Compound hydrate or solvate

(12) PATENT DESCRIPTION (19) PL (21) Notification number: 391780 (22) Date of notification: 11.04.2003 (62) Number of the notification from which the separation took place:

373464 (86) Date and number of the international application:

2003-04-11, PCT / US03 / 011076 (87) International application publication date and number:

2003-10-23, WO03 / 086306 (11) 211333 (13) B1 (51) Int.Cl.

C07D 223/16 (2006.01) A61K 31/55 (2006.01)

<td colspan="2">₍₅₄₎ Hydrate or solvate of the hydrate or solvate of the benzazepine derivative, its use,⁽⁵⁴⁾ a pharmaceutical composition containing it, and a method of making the composition</td>

<td>(30) Priority:</td><td></td>

<td>2002-04-12, US, 60 / 372,058</td><td>(73) The right holder of the patent:</td>

<td>2002-08-23, US, 60 / 405,495</td><td>Arena Pharmaceuticals, Inc., San Diego, US</td>

<td>2002-12-18, US, 60 / 434,607 2003-04-10, US, 10 / 410,991</td><td>(72) Inventor (s):</td>

<td></td><td>JEFFREY SMITH, San Diego, US</td>

<td>(43) Application was announced:</td><td>BRIAN SMITH, San Diego, US</td>

<td>30.08.2010 BUP 18/00</td><td>(74) Representative:</td>

<td>(45) The grant of the patent was announced: May 31, 2012 WUP 05/12</td><td>item. stalemate. Agnieszka Żebrowska-Kucharzyk</td>

PL 211 333 B1

Description of the invention

This application claims priority to US provisional patent application Serial No. 60/372058, filed April 12, 2002; U.S. Provisional Patent Application Serial No. 60/405495, filed August 23, 2002, U.S. Provisional Patent Application Serial No. 60 / 434,607, filed December 18, 2002, and U.S. Patent Application Serial No. (not yet issued), filed April 10, 2003, which are incorporated herein by reference. as literature references.

The invention relates to a hydrate or a solvate of a benzazepine derivative hydrate or solvate, the use thereof, a pharmaceutical composition containing the same, and a method for the preparation of the composition. The hydrate or solvate of a benzazepine derivative hydrate or solvate of the invention finds use as a modulator of 5HT2C receptors and as such is useful in the fight against obesity.

Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality from comorbid conditions such as type II diabetes, hypertension, stroke, cancer, and gallbladder disease.

Obesity is now a staple healthcare issue in Western countries as well as an issue of growing importance in some third world countries. The increase in the number of obese people is largely due to the increasing demand for high-fat foods, but also, and this may be a much more significant factor, to the decline in the activity of life for a large group of people. Over the past 10 years, there has been a 30% increase in the prevalence of obesity in the United States, such that approximately 30% of the population of the United States of America is considered obese.

Whether someone can be classified as overweight or obese is generally determined by their body mass index (BMI), which is calculated by dividing weight (kg) by height squared (m²). Thus, the units of BMI are kg / m² and it is possible to estimate the range of BMI associated with minimum mortality for each decade of life. Overweight is defined as BMI between 25-30 kg / m², and obesity as a BMI greater than 30 kg / m² (see TABLE below).

Table 1

Weight classification based on body mass index (BMI)

<td>BMI</td><td>Classification</td>

<td> &lt; 18,5</td><td>Underweight</td>

<td> 18,5-24,9</td><td>Normal</td>

<td> 25,0-29,9</td><td>Overweight</td>

<td> 30,0-34,9</td><td>Obesity (Grade I)</td>

<td> 35,0-39,9</td><td>Obesity (Class II)</td>

<td> &gt;40</td><td>Extreme obesity (Class III)</td>

As BMI increases, the risk of dying from multiple causes beyond the control of other risk factors increases. The most common diseases accompanying obesity are cardiovascular diseases (especially hypertension), diabetes mellitus (obesity worsens the development of the disease), gallbladder diseases (especially cancer) and diseases of reproductive capacity disorders. Studies have shown that even a modest reduction in weight can represent a significant reduction in the risk of developing coronary heart disease.

However, there is a problem with the definition of BMI that it does not take into account the proportion of body weight, i.e. the ratio of muscle mass to fat (adipose tissue). With this in mind, obesity can also be defined by the percentage of body fat: greater than 25% in men and than 30% in women.

Obesity also significantly increases the risk of developing cardiovascular disease. Coronary insufficiency, atherosclerotic disease, and heart failure are the major cardiovascular complications caused by obesity. It is estimated that if the entire human population were of an ideal weight, the risk of coronary insufficiency would decrease by 25% and the risk of heart failure and cerebrovascular accident by 35%. The incidence of coronary artery disease is twice as high in diagnosed patients under 50 years of age

PL 211 333 B1

30% overweight. Patients with diabetes are exposed to a 30% shorter life expectancy. After the age of 45, people with diabetes are about three times more likely than people without diabetes to develop serious heart disease and more than five times more likely to have a stroke. The above research results highlight the interdependence between risk factors for NIDDM (Noninsulin Dependent Diabetes Mellitus Type II) and coronary artery diseases, and the potential value of an integrated approach to preventing such a condition by preventing obesity (Perry, IJ, et al., BMJ 310). , 560-564 (1995)).

Diabetes has also been linked to the development of kidney disease, diseases of the visual system, and disorders of the nervous system. Kidney disease, also known as nephropathy, occurs when the kidney's filtering mechanism is damaged and excess protein leaks into the urine, and eventually the kidneys stop working. Diabetes mellitus is also a major cause of fundus retinal damage and an increased risk of cataracts and glaucoma. Additionally, diabetes is associated with nerve damage, particularly in the legs and feet, which affects the ability to feel pain and contributes to a variety of infections. Taken together, the complications of diabetes are one of the leading causes of death nationwide.

The first line of treatment is to propose diet and lifestyle changes to patients, such as reducing dietary fat and increasing physical activity. However, most patients find this difficult and require additional help, such as drug treatment, to maintain the results of the above efforts.

The latest products on the market have proven to be ineffective in treating obesity due to a reported lack of efficacy or unacceptable side effect profiles.

The most successful drug to date has been the 5-hydroxytryptamine (5-HT) indirect agonist d-fenfluramine (Redux ™), but reports of cardiac valve damage in at least one third of patients led to its FDA recall in 1998.

In addition, two drugs have recently been approved in the US and Europe: Orlistat (Xenical ™), a drug that prevents fat absorption by inhibiting pancreatic lipase, and Sibutramine (Reductil ™), a 5-HT / norepinephrine reuptake inhibitor. However, the side effects associated with the use of these products may limit their long-term use. Treatment with Xenical ™ has been reported to induce gastrointestinal disturbances in some patients, and the use of Sibutramine has been associated with elevated blood pressure levels in some patients.

The neurotransmission of serotonin (5-HT) plays an important role in numerous physiological processes in both health and psychiatric disorders. 5-HT is sometimes associated with regulating eating habits. 5-HT seems to work by inducing a feeling of fullness or satiety so that eating is interrupted earlier and fewer calories are consumed. The stimulating effect of 5-HT at 5HT2C receptors has been shown to play an important role in food control and the obesity-preventing effect of d-fenfluramine. Because the 5-HT2C receptor is secreted at high density in the brain (in particular in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus, i.e. the parventricular nucleus (PVN) and the dorsomedial nucleus (PVN)). dorsomedial nucleus (DMH), especially in the choroid plexus) and is secreted in low density or is absent in peripheral tissues, selective 5-HT2C receptor agonists may be more effective and safer anti-obesity agents. The above thesis is also supported by the fact that mice deprived of 5-HT2C are overweight and impaired cognitive ability and susceptibility to seizures.

As used herein, 5HT2C may play a role in obsessive-compulsive and compulsive disorder, some forms of depression and epilepsy. Therefore, agonists may possess anti-panic properties, and properties useful in the treatment of sexual dysfunction.

In summary, the 5HT2C receptor is an established and well-accepted receptor target in the treatment of obesity and psychiatric disorders, and therefore there is an established need for selective 5HT2C agonists that can easily and safely reduce food intake and body weight. The present invention provides such compounds.

Accordingly, the present invention relates to a hydrate or solvate of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and its pharmaceutically acceptable salts, especially (R) -8- chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or (S) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

PL 211 333 B1

Another object of the invention is the use of a benzazepine derivative hydrate or solvate of the invention for the manufacture of a medicament useful in a method of treatment of the human or animal body.

According to another aspect, the present invention relates to the use of a benzazepine derivative hydrate or solvate in the manufacture of a medicament useful for use in the prevention or treatment of obesity in a mammal.

The invention also relates to the use of a benzazepine derivative hydrate or solvate in the manufacture of a medicament useful for reducing food intake in a mammal.

According to yet another aspect, the invention provides the use of a benzazepine derivative hydrate or solvate of the invention for the manufacture of a medicament useful for inducing satiety in a mammal.

The invention also relates to the use of a benzazepine derivative hydrate or solvate in the manufacture of a medicament useful for controlling weight gain in a mammal.

Another object of the invention is a pharmaceutical composition containing the active ingredient and pharmaceutically acceptable excipients, the composition containing as active ingredient a hydrate or a solvate of a benzazepine derivative according to the invention.

The invention also relates to a process for preparing a composition comprising combining pharmaceutically acceptable excipients and a hydrate or solvate of a benzazepine derivative of the invention.

In practicing some of the embodiments of the invention, it is necessary to identify the subject in need of food reduction, weight gain control, or treatment of obesity. This identification step is performed prior to administering to said subject a pharmaceutically effective amount of a compound or composition of the invention.

Brief Description of Figures

Figures 1A-1G show the effect of seven different compounds of general formula I as defined below, including 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Fig. 1G) on food intake by food deprived rats.

Detailed Description of the Invention

The invention relates to a 5HT2C receptor agonist hydrate or solvate of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, thereby disclosing methods of modulating 5HT2C receptors by contacting the receptors with a hydrate or solvate of the invention. The invention also relates to uses of the hydrates or solvates of the invention for reducing food intake, controlling weight gain, or treating obesity.

As used herein, the term antagonist refers to molecules that competitively bind to the receptor at the same site as agonists (e.g., an endogenous ligand), but that do not activate the intracellular response initiated by the active form of the receptor, and can therefore inhibit the receptor. intracellular agonist or partial agonist responses. The antagonists do not reduce the basal intracellular response in the absence of an agonist or partial agonist. As used herein, the term agonist refers to molecules that activate an intracellular response when they bind to a receptor or enhance binding of GTP to membranes. With respect to the present invention, a pharmaceutical composition of the invention comprising a 5HT2C receptor agonist can be used to modulate 5HT2C receptor activity, reduce food intake, induce gratification (i.e. fullness), controlled weight gain, treat obesity, reduce body weight and / or or influencing metabolism such that the recipient loses weight and / or maintains weight. Such pharmaceutical compositions can be used in diseases and / or disorders in which weight gain is one of the components of the disease and / or disorder, such as, for example, obesity.

As used herein, the term contact or contacting should mean bringing the indicated molecules together, whether in an in vitro system or an in vivo system. Thus, contacting a 5HT2C receptor with a compound of the invention comprises administering a compound of the invention to an animal having a 5HT2c receptor as well as, for example, introducing a compound of the invention into a sample containing a cellular or further purified 5HT2C receptor containing preparation.

The hydrates or solvates of the benzazepine derivative of the invention include the hydrate or solvate of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and the hydrate or solvate of the (R) -8-chloro-1PL enantiomers thereof. 211 333 B1

-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and (S) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, both of which are derivatives Benzazepines can be described by the general formula (I), shown below:

<img file="PL211333B1_D0001.tif" />

wherein:

R1 is H or C1-8 alkyl;

R2 is C1-8 alkyl, -CH2-O-C1-8 alkyl, -C (= O) -O-C1-8 alkyl, -C (= O) -NH-C1-8 alkyl, or CH2OH;

R2a is H; or R2 and R2a together form -CH2-CH2-;

R3 and R4 are each independently H, halogen, perhaloalkyl, (preferably CF3), CN, OR5, SR5, NHR5, N (R5) 2, aryl, or heteroaryl, wherein said aryl may be optionally substituted with up to two substituents selected from C1-8 alkyl, halogen and alkoxy, and said heteroaryl may be optionally substituted with up to two substituents selected from halogen and C1-8 alkyl;

or R3 and R4 together with the atoms to which they are attached may form a 5- or 6-membered heterocyclic ring containing one O atom;

each R5 is independently C1-8 alkyl, C2-8 alkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or perhaloalkyl; and

R6 is H or C1-8 alkyl; only if:

(A) if R2 is methyl and both R1 and R3 are H, then R4 is not a thiazole, substituted thiazole or a thiazole derivative:

(B) if R6 is other than H, then neither R3 nor R4 can be H;

(C) if R1 and R2 are methyl, and R4 is H, then R3 cannot be NHR5 or N (R5) 2;

(D) if R1 and R2 are methyl, and R4 is H, then R3 cannot be imidazole, substituted imidazole, or an imidazole derivative; and (E) if R3 is OH, and R1 is methyl then R2 cannot be cyclopentyl, -CH2-cyclohexyl, cyclopropylmethyl, or cyclohexyl.

or under the conditions (A), (B), (C), (D) mentioned above, and if R4 is OR5 then R2 cannot be alkyl.

Looking at formula (I), it is evident that compounds of formula I, including 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, may have one or more chiral centers, and exist in enantiomeric or diastereoisomeric forms. As used herein, the invention is intended to apply to all such enantiomers, diastereomers, and mixtures thereof, including the racemic mixture. Formula (I) and the formulas hereinafter are intended to represent all individual isomers and mixtures thereof, unless otherwise stated or shown.

As used herein, the term alkyl denotes straight chain, branched, and cyclic hydrocarbons, including, for example, but not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl. , tert-butyl, cyclobutyl, cyclopropylmethyl, n-pentyl, isopentyl, tert-pentyl, cyclopentyl, cyclopentylmethyl, n-hexyl, cyclohexyl, and the like. As specified above, it is understood that the term alkyl is intended to include both non-cyclic hydrocarbon groups and cyclic hydrocarbon groups. In some embodiments of the compounds of the invention, the alkyl groups are non-cyclic. In other embodiments, the alkyl groups are cyclic groups, and in still other embodiments, the alkyl groups are both cyclic and non-cyclic. Unless otherwise specified, the term alkyl is intended to mean both groups that are cyclic and non-cyclic.

