Modulators of 5-ht2c receptors

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 means hydrogen atom (H) or (C1-C8)-alkyl; R2 means (C1-C8)-alkyl, -CH2-O-(C1-C8)-alkyl, -OH or -CH2OH; R2a means H; or R2 and R2a for in common -CH2-CH2-; R3 means halogen atom, perhalogenalkyl, -CN, -SR5, -NHR5, -N(R5)2, aryl or heteroaryl wherein indicated aryl can comprise optionally up to two substitutes chosen from (C1-C8)-alkyl, halogen atom, perhalogenalkyl and alkoxy-group, and indicated heteroaryl can comprise optionally up to two substitutes chosen from halogen atom and (C1-C8)-alkyl; R4 means H, halogen atom, perhalogenalkyl, -CN, -OR5, -SR5, -NHR5, -N(R5)2, -OH, aryl or heteroaryl wherein indicated aryl can comprise optionally up to two substitutes chosen from (C1-C8)-alkyl, halogen atom, perhalogenalkyl and alkoxy-group, and indicated heteroaryl can comprise optionally up to two substitutes chosen from halogen atom and (C1-C8)-alkyl; or R3 and R in common with atoms to which they are added can form 5- or 6-membered heterocyclic ring comprising one oxygen atom (O); each R5 means independently (C1-C8)-alkyl, (C2-C8)-alkenyl, aryl, heteroaryl, arylalkyl, alheteroarylalkyl, perhalogenalkyl or allyl; R6 means H or (C1-C8)-alkyl, or their pharmaceutically acceptable salts, solvates or hydrates under condition that if R6 differs from H then R4 can't mean H; if R1 and R2 mean methyl and R4 means H then R3 can't -NHR5 or -N(R5)2; if R1 and R2 mean methyl and R4 means H then R3 can't imidazole, substituted imidazole or imidazole derivative. Also, invention relates to a pharmaceutical composition used for modulation of 5-HT2C receptors, a method for modulation of 5-HT2C receptors, a method for prophylaxis or treatment of disorders of the central nervous system and obesity, a method for reducing food consumption in mammals, a method for inducing the satisfying sense in mammals and to a method for preparing the composition. Invention provides synthesis of novel compounds possessing useful biological properties and preparing pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

70 cl, 1 tbl, 57 ex

 

The technical field

This invention relates to compounds acting as modulators NT2Creceptors, compositions comprising these compounds, and to methods of using the compounds.

The level of technology

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

Currently, obesity is a major health issue in the West and is becoming increasingly important in third world countries. The increase in the number of obese people, is mainly due to the preference of food with high fat content, and that may be even more important factor in reducing the activity of most people. Over the last 10 years there has been a 30% increase in obesity in the United States, and currently, about 30% of the U.S. population are suffering from obesity.

Classification of a patient as having overweight or suffering from obesity, in General, is determined by the body mass index (BMI), which is calculated by dividing body weight (kg) by height squared (m2). Thus, the unit of BMI is expressed in kg/m2and thus, it is possible to calculate the interval BMI associated with minimum CME is testu, for each decade of life. Overweight is defined by a BMI in the range of 25-30 kg/m2obesity is defined with a BMI above 30 kg/m2(see table).

Classification of weight by using body mass index (BMI)
BMIClassification
<18,5underweight
18,5-24,9Norma
25,0-29,9overweight
30,0-34,9obesity (class I)
35,0-39,9obesity (class II)
>40extreme obesity (class III)

With the increase in BMI increases the risk of death from various causes, which do not depend on other risk factors. The most common diseases associated with obesity include cardiovascular disease (particularly hypertension), diabetes (obesity increases the development of diabetes), gallbladder disease (especially cancer) and diseases related to reproductive function. Studies have shown that even moderate weight loss can give a significant reduction in risk of coronary disease.

However, when determining the BMI of the problem, namely, that it does not take into attention to detail the proportions of body weight, namely muscle mass relative to fat (adipose tissue). Taking this into consideration, obesity can also be determined on the basis of fat content in the body: more than 25% in men and more than 30% in women.

