -N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) The solution was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred at 75 ° C for 60 hours. The mixture of products is poured into water (200 mL), extracted with EtOAc (200 mL) and the organic phase is saturated with aqueous LVDS.₃Wash with (2 x 100 mL), brine (100 mL) and Na₂SO₄Dried and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexanes, silica) to give 0.6 g of a white solid. C₁₃H₁₂ClF₄Calculated value for NO + H: 310, observed value: 310.

(Step 2: Preparation of (S) -8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) Of (S) -N-trifluoroacetyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (160 mg, 0.22 mmol) in methanol (3 mL) The solution was treated with 15% aqueous NaOH (2 mL) and stirred for 3.5 hours at 25 ° C. Concentrate the product mixture, 3 times, CH₂Cl₂Extract with (5 mL) and Na₂SO₄It was dried in and concentrated to give 93 mg of a clear oil.¹1 H NMR (400MHz, CDCl₃) δ7.06 (dd, J = 8,8Hz, 1H), 6.75 (d, J = 8Hz, 1H), 3.58 (m, 1H), 3.25-3.15 (m, 3H), 2.93 (d, J = 13Hz) , 1H) 2.75-2.60 (m, 3H), 1.96 (bs, 1H), 1.33 (d, J = 8Hz, 3H). MS C₁₁H₁₃Calculated value: 214, observed value: 214 for ClFN + H.

(Example 3.7: Preparation of (R) -8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 7))

<chemistry num="26"><img file="JP4782003B2_D0029.tif" /></chemistry> (Step 1: Preparation of 2- (4-chlorophenyl) ethyl-N-2-chloropropionamide) 2- (4-Chlorophenyl) ethylamine (30 g, 193 mmol), 400 mL acetonitrile, triethylamine (19.5 g, 193 mmol) continuously under an argon balloon in a 1 liter three-necked round-bottom flask equipped with a reflux condenser and an addition funnel. And 80 mL of acetonitrile was added. The clear, colorless solution was stirred and cooled to 0 ° C. 2-Chloropuopionyl chloride (24.5 g, 193 mmol, distilled) in 5 mL acetonitrile was added slowly over 20 minutes to generate a white gas, form a white precipitate, and change the color of the reaction mixture to pale yellow. occured. The added funnel was rinsed with an additional 10 mL of acetonitrile. The mixture was stirred at 0 ° C. for 30 minutes, then warmed to room temperature and vigorously stirred for an additional hour. The yellow reaction mixture was concentrated on a solid (76.36 g) containing triethylamine hydrochloride on a rotary evaporator. The material was taken in 100 mL ethyl acetate and 200 mL water and stirred vigorously. The layers were separated and the aqueous layer was further extracted with 100 mL of ethyl acetate. The combined organic layers were washed with 25 mL saturated brine, dried over magnesium sulphate, filtered and concentrated to a pale yellowish brown solid (41.6 g, 88%). Ethyl acetate-hexane 8: 2 TLC showed major spots in two-thirds of the plate pathway and small spots at baseline. Baseline spots were removed as follows: This material was taken in 40 mL ethyl acetate and hexane was added until the solution became cloudy. The mixture was cooled to 0 ° C. to obtain a white crystalline solid (40.2 g, 85% yield). This product is a known compound (Hasan et al., Indian J. Chem., 1971, 9 (9), 1022), CAS Registry No. 34164-14-2. LC / MS gave the product at 2.45 minutes; 246.1 M⁺+ H⁺。¹1 H NMR (CDCl₃): δ7.2 (dd, 4H, Ar), 6.7 (br S, 1H, NH), 4.38 (q, 1H, CHCH₃), 3.5 (q, 2H, ArCH₂C<u style="single">H</u>₂NH), 2.8 (t, 2H, ArCH₂), 1.7 (d, 3H, CH₃)。¹³C NMR (CDCl₃): 169 (1C, C = O), 136 (1C, Ar-Cl), 132 (1C, Ar), 130 (2C, Ar), 128 (2C, Ar), 56 (1C, CHCl), 40 ( 1C, CHN), 34 (1C, CHAr), 22 (1C, CH₃)。