As used herein, the term alkenyl denotes straight chain, branched and cyclic hydrocarbons that contain at least one double bond, including

Example but not limited to allyl, 2-methyl-allyl, 4-but-3-enyl, 4-hex-5-enyl, 3-methylbut-2-enyl, cyclohex-2-enyl and the like.

In the present specification, it is assumed that the term halogen is retaining its normal meaning and refers to the elements of group 7 of the periodic table of the elements, including F, Cl, Br and I.

As used herein, the term alkoxy denotes substituents of the formula -O-alkyl, including -O-allyl. The term lower when used with substituents such as alkyl means 6 carbon atoms or less.

As used herein, arylalkyl or aralkyl is understood to mean an alkyl group that is substituted with an aryl substituent, for example, a benzyl group. As used herein, the term alkylaryl or alkaryl denotes an aryl group that is substituted with an alkyl substituent, for example a 4-methylphenyl group.

As used herein, the term aryl is understood to mean a monocyclic and polycyclic aromatic group. Although aryl groups can contain as few as 3 carbon atoms, preferably aryl groups contain from 6 to about 14 carbon atoms, more preferably from 6 to about 10 carbon atoms. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, anthracyl, phenanthryl, and pynyl.

As used herein, the term heteroaryl denotes an aryl group containing at least one, and preferably from one to four hetero atoms (ie, non-carbon atoms, e.g., O, N or S) in the ring.

Examples of "heteroaryl" groups are radicals derived from 5- and 6-membered aryl ring compounds containing from one to four nitrogen, sulfur and / or oxygen atoms, for example pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, furan, pyran, thiophene, benzimidazole, quinoline, isoquinoline, oxazole, thiazole, and thiadiazole.

As used herein, the term heteroarylalkyl is an alkyl group that is substituted with a heteroaryl substituent, for example a group of the chemical structure -CH2-pyrrol-2-yl.

As used herein, the term substituted thiazole denotes a radical derived from a thiazole that is substituted with at least one substituent group. In the present description, the term thiazole derivative is understood to mean a fused ring system in which one of the fused rings is a thiazole.

As used herein, the term substituted imidazole means a radical derived from an imidazole that is substituted with at least one substituent group. As used herein, the term imidazole derivative means a fused ring system in which one of the fused rings is imidazole.

In certain embodiments of compounds of formula (I), R4 is OR5. In certain such embodiments, R2 cannot be cyclopentyl, -CH2-cyclohexyl, 3,3-dimethyl-2-allyl, 3,3-dimethyl-2-methylallyl, 2-methylallyl, 2-butenyl, cyclopropylmethyl, cyclohexyl or allyl . In further such embodiments, R2 cannot be alkyl.

In certain embodiments of compounds of formula (I), R3 is halogen and R4 is -OR5. In certain embodiments of compounds of formula (I), R5 is allyl, 2-methyl-allyl, 4-but-3-enyl, 4-hex-5-enyl, 3-methyl-but-2-enyl, or cyclohex-2. -enyl. In certain embodiments of compounds of Formula (I), R 5 is methyl, ethyl, n-propyl, isopropyl, or allyl. In certain embodiments of compounds of formula (I), R5 is methyl or allyl.

Certain substituents of the compounds disclosed herein may be optionally substituted, ie, may optionally contain further substituent groups. Some preferred substituent groups include halogen, lower alkyl (including but not limited to methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, and methylcyclopropyl), alkoxy, mono-, di-, or trihaloalkoxy (e.g., -O-CX3 where X is halogen), - (CH2) yNH2, - (CH2) yNHBoc, -N (R4a) (R4b), phenyl, methoxyphenyl and naphthyl.

Various places in this listing disclose substituents for compounds of formula (I) in groups or ranges. It is expressly intended that the invention covers all and each individual individual subcombinations of members of such groups and ranges. For example, the term C1-8 alkyl in particular with respect to the individual disclosures means methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl. C6 alkyl, C7 alkyl, and C8 alkyl.

Since the compounds of formula (I) disclosed herein may contain one or more asymmetric carbon atoms, the compounds may exist in various stereoisomeric forms. The compounds can be, for example, racemates or optically active forms. Optically active forms can be generated by resolution of a racemic mixture or

Controlled synthesis. In accordance with certain embodiments and with respect to certain compounds disclosed herein but not claimed, the compounds of formula (I) are R enantiomers, others are S enantiomers, and some compounds of formula (I) are different mixtures of enantiomers.

According to further aspects of the invention, there are provided 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrates or solvates of the invention for use in therapy. The 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrates or solvates of the invention can be used in the prevention or treatment of disorders related to the functioning of the 5-HT2C receptor.

Thus, they can be used in the prevention or treatment of central nervous system disorders such as depression, atypical depression, bipolar disorders, anxiety disorders, obsessive compulsive disorders, social phobias or panic states, sleep disorders, sexual disorders, psychoses, schizophrenia, migraine and other conditions associated with headache or other pain, increased intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, dementia-related behavioral disorders, organic mental disorders, childhood psychiatric disorders, aggressiveness, age-related mental disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia nervosa, anorexia nervosa and premenstrual tension; central nervous system injuries such as trauma, stroke, neurodegenerative diseases, or toxic or infectious diseases of the central nervous system such as encephalitis and meningitis; cardiovascular disorders such as venous thrombosis; gastrointestinal disorders; renal glucosuria; and sleep apnea.

Accordingly, according to a further aspect of the invention, there is provided the use of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrates or solvates according to the invention for the manufacture of a medicament useful in the prophylaxis or treatment of the human and animal body. The invention relates in particular to the use of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrates or solvates for the preparation of a medicament useful in the prophylaxis or treatment of obesity.

The hydrates or solvates of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine according to the invention may optionally be the hydrates or solvates of 8-chloro-1-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine in the form of pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethylenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, almond, oxalic, nitric acid, embonic, pantothenic, phosphoric, amber, sulphite, tartaric, oxalic, p-toluenesulphonic and the like, such as the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977), which article is hereby incorporated by reference.

Acid addition salts can be obtained as end products of compound synthesis. Alternatively, the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise by separating the salt and solvent.

It should be emphasized that according to the present invention, the hydrates or solvates of the invention are hydrates or solvates with traditional low molecular weight solvents prepared by any means known to those skilled in the art.

The compositions of the invention may be conveniently administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980).

The 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrates or solvates according to the invention may be present in pharmaceutical preparations as individual active agents or they may be used in combination with other active ingredients that may enhance the healing effect of the compound.

The 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrates or solvates of the present invention or their physiologically functional derivatives can be used as active ingredients of pharmaceutical compositions, in particular as 5HT2C receptor agonists. By the term active ingredient as defined in connection with the term pharmaceutical composition is meant a component of the pharmaceutical composition which provides a primary pharmaceutical benefit, as opposed to an inactive ingredient which could generally be recognized as being

Does not provide a pharmaceutical benefit. The term pharmaceutical composition should mean a composition comprising at least one active ingredient and at least one non-active ingredient (e.g., without limiting the active ingredient, a filler, dye, or sustained release agent) that makes the composition suitable for use in a specific period. long-lasting, effective recipients among mammals (for example, and not limited to humans).

The data presented herein support the claim that the 5HT2C receptor agonists presently disclosed have utility in the treatment or clinical prophylaxis of obesity or overweight disorders in mammals, including, but not limited to, humans. The 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrates or solvates of the present invention may be administered orally, sublingually, parenterally, rectally, topically or via a transdermal patch. The transdermal patches release the drug at a controlled rate by exposing the drug to absorption in an efficient manner with minimized drug degradation. Typically, the transdermal patches include an impermeable topsheet, a single pressure-sensitive adhesive, and a removable release liner. One skilled in the art will understand and appreciate techniques appropriate to the manufacture of the desired high-performance transdermal patches based on the needs of the skilled artisan.

Moreover, in addition to the neutral forms of the benzazepine derivatives of the present invention, physiologically acceptable salts of the compounds can also be formed and used as therapeutic agents by the appropriate addition of an ionized substituent which does not affect the specificity of the compound for the receptor. Different amounts of the benzazepine derivatives of the present invention will be required to achieve the desired biological effect. The amount will depend on factors such as the use for which the derivative of the invention is intended, the route of administration, and the condition of the patient to be treated - all of these dosage parameters are within the range that would be determinable by those of ordinary skill in the art of medicine. A typical dosage is expected to be between 0.001 and 200 mg per kilogram body weight of the mammal. Unit doses may contain from 1 to 200 mg of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrates or 8-chloro-1-methyl-2,3,4 solvates The 5-tetrahydro-1H-3-benzazepines of the present invention may be administered one or more times a day, singly or in multiple doses.

Pharmaceutical compositions include, but are not limited to, pharmaceutical compositions containing at least 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrate or solvate or an acceptable salt thereof as an active ingredient. (e.g., a pharmaceutically acceptable salt or solvate) of the present invention in association with at least one carrier or excipient (e.g., pharmaceutical carrier or excipient) and can be used to treat clinical conditions where a 5HT2C receptor agonist is indicated. The 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrates or solvates of the present invention may be combined with a carrier in solid or liquid form in preparing the dosage unit. The pharmaceutical carrier must be compatible with the other ingredients of the composition and must be compatible with the individual recipient. Other physiologically active ingredients may be incorporated into the pharmaceutical compositions of the invention, if desired, and when these ingredients are compatible with the other ingredients of the composition. The pharmaceutical preparations may be prepared by any suitable means, usually by uniformly mixing the active compound (s) with liquids or finely divided solid carrier, or both, in the desired proportions, and then shaping the resulting mixture into the desired shape if necessary.

Conventional excipients such as binders, fillers, acceptable wetting agents, tabletting lubricants, and disintegrants can be used for tablets and capsules for oral administration. Liquid pharmaceutical preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, pharmaceutical preparations for oral administration may be in the form of a dry powder which may be reconstituted with water or other suitable liquid carrier before use. Adjunctive additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring and coloring agents can be added to the liquid pharmaceutical preparations. Dosage forms for parenteral administration can be prepared by dissolving a compound of the invention in a suitable liquid carrier and sterilizing the solution by sterilizing filtration before filling and sealing appropriate vials or ampoules. These are merely individual examples of the numerous appropriate methods well known in the art for preparing dosage forms.

PL 211 333 B1

It has been found that when 5HT2C receptor agonists are used as active ingredients in a pharmaceutical composition, such compositions are intended not only for humans but also for other non-human mammals. In fact, recent efforts in the field of animal health care for the use of 5HT2C receptor agonists in the treatment of obesity in pets (e.g., cats and dogs), and the use of 5HT2C agonists in other domestic animals with the disease or disorder not affecting obesity. is obvious (e.g., farm animals such as cows, chickens, fish, etc.). All ordinary skilled artisans will come to terms easily with understanding the applicability of such a compound in such cases.

The benzazepine derivative hydrate or solvate of the present invention can be readily prepared according to a number of synthetic techniques, all of which should be known to those skilled in the art. Scheme I below gives an overview of the reactions that may be used in the synthesis of a hydrate or a solvate of a benzazepine derivative of the invention:

<img file="PL211333B1_D0002.tif" />

PL 211 333 B1

It will be understood by those skilled in the art that numerous other compounds disclosed herein, their salts, hydrates, and solvates of general formula Ia, which are the subject of separate applications, can also be prepared in accordance with Scheme I. For example, starting from a properly substituted 2-phenyl-ethylamino compound A having any of a variety of different R1 and R2 substituents, a 7- and / or 8-substituted compound-1-methyl-2,3,4,5 can be prepared, respectively. -tetrahydro-1H-3-benzazepine (compound H), including in particular the compound of the invention 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. N-alkylation can be performed by, for example, treatment with excess paraformaldehyde (for methylation) or a higher aldehyde followed by reduction of NaBH3CN according to the general procedure of Synthesis Examples 9 and 10, infra. In addition, starting from an appropriately substituted 1-alkyl-2-phenyl-ethylamino compound A having any of a variety of R1 and R2 substituents, a 7- and / or 8-substituted 2,5-dialkyl-2,3-compound can be prepared, respectively. , 4,5-tetrahydro-1H-3-benzazepine.

During the synthesis of the numerous compounds of general formula I disclosed herein, it may be required to protect multiple single or multiple functional groups disclosed in the preparation of a protecting group. exemplary protecting groups useful for a wide variety of synthetic transformations are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis, 2d ed, John Wiley &amp; Sons, New York, 1991, the disclosure of which is hereby incorporated by reference in its entirety. .

As will be appreciated by one skilled in the art, the steps of the methods need not be performed a particular number of times or in a particular sequence. Additional objects, advantages, and new features of the present invention will become apparent to those skilled in the art from reviewing the following examples, which are presented for illustrative purposes and are not intended to limit the invention.

Examples

Comparative examples of the synthesis of compounds of the general formula I.

Example 1: (R, S) 8-Bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Br

NH

MeO

N-trifluoroacetyl-3-methoxyphenethylamine

A solution of 3-methoxyphenethylamine (10.0 g, 64.0 mmol) in dichloromethane (150 ml) was cooled to 0 ° C, and treated with pyridine (6.5 ml, 83.5 mmol) followed by the dropwise addition of acetic trifluoranhydride (17 9 g, 83.5 mmol) and the resulting mixture was stirred for 3 hours while warming to 20 ° C. The resulting mixture was diluted with EtOAc (500 mL), washed sequentially with 10% aqueous HCl (100 mL), water (100 mL), brine (100 mL), dried with Na2SO4, and concentrated to give 15.8 g of a yellow oil. 1 H NMR (400 MHz, CDCl 3) d 7.26 (dd, J = 8.8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 6.72 (s, 1H), 6.30 (bs, 1H), 3.80 (s, 3H), 3.62 (dd, J = 7.7Hz, 2H), 2.86 ( dd, J = 7.7 Hz, 2H). MS calculated for C11H12F3NO2 + H: 248, recorded: 248.