Obesity significantly increases the risk of developing cardiovascular disease. Coronary insufficiency, atheromatous disease and heart failure are at the head of cardiovascular complications caused by obesity. It is calculated that if the entire population will have the perfect weight, the risk of coronary heart disease will drop to 25% and the risk of heart failure and injury of cerebral vessels will be reduced by 35%. Cases of coronary disease doubled in patients younger than 50 years who have a 30% excess weight. Patients with diabetes have a vital resource for 30% less. After 45 years in people with diabetes, the likelihood of heart disease is three times more than people without diabetes, and the probability of hit five times. These findings confirm the relationship between risk factors for NIDDM and coronary heart disease and the potential value of an integrated approach to the prevention of these conditions based on the prevention of obesity (Perry, I. J., et al., BMJ 310, 560-564 (1995)).

Diabetes is also involved in the development of kidney disease, eye diseases and problems of the nervous system. Kidney disease, also on the " nephropathy, occurs when a filtering mechanism of the kidneys are damaged, protein leaks into the urine in excessive amounts, which leads to kidney failure. Diabetes is a major cause of damage to the retina at the rear of the eyeball, and increases the risk of cataracts and glaucoma. Finally, diabetes is associated with damage to the nerves, especially in the legs and feet, which disrupts the ability to feel pain, and contributes to serious infections. Taken together, diabetic complications are one of the leading causes of death in the nation.

The first line of treatment is diet and change in lifestyle of patients, such as decreased fat in the diet and increasing physical activity. However, many patients find it difficult and need additional help in the form of drug therapy to maintain the results of these efforts.

Most of the products presented on the market were not successful from the point of view of the treatment of obesity because of lack of efficacy or unacceptable side effects. The most successful drug is now considered to be indirectly acting as an agonist at 5-hydroxytryptamine (NT) d-fenfluramine (Redux™), but cases of defects of the heart valves, one third of patients have caused its cancellation by the FDA in 1998

In addition, in the United States and Europe have recently been released two drug what s means: orlistat (Xenical™ ), a drug that prevents the absorption of fat by inhibiting pancreatic lipase, and sibutramine (Reductil™), an inhibitor of the reuptake NT/norepinephrine. However, side effects associated with these products may limit their use for a long time. Treatment Xenical™as described, increases the disorder of the gastrointestinal tract in some patients, and treatment with sibutramine is associated with increased blood pressure in some patients.

Neurotransmission serotonin (NT) plays an important role in many physiological processes in health disorders and mental disorders. NT involved in the regulation of the conduct of food for a certain period of time. It is believed that T causes a feeling of fullness or satiety, thus the intake ends earlier and consumed fewer calories. It was shown that the stimulatory effect NT on T2Cthe receptor plays an important role in the control of power, and in action against obesity d-fenfluramine. As T2Creceptor expressives in large quantities in the brain (namely, in the limbic structure, extrapyramidal tracts, optic tubercle and the hypothalamus, i.e. VAT and DMH, and mainly in gorodno plexus) and is expressed in fewer or who has in peripheral tissues, selective agonist NT2Cthe receptor may be more effective and safe agent against obesity. Mouse without NC2Coverweight with cognitive deterioration and prone to attacks.

I believe that NT2Cmay play a role in obsessive-compulsive condition, some forms of depression and epilepsy. Therefore, agonists may have antipanicescoe action and action, which is useful for the treatment of sexual dysfunction.

In General, T2Cthe receptor is an active and well-known target receptor for the treatment of obesity and psychiatric disorders, and it is obvious that there is a need for selective agonists NT2Cthat safely reduce the amount of food intake and body weight. This invention relates to these and other important purposes.

Brief description of the invention

This invention, in one aspect, relates to compounds represented by formula (I)

where

R1is N or C1-8by alkyl;

R2is1-8by alkyl, -CH2-O-C1-8by alkyl, -C(=O)-O-C1-8by alkyl, -C(=O)-NH-C1-8the alkyl or CH2IT;

R2ais N or CH3;

or R2and R2atogether form-CH2-CH2-;

R3and R each independently is H, halogen, perhalogenated (preferably CF3), CN, OR5, SR5, Other5N(R5)2, aryl or heteroaryl, where specified, the aryl may optionally having up to two substituents selected from C1-8of alkyl, halogen and alkoxy, and the specified heteroaryl may not necessarily be up to two substituents selected from halogen and C1-8of alkyl;

or R3and R4together with the atoms to which they are attached, may form a 5 - or 6-membered heterocyclic ring having one atom Of;

each R5independently is C1-8the alkyl, C1-8alkenyl, aryl, heteroaryl, arylalkyl, heteroallyl or perhalogenated; and