(Step 2: Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one) 2- (4-Chlorophenyl) ethyl-N-2-chloropropionamide (10 g, 40.6 mmol) and aluminum chloride (16 g, 119.9 mmol) are added to a dry 100 mL round bottom flask equipped with an argon balloon, stirrer and heating device. did. The white solid was melted into a tan oil while bubbling at 91 ° C (Note: when using an impure initiator, black tar is produced, but a clean product can still be isolated). The mixture was heated and stirred at 150 ° C. for 12 hours. The reaction was followed by LC / MS, and the starting material was 2.45 minutes (246.M) from 5-95% w / 0/01% TFA (in water / MeCN (50:50)) with a reaction time of 5 minutes.⁺H⁺), The product is 2.24 minutes (209.6M)⁺H⁺). After cooling to room temperature, the reaction mixture was quenched with a slow addition of 10 mL of MeOH followed by 5 mL of 5% HCl water and 5 mL of ethyl acetate. After separation of the resulting layers, the aqueous layer was extracted twice with 10 mL ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated to a tan solid (6.78 g, 80% yield). LC / MS showed one peak at 209.6 MI at 2.2 minutes. The material was taken with 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 the final product (4.61 g, 54% yield). rate).¹1 H NMR (CDCl₃): δ7.3-7.1 (m, 3H, Ar), 5.6 (br s, 1H, NH), 4.23 (q, 1H, CHCH)₃), 3.8 (m, 1H, ArCH₂C<u style="single">H</u>₂NH), 3.49 (m, 1H, ArCH₂C<u style="single">H</u>₂NH), 3.48 (m, 1H, ArC<u style="single">H</u>₂CH₂NH), 3.05 (m, 1H, ArC<u style="single">H</u>₂CH₂NH), 1.6 (d, 3H, CH₂)。¹³C NMR (CDCl₃): 178 (1C, C = O), 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-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) 8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (150 mg, 0.716 mmol, purified by HPLC or recrystallization) in 2M borane-tetrahydrofuran solution (2 mL, 2. 15 mmol) was added to a 50 mL round bottom flask. The mixture was stirred for 10 hours at room temperature under an argon balloon. LC / MS showed the desired product as the major peak, with 5% anther starting material still present. The reaction mixture was quenched with 5 mL methanol and the solvent was removed on a rotary evaporator. This procedure was repeated with methanol addition and evaporation. The mixture was evaporated on a rotary evaporator and after 2 hours the pressure was reduced to give the product as a white solid (117 mg, 70% yield).¹1 H NMR (CDCl₃): δ10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J = 2,8Hz), 7.11 (d, 1H, J = 2Hz), 7.03 (d, 1H, J = 8Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3H), 1.5 (d, 3H, J = 7Hz). LC / MS: 1.41 minutes, 196.1 M + H⁺And 139 major fragments.

(Step 4: Preparation of L- (+)-tartrate of (R) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) 11.5 g (0.06 mol) of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 2.23 g (0.015 mol) of L- in a clean, dry 50 mL round-bottom flask. (+)-Added to tartaric acid. Suspension with 56 g tert-butanol and 6.5 mL H₂Diluted with O. The mixture was heated to reflux (75-78 ° C) and stirred for 10 minutes to give a colorless solution. The solution was slowly cooled to room temperature (1 hour) and stirred at room temperature for 3 hours. The suspension was filtered and the residue was washed twice with acetone (10 mL). The product was dried at 60 ° C. under reduced pressure (50 mbar) to give 6.3 g of tartrate (ee = 80). This tartrate was added to 56 g tert-butanol and 6.5 mL H₂Added to O. The resulting suspension was heated to reflux and 1 to 2 g of H₂O was added to give a colorless solution. The solution was slowly cooled to room temperature (over 1 hour) and stirred at room temperature for 3 hours. 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 give 4.9 g (48% yield) of product (ee&gt; 98.9).

(Step 5: Conversion of free amine- (R) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine to salt) 8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-tartrate (300 mg, 0.87 mmol) with 50% sodium hydroxide solution (114 μL, 2.17 mmol) It was added to a 25 mL round bottom flask with an additional 2 mL of water. The mixture was stirred for 3 minutes at room temperature. The solution was extracted twice with methylene chloride (5 mL). The combined organic extracts were washed with water (5 mL), pumped and dried to dryness to give free amines (220 mg crude weight). LC / MS196 (M + H).

(Step 6: Preparation of (R) -N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) A solution of (R) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.0 g, 4.31 mmol) in dichloromethane (50 mL) at 0 ° C, pyridine. Treated with (1.0 mL) and trifluoroacetic anhydride (1.35 g, 6.46 mmol). It was warmed to 20 ° C, stirred for 3 hours and diluted with 1M HCl (25 mL). This is extracted with dichloromethane (2 x 50 mL) and the organic matter is EDTA₄It was dried in, filtered and concentrated to give 1.7 g as an off-white solid.¹1 H NMR (400MHz, CDCl₃, Mixture of rotational isomers) δ7.27 (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 C₁₃H₁₃ClF₃Calculated value for NO + H: 292, observed value: 292.

(Step 7: (R) -8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) The preparation of compound 5 from compound 7 from (R) -N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is described herein. Prepared using a similar two-step procedure described.¹1 H NMR (400MHz, CDCl₃) δ7.40 (d, J = 8Hz, 1H), 7.16 (d, J = 8Hz, 1H), 4.17 (m, 1H), 3.55 (m, 2H), 3.5-3.3 (m, 2H), 3.2- 3.0 (m, 2H), 1.43 (d, J = 7Hz, 3H). MS C₁₁H₁₃Cl₂Calculated value for N + H: 230, observed value: 230.