N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-3-methoxyphenethylamine (15.8 g, 64 mmol) in methanol (325 mL) was cooled to -78 ° C, and treated with CaCO3 (14.7 g, 145 mmol) followed by a solution of ICl (29 g , 181 mmol) in methanol (40 mL). The reaction mixture was allowed to warm to 20 ° C with stirring overnight then filtered, concentrated, dissolved in EtOAc (200 mL), washed twice with 5% aqueous sodium bisulfate (100 mL), brine (100 mL), dried with Na2SO4 and concentrated to give 23.8 g of white solid powder. 1 H NMR (400 MHz, CDCl 3) d 7.68 (d, J = 9 Hz, 1H), 6.76 (s, 1H), 6.57 (d, J = 9 Hz, 1H), 6.42 ( bs, 1H), 3.77 (s, 3H), 3.61 (dd, J = 7.7 Hz, 2H), 2.99 (dd, J = 7.7 Hz, 2H). MS calculated for C11H11F3INO2 + H: 374, recorded: 374.

N-Allyl N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (23.8 g, 63.8 mmol) in toluene (425 mL) was sequentially treated with K2CO3 (12.4 g, 89.8 mmol), KOH (11.6 g, 207 mmol), n-Bu4NBr (2.2 g, 6.9 mmol) and allyl bromide (10.7 g, 89.8 mmol). The mixture was stirred at 80 ° C for 3.5 hours, cooled to 20 ° C, acidified with 10% aqueous HCl, separated and the aqueous phase was extracted with ether (500 ml). The combined organic phase was washed with brine (200 mL), dried with Na2SO4, and concentrated to give 20.5 g of a brown oil. 1 H NMR (400 MHz, CDCl 3), mixed rotamers d 7.67 (m, 1H), 6.80 (m, 1H), 6.57 (m, 1H), 5.9-5.6 (bm, 1H ), 5.27 (m, 2H), 4.11 (d, J = 6Hz, 0.5H), 3.85 (d, J = 6Hz, 0.5H), 3.77 (m , 3H), 3.55 (m, 2H), 3.00 (m, 2H). MS calculated for C14H15F3INO2 + H: 414, recorded: 414.

N-trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-allyl, N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (20.5 g, 50 mmol) in dimethylformamide (250 mL) was treated with KOAc (14.6 g, 149 mmol), n-Bu4NBr (16.0 g, 50 mmol), PPh3 (1.3 g, 5.0 mmol), Pd (OAc) 2 (0.56 g, 2.5 mmol) and stirred overnight at 90 &amp; lt; 0 &amp; gt; C. The resulting mixture was cooled to 20 ° C, filtered, diluted with water (500 ml) and extracted with ether (3 x 500 ml). The combined organic phases were washed with water (100 ml), brine (100 ml), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexane, silica gel) gave 6.6 g of a yellow oil. 1 H NMR (400 MHz, CDCl 3) d 7.26 (d, J = 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 6.66 (s, 1H), 5.34- 5.19 (m, 2H), 4.40 (m, 2H), 3.83 (m, 2H), 3.80 (s, 3H), 3.00 (m, 2H). MS calculated for C14H14F3NO2 + H: 285, recorded: 285.

N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Solution of N-trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-trihydro-1H-3-benzazepine (6.6 g,

23.2 mmol) in ethanol (100 ml), treated with 10% Pd / C (0.75 g, 2.3 mmol) and stirred overnight under a hydrogen atmosphere. The resulting mixture was filtered through celite and silica gel, and the solvent was removed to give 6.27 g of a white solid. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.10 (m, 1H), 6.74 (m, 1H), 6.68 (m, 1H), 4.1-3.8 (bm, 2H ), 3.8 (s, 3H), 3.5 (m, 1.5H), 3.4 (m, 0.5H), 3.2-2.9 (bm, 4H), 1, 32 (m, 3H). MS calculated for C14H16F3NO2 + H: 288, recorded: 288.

N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.25 g, 4.35 mmol) in acetonitrile (40 mL) was treated with N-bromosuccinimide ( 0.852 g, 4.79 mmol) and stirred overnight at 20 ° C. The resulting mixture was diluted with EtOAc (200 mL), washed with saturated aqueous sodium bisulfite (100 mL) and brine (100 mL), dried with Na2SO4, and concentrated. Equilibrium chromatography (15% EtOAc in hexane, silica gel) gave 1.55 g of pure oil. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.34 (s, 1H), 6.65 (m, 1H), 3.87 (s, 3H), 3.81 (m, 1H), 3. 55 (m, 1.3H), 3.37 (m, 0.7H), 3.2-2.9 (bm, 4H), 1.30 (m, 3H). MS calculated for C14H15BrF3NO2 + H: 366, recorded: 366.

8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.95 g, 2.59 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (25 mL), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4, and concentrated to give 0.687 g of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.92 (s, 1H), 6.34 (s, 1H), 3.87 (s, 3H), 3.1-2.9 (m, 6H), 2 , 75 (m, 1H), 2.60 (bs, 1H), 1.31 (d, J = 7Hz, 3H). MS calculated for C12H16BrNO + H: 270, registered: 270.

Example 2: (R, S) 8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0003.tif" />

N-trifluoroacetyl- 8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.900 g,

2.67 mmol) in acetonitrile (30 ml) treated with N-chlorosuccinimide (0.357 g, 2.67 mmol) and stirred overnight at 70 ° C. The resulting mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4, and concentrated. Equilibrium chromatography (20% EtOAc in hexane, silica gel) gave 0.399 g of pure oil. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.17 (s, 1H), 6.68 (m, 1H), 3.88 (s, 3H), 3.78 (m, 1H), 3. 6-3.3 (m, 2H), 3.2-2.9 (m, 4H), 1.34 (m, 3H). MS calculated for C14H15CIF3NO2 + H: 322, recorded: 322.

8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.399 g, 1.24 mmol) in methanol (20 ml) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (100 mL), extracted twice with EtOAc

(100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.306 g of a yellow solid. 1 H NMR (400 MHz, CDCl 3) d 7.05 (s, 1H), 6.59 (s, 1H), 3.80 (s, 3H), 3.0-2.8 (m, 6H), 2 , 62 (m, 1H), 2.16 (bs, 1H), 1.24 (d, J = 7Hz, 3H). MS calculated for C12H16CINO + H: 226, recorded: 226.

Example 3: (R, S) 8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0004.tif" />

N-trifluoroacetyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4 solution, 5-tetrahydro-1H-3-benzazepine (1.50 g, 5.22 mmol) in methanol (70 ml) was treated with CaCO3 (1.06 g, 10.44 mmol) followed by ICl solution (1.70 g, 10 , 44 mmol) in methanol (10 ml), and stirred overnight at 20 ° C. The resulting mixture was filtered, concentrated, dissolved in EtOAc (200 mL), extracted twice with 5% aqueous sodium bisulfite (100 mL), then with brine (100 mL), dried with Na2SO4, and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 1.54 g of a white solid. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.55 (m, 1H), 6.57 (m, 1H), 3.86 (s, 3H), 3.80 (m, 1H), 3. 60-3.30 (m, 2H), 3.20-2.80 (m, 4H), 1.30 (m, 3H). MS calculated for C14H15F3INO2 + H: 414, recorded: 414.

8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Solution of N-trifluoroacetyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.600 g,

1.45 mmol) in methanol (20 ml) treated with 15% aqueous NaOH (20 ml), and stirred for 3 hours at 50 ° C. The resulting mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4, and concentrated to give 0.425 g of a yellow solid. 1 H NMR (400 MHz, CDCl 3) d 7.52 (s, 1H), 6.57 (s, 1H), 3.86 (s, 3H), 3.12-3.06 (m, 4H), 2.95 (m, 2H), 2.75 (m, 1H), 2.43 (bs, 1H), 1.33 (d, J = 8Hz, 3H). MS calculated for C12H16INO + H: 318, registered: 318.

Example 4: (R, S) 8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0005.tif" />

N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine For N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2 solution , 3,4,5-tetrahydro-1H-3-benzazepine (1.50 g, 4.10 mmol) in dichloromethane (80 ml) was added dropwise BBr3 (9.4 ml 1.0M solution in CH2Cl2, 9.4 mmol ), and the mixture was stirred overnight while warming to 20 ° C. The excess BBr3 was taken up by dropwise addition of water, the mixture was diluted with ether (200 ml), washed with Na2CO3 (100 ml) and brine (100 ml), dried with Na2SO4 and concentrated. Equilibrium chromatography (15% EtOAc in hexane, silica gel) gave a 1.25 g of a white solid foam. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.25 (s, 1H), 6.79 (m, 1H), 3.79 (m, 1H), 3.7-3.3 (m, 2H ), 3.2-2.8 (m, 4H), 1.32 (m, 3H).

8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.655 g, 1.89 mmol) in methanol (20 ml) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.460 g of pure oil. 1H NMR (400MHz, DMSO-d6) d 7.11 (s, 1H), 6.65 (s, 1H), 2.90 (m, 1H), 2.73 (m, 5H), 2.55 (m, 1H). 1.19 (d, J = 7Hz, 3H). MS calculated for C11H14BrNO + H: 256, recorded: 256.

PL 211 333 B1

Example 5: (R, S) 7-allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

NH

N-trifluoroacetyl-7-allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.150 g, 0.426 mmol) in dichloromethane (5 mL) was treated with allyl bromide (0.155 g, 1.28 mmol) and DBU (0.195 g, 1.28 mmol) followed by stirring for 2 hours at 20 ° C. The resulting mixture was diluted with EtOAc (50 mL), washed with 5% aqueous HCl (20 mL), brine (20 mL), dried with Na2SO4, and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 0.149 g of pure oil. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.34 (s, 1H), 6.65 (m, 1H), 6.04 (m, 1H), 5.47 (d, J = 17Hz, 1H), 5.30 (d, J = 9Hz, 1H), 4.59 (s, 2H), 3.80 (m, 1H), 3.6-3.3 (m, 3H), 3, 2-2.8 (m, 4H), 1.31 (m, 3H). MS calculated for C16H17BrF3NO2 + H: 392, recorded: 392.

7-allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.18 g, 3.00 mmol) in methanol (35 mL) was treated with 15% aqueous NaOH (35 mL), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (200 mL), extracted twice with EtOAc (200 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4, and concentrated to give 0.880 g of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.29 (s, 1H), 6.63 (s, 1H), 6.04 (m, 1H), 5.47 (d, J = 17Hz, 1H), 5.29 (d, J = 11 Hz, 1H), 4.58 (s, 2H), 3.01 (m, 3H), 2.89 (m, 3H), 2.75 (m, 1H), 1.31 (d, J = 7 Hz, 3H). MS calculated for C14H18BrNO + H: 296, recorded: 296.

Example 6: (R, S) 7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

NH

N-trifluoroacetyl-7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.075 g, 0.213 mmol) in dichloromethane (5 mL) was treated with benzyl bromide (0.072 g, 0.64 mmol), DBU (0.100 g, 0.64 mmol), and stirred 2 hours at 20 ° C. The resulting mixture was diluted with EtOAc (50 mL), washed with 5% aqueous HCl (20 mL), brine (20 mL), dried with Na2SO4, and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 0.081 g of pure oil. MS calculated for C20H19BrF3NO2 + H: 442, recorded: 442.

7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.81 g, 1.83 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (200 mL), extracted twice with EtOAc (200 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.412 g of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.38 (d, J = 8 Hz, 2H), 7.30 (dd, J = 7.8 Hz, 2H), 7.23 (m, 2H), 6, 61 (s, 1H), 5.03 (s, 2H), 2.94 (m, 3H), 2.81 (m, 3H), 2.62 (m, 1H), 2.30 (bs, 1H ), 1.24 (d, J = 7Hz, 3H). MS calculated for C18H20BrNO + H: 346, registered: 346.

Example 7: (R, S) 8-Bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

NH

PL 211 333 B1

N-trifluoroacetyl-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.015 g, 0.043 mmol) in dichloromethane (1 mL) was treated with ethyl iodide (0.016 g, 0.102 mmol), DBU (0.016 g, 0.102 mmol) and stirred for 2 hours at 20 ° C. The resulting mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4, and concentrated. Equilibrium chromatography (15% EtOAc in hexane, silica gel) gave 0.010 g of pure oil.

8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.010 g, 0.026 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 ml), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (3 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (3 mL), dried with Na2SO4, and concentrated to give 0.007 g of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.29 (s, 1H), 6.63 (s, 1H), 4.07 (q, J = 6 Hz, 2H), 3.03 (m, 3H), 2.91 (m, 3H), 2.73 (m, 1H), 2.26 (bs, 1H), 1.46 (t, J = 6Hz, 3H), 1.32 (d, J = 7 Hz, 3H). MS calculated for C15H17BrF3NO2 + H: 380, recorded: 380.

Example 8: (R, S) 8-Bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0006.tif" />

N-trifluoroacetyl-8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2 solution, 3,4,5-tetrahydro-1H-3-benzazepine (0.035 g, 0.099 mmol) in dichloromethane (1 ml) was treated with isopropyl bromide (0.037 g, 0.297 mmol), DBU (0.048 g, 0.205 mmol) and stirred for 2 hours in 20 ° C. The resulting mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4, and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 0.014 g of pure oil. MS calculated for C16H19BrF3NO2 + H: 394, registered: 394.

8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.014 g, 0.035 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 ml), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (3 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (3 mL), dried with Na2SO4, and concentrated to give 0.008 g of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.24 (s, 1H), 6.64 (s, 1H), 4.48 (m, 1H), 2.98 (m, 3H), 2.87 (m , 3H), 1.36 (m, 6H), 1.30 (d, J = 7Hz, 3H). MS calculated for C14H20BrNO + H: 298, registered: 298.

Example 9: (R, S) N-Methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0007.tif" />

A solution of 8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (6 mg, 0.022 mmol) in methanol (1 mL) was treated with excess paraformaldehyde, 1.0 M HCl in ether (0.004 mL, 0.004 mmol), NaBH3CN (1.0 mg, 0.013 mmol), and stirred overnight at 20 ° C. The resulting mixture was diluted with 5% aqueous NaOH (5 mL), extracted 3 times with CH2Cl2 (5 mL each time), the combined organic phases were dried with Na2SO4 and concentrated. Flash chromatography (10% MeOH in CH2Cl2, silica gel) gave 5 mg of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.31 (s, 1H), 6.66 (s, 1H), 3.87 (s, 3H), 3.26 (bm, 2H), 3.01 (bs , 1H), 2.85 (m, 2H), 2.45 (s, 3H), 2.45-2.25 (m, 2H), 1.36 (d, J = 7Hz, 3H). MS calculated for C13H18BrNO + H: 284, registered: 284.