R6is N or C1-8by alkyl;

or their pharmaceutically acceptable salt, solvate or hydrate,

provided that:

(A) if R2is stands and R1and R3both are H, R4is not a thiazole, substituted thiazole or a derivative of thiazole;

(B) if R6different from N, any R3or R4cannot be N;

(C) if R1and R2are the stands and R4is H, R3there can be other5or N(R5)2;

(D) if R1and R2are the stands and R4is H, R3cannot be established, umestnim the imidazole or imidazole derivative; and

(E) if R3is HE and R1is stands, R2can't be cyclopentyl, -CH2-cyclohexyl, cyclopropylmethyl or cyclohexyl.

In some embodiments, compounds and methods in accordance with this invention, if R1, R2a, R3and R6are H and R2is stands, R4may not be a chlorine atom.

In other embodiments, the compounds and methods in accordance with this invention, if R1, R2a, R3and R6is H and R2is stands, R4may be a chlorine atom.

In some alternative embodiments of compounds of formula (I), if R4is OR5, R2may not be alkyl.

In some embodiments of compounds of formula (I) R1is N. In some embodiments of compounds of formula (I) R1is1-8the alkyl. In some embodiments of compounds of formula (I) R1is stands. In some embodiments of compounds of formula (I) R1is n-propylene.

In some embodiments of compounds of formula (I) R2is1-8the alkyl. In some embodiments of compounds of formula (I) R2is stands. In some embodiments of compounds of formula (I) R2is ethyl. In some embodiments of compounds of formula (I) R2is isopropyl. In some is, some embodiments of compounds of formula (I) R 2and R2atogether form-CH2-CH2-.

In some embodiments of compounds of formula (I) R3is a halogen. In some embodiments of compounds of formula (I) R3is chlorine. In some embodiments of compounds of formula (I) R3is bromine. In some embodiments of compounds of formula (I) R3is iodine. In some embodiments of compounds of formula (I) R3is perhalogenated. In some embodiments of compounds of formula (I) R3is CF3. In some embodiments of compounds of formula (I) R3is 5-membered heteroaryl ring having up to two heteroatoms selected from O, N and S. In some embodiments of compounds of formula (I) R3is a radical derived from thiophenyl, furanyl, pyrrolyl, pyrazolyl or imidazolyl.

In some embodiments of compounds of formula (I) R4is perhalogenated. In some embodiments of compounds of formula (I) R4is CF3. In some embodiments of compounds of formula (I) R4is-OR5. In some embodiments, R5is stands, ethyl, n-propylene, isopropyl or allyl. In some embodiments of compounds of formula (I) R5is stands or allyl. In some embodiments of compounds of formula (I) R4is 5-membered heteroaryl ring having IDPs shall be up to two heteroatoms, selected from O, N and S, and up to two substituents selected from halogen and C1-8the alkyl. In some embodiments, R4is a radical derived from thiophenyl, furanyl, pyrrolyl, pyrazolyl or imidazolyl, which may be optionally mono - or tizamidine substituents selected from halogen or methyl. In some embodiments of compounds of formula (I) R4is phenyl, optionally having up to two substituents selected from C1-8of alkyl, halogen and alkoxy. In some embodiments of compounds of formula (I) R4and R3taken together form-O-CH=C(CH3)-.

In some embodiments of compounds of formula (I) R3is halogen and R4is-OR5where R5is1-8the alkyl. In some embodiments of compounds of formula (I) R3is chlorine and R4is-OR5where R5is1-8the alkyl. In some embodiments of compounds of formula (I) R3is bromine and R4is-OR5where R5is1-8the alkyl. In some embodiments of compounds of formula (I) R3is iodine and R4is-OR5where R5is1-8the alkyl. In some embodiments of compounds of formula (I) R3is halogen and R4is methoxy. In some embodiments, compounds of the forms of the crystals (I) R 3is halogen and R4is allyloxy.