(Example 3.8: Preparation of (S) -9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 8))

<chemistry num="27"><img file="JP4782003B2_D0030.tif" /></chemistry> (Step 1: Preparation of (S) -N-trifluoroacetyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (S) -N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.875g, 3.0) in dichloroethane (7mL) in dichloroethane (7mL) A solution of mmol) was treated with N-bromosuccinimide (0.284 g, 2.1 mmol) and trifluoromethanesulfonic acid (0.639 g, 4.2 mmol). The reaction was stirred at room temperature for 16 hours, diluted with ethyl acetate (20 mL) and extracted with water (2 x 10 mL). Debug organic matter₄It was dried in, filtered and concentrated. Flash chromatography (5% EtOAc in hexanes, silica) gave 0.13 g of a colorless oil. MS C₁₃H₁₂BrClF₃Calculated value for NO + H: 370, observed value: 370.

(Step 2: Preparation of (S) -9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) The preparation of compound 5 from compound 8 from (S) -N-trifluoroacetyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is described herein. Prepared using similar procedures described in the document. (S) -9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, (S) -N-trifluoroacetyl-9-bromo-8-chloro Obtained from -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.¹1 H NMR (400 MHz, CDCl₃) δ7.17 (d, J = 8Hz, 1H), 6.92 (d, J = 8Hz, 1H), 3.92-3.87 (m, 1H), 3.29-3.20 (m, 2H), 3.11 (dd, J = 14) , 5Hz, 1H), 2.99 (dd, J = 14,2Hz, 1H), 2.74-2.65 (m, 2H), 1.32 (d, J = 7Hz, 3H). MS C₁₁H₁₃Calculated for BrClN + H: 274, Observed: 274.

(Example 3.9: Preparation of (R) -N-methyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 9))

<chemistry num="28"><img file="JP4782003B2_D0031.tif" /></chemistry> A solution of (R) -8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.05 g, 0.20 mmol) in dichloroethane (3 mL) was added to sodium triacetoxyboro. Treated with hydride (0.073 g, 0.35 mmol) and formaldehyde (0.017 mL, 37% aqueous solution). This was stirred at 20 ° C. for 2 hours. The reaction was diluted with 15% NaOH and extracted with ethyl acetate (2 x 10 mL). Debug organic matter₄It was dried in, filtered and concentrated to give 0.42 g as an oil. ¹1 H NMR (400MHz, CDCl₃) δ7.19 (d, J = 8Hz, 1H), 6.89 (d, J = 8Hz, 1H), 3.91-3.88 (m, 1H), 3.28 (ddd, J = 15,12,2Hz, 1H), 2.99 -2.88 (m, 2H), 2.68 (ddd, J = 15,5,1Hz, 1H), 2.36-2.32 (m, 4H), 2.13 (t, J = 11Hz, 1H), 1.27 (d, J = 7Hz) , 3H). MS C₁₂H₁₅Cl₂Calculated value for N + H: 243, observed value: 243.

(Example 3.10: Preparation of (S) -N-methyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine)

<chemistry num="29"><img file="JP4782003B2_D0032.tif" /></chemistry> (Step 1: Preparation of (S) -N-methyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) Compound 10 is derived from (S) -8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, similar to those described herein for the preparation of compound 9. use the procedure, adjustment was made.¹1 H NMR (400MHz, CDCl₃) δ7.19 (d, J = 8Hz, 1H), 6.89 (d, J = 8Hz, 1H), 3.91-3.88 (m, 1H), 3.28 (ddd, J = 15,12,2Hz, 1H), 2.99 -2.88 (m, 2H), 2.68 (ddd, J = 15,5,1Hz, 1H), 2.36-2.32 (m, 4H), 2.13 (t, J = 11Hz, 1H), 1.27 (d, J = 7Hz) , 3H). MS C₁₂H₁₅Cl₂Calculated value for N + H: 243, observed value: 243.

(Example 3.11: Preparation of (S) -N-methyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 11))

<chemistry num="30"><img file="JP4782003B2_D0033.tif" /></chemistry> Compound 11 is described herein for the preparation of compound 9 from (S) -9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Prepared using a similar procedure.¹1 H NMR (400MHz, CDCl₃) δ7.18 (d, J = 8Hz, 1H), 6.92 (d, J = 8Hz, 1H), 3.94-3.88 (m, 1H), 3.29 (ddd, J = 15,12,2Hz, 1H), 2.98 -2.93 (m, 1H), 2.90 (ddd, J = 15,6,1Hz, 1H), 2.36-2.32 (m, 4H) 2.13 (t, J = 11Hz, 1H), 1.33 (d, J = 7Hz, 3H). MS C₁₂H₁₅Cl₂Calculated value for N + H: 288, observed value: 288.

(Example 4 Separation of enantiomers for selected compounds of the present invention) The compounds of the present invention use a Varian ProStar HPLC system with a 20 mm × 250 mm Chiralcel OD chiral column, such as isopropanol (IPA) in various concentrations of hexane (eg, 5% IPA in hexane, 1% IPA in hexane, etc.) It can be eluted with 0.2% diethylamine in (concentration) and separated into each enantiomer.

It is understood that each of the patents, applications, printed publications, and other published documents referred to or referenced herein is incorporated herein by reference in their entirety. To.

Those skilled in the art will appreciate that many modifications and modifications can be made to preferred embodiments of the invention and such modifications and modifications can be made without departing from the spirit of the invention. It is therefore understood that the appended claims cover all such equivalent modifications within the true spirit and scope of the invention.