PL 211 333 B1

Example 10: (R, S) N-propyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0008.tif" />

A solution of 8-bromo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine (6 mg, 0.022 mmol) in methanol (1 mL) was treated with propionaldehyde (5.0 mg, 0.067 mmol), 1.0 M HCl in ether (0.004 mL, 0.004 mmol), NaBH3CN (1.0 mg, 0.013 mmol), and stirred overnight at 20 ° C. The resulting mixture was diluted with 5% aqueous NaOH (5 mL), extracted 3 times with CH2Cl2 (5 mL each time), the combined organic phases were dried with Na2SO4 and concentrated. Flash chromatography (10% MeOH in CH2Cl2, silica gel) gave 4 mg of pure oil. 1 H NMR (400 MHz, CD 3 OD) d 7.33 (s, 1H), 6.87 (s, 1H), 3.84 (s, 3H), 3.25 (m, 2H), 3.11 (m , 2H), 2.97 (m, 1H), 2.78 (bm, 2H), 2.63 (bm, 2H), 1.67 (m, 2H), 1.38 (d, J = 7 Hz, 3H), 0.96 (t, J = 7Hz, 3H). MS calculated for C15H22BrNO + H: 312, registered: 312.

Example 11: (R, S) 7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0009.tif" />

N-trifluoroacetyl -7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (80 mg, 0.19 mmol) in dichloromethane (3 mL) was treated with BBr3 ( 0.40 ml of a 1.0M solution in CH2Cl2, 0.40 mmol) and stirred overnight at 20 ° C. Excess BBr3 was taken up with water and the resulting mixture was diluted with ether (20 mL), washed with Na2CO3 (10 mL) and brine (10 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 74 mg of a white solid. MS calculated for C13H13F3INO2 + H: 400, recorded: 400.

7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-henzazepine

A solution of N-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (25 mg, 0.063 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 ml), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4, and concentrated to give 13 mg of a white solid. 1 H NMR (400 MHz, CD 3 OD) d 7.46 (s, 1H), 6.64 (s, 1H), 3.16 (m, 3H), 2.94 (m, 3H), 2.81 (m , 1H). 1.35 (d, J = 7Hz, 3H). MS calculated for C11H14INO + H: 304, registered: 304.

Example 12: (R, S) 7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0010.tif" />

N-trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (30 mg, 0.075 mmol) in dichloromethane (2 mL) was treated with allyl bromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred for 2 hours at 20 ° C. The resulting mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4, and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 23 mg of pure oil. MS calculated for C16H17F3INO2 + H: 440, recorded: 440.

7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-henzazepine

A solution of N-trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (23 mg, 0.058 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for

Overnight at 20 ° C. The resulting mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4, and concentrated to give 18 mg of a white solid. MS calculated for C14H18INO + H: 344, registered: 344.

Example 13: (R, S) 3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptainden

ΝΗ

N-trifluoroacetyl-3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptainden

A solution of N-trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (158 mg, 0.360 mmol) in dimethylformamide (4 mL) was treated with KOAc (106 mg , 1.08 mmol), n-Bu4NBr (116 mg, 0.360 mmol), PPh3 (13 mg, 0.036 mmol), Pd (OAc) 2 (4 mg, 0.018 mmol) and stirred overnight at 100 ° C. The resulting mixture was filtered, water (10 mL) was added then extracted twice with EtOAc (10 mL). The combined organic phases were washed with brine (10 mL), dried with Na2SO4, and concentrated. Flash chromatography (5% EtOAc in hexane, silica gel) gave 15 mg of pure oil. MS calculated for C16H16F3NO2 + H: 312, recorded: 312.

3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptainden

A solution of N-trifluoroacetyl-3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptainden (15 mg, 0.048 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 ml), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 10 mg of a white solid. 1 H NMR (400 MHz, CDCl 3) d 7.25 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 3.12 (m, 1H), 2.97 (m , 4H), 2.85 (m, 1H), 2.64 (bm, 1H), 2.15 (s, 3H), 1.34 (d, J = 8Hz, 3H). MS calculated for C14H17NO + H: 216, registered: 216.

Example 14: (R, S) 7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

ΝΗ

N-trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (48 mg, 0.15 mmol) in dichloromethane (2 mL) was treated with BBr3 ( 0.30 ml of a 1.0M solution in CH2Cl2, 0.30 mmol) and stirred overnight at 20 ° C. Excess BBr3 was taken up with water and the resulting mixture was diluted with ether (20 mL), washed with Na2CO3 (10 mL) and brine (10 mL), dried with Na2SO4 and concentrated. Equilibrium chromatography (15% EtOAc in hexane, silica gel) gave 24 mg of a white solid. MS calculated for C13H13CIF3NO2 + H: 308, recorded: 308.

N-trifluoroacetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (24 mg, 0.078 mmol) in dichloromethane (2 mL) was treated with allyl bromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred for 2 hours at 20 ° C. The resulting mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4, and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 23 mg of a white solid. MS calculated for C16H17CIF3NO2 + H: 348, recorded: 348.

7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-henzazepine

Solution of N-trifluoroacetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (23 mg,

0.066 mol) in methanol (2 ml) was treated with 15% aqueous NaOH (2 ml), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4, and concentrated to give 19 mg of a white solid. 1 H NMR (400 MHz, CD 3 OD) d 7.12 (s, 1H), 6.81 (s, 1H), 6.03 (m, 1H), 5.43 (d, J = 17Hz, 1H), 5.24 (d, J = 10 Hz, 1H), 4.57 (d, J = 5 Hz, 2H), 3.1-2.9 (m, 5H), 2.81 (m, 1H), 2.63 (m, 1H), 1.30 (d, J = 7Hz, 3H).

PL 211 333 B1

Example 15: (R, S) 7-methoxy-1-methyl-8- (2-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0011.tif" />

N-trifluoroacetyl-7-methoxy-1-methyl-8- (2-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluoromethylacetyl-8-bromo-7-methoxy-1- solution methyl-1,2,4,5-tetrahydro-3H-3-benzazepine (51 mg, 0.14 mmol) in 1,4-dioxane (2 mL) was treated with thiophenyl-2-boronic acid (36 mg, 0.28 mmol), K2CO3 (58 mg, 0.42 mmol), water (0.1 ml), Pd (PPh3) 4 (16 mg, 0.014 mmol) and stirred overnight at 100 &amp; lt; 0 &amp; gt; C. The resulting mixture was diluted with EtOAc, filtered, adsorbed onto silica gel, and purified by flash chromatography (10% EtOAc in hexane, silica gel) to provide 28 mg of a yellow solid. MS calculated for C18H18F3NO2S + H: 370, recorded: 370.

7-methoxy-1-methyl-8- (2-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-7-methoxy-1-methyl-8- (2-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (28 mg, 0.076 nmol) in methanol (2 ml) was treated with 15% aqueous NaOH (2 mL), and stirred for 0.5 hours at 50 ° C. The resulting mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4, and concentrated to give 18 mg of a yellow oil. 1 H NMR (400 MHz, CDCl 3) d 7.45 (d, J = 4 Hz, 1H), 7.39 (s, 1H), 7.27 (d, J = 6 Hz, 1H), 7.07 ( dd, J = 4.6 Hz, 1H), 6.71 (s, 1H), 3.90 (s, 3H), 3.1-2.9 (m, 6H), 2.80 (m, 1H ), 2.22 (bs, 1H), 1.38 (d, J = 7Hz, 3H). MS calculated for C16H19NOS + H: 274, registered: 274.

Example 16: (R, S) 8-Cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0012.tif" />

N-trifluoroacetyl-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2 solution, 3,4,5-tetrahydro-1H-3-benzazepine (18mg, 0.05mmol) in dimethylformamide (1ml) was treated with CuCN (20mg, 0.24mmol) and the mixture was microwaved at 200 ° C for 0. 5 hours. The resulting mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4, and concentrated. Flash chromatography (35% EtOAc in hexane, silica gel) gave 10 mg of pure oil. MS calculated for C15H15F3N2O2 + H: 313, registered: 313.

3-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (10 mg, 0.032 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 ml), and stirred for 1 hour at 50 ° C. The resulting mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 6.0 mg of a white solid. 1 H NMR (400 MHz, CD 3 OD) d 7.33 (s, 1H), 6.93 (s, 1H), 3.91 (s, 3H), 3.18-2.97 (m, 5H), 2 , 80 (m, 1H), 2.60 (m, 1H), 1.33 (d, J = 8Hz, 3H). MS calculated for C13H16N2O + H: 217, registered: 217.

Example 17: (R, S) 8-Bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0013.tif" />

N-trifluoroacetyl-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine A solution of diethyl zinc (1 mL, 1 M in hexane) in dichloromethane (1 mL) at 0 ° C treated with acid trifluoroacetic acid in dichloromethane (0.5 ml) and the mixture was stirred for 15 min. Then

Diiodomethane (0.280 g, 1.0 mmol) in dichloromethane (0.5 ml) was added and the mixture was stirred for 15 minutes. N-trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (0.075 g, 0.26 mmol) in dichloromethane (1 ml) was added and the mixture was stirred for 30 minutes at 0 ° C followed by 2 hours at 20 ° C. The resulting mixture was taken up with aqueous saturated NH4Cl (5 mL), extracted twice with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 (10 mL), washed with H2O (10 mL), and concentrated. Flash chromatography (7% EtOAc in hexane, silica gel) gave 0.050 g of a white solid. MS calculated for C15H16F3NO2 + H: 300, recorded: 300.

N-trifluoroacetyl-8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluoroacetyl-1-cyclopropyl-7-methoxy-2,3,4 solution, 5-tetrahydro-1H-3-benzazepine (0.025 g,

0.08 mmol) in acetonitrile (1 ml) was treated with N-bromosuccinimide (0.032 g, 0.18 mmol) and stirred for 2 hours at 50 ° C. The resulting mixture was concentrated then purified by flash chromatography (10% EtOAc in hexane, silica gel) to give 0.014 g of a white solid. MS calculated for C15H15BrF3NO2 + H: 378, recorded: 378.

8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.014 g, 0.037 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 ml), and stirred for 2 hours at 50 ° C. The resulting mixture was diluted with brine (10 mL), extracted twice with EtOAc (10 mL), dried with MgSO4, and concentrated to give 0.008 g of pure oil. 1 H NMR (400 MHz, CD 3 OD) d 7.26 (s, 1H), 6.78 (s, 1H), 3.83 (s, 3H), 3.02 (m, 2H), 2.92 (m , 2H), 2.67 (s, 2H), 0.91 (m, 2H), 0.85 (m, 2H). MS calculated for C13H16BrNO + H: 282, registered: 282.

Example 18: (R, S) 8-Bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0014.tif" />

N-trifluoroacetyl-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

Solution of N-trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (0.100 g,

0.35 mmol) in tetrahydrofuran (1 mL) was treated with a solution of BH3-THF complex compound (0.36 mL, 1 M in THF), and stirred for 30 minutes at 20 ° C. Then water (0.5 ml), saturated aqueous NaHCO3 (0.5 ml), and 30% H2O2 (0.2 ml) were successively added and the reaction mixture was stirred for 30 minutes at 20 ° C. The resulting mixture was diluted with EtOAc (10 mL), washed with brine (10 mL), and concentrated. Flash chromatography (33% EtOAc in hexane, silica gel) gave 0.035 g of pure oil. MS calculated for C14H16F3NO3 + H: 304, registered: 304.

N-trifluoroacetyl-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluoromethylacetyl-1-hydroxymethyl-7-methoxy-2,3,4 solution, 5-tetrahydro-1H-3-benzazepine (0.035 g, 0.12 mmol) in acetonitrile (1 ml) was treated with N-bromosuccinimide (0.025 g, 0.14 mmol), and stirred for 30 minutes at 20 ° C. The resulting mixture was concentrated then purified by flash chromatography (33% EtOAc in hexane, silica gel) to give 0.019 g of pure oil. MS calculated for C14H15BrF3NO3 + H: 382, ​​recorded: 382.

8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.009 g, 0.024 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 ml), and stirred for 1 hour at 50 ° C. The resulting mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.006 g of pure oil. 1 H NMR (400 MHz, CD 3 OD) d 7.28 (s, 1H), 6.79 (s, 1H), 3.84 (m, 2H), 3.0-2.8 (m, 7H). MS calculated for C12H16BrNO2 + H: 286, recorded: 286.

PL 211 333 B1

Example 19: (R, S) 8-Bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0015.tif" />

N-crotyl N-trifluoroacetyl-2-iodo-5-methoxy-phenethylamine

A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (6.68 g, 17.9 mmol) in toluene (100 mL) was treated with K2CO3 (3.22 g, 23.3 mmol), KOH (3.01 g, 53.7 mmol), n-Bu4NBr (0.580 g, 1.80 mmol) and crotyl bromide (3.15 g, 23.3 mmol). The mixture was stirred at 75 ° C for 16 hours, cooled to 20 ° C, diluted with Et 2 O (500 ml), washed with 10% aqueous HCl (500 ml) and concentrated. Equilibrium chromatography (10% EtOAc in hexane, silica gel) gave 5.22 g of pure oil. MS calculated for C15H17F3INO2 + H: 428, recorded: 428.

N-trifluoroacetyl-1-ethylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-crotyl N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (5.20 g, 12.2 mmol) in dimethylformamide (80 mL) was treated with KOAc (3.59 g, 36.6 mmol), n-Bu4NBr ( 3.93 g, 12.2 mmol), PPh3 (0.320 g, 1.22 mmol), Pd (OAc) 2 (0.137 g, 0.61 mmol) and stirred overnight at 90 ° C. The resulting mixture was cooled to 20 ° C, diluted with water (200 mL), extracted twice with ether (500 mL), the combined organic phases were washed twice with brine (200 mL), and concentrated. Flash chromatography (10% EtOAc in hexane, silica gel) gave 2.29 g of a pure oil that was composed of a mixture of olefinic isomers. MS calculated for C15H16F3NO2 + H: 300, recorded: 300.