In some embodiments of compounds of formula (I) R3is H and R4is 5-membered heteroaryl ring having up to two heteroatoms selected from O, N and S, and up to two substituents selected from halogen and C1-8the alkyl, or R4is phenyl, optionally having up to two substituents selected from C1-8of alkyl, halogen and alkoxy.

In some embodiments of compounds of formula (I) R3is H and R4is disubstituted with pyrazole or mangalasasanam by phenyl. In some such embodiments, compounds of formula (I) Deputy of pyrazole is bromine and methyl.

In some embodiments of compounds of formula (I) R3is OR5. In some embodiments of compounds of formula (I) R3is OR5where R5is1-8the alkyl. In some embodiments of compounds of formula (I) R3is OR5where R5is aryl. In some embodiments of compounds of formula (I) R3is OR5where R5is heteroaryl. In some embodiments of compounds of formula (I) R3is OR5where R5is arylalkyl. In some embodiments of compounds of formula (I) R3is OR5where R5is arylmethyl. In some Islands Ianto compounds of formula (I) R 3is OR5where R5is heteroallyl. In some embodiments of compounds of formula (I) R3is OR5where R5is heteroaromatic. In some embodiments of compounds of formula (I) R3is OR5where R5is perhalogenated. In some embodiments of compounds of formula (I) R3is OR5where R5is allyl.

In some embodiments of compounds of formula (I)

R2is stands, ethyl, isopropyl or CH2IT; or R2and R2atogether form-CH2-CH2-;

R3is H, halogen, or a 5-membered heteroaryl ring having up to two heteroatoms selected from O, N and S, and up to two substituents selected from halogen and C1-8of alkyl;

R4is alkoxy, 5-membered heteroaryl ring having up to two heteroatoms selected from O, N and S, and up to two substituents selected from halogen and C1-8the alkyl, or phenyl, optionally having up to two substituents selected from C1-8of alkyl, halogen and alkoxy;

or R3and R4together form-O-CH=C(CH3)-; and

R6is H or stands;

or their pharmaceutically acceptable salt, solvate or hydrate.

In some embodiments of compounds of formula (I)

R2 is stands, ethyl, isopropyl or CH2IT; or R2and R2atogether form-CH2-CH2-;

R3is chlorine, bromine or iodine;

R4is alkoxy; and

R6is H or stands;

or their pharmaceutically acceptable salt, solvate or hydrate.

In some embodiments of compounds of formula (I)

R1is N;

R2is stands;

R3is H, chlorine, bromine or thiophene;

R4is alkoxy, pyrazole-3-yl or phenyl, optionally having up to two substituents selected from C1-8of alkyl and halogen, where specified phenyl has one halogen Deputy; and

R6is N;

or their pharmaceutically acceptable salt, solvate or hydrate.

In some embodiments of compounds of formula (I) compound is a member of the group, including: 8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7 allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; N-propyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-hydroxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7 allyloxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; 3,5-DIMET the l-6,7,8,9-tetrahydro-5H-1-oxa-7-Aza-Cycloheptane; 7 allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7 allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-7-methoxy-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepin; 7 allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(4-bromo-2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(3-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(2-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; 7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; N-methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; 1-methyl-7-triptoreline-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-iodine-1-methyl-7-triptoreline-2,3,4,5-tetrahydro-1H-3-benzazepin; N-propyl-8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; 1-ethyl-8-iodine-7-methoxy-2,3,4,5-tetrahydro-1H-benzazepin; 7-(3-methoxyphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(2,6-differenl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(2-forfinal)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(2-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(3-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(4-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-(2-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin and 8-bromo-1-methoxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin or their pharmaceutically acceptable salt, solvate or hydrate.

In some embodiments of compounds of formula (I) compound is a member of the group, including: 8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; N-methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-iodine-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepin and 7-methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepin or their pharmaceutically acceptable salt, solvate or hydrate.

In some embodiments of compounds of formula (I) compound is a member of the group, including: 8-chloro-1-methyl-2,3,4,5-tetrahed is about-1H-3-benzazepin; 8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-iodine-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin; 7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; 7,8-dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin and 8-chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin or their pharmaceutically acceptable salt, solvate or hydrate.

This invention also provides compositions containing one or more compounds in accordance with this invention and one or more pharmaceutically acceptable carriers.

This invention also presents methods of modulating T2Creceptor, comprising contacting a specified receptor with a pharmaceutically effective amount of the compounds or compositions in accordance with this invention. Preferably the specified compound is an agonist of a specified receptor.

This invention also presents methods of prevention or treatment of disorders of the Central nervous system; damage to the Central nervous system; cardiovascular disorders; gastrointestinal RA the housing; diabetes insipidus, and sleep apnea, comprising the administration to a patient in need of such prevention or treatment an effective dose of the compounds in accordance with this invention.

In some embodiments, Central nervous system disorders include depression, atypical depression, bipolar disorders, anxiety, obsessive-compulsive condition, social phobias or panic States, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with headache or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related mental disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, nervous nervosa and premenstrual syndrome. In some embodiments, the disorder of the Central nervous system is obesity.

In some embodiments, the damage to the Central nervous system occurs due to shock, trauma, neurodegenerative diseases or toxic or infective CNS diseases, including encephalitis and meningitis.

In some embodiments, a heart condition what about the vascular disease is thrombosis. In other embodiments, the gastrointestinal disorder is a dysfunction of gastrointestinal motility.

This invention further is a way of reducing food intake in a mammal, comprising the introduction of a specified mammal pharmaceutically effective amount of the compounds or compositions in accordance with this invention.

This invention also presents methods of inducing satiety in a mammal, comprising the introduction of a specified mammal pharmaceutically effective amount of the compounds or compositions in accordance with this invention.

This invention further is a means of weight control mammals, including the introduction of specified mammal pharmaceutically effective amount of the compounds or compositions in accordance with this invention.

This invention also presents methods of treating obesity, comprising administration to a patient in need of such treatment, a pharmaceutically effective amount of the compounds or compositions in accordance with this invention.

In some embodiments, some of the above methods in accordance with this invention also include the stage of identification of the object when the specified object needs to reduce food intake, weight control or Le is the situation of obesity, where this stage of identification is carried out before the introduction of the specified object to the specified pharmaceutically effective amount of the compounds or compositions in accordance with this invention.

One aspect of this invention relates to the compound of formula (I) for use in the method of treatment of the human or animal body by therapy.

One aspect of this invention relates to the compound of formula (I) for use in a method of prevention or treatment of disorders of the Central nervous system; damage to the Central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus, and sleep apnea. In some embodiments, Central nervous system disorders selected from the group including depression, atypical depression, bipolar disorders, anxiety, obsessive-compulsive condition, social phobias or panic States, sleep disorders, sexual dysfunction, psychosis, schizophrenia, migraine and other conditions associated with headache or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, vozrast the e memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, nervous anorexia and premenstrual syndrome. In some embodiments, the disorder is obesity.

One aspect of this invention relates to compounds of formula (I) for the manufacture of a medicinal product for use in the prevention or treatment of disorders of the Central nervous system; damage to the Central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus, and sleep apnea. In some embodiments, Central nervous system disorders selected from the group including depression, atypical depression, bipolar disorders, anxiety, obsessive-compulsive condition, social phobias or panic States, sleep disorders, sexual dysfunction, psychosis, schizophrenia, migraine and other conditions associated with headache or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related mental disorders, chronic fatigue syndrome, drug and alcohol dependence, obesity, bulimia, the nerve is th nervosa and premenstrual syndrome. In some embodiments, the disorder is obesity.

In some embodiments, the invention is ways to relieve symptoms of any diseases, conditions or disorders mentioned above.

The applicants of the present invention reserves the right to exclude any one or more compounds of any variant of the present invention. The applicants of the present invention also reserves the right to exclude any disorder of any variant of the present invention.

Brief description of drawings

On figa-1G presents the effect of seven different compounds in accordance with this invention on food consumption have been fasting rats.

Detailed description of the invention

This invention relates to compounds of the agonists NT2Creceptor, methods of modulating T2Creceptor by contacting the receptor with one or more compounds in accordance with this invention. This invention also relates to methods of reducing food intake, weight control or treatment of obesity with the use of compounds in accordance with this invention.