N-trifluoroacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-henzazepine

Solution of N-trifluoroacetyl-1-ethylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2.29 g,

7.65 mmol) in methanol (100 ml) was treated with 10% Pd / C (4.0 g, 0.77 mmol)) and stirred overnight under a hydrogen atmosphere. The resulting mixture was filtered over celite and silica gel, and the solvent was removed to give 2.14 g of pure oil. MS calculated for C15H18F3NO2 + H: 302, recorded: 302.

N-trifluoroacetyl-8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

Solution of N-trifluorolacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.710 g,

2.36 mmol) in acetonitrile (20 mL) was treated with N-bromosuccinimide (0.504 g, 2.83 mmol), and stirred overnight at 20 ° C. The resulting mixture was concentrated, diluted with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated. Flash chromatography (10% EtOAc in hexane, silica gel) gave 0.561 g of pure oil. MS calculated for C15H17BrF3NO2 + H: 380, recorded: 380.

8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.561 g, 1.48 mmol) in methanol (30 ml) was treated with 15% aqueous NaOH (30 mL), and stirred overnight at 20 ° C. The resulting mixture was diluted with brine (100 mL), extracted twice with EtOAc (200 mL), dried with MgSO4, and concentrated to give 0.412 g of pure oil. 1 H NMR (400 MHz, CD 3 OD) d 7.24 (s, 1H), 6.76 (s, 1H), 3.83 (s, 3H), 3.02 (m, 3H), 2.91 (s , 1H), 2.85-2.76 (m, 3H), 2.63 (m, 1H), 1.78 (m, 1H), 1.72 (m, 1H), 0.94 (dd, J = 8.8 Hz, 3H). MS calculated for C13H18BrNO + H: 284, registered: 284.

Example 20: (R, S) 8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0016.tif" />

N-trifluoroacetyl-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-henzazepine

Solution of N-trifluorolacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.600 g,

1.99 mmol) in acetonitrile (20 mL) was treated with N-chlorosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 60 ° C. The resulting mixture was concentrated, diluted with EtOAc (100 mL), washed

Water (50 ml) and brine (50 ml), dried with Na2SO4 and concentrated. Flash equilibrium chromatography (10% EtOAc in hexane, silica gel) gave 0.421 g of pure oil. MS calculated for C15H17CIF3NO2 + H: 336, recorded: 336.

8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.421 g, 1.25 mmol) in methanol (30 ml) was treated with 15% aqueous NaOH (30 mL), and stirred overnight at 20 ° C. The resulting mixture was diluted with brine (100 mL), extracted twice with EtOAc (200 mL), dried with MgSO4, and concentrated to give 0.241 g of pure oil. 1 H NMR (400 MHz, CD 3 OD) d 7.05 (s, 1H), 6.79 (s, 1H), 3.84 (s, 3H), 3.03 (m, 3H), 2.91 (s , 1H), 2.86-2.76 (m, 3H), 2.64 (m, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 0.93 (dd, J = 8.8 Hz, 3H). MS calculated for C13H18CINO + H: 240, recorded: 240.

Example 21: (R, S) 8-Bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

Br.

NH

MeO '

N- (3-methylbut-2-enyl), N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (0.700 g, 1.88 mmol) in toluene (25 mL) was treated with K2CO3 (0.340 g, 2.4 mmol), KOH (0.210 g, 3.76 mmol), n-Bu4NBr (0.060 g, 0.19 mmol) and 4-bromo-2-methyl-2-butene (0.364 g, 2.44 mmol). The mixture was stirred at 80 ° C for 3 hours, cooled to 20 ° C, diluted with ether (100 ml), washed with 10% HCl (50 ml) and concentrated. Flash chromatography (10% EtOAc in hexane, silica gel) gave 0.272 g of pure oil. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.65 (m, 1H), 6.75 (m, 1H), 6.54 (m, 1H), 5.20 (m, 4H), 5. 0 (m, 6H), 4.10 (m, 1H), 3.82 (m, 1H), 3.76 (d, 2H), 3.50 (m, 2H), 3.02 (m, 2H), 1.75 (m, 3H), 1.66 (m, 3H).

N-trifluoroacetyl-1-isopropylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

Solution of N- (3-methylbut-2-enyl) N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (0.272 g,

0.62 mmol) in dimethylformamide (12 ml) treated with KOAc (0.183 g, 1.86 mmol), n-Bu4NBr (0.200 g, 0.062 mmol), PPh3 (0.016 g, 0.062 mmol), Pd (OAc) 2 (0.183 g, 1.86 mmol) and stirred overnight at 90 ° C. The resulting mixture was cooled to 20 ° C, diluted with water (50 mL), extracted twice with ether (50 mL), the combined organic phases were washed with brine (50 mL), and concentrated. Flash chromatography (10% EtOAc in hexane, silica gel) gave 0.096 g of pure oil. MS calculated for C16H18F3NO2 + H: 314, registered: 314.

N-trifluoroacetyl-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

Solution of N-trifluoroacetyl-1-isopropylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.096 g,

0.31 mmol) in ethanol (2 ml) was treated with 10% Pd / C (0.033 g, 0.031 mmol)) and stirred overnight under a hydrogen atmosphere. The resulting mixture was filtered through celite and silica gel, and the solvent was removed to yield 0.091 g of pure oil. MS calculated for C16H20F3NO2 + H: 316, recorded: 316.

N-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluorolacetyl-1-isopropyl-7-methoxy-2,3,4 solution, 5-tetrahydro-1H-3-benzazepine (0.091 g,

0.29 mmol) in acetonitrile (3 mL) was treated with N-bromosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 20 ° C. After removal of the solvent, flash chromatography (10% EtOAc in hexane, silica gel) gave 0.056 g of pure oil. MS calculated for C16H19BrF3NO2 + H: 394, registered: 394.

8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.013 g, 0.03 mmol) in methanol (0.5 mL) was treated with 15% aqueous NaOH (0.5 mL), and stirred overnight at 20 ° C. The resulting mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.10 g of pure oil. 1 H NMR (400 MHz, CD 3 OD) d 7.08 (s, 1H), 6.64 (s, 1H), 3.72 (s, 3H), 3.2-3.10 (m, 3H), 2 , 7-2.5 (m, 3H), 2.3-2.1 (m, 2H), 0.96 (d, 3H), 0.63 (d, 3H). MS calculated for C14H20BrNO + H: 298, registered: 298.

PL 211 333 B1

Example 22: (R, S) 8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0017.tif" />

N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2 solution, 3,4,5-tetrahydro-1H-3-benzazepine (0.041 g, 0.10 mmol) in dichloromethane (1 mL) was treated with BBr3 (0.32 mL, 1.0 M solution in CH2Cl2) and stirred overnight at 20 ° C. Excess BBr3 was taken up with water and the resulting mixture was diluted with ether (50 mL), washed twice with saturated aqueous Na2CO3 (20 mL), and concentrated. Flash chromatography (20% EtOAc in hexane, silica gel) gave 0.037 g of pure oil. MS calculated for C15H17BrF3NO2 + H: 380, recorded: 380.

8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.018 g, 0.047 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 ml), and stirred for 3 hours at 50 ° C. The resulting mixture was adjusted to pH 7-8 with 10% aqueous HCl, extracted three times with EtOAc (50 mL), dried with MgSO4, and concentrated to give 0.013 g of a white solid. 1H NMR (400MHz, CD3OD) d 7.10 (s, 1H), 6.60 (s, 1H), 3.30 (m, 1H), 3.2-3.0 (m, 2H), 2, 78 (m, 1H), 2.7-2.5 (m, 2H), 2.3-2.1 (m, 2H), 1.05 (d, 3H), 0.73 (d, 3H) . MS calculated for C13H18BrNO + H: 284, registered: 284.

Example 23: (R, S) 7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0018.tif" />

N-trifluoroacetyl-7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-henzazepine

A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.017 g, 0.045 mmol) in dichloromethane (1 mL) was treated with N 'triamide '-tert-butyl-N, N, N', N ', N' ', N' '- hexamethylphosphorimide (0.016 g, 0.068 mmol), allyl bromide (0.011 g, 0.09 mmol) and stirred for 3 hours in 20 ° C. The resulting mixture was diluted with 10% aqueous HCl, extracted twice with dichloromethane (20 mL), and concentrated. Flash chromatography (10% EtOAc in hexane, silica gel) gave 0.011 g of pure oil. MS calculated for C18H21BrF3NO2 + H: 420, recorded: 420.

7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.011 g, 0.026 mmol) in methanol (0.5 mL) was treated with 15% aqueous NaOH (0.5 mL), and stirred for 3 hours at 50 ° C. The resulting mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.010 g of pure oil. 1 H NMR (400 MHz, CD 3 OD) d 7.09 (s, 1H), 6.62 (s, 1H), 5.94 (m, 1H), 5.32 (dd, 1H), 5.12 (dd , 1H), 4.46 (d, 2H), 3.19 (m, 1H), 3.05 (m, 2H), 2.66 (m, 1H), 2.5 (bm, 2H), 2 , 3-2.1 (m, 2H), 0.95 (d, 3H), 0.63 (d, 3H). MS calculated for C16H22BrNO + H: 324, registered: 324.

Example 24: 8-Bromo-7-methoxy-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0019.tif" />

N-trifluoroacetyl-1- (3-methoxyphenyl) -2-propylamine

PL 211 333 B1

A solution of 1- (3-methoxyphenyl) -2-propylamine (3.59 g, 21.7 mmol) in dichloromethane (75 ml) at 0 ° C, treated with pyridine (2.1 ml, 28.2 mmol), trifluoroacetic anhydride (5.9 g, 28.2 mmol) then stirred for 3 hours while warming to 20 ° C. The resulting mixture was diluted with EtOAc (300 mL), washed sequentially with 10% aqueous HCl (100 mL), water (100 mL), brine (100 mL), dried with Na2SO4, and concentrated. Equilibrium chromatography (20% EtOAc in hexane, silica gel) gave 4.29 g of a yellow solid. 1 H NMR (400 MHz, CD 3 OD) d 7.17 (dd, J = 8.8 Hz, 1H), 6.76 (m, 3H), 4.19 (m, 1H), 3.77 (s, 3H ), 2.78 (m, 2H), 1.21 (d, J = 7Hz, 2H).

N-trifluoroacetyl-1- (2-iodo-5-methoxyphenyl) -2-propylamine

A solution of N-trifluoroacetyl-1- (3-methoxyphenyl) -2-propylamine (4.29 g, 15.7 mmol) in methanol (100 mL) was cooled to -78 ° C and treated with CaCO3 (3.17 g, 31, 4 mmol) followed by the addition of a solution of ICl (6.37 g, 39.3 mmol) in methanol (50 mL). The reaction mixture was allowed to warm to 20 ° C and was stirred overnight. The resulting mixture was filtered, concentrated, dissolved in EtOAc (200 mL), washed twice with 5% aqueous sodium bisulfite (100 mL), then brine (100 mL), dried with Na2SO4, and concentrated to give 6.72 g of a white solid powder. MS calculated for C12H13F3INO2 + H: 388, recorded: 388.

N-trifluoroacetyl-1- (2-iodo-5-methoxyphenyl) -2-propylamine N-allyl

A solution of N-trifluoroacetyl-1- (2-iodo-5-methoxyphenyl) -2-propylamine (6.09 g, 15.7 mmol) in toluene (450 mL) was treated with K2CO3 (2.82 g, 20.4 mmol) , KOH (2.45 g, 47.1 mmol), n-Bu4NBr (0.506 g, 1.57 mmol) and allyl bromide (2.47 g, 20.4 mmol), and stirred overnight at 80 ° C. The resulting mixture was acidified with 10% aqueous HCl, separated, the aqueous phase was extracted with ether (500 mL), the combined organic phases were washed with brine (200 mL), dried with Na2SO4 and concentrated to give 4.45 g of a brown oil.

N-trifluoroacetyl-7-methoxy-4-methyl-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-1- (2-iodo-5-methoxyphenyl) -2-propylamine N-allyl (4.45 g, 10.8 mmol) in dimethylformamide (120 mL) was treated with KOAc (3.17 g, 32, 3 mmol), n-Bu4NBr (3.47 g, 10.8 mmol), PPh3 (0.283 g, 1.08 mmol), Pd (OAc) 2 (0.242 g, 1.08 mmol) and stirred overnight at 80 ° C. The resulting mixture was cooled to 20 ° C, filtered, diluted with water (200 ml), extracted with ether (3 x 200 ml), the combined organic phases were washed with water (100 ml), brine (100 ml), dried with Na2SO4 and concentrated. Equilibrium chromatography (10% EtOAc in hexane, silica gel) gave 1.39 g of a yellow oil.

N-trluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-7-methoxy-4-methyl-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (1.39 g, 4.64 mmol) in ethanol (40 mL) was treated with 10% Pd / C (0.49 g, 0.46 mmol) and stirred overnight under a hydrogen atmosphere. The resulting mixture was filtered through celite and silica gel and then concentrated. Flash chromatography (20% EtOAc in hexane, silica gel) afforded 0.77 g of pure oil. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.06 (m, 1H), 6.71 (m, 1H), 6.63 (m, 1H), 4.38 (bm, 1H), 3. 8 (s, 3H), 3.6 (m, 1H), 3.25 (m, 1H), 3.18 (bm, 2H), 2.72 (m, 1H), 1.34 (m, 3H ) 1.22 (m, 3H).

N-trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

Solution of N-trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.452 g,

1.50 mmol) in acetonitrile (20 ml) treated with N-bromosuccinimide (0.294 g, 1.65 mmol) and stirred overnight at 20 ° C. The resulting mixture was diluted with EtOAc (100 mL), washed with sodium bisulfite (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica gel) gave a pure oil. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.32 (s, 1H), 6.62 (m, 1H), 4.37 (m, 1H), 3.87 (s, 3H), 3. 81 (m, 1H), 3.28-3.10 (m, 3H), 2.73 (m, 1H), 1.31 (m, 3H), 1.25 (m, 3H).