The term "antagonist" means groups that are competitive in contact with the receptor in the same place as agonists (e.g., the endogenous ligand), but which does not activate within kletocny reply caused by the active form of the receptor, and thereby inhibit the intracellular responses induced by agonists or partial agonists. Antagonists do not reduce the baseline intracellular response in the absence of the agonist or partial agonist. In this description, the term "agonist" means a group that activate the intracellular response when binding with the receptor or enhance GTP binding to membranes. In the context of this invention, a pharmaceutical composition comprising the agonist NT2Creceptor in accordance with this invention, can be used to modulate activity T2Creceptor, reducing food intake, including saturated (for example, the feeling of fullness), weight control, obesity, weight loss and/or impact on the metabolism so that the patient lose weight and/or maintained weight. Such pharmaceutical compositions can be used for disorders and/or diseases in which increased weight is a component of the disease and/or disorders, such as obesity.

In this description, the term "contact" or "contacting" means the connection of these groups together, in in vitro or in vivo system. Thus, "contacting" NT2Creceptor with the compound in accordance with this invention includes an introduction connections in the accordance with this invention the animal, having NC2Creceptor, but also, for example, the introduction of compounds in accordance with this invention in a sample containing a cellular or a more purified preparation containing NC2Cthe receptor.

Compounds in accordance with this invention include compounds having the formula (I)shown below

where

R1is N or C1-8by alkyl;

R2is1-8by alkyl, -CH2-O-C1-8by alkyl, -C(=O)-O-C1-8by alkyl, -C(=O)-NH-C1-8the alkyl or CH2IT;

R2ais H; or R2and R2atogether form-CH2-CH2-;

R3and R4each independently is H, halogen, perhalogenated (preferably CF3), CN, OR5, SR5, Other5N(R5)2, aryl or heteroaryl, where specified, the aryl may optionally having up to two substituents selected from C1-8of alkyl, halogen and alkoxy, and the specified heteroaryl may not necessarily be up to two substituents selected from halogen and C1-8of alkyl;

or R3and R4together with the atoms to which they are attached, may form a 5 - or 6-membered heterocyclic ring having one atom Of;

each R5independently is C1-8the alkyl, C1-8alkenyl, aryl, heteroaryl, and what jalkala, heteroallyl or perhalogenated; and

R6is N or C1-8by alkyl;

or their pharmaceutically acceptable salt, solvate or hydrate,

provided that:

(A) if R2is stands and R1and R3both are H, R4is not a thiazole, substituted thiazole or a derivative of thiazole;

(B) if R6different from N, any R3or R4cannot be N;

(C) if R1and R2are the stands and R4is H, R3there can be other5or N(R5)2;

(D) if R1and R2are the stands and R4is H, R3can't be imidazole, substituted imidazole or imidazole derivative; and

(E) if R3is HE and R1is stands, R2can't be cyclopentyl, -CH2-cyclohexyl, cyclopropylmethyl or cyclohexyl;

or when conditions (A), (B), (C), (D) above, and if R4is OR5, R2may not be alkyl.

In some embodiments, compounds and methods in accordance with this invention, if R1, R2a, R3and R6are H and R2is stands, R4may not be a chlorine atom.

In other embodiments, the compounds and methods in accordance with this invention, if R1, R2a, R3and R6javljaetsja and R 2is stands, R4may be a chlorine atom.

In some embodiments, if R4is OR5, R2can't be cyclopentyl, -CH2-cyclohexyl, 3,3-dimethyl-2-allyl, 3,3-dimethyl-2-methylallyl, 2-methylallyl, 2-butanolom, cyclopropylmethyl, cyclohexyl or allyl.

It is clear that the compounds of formula (I) can have one or more chiral centers and can exist as enantiomers or diastereomers. It is clear that this invention extends to all such enantiomers, diastereomers and mixtures thereof, including racemates. Formula (I) and the following formulas are all individual isomers and mixtures thereof, unless stated or shown otherwise.

In this description, the term "alkyl" refers to hydrocarbon groups, including straight, 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. In this description should be understood that the term alkyl includes both acyclic hydrocarbon groups and cyclic hydrocarbon groups. In some embodiments, compounds in accordance with this invention alkyl gruppenleiter acyclic. In other embodiments, alkyl groups are cyclic, and third embodiments, alkyl groups are cyclic, and acyclic. Unless defined preferences, the term "alkyl" refers to both cyclic and acyclic groups.

In this description, the term "alkenyl" means hydrocarbon compounds, including straight, branched and cyclic hydrocarbons that contain at least one double bond, including, for example, but not limited to, allyl, 2-methylallyl, 4-but-3-enyl, 4-Gex-5-enyl, 3-methylbut-2-enyl, cyclohex-2-enyl and the like.

In this description, the term "halogen" has its ordinary meaning of the elements of the seventh period, including F, Cl, Br and I.

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

The term "arylalkyl" or "aralkyl" means an alkyl group which has aryl Deputy, for example, benzyl group. The term "alkylaryl" or "alkaryl" means an aryl group which has an alkyl substituent, such as 4-methylphenylene group.

In this description, the term "aryl" means a monocyclic or polycyclic aromatic group. Although the aryl group may contain from 3 carbon atoms, prepact the positive aryl groups have from 6 to 14 carbon atoms, more preferably from 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, antracol, tenantry and pyrenyl.

The term "heteroaryl" means an aryl group which contains at least one, preferably from one to four hetero atoms in the ring (i.e. atoms other than carbon, such as O, N or S). Examples of "heteroaryl" groups include radicals derived from 5 - and 6-membered aryl ring having from one to four nitrogen atoms, sulfur and/or oxygen, for example, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, furan, Piran, thiophene, benzimidazole, quinoline, isoquinoline, oxazole, thiazole and thiadiazole.

In this description, the term "heteroaromatic" means an alkyl group that has heteroaryl Deputy, for example, a group having the structure-CH2-pyrrol-2-yl.

The term "substituted thiazole" means a radical derived from thiazole, which has at least one Deputy. The term "derived thiazole" means a condensed ring system in which one of the condensed ring is a thiazole.

The term "substituted imidazole" means a radical derived from imidazole, which has at least one Deputy. The term "imidazole derivative" means a condensed ring system is, in which one of the condensed ring is imidazole.

In some embodiments of this invention R4is OR5. In some such embodiments, R2can't be cyclopentyl, -CH2-cyclohexyl, 3,3-dimethyl-2-allyl, 3,3-dimethyl-2-methylallyl, 2-methylallyl, 2-butanolom, cyclopropylmethyl, cyclohexyl or allyl. In other such embodiments, R2may not be alkyl.

In some embodiments of compounds of formula (I) R3is halogen and R4is-OR5. In some embodiments of compounds of formula (I) R5is allyl, 2-methylallyl, 4-but-3-anilam, 4-Gex-5-anilam, 3-methylbut-2-anilam or cyclohex-2-anilam. In some embodiments of compounds of formula (I) R5is stands, ethyl, n-propylene, isopropyl or allyl. In some embodiments of compounds of formula (I) R5is stands or allyl.

Certain substituents of the compounds presented herein, may optionally be substituted, i.e. they do not need to have their deputies. Some preferred substituents are halogen, lower alkyl (including, but not limited to, methyl, ethyl, isopropyl, cyclopropyl, tert-butyl and methylcyclopropyl), alkoxy, mono-, di - or trialgenericsi (for example, -O-CX3where X is halogen), -(CH2 yNH2, -(CH2)yNHBoc, -N(R4a)(R4b), phenyl, methoxyphenyl and naphthyl.

In various places of this description, the substituents of the compounds in accordance with this invention are described in groups or in intervals. Separately noted that the invention includes each and every individual subcombination members of such groups and intervals. For example, the term "C1-8alkyl" includes individually methyl, ethyl,3alkyl, C5alkyl, C6alkyl, C7alkyl and C8alkyl.

In preferred embodiments, the compounds of formula (I) chosen from:

8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7 allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-propyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-hydroxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7 allyloxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-Aza-cycloheptadiene; 7 allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-N-3-benzazepine; 8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7 allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-7-methoxy-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7 allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(4-bromo-2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(3-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(2-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 1-methyl-7-triptoreline-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-iodine-1-methyl-7-triptoreline-2,3,4,5-tetrahydro-1H-3-benzazepine; N-propyl-8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 1-ethyl-8-iodine-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(3-methoxyphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(2,6-differenl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(2-forfinal)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(2-triptoreline)--methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(3-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-(4-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-(2-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 8-bromo-1-methoxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine or their pharmaceutically acceptable salts, solvate or hydrate.