8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (21mg, 0.055mmol) in methanol (2ml) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20 ° C. The resulting mixture was diluted with water (5 mL), extracted twice with EtOAc (10 mL), the combined organic phases were washed with brine (10 mL), dried with Na2SO4, and concentrated to give 11 mg of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.29 (s, 1H), 6.64 (s, 1H), 3.88 (s, 3H), 3.02 (m, 2H), 2.89 (dd , J = 9.14 Hz, 1H), 2.80 (m, 1H), 2.67 (d, J = 14 Hz, 1H), 2.53 (dd, J = 10.13, 1H) 1, 30 (d, J = 7 Hz, 3H), 1.19 (d, J = 6 Hz, 3H). MS calculated for C13H18BrNO + H: 284, registered: 284.

PL 211 333 B1

Example 25: 7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

ΝΗ

N-trifluoroacetyl-8-bromo-1,4-dimethyl-7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluoroacetyl-8-bromo-1,4-dimethylmethoxy-2 solution, 3,4,5-tetrahydro-1H-3-benzazepine (0.383g, 1.01mmol) in dichloromethane (30ml) was treated with BBr3 (2.35ml of a 1.0M solution in CH2Cl2, 2.35mmol) and stirred for overnight by heating to 20 ° C. Excess BBr3 was taken up with water, and the resulting mixture was diluted with ether (100 mL), washed with saturated aqueous Na2CO3 (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 0.302 g of a white solid. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.22 (m, 1H), 6.77 (m, 1H), 5.34 (s, 1H), 4.35 (m, 1H), 3. 62 (m, 1H), 3.24 (m, 1H), 3.13 (m, 2H), 2.69 (m, 1H), 1.31 (m, 3H), 1.22 (m, 3H ).

N-trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluoroacetyl-8-bromo-1,4-dimethyl-7- solution hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.030 g, 0.082 mmol) in dichloromethane (2 mL) was treated with allyl bromide (0.030 g, 0.246 mmol), DBU (0.037 g, 0.246 mmol) and stirred for 2 hours at 20 ° C. The resulting mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (2 mL), brine (5 mL), dried with Na2SO4, and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 0.028 g of pure oil. 1 H NMR (400 MHz, CDCl 3, mixed rotamers) d 7.32 (s, 1H), 6.62 (m, 1H), 6.02 (m, 1H), 5.45 (d, J = 17Hz, 1H), 5.30 (d, J = 11Hz, 1H), 4.58 (s, 2H), 4.36 (m, 1H), 3.62 (m, 1H), 3.23 (m, 1H), 3.11 (m, 1H), 2.81 (d, J = 10Hz, 1H), 2.70 (m, 1H), 1.34 (m, 3H), 1.21 (m, 3H).

7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.028 g, 0.069 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 ml), and stirred for 3 hours at 20 ° C. The resulting mixture was diluted with water (10 mL), extracted twice with EtOAc (10 mL), the combined organic phases were washed with brine (10 mL), dried with Na2SO4, and concentrated to give 0.020 g of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.30 (s, 1H), 6.64 (s, 1H), 6.06 (m, 1H), 5.47 (d, J = 17Hz, 1H), 5.30 (d, J = 11 Hz, 1H), 4.56 (s, 2H), 3.03 (m, 2H), 2.90 (dd, J = 9.14 Hz, 1H), 2, 80 (m, 1H), 2.65 (d, J = 14Hz, 1H), 2.55 (dd, J = 10, 14Hz, 1H), 1.77 (bs, 1H), 1.30 ( d, J = 7Hz, 3H), 1.20 (d, J = 6Hz, 3H).

Example 26: (R, S) 7- (2-methyl-2H-pyrazol-3-yl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

ΝΗ

N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5 tetrahydro-1H-3-benzazapine

Solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.506 g,

1.76 mmol) in dichloromethane (20 mL) was treated with BBr3 (4.1 mL, 1.0M solution in CH2Cl2, 4.1 mmol) and stirred overnight while warming to 20 ° C. The excess BBr3 was taken up with water, and the resulting mixture was diluted with ether (200 mL), washed with Na2CO3 (100 mL) and brine (100 mL), dried with Na2SO4, and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 0.460 g of a white solid foam. MS calculated for C13H14F3NO2 + H: 274, registered: 274.

N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine O-trifluoromethanesulfonate

PL 211 333 B1

A solution of N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (460 mg, 1.76 mmol) in dichloromethane (15 mL) was treated with pyridine (417 mg, 5 , 27 mmol), trifluoromethanesulfonic anhydride (991 mg, 3.52 mmol) and) stirred for 1.5 hours at 20 ° C. The resulting mixture was diluted with dichloromethane (100 mL), washed with water (50 mL), 5% aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried with Na2SO4, and concentrated. Flash chromatography (15% EtOAc in hexane, silica gel) gave 658 mg of pure oil. MS calculated for C14H13F6NO4S + H: 406, registered: 406.

N-trifluoroacetyl-7- (2-methyl-2H-pyrazol-3-yl) -1-methyl-2,3,4,5-tetrahydro-1H-3-henzazepine

A solution of N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, O-trifluoromethanesulfonate (100mg, 0.25mmol) in dimethylformamide (2ml) was treated with (2 -methyl-2H-pyrazol-3-yl) -tri-n-butyltine (138 mg, 0.37 mmol), LiCl (21 mg, 0.50 mmol), Pd (PPh3) 2Cl2 (35 mg, 0.05 mmol) and stirred at 100 ° C for 4 hours. The resulting mixture was diluted with EtOAc (20 mL), washed twice with water (10 mL), once with brine (10 mL), dried with Na2SO4, and concentrated. Flash chromatography (30% EtOAc in hexane, silica gel) gave 80 mg of pure oil. MS calculated for C17H18F3N3O + H: 338, registered: 338.

7- (2-methyl-2H-pyrazol-3-yl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Solution of N-trifluoroacetyl-7- (2-methyl-2H-pyrazol-3-yl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (48 mg, 0.14 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and the solution was stirred overnight at 20 ° C. The resulting mixture was concentrated, extracted 3 times with CH2Cl2 (5 ml), dried with Na2SO4 and the solvent was evaporated. Flash chromatography (0-15% MeOH in CH2Cl2, silica gel) gave 30 mg of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.48 (s, 1H), 7.21 (m, 2H), 7.13 (s, 1H), 6.27 (s, 1H), 3.89 (s , 3H), 3.3-2.9 (m, 9H), 2.79 (dd, J = 7.14 Hz, 1H), 1.40 (d, J = 8 Hz, 3H). MS calculated for C15H19N3 + H: 242, recorded: 242.

Example 27: (R, S) 7- (4-bromo-2-methyl-2H-pyrazol-3-yl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

ΝΗ

N-trifluoroacetyl-7- (4-bromo-2-methyl-2H-pyrazol-3-yl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine N-trifluoroacetyl-7- solution (2-methyl-2H-pyrazol-3-yl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (30 mg, 0.082 mmol) in dichloromethane (1 ml) was treated with N-bromosuccinimide (15.3 mg, 0.086 mmol) and stirred overnight at 20 ° C. The resulting mixture was absorbed onto silica gel and purified by flash chromatography (2-5% MeOH in CH2Cl2, silica gel) to yield 37 mg of a white crystalline solid. MS calculated for C17H17BrF3N3O + H: 416, registered: 416.

7- (4-bromo-2-methyl-2H-pyrazol-3-yl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Solution of N-trifluoroacetyl-7- (4-bromo-2-methyl-2H-pyrazol-3-yl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (37 mg, 0.089 mmol ) in methanol (2 ml) was treated with 15% aqueous NaOH (2 ml), and stirred overnight at 20 ° C. The resulting mixture was concentrated, extracted 3 times with CH2Cl2 (5 ml), dried with Na2SO4 and the solvent was evaporated. Flash chromatography (0-15% MeOH in CH2Cl2, silica gel) gave 28 mg of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.50 (s, 1H), 7.25 (d, J = 8 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 7.10 ( s, 1H), 3.83 (s, 3H), 3.17 (m, 1H), 3.1-2.9 (m, 8H), 2.80 (dd, J = 7.13 Hz, 1H ), 2.48 (bs, 1H), 1.40 (d, J = 8Hz, 3H). MS calculated for C15H18BrN3 + H: 320, recorded: 320.

Example 28: (R, S) 7- (3-chlorophenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Cl

ΝΗ

PL 211 333 B1

A solution of N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, O-trifluoromethanesulfonate (50 mg, 0.123 mmol) in 1,4-dioxane (1.5 ml ) treated with 2-chlorophenylboronic acid (39 mg, 0.243 mmol), CsF (56 mg, 0.37 mmol), water (50 mg, 2.78 mmol), Pd (PPh3) 4 (29 mg, 0.025 mmol) and stirred overnight at 75 ° C. The resulting mixture was diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried with Na2SO4, and concentrated. Flash chromatography (10-20% EtOAc in hexane, silica gel) gave 45 mg of pure oil. MS calculated for C19H17CIF3NO + H: 368, recorded: 368.

The product (27 mg, 0.073 mmol) was dissolved in methanol (2 ml) treated with 15% aqueous NaOH (2 ml), and stirred overnight at 20 ° C. The resulting mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and the solvent was evaporated to give 18 mg of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.54 (s, 1H), 7.42 (d, J = 6 Hz, 1H), 7.35-7.21 (m, 5H), 3.14 ( m, 1H), 3.1-2.9 (m, 8H), 2.80 (bm, 2H), 1.38 (d, J = 8Hz, 3H). MS calculated for C17H18CIN3 + H: 272, recorded: 272.

Example 29: (R, S) 7- (2-chlorophenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0020.tif" />

A solution of N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine O-trifluoromethanesulfonate (50 mg, 0.123 mmol) in 1,4-dioxane (1.5 ml) treated with 2-chlorophenylboronic acid (39 mg, 0.243 mmol), CsF (56 mg, 0.37 mmol), water (50 mg, 2.78 mmol), Pd (PPh3) 4 (29 mg, 0.025 mmol) and stirred for overnight at 75 ° C. The resulting mixture was diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried with Na2SO4, and concentrated. Flash chromatography (10-20% EtOAc in hexane, silica gel) gave 36 mg of pure oil. MS calculated for C19H17CIF3NO + H: 368, recorded: 368.

The product (27 mg, 0.073 mmol) was dissolved in methanol (2 ml) treated with 15% aqueous NaOH (2 ml), and stirred overnight at 20 ° C. The resulting mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and the solvent was evaporated to give 24 mg of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.44 (d, J = 8 Hz, 1H), 7.5-7.22 (m, 5H), 7.15 (s, 1H), 3.14 (m , 1H), 3.12.9 (m, 8H), 2.80 (dd, J = 13Hz, 1H), 2.51 (bs, 1H), 1.38 (d, J = 8Hz, 3H). MS calculated for C17H18CIN3 + H: 272, recorded: 272.

Example 30: (R, S) 8-Chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine

HO

<img file="PL211333B1_D0021.tif" />

N-trifluoroacetyl-8-chloro-1-oxo-3,4,5-trihydro-1H-3-benzazepine

Solution of N-trifluoroacetyl-8-chloro-1-methylene-3,4,5-trihydro-1H-3-benzazepine (0.23 g, 0.80 mmol) in 1: 1 methanol / dichloromethane (45 ml) cooled to -78 ° C, treated with ozone until the solution turned blue (about 20 minutes), PPh3 (0.21 g, 0.80 mmol) was added and the resulting solution was stirred for 90 minutes while warming to 20 ° C. The resulting mixture was concentrated and purified by flash chromatography (30% EtOAc in hexane, silica gel) to provide 0.215 g of a white solid. MS calculated for C12H9CIF3NO2 + H: 292, recorded: 292.

8-chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-chloro-1-oxo-3,4,5-trihydro-1H-3-benzazepine (50 mg, 0.17 mmol) in methanol (2 ml) was treated with NaBH4 and the resulting mixture was stirred for 16 hours. at 20 ° C. The obtained product as a white solid was collected by filtration, washed with water and dried to give 30 mg of a white solid. 1 H NMR (400 MHz, CD 3 OD) d 7.39 (s, 1H), 7.12 (d, J = 8 Hz, 1H), 7.06 (d, J = 8 Hz, 1H), 4.74 ( d, J = 8Hz, 1H), 3.1-2.7 (m, 6H). MS calculated for C10H12ClNO + H: 198, registered: 198.

PL 211 333 B1

Example 31: (R, S) 8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0022.tif" />

Basically following the same general procedure as in Example 26, starting from 4-bromophenethylamine gave (R, S) 8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil . 1 H NMR (400 MHz, CDCl 3) d 7.27 (s, 1H), 7.22 (d, J = 8 Hz, 1H), 6.94 (d, J = 8 Hz, 1H), 3.1- 2.85 (m, 6H), 2.72 (m, 1H), 2.25 (bs, 1H), 1.33 (d, J = 7Hz, 3H). MS calculated for C11H14BrN + H: 240, registered: 240.

Example 32: (R, S) 8-Fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0023.tif" />

Basically following the same general procedure as in Example 26, starting from 4-fluorophenethylamine gave (R, S) 8-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil . 1 H NMR (400 MHz, CDCl 3) d 7.00 (dd, J = 8.1 Hz, 1H), 6.86 (d, J = 10 Hz, 1H), 6.76 (d, J = 8 Hz, 1H), 3.08-2.56 (m, 7H), 1.85 (bs, 1H), 1.31 (d, J = 7Hz, 3H). MS calculated for C11H14FN + H: 180, registered: 180.

Example 33: (R, S) 7-Fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0024.tif" />

Basically following the same general procedure as in Example 26, starting from 3-fluorophenethylamine, there was obtained (R, S) 7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil . 1 H NMR (400 MHz, CDCl 3) d 7.09 (dd, J = 6.8 Hz, 1H), 6.85-6.78 (m, 2H), 3.10-2.89 (m, 6H) , 2.71 (dd, J = 7.13 Hz, 1H), 1.91 (bs, 1H), 1.33 (d, J = 7 Hz, 3H). MS calculated for C11H14FN + H: 180, registered: 180.