In a preferred embodiment, the compounds of formula (I) chosen from:

N-methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-iodine-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-7-methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine and N-methyl-7-methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or their pharmaceutically acceptable salts, solvate or hydrate.

In a preferred embodiment, the compounds of formula (I) chosen from:

N-methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-t is iformity-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-iodine-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-7,8-dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and N-methyl-8-chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or their pharmaceutically acceptable salts, solvate or hydrate.

In a preferred embodiment, the compounds of formula (I) chosen from:

8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-iodine-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 7-methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or their pharmaceutically acceptable salts, solvate or hydrate.

In a preferred embodiment, the compounds of formula (I) chosen from:

8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-thrift metil-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-iodine-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7,8-dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 8-chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or their pharmaceutically acceptable salts, solvate or hydrate.

Compounds in accordance with this invention can contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. Connections can be, for example, racemates or optically active forms. Optical active forms can be obtained by separation of racemates or asymmetric synthesis. In some embodiments, the compounds of formula (I) are R-enantiomers. In some embodiments, the compounds of formula (I) are S-enantiomers. In some embodiments, the compounds of formula (I) are different mixtures of enantiomers.

According to another aspect of the present invention the compounds of formula (I) are intended for use in therapy. The compounds of formula (I) can be used in the prevention or treatment of disorders related to the function T2Cthe receptor.

Connection is ormula (I) can be used in the prevention or treatment of disorders of the Central nervous system, including depression, atypical depression, bipolar disorders, anxiety, obsessive-compulsive condition, social phobias or panic States, sleep disorders, sexual dysfunction, psychosis, schizophrenia, migraine and other conditions associated with headache or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related mental disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, nervous anorexia and premenstrual syndrome; damage the Central nervous system, such as trauma, stroke, neurodegenerative diseases or toxic or infective CNS diseases, such as encephalitis or meningitis; cardiovascular diseases such as thrombosis; gastrointestinal disorders such as dysfunction of gastrointestinal motility; diabetes insipidus, and sleep apnea.

According to another aspect of the present invention presents the use of the compounds of formula (I) in the manufacture of a medicine for the prevention or treatment of the above diseases. In a preferred embodiment, the stand is established with representation from the use of the compounds of formula (I) in the manufacture of a medicine for the prevention or treatment of obesity.

Compounds in accordance with this invention may not necessarily exist in the form of pharmaceutically acceptable salts, including pharmaceutically acceptable acid additive salts of pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzosulfimide, benzoic, camphorsulfonic, lemon, atenololbuy, dichloracetic, formic, fumaric, gluconic, glutamic, hippuric, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate, mucus, nitric, oxalic, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluensulfonate and similar acids, such as pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977), which is included here by reference.

Acid additive salts can be obtained as direct product of the synthesis of compounds. Alternatively, the free base can be dissolved in a suitable solvent containing the appropriate acid and the salt can be isolated by evaporating the solvent or other separation of the salt and solvent. Compounds in accordance with this invention may form a solvate with conventional solvents with low molecularism using methods well-known experts in this field.

Compositions in accordance with this invention can be administered in unit dosage forms and may be obtained by any methods well known in the pharmaceutical field, for example, those described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980).

Compounds in accordance with this invention can be used as the sole active agent in the pharmaceutical composition or may be applied in combination with other active ingredients, which can improve therapeutic effect of the compound.

Compounds in accordance with this invention, or their solvate, or physiologically functional derivatives may be used as active ingredients in pharmaceutical compositions, particularly as agonists NT2Cthe receptor. The term "active ingredient" in the context of a "pharmaceutical composition" is understood component of the pharmaceutical composition that provides primary pharmaceutical favorable action, as opposed to the "inactive ingredient", which usually gives no pharmaceutical favorable action. The term "pharmaceutical composition" means a composition comprising at least one active ingredient and at least one ingredient is, which is not an active ingredient (for example, and not limited to, filler, dye or agent for sustained release), where the composition is intended for use for a specific, effective results in mammals (for example, and not limited to, a person).

The data presented here support the conclusion that described agonists NT2Creceptor intended for use for the treatment or prevention of