Example 34: (R, S) 7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0025.tif" />

Basically following the same general procedure as in Example 26, starting from 3-chlorophenethylamine gave (R, S) 7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil . 1 H NMR (400 MHz, CDCl 3) d 7.10 (d, J = 8 Hz, 1H), 7.06 (m, 2H), 3.1-2.9 (m, 6H), 2.70 (dd , J = 13.7 Hz, 1H), 1.89 (bs, 1H), 1.31 (d, J = 7 Hz, 3H). MS calculated for C11H14CIN + H: 196, registered: 196.

Example 35: (R, S) 7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0026.tif" />

PL 211 333 B1

Basically following the same general procedure as in Example 26, starting from 3,4-dichlorophenethylamine gave (R, S) 7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-. benzazepine as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.20 (s, 1H), 7.16 (s, 1H), 3.05-2.86 (m, 6H), 2.71 (dd, J = 7, 13 Hz, 1H), 1.83 (bs, 1H), 1.33 (d, J = 7Hz, 3H). MS calculated for C11H13Cl2N + H: 230, registered: 230.

Example 36: (R, S) N-methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0027.tif" />

Basically following the same general procedure as in Example 9, starting with (R, S) 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine gave (R, S) N -methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil. MS calculated for C12H16CIN + H: 210, registered: 210.

Example 37: (R, S) 1-Methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0028.tif" />

Basically following the same general procedure as in Example 26, starting with 3-trifluoromethoxyphenethylamine (R, S), 1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine was obtained as a colorless oil . 1 H NMR (400 MHz, CD 3 OD) 7.39 (d, J = 8 Hz, 1H), 7.19 (m, 1H), 3.46 (m, 2H), 3.38 (d, J = 13 Hz , 1H), 3.29 (m, 1H), 3.16 (m, 2H), 3.05 (dd, J = 13.9Hz, 1H), 1.50 (d, J = 8Hz, 3H ). MS calculated for C12H14F3NO + H: 246, recorded: 246.

Example 38: (R, S) 8-iodo-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.

<img file="PL211333B1_D0029.tif" />

Based on the same general procedure as in Example 3, starting with N-trifluoroacetyl-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, the (R, S) 8- iodo-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil. 1 H NMR (400 MHz, CD 3 OD) d 7.79 (s, 1H), 7.25 (s, 1H), 3.46-3.40 (m, 3H), 3.28-3.12 (m, 3H), 3.07 (dd, J = 13.9 Hz, 1H), 1.47 (d, J = 7 Hz, 3H). MS calculated for C12H14F3INO + H: 372, recorded: 372.

Example 39: (R, S) N-propyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0030.tif" />

Basically following the same general procedure as in Example 10, starting with (R, S) 8-iodo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine gave (R, , S) N-propyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil. MS calculated for C15H22INO + H: 360, registered: 360.

PL 211 333 B1

Example 40: (R, S) 1-Ethyl-8-iodo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0031.tif" />

Based on the same general procedure as in Example 19, starting from N-trifluorolacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine gave (R, S) 1- ethyl-8-iodo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.47 (s, 1H), 6.54 (s, 1H), 3.86 (s, 3H), 3.20-2.97 (m, 4H), 2 , 93-2.75 (m, 3H), 2.64 (m, 1H), 1.78 (m, 2H), 0.95 (dd, J = 8.8 Hz, 3H). MS calculated for C13H18INO + H: 332, registered: 332.

Example 41: (R, S) 7- (3-methoxyphenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0032.tif" />

Basically following the same general procedure as in Example 29, starting with N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine O-trifluoromethanesulfonate, the (R, S ) 7- (3-methoxyphenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.37 (dd, J = 7.7 Hz, 1H), 7.30 (m, 2H), 7.21 (d, J = 7 Hz, 1H), 7, 14 (d, J = 7 Hz, 1H), 7.09 (s, 1H), 6.86 (d, J = 8 Hz, 1H), 3.85 (s, 3H), 3.2-2, 9 (m, 6H), 2.80 (m, 1H), 2.64 (bs, 1H), 1.38 (d, J = 7Hz, 3H). MS calculated for C18H21NO + H: 268, registered: 268.

Example 42: (R, S) 7- (2,6-difluorophenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0033.tif" />

Basically following the same general procedure as in Example 29, starting with N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine O-trifluoromethanesulfonate (R, S ) 7- (2,6-difluorophenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.35-7.10 (m, 5H), 6.95 (dd, J = 7.8 Hz, 1H), 3.2-2.9 (m, 6H ), 2.79 (dd, J = 8.13 Hz, 1H), 2.70 (bs, 1H), 1.38 (d, J = 8 Hz, 3H). MS calculated for C17H17F2N + H: 274, registered: 274.

Example 43: (R, S) 7- (2-Fluorophenyl) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0034.tif" />

Based on the same general procedure as in Example 29, starting with N-trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, there was obtained (R, S)

PL 211 333 B1

7- (2-fluorophenyl) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.35-7.23 (m, 3H), 7.19-7.09 (m, 2H), 7.03 (s, 1H), 3.15-2, 85 (m, 7H), 2.76 (dd, J = 8.13 Hz, 1H), 1.36 (d, J = 8 Hz, 3H). MS calculated for C17H17CIFN + H: 290, registered: 290.

Example 44: (R, S) 7- (2-trifluoromethylphenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0035.tif" />

Basically following the same general procedure as in Example 29, starting from N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine O-trifluoromethanesulfonate was obtained (R, S ) (2-trifluoromethylphenyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.71 (d, J = 8 Hz, 1H), 7.52 (dd, J = 7.8 Hz, 1H), 7.42 (dd, J = 7.8 Hz, 1H), 7.31 (d, J = 7 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 7.11 (d, J = 8 Hz, 1H), 3.15 (m, 1H), 3.1-2.9 (m, 5H), 2.76 (dd, J = 8.13Hz, 1H), 2.37 (bs, 1H), 1.38 (d, J = 8 Hz, 3H). MS calculated for C18H18F3N + H: 306, registered: 306.

Example 45: (R, S) 7- (3-trifluoromethylphenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0036.tif" />

Basically following the same general procedure as in Example 29, starting with N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine O-trifluoromethanesulfonate, the (R, S ) 7- (3-trifluoromethylphenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.80 (s, 1H), 7.73 (d, J = 8 Hz, 1H), 7.57-7.48 (m, 2H), 7.38 (d , J = 8Hz, 1H), 7.30 (s, 1H), 7.24 (d, J = 7Hz, 1H), 3.16 (m, 1H), 3.1-2.9 (m , 6H), 2.79 (dd, J = 8.13 Hz, 1H), 1.38 (d, J = 8 Hz, 3H). MS calculated for C18H18F3N + H: 306, registered: 306.

Example 46: (R, S) 7- (4-trifluoromethylphenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0037.tif" />

Basically following the same general procedure as in Example 29, starting with N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine O-trifluoromethanesulfonate, the (R, S ) 7- (4-trifluoromethylphenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.65 (s, 4H), 7.38 (d, J = 8 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J = 8 Hz, 1H), 3.15 (m, 1H), 3.1-2.9 (m, 5H), 2.80 (dd, J = 8, 13Hz, 1H), 2.48 (bs, 1H ). 1.38 (d, J = 8Hz, 3H). MS calculated for C18H18F3N + H: 306, registered: 306.

PL 211 333 B1

Example 47: (R, S) 8- (2-chlorophenyl) -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0038.tif" />

A solution of N-trifluoroacetyl-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (84 mg, 0.229 mmol) in dimethylformamide (2.5 mL) was treated with 2-chlorophenylboronic acid (43 mg, 0.275 mmol), CsF (52 mg, 0.34 mmol), water (70 mg, 3.9 mmol), Pd (PPh3) 4 (27 mg, 0.023 mmol) and stirred overnight at 75 ° C. The resulting mixture was diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried with Na2SO4, and concentrated. Flash chromatography (10-20%) EtOAc in hexane, silica gel) gave 36 mg of pure oil. MS calculated for C19H17CIF3NO + H: 368, recorded: 368.

The product (39 mg, 0.106 mmol) was dissolved in methanol (2 ml) treated with 15% aqueous NaOH (2 ml), and stirred overnight at 20 ° C. The resulting mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and the solvent was evaporated to give 18 mg of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.44 (d, J = 8 Hz, 1H), 7.35-7.17 (m, 5H), 7.12 (d, J = 8 Hz, 1H) , 3.14 (m, 1H), 3.1-2.9 (m, 5H), 2.79 (dd, J = 7.3 Hz, 1H), 2.36 (bs, 1H), 1. 36 (d, J = 7Hz, 3H). MS calculated for C17H18CIN3 + H: 272, recorded: 272.

Example 48: (R, S) 7-methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0039.tif" />

A solution of N-trifluoromethylacetyl-8-iodo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine (135 mg, 0.327 mmol) in dimethylformamide (3 ml) and toluene (0, 5 mL) was treated with sodium trifluoroacetate (133 mg, 0.981 mmol), copper (I) iodide (124 mg, 0.654 mmol) and distilled toluene to remove residual water impurities. The reaction mixture was stirred at 155 ° C for 3.5 hours, diluted with EtOAc, filtered, adsorbed onto silica gel and purified by flash chromatography (10% EtOAc in hexane, silica gel) to give 26 mg of a colorless oil. MS calculated for C15H15F6NO2 + H: 356, recorded: 356.

The intermediate (26 mg, 0.073 mmol) suspended in methanol (2 ml) was treated with 15% aqueous NaOH (2 ml), and stirred for 0.5 hours at 50 ° C. The resulting mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4, and concentrated to give 14 mg of a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.32 (s, 1H), 6.73 (s, 1H), 3.89 (s, 3H), 3.1-2.9 (bm, 6H), 2 , 75 (bm, 1H), 2.23 (bs, 1H), 1.36 (d, J = 8Hz, 3H). MS calculated for C13H16F3NO + H: 260, registered: 260.

Example 49: (R, S) 7-methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0040.tif" />

A solution of N-trifluoromethylacetyl-8-iodo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine (100 mg, 0.242 mmol) in dimethylformamide (3 ml) and toluene (1 ml ) was treated with sodium pentafluoropropionate (64 mg, 0.344 mmol), copper (I) iodide (92 mg, 0.484 mmol) and distilled toluene to remove residual water impurities. The reaction mixture was stirred at 160 ° C for 3.5 hours, diluted with EtOAc, filtered, adsorbed onto silica gel and purified by flash chromatography (10% EtOAc in hexane, silica gel) to give mg of a colorless oil. MS calculated for C16H15F8NO2 + H: 406, registered: 406.

The intermediate (22 mg, 0.054 mmol) suspended in methanol (2 ml) was treated with 15% aqueous NaOH (2 ml), and stirred for 0.5 hours at 50 ° C. The resulting mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4, and concentrated to give 14 mg of a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.25 (s, 1H), 6.74 (s, 1H), 3.85 (s, 3H), 3.1-2.9 (bm, 6H), 2 , 76 (bm, 1H), 2.37 (bs, 1H), 1.35 (d, J = 8Hz, 3H). MS calculated for C14H16F5NO + H: 310, registered: 310.

Example 50: (R, S) 8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0041.tif" />

Basically following the same general procedure as in Example 26, starting from 4-trifluoromethylphenethylamine, there was obtained (R, S) 8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless oil . 1 H NMR (400 MHz, DMSO) d 7.55 (d, J = 8 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J = 8 Hz, 1H), 3.55- 3.50 (m, 1H) 3.43-3.23 (m, 7H), 3.13 (dd, J = 16.7 HZ, 1H), 3.0-2.91 (m, 2H), 1.36 (d, J = 7 Hz, 3H). MS calculated for C12H14F3N + H: 230.19, recorded: 230.4

Example 51: (R, S) 8-Bromo-1-methoxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0042.tif" />

A solution of 8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.075 g, 0.26 mmol) in dichloromethane (2 mL) was treated with BOC2O (0.062 g, 0 , 29 mmol), and stirred overnight at 20 ° C. The product was adsorbed onto silica gel and purified by flash chromatography (33% EtOAc in hexane, silica gel) to give 0.034 g of pure oil. MS calculated for C17H24BrNO4 + H: 386, recorded: 386.

The BOC-protected intermediate was dissolved in dimethylformamide (1 ml), treated sequentially with excess NAH and excess iodomethane, then stirred for 1 hour at 20 ° C. The reaction mixture was taken up with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 0.019 g of pure oil. MS calculated for C18H26BrNO4 + H: 400, recorded: 400. The N-BOC protected methyl ether was then treated with 4M HCl in dioxane (1 ml) and stirred for 2 hours at 20 ° C. After evaporation, 0.009 g of the desired product were obtained in the form of a pure oil. 1 H NMR (400 MHz, CD 3 OD) d 7.30 (s, 1H), 6.92 (s, 1H), 3.87 (s, 3H), 3.65 (s, 3H) 3.5-3. 1 (m, 9H). MS calculated for C13H18BrNO2 + H: 300, recorded: 300.

Example 52: (RS) 8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0043.tif" />

N-crotyl N-trifluoroacetyl-2-iodo-4-chlorophenethylamine

A solution of N-trifluoroacetyl-2-iodo-4-chloro-phenethylamine (6.2 g, 15.8 mmol) in dimethylformamide (350 mL) was treated sequentially with K2CO3 (15.8 g, 114 mmol) and crotyl bromide (6.0 g, 44 mmol), the mixture was stirred at 60 ° C for 16 hours and then cooled to 20 ° C. The mixture was diluted with EtOAc

(350 ml), washed with water (3 x 300 ml), dried with Na2SO4 and concentrated. Flash chromatography (5-15% EtOAc in hexanes) provided 2.5 g of pure oil. MS calculated for C14H14CIF3INO + H: 432, recorded: 432.

N-trifluoroacetyl-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-crotyl N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (2.5 g, 5.8 mmol) in dimethylformamide (250 mL) was treated with KOAc (1.07 g, 10.9 mmol), n-Bn2Et2NBr ( 1.33 g, 5.84 mmol), Pd (OAc) 2 (0.063 g, 0.28 mmol) and stirred overnight at 77 ° C. The resulting mixture was cooled to 20 ° C, filtered, diluted with water (100 mL), extracted with EtOAc (3 X 100 mL), the combined organic phases were washed with water (100 mL), brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (2-20% EtOAc in hexane, silica gel) gave 0.339 g of pure oil.

The product, assumed to be a mixture of isomers due to the position of the double bond, was dissolved in methanol (50 ml) and treated with Et3N (0.2 ml), 10% Pd / C (0.10 g) and stirred for 16 hours under pressure. 100 atmospheres of hydrogen. The resulting mixture was filtered, concentrated, and purified by flash chromatography (5% EtOAc in hexane, silica gel) to provide 0.20 g of a white solid. MS calculated for C14H15CIF3NO + H: 306, recorded: 306.

8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (63 mg, 0.207 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 ml), and stirred for 3.5 hours at 60 ° C. The resulting mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 35 mg of pure oil. 1H NMR (400MHz, DMSO-d6) d 7.2 (m, 3H), 3.3-3.0 (m, 7H), 1.9-1.6 (m, 2H), 0.91 ( t, J = 7Hz, 3H). MS calculated for C12H16CIN + H: 210, registered: 210.

Example 53: (R, S) 8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0044.tif" />

N-trifluoroacetyl-8-chloro-7-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) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 ml, 90 mmol) and stirred for 60 hours at 75 ° C. The resulting mixture was poured into water (200 ml), extracted with EtOAc (200 ml), the organic phase was washed with saturated aqueous NaHCO3 (2 x 100 ml), brine (100 ml), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica gel) to yield 1.6 g of a white solid. MS calculated for C13H12CIF4NO + H: 310, recorded: 310.

8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (160 mg, 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 25 ° C. The resulting mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 93 mg of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.11 (m, 1H), 6.85 (m, 1H), 3.05-2.95 (m, 3H), 2.95-2.80 (m, 3H), 2.68 (m, 1H), 2.38 (bm, 1H), 1.31 (m, 3H). MS calculated for C11H13CIFN + H: 214, recorded: 214.

Invention Example: (R, S) 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

<img file="PL211333B1_D0045.tif" />

N-trifluoroacetyl-4-chlorophenethylamine

A solution of 4-chlorophenethylamine (1.0 g, 6.4 mmol) in dichloromethane (20 mL) was cooled to 0 ° C, treated with pyridine (1.0 mL, 12.8 mmol), trifluoroacetic anhydride (1.6 g, 7 , 7 mmol) and then stirred for 1 hour while warming to 20 ° C. The resulting mixture was diluted with EtOAc (100 mL), washed sequentially with 10% aqueous HCl (50 mL), water (50 mL), brine (50 mL), dried with Na2SO4, and concentrated to give 1.6 g of a white solid.

PL 211 333 B1

N-trifluoroacetyl-2-iodo-4-chlorophenethylamine

A solution of N-trifluoroacetyl-4-chlorophenethylamine (1.6 g, 6.4 mmol) in dichloromethane (20 mL) was treated with bis (pyridine) iodonio (I) tetrafluoroborate (2.6 g, 7.0 mmol), CF3SO3H (2 , 1 g, 14.1 mmol) and stirred overnight at 20 ° C. The resulting mixture was concentrated, dissolved in EtOAc (100 mL), washed twice with 5% aqueous sodium bisulfite (50 mL), twice with saturated aqueous NaHCO3, (50 mL) once with brine (50 mL), dried with Na2SO4 and concentrated to give 0.94 g pure oil. MS calculated for C10H8ClF3INO + H: 378, recorded: 378.

N-allyl N-trifluoroacetyl-2-iodo-4-chlorophenethylamine

A solution of N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (0.94 g, 2.4 mmol) in toluene (25 mL) was treated sequentially with K2CO3 (0.43 g, 3.12 mmol), KOH (0.40 g , 7.2 mmol), n-Bu4NBr (0.077 g, 0.24 mmol), and allyl bromide (0.43 g, 3.6 mmol). The mixture was stirred at 80 ° C for 3.5 hours, cooled to 20 ° C, and acidified with 10% aqueous HCl. The phases were separated, the aqueous phase was extracted with ether (100 ml), the combined organic phases were washed with brine (50 ml), dried with Na2SO4 and concentrated to give 0.76 g of pure oil. MS calculated for C13H12CIF3INO + H: 418, recorded: 418.

N-trifluoroacetyl-8-chloro-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-2-iodo-4-chlorophenethylamine of N-allyl (0.76 g, 1.8 mmol) in dimethylformamide (20 mL) was treated with KOAc (0.53 g, 5.4 mmol), n-Bu4NBr ( 0.58 g, 1.8 mmol), PPh3 (0.047 g, 0.18 mmol), Pd (OAc) 2 (0.041 g, 0.18 mmol) and stirred overnight at 105 ° C. The resulting mixture was cooled to 20 ° C, filtered, diluted with water (100 ml), extracted with ether (3 x 100 ml), the combined organic phases were washed with water (100 ml), brine (100 ml), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexane, silica gel) gave a 0.228 g of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.29 (s, 1H), 7.18 (m, 1H), 7.04 (m, 1H), 5.38 (m, 2H), 5.40 (d , J = 16Hz, 2H), 3.80 (m, 2H), 3.00 (m, 2H). MS calculated for C13H11CIF3NO + H: 290, recorded: 290.

N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-trifluoroacetyl-8-chloro-1-methylene-2,3,4,5-trihydro-1H-3-benzazepine (0.16 g, 0.55 mmol) in methanol (10 mL) treated with 10% Pd / C (0.02 g) and stirred 30 minutes under a hydrogen atmosphere. The resulting mixture was filtered, concentrated, and purified by flash chromatography (5% EtOAc in hexane, silica gel) to provide 0.057 g of a white solid. MS calculated for C13H13CIF3NO + H: 292, recorded: 292.

8-chloro-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 (65 mg, 0.22 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 ml), and stirred for 3.5 hours at 60 ° C. The resulting mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 35 mg of pure oil. 1 H NMR (400 MHz, CDCl 3) d 7.11 (s, 1H), 7.05 (d, J = 8 Hz, 1H), 6.98 (d, J = 8 Hz, 1H), 3.1- 2.9 (m, 6H), 2.71 (m, 1H), 2.68 (bs, 1H), 1.32 (d, J = 8Hz, 3H). MS calculated for C11H14CIN + H: 196, registered: 196.

The resulting 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine compound is then converted to the desired hydrate or solvate with a suitable low molecular weight solvent by any method known in the art.

Biological examples

Example 1

Separation of enantiomers of selected compounds of general formula I and 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

The following compounds were separated into their respective enantiomers by a Varian ProStar HPLC system on a 20mm x 250mm chiral Chiralcel OD column, washing with 0.2% diethylamine at various concentrations of isopropanol (IPA) in hexane, see Table 1 below.

In some cases, the resolution was performed on the intermediate amine protected trifluoroacetamide.

Table 1

<td>Example</td><td>Enantiomer</td><td>Retention time for free amine (in)</td><td>Retention time for trifluoroacetamide</td><td>Conditions</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td rowspan="2"> 1</td><td> 1</td><td> 21,9</td><td></td><td>5% IPA in hexane</td>

<td> 2</td><td> 24,5</td><td></td><td>10 ml / min</td>

PL 211 333 B1 cont. Of Table 1

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td rowspan="2"> 2</td><td> 1</td><td> 42</td><td></td><td>5% IPA in hexane</td>

<td> 2</td><td> 47</td><td></td><td>9 ml / min</td>

<td rowspan="2"> 3</td><td> 1</td><td> 20,8</td><td></td><td>5% IPA in hexane</td>

<td> 2</td><td> 24,2</td><td></td><td>10 ml / min</td>

<td rowspan="2"> 19</td><td> 1</td><td> 34,9</td><td></td><td>1% IPA in hexane</td>

<td> 2</td><td> 39,5</td><td></td><td>9 ml / min</td>

<td rowspan="2"> 36</td><td> 1</td><td></td><td> 23,8³</td><td>5% IPA in hexane</td>

<td> 2</td><td></td><td> 29,2⁴</td><td>7 ml / min</td>

<td rowspan="2"> 50</td><td> 1</td><td></td><td> 18,6⁵</td><td>1% IPA in hexane</td>

<td> 2</td><td></td><td> 21,4⁶</td><td>9 ml / min</td>

<td rowspan="2"> 52</td><td> 1</td><td></td><td> 13,7⁷</td><td>5% IPA in hexane</td>

<td> 2</td><td></td><td> 20,2⁸</td><td>10 ml / min</td>

<td rowspan="2">8-chloro-1-methyl- 2,3,4,5-tetrahydro- 1H-3-benzazepine</td><td> 1</td><td></td><td> 23,8¹</td><td>5% IPA in hexane</td>

<td> 2</td><td></td><td> 29,2²</td><td>7 ml / min</td>

¹ The separated trifluoroacetamide enantiomer was subjected to hydrolysis to obtain Enantiomer 1 of the hydrate or solvate of the benzazepine derivative of the invention.

² The separated trifluoroacetamide enantiomer was hydrolyzed to give the enantiomer 2 L of a hydrate or solvate of the benzazepine derivative of the invention.

³ The separated trifluoroacetamide enantiomer was subjected to hydrolysis followed by N-methylation to yield Enantiomer 1 of compound 36.

⁴ The separated trifluoroacetamide enantiomer was hydrolyzed followed by N-methylation to yield Enantiomer 2 of compound 36.

⁵ The separated trifluoroacetamide enantiomer was subjected to hydrolysis to obtain Enantiomer 1 of compound 50.

⁶ The separated trifluoroacetamide enantiomer was hydrolyzed to obtain Enantiomer 2 of compound 50.

⁷ The separated trifluoroacetamide enantiomer was subjected to hydrolysis to obtain Enantiomer 1 of compound 52.

⁸ The separated trifluoroacetamide enantiomer was hydrolyzed to give Enantiomer 2 of compound 52.

Example 2 IP3 Intracellular Accumulation Assay

HEK293 cells were transfected in 15 cm sterile vessels with or without (control) µg of human 5-HT cDNA_2C receptor use 25 μl of lipofectamine. Cells were then incubated for 3-4 hours at 37 ° C / 5% CO₂and then the transfection medium was removed and replaced with 100 µl of DMEM. The cells were plated on 100 cm sterile vessels. The next day, cells were transferred to a PDL 96-well microtiter plate at 55K / 0.2 ml. Six hours later, the medium was replaced with [³H] inositol (0.25 µCi / well) in inositol-free DMEM and the plates were incubated at 37 ° C / 5% CO 2 overnight. The next day, the wells were aspirated and 200 µL of DMEM containing the test compound, 10 µL of pargilline, and 10 mM LiCl were added to the appropriate wells. The plates were then incubated at 37 ° C / 5% CO 2 for three hours after which they were aspirated and fresh cold ice frozen solution (1M KOH, 19mM Na-borate, 3.8mM EDTA) was added to each well. The plates were kept on ice for 5-10 min and the wells were neutralized with the addition of 200 µl of fresh cold ice constituting a frozen neutralizing solution (7.5% HCl). The plates were frozen until further processing became desired. The lysate was then transferred to 1.5 ml Eppendorf tubes and 1 ml of chloroform / methanol (1: 2) was added to each tube. The solution was vortexed for 15 seconds and the top phase was applied to a Biorad AG1-X8 ™ anion exchange resin (100-200 mesh). First, the resin was washed with 1: 1.25 w / v with water and 0.9 ml of the top phase was applied to the column. Then, the column was washed with 10 ml of 5 mM myo-inositol and 10 ml of 5 mM Na-borate / 60mM Na-formate. Inositol triphosphate was eluted into scintillation vials containing 10 ml of scintillation mix with 2 ml of 0.1 M formic acid / 1 M ammonium formate. The columns were regenerated by washing with 10 ml of 0.1 M formic acid / 3M ammonium formate and washing twice with d H 2 O and stored at 4 ° C in water.

PL 211 333 B1

The biological activities in the IP accumulation test for several representative compounds are shown in Table 2 below:

Table 2

<td>Relationship (Example Number :)</td><td>5-HT2C (IC50) * IP accumulation test (nM)</td>

<td> 1</td><td> 4,2</td>

<td> 2</td><td> 4,5</td>

<td> 3</td><td> 1,4</td>

<td> 4</td><td> 2,1</td>

<td> 5</td><td> 12,1</td>

<td> 12</td><td> 6,3</td>

<td> 19</td><td> 18</td>

<td> 32</td><td> 2,1</td>

<td>8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine</td><td> 5,8</td>

* The values ​​shown are mean values ​​of at least two trials.

Most of the other comparative examples compounds were tested at least once and found to have activity in the IP Accumulation assay ranging between ~ 1.4 nM and ~ 5 μΜ.

Example 3

Inhibition of food intake in food deprived rats

Male Sprague-Dawley rats (250-350 g) were deprived of food overnight prior to study entry. Before depriving food, animals were weighed and divided into study groups to balance the groups based on their body weight. On the day of the study, animals were placed in individual cages (without bedding) at 9:00 am without water. At 10:00 a.m., the animals are administered the test compound of the comparative examples and the benzazepine derivative of the invention (parenterally, intraperitoneally, or subcutaneously), followed by either 60 min (parenteral drug administration) or 30 min (intraperitoneal or subcutaneous drug administration). after administration of the drug, a pre-weighed amount of food in the dish was administered. The food consumption at different times was then determined by weighing the food bowl at 1, 2, 4 and 6 hours after the food was given. Thus, food consumption was measured at 2, 3, 5 and 7 hours after drug administration by parenteral route, and at 1.5, 2.5, 4.5, and 6.5 hours after drug administration by intraperitoneal or subcutaneous route.

Figures 1A-G illustrate the effect of seven different compounds of general formula I disclosed herein on the food intake of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. This effect was generally most pronounced one hour after feeding. The action of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is illustrated in Fig. 1G.

As used herein, it is understood that each patent specification, application, and other published documents mentioned or referred to in this application are hereby incorporated by reference in their entirety.

It will be understood by those skilled in the art that numerous changes and modifications can be made to the preferred embodiments of the present invention and that such changes and modifications can be made without departing from the scope of the present invention as defined in the appended claims.

PL 211 333 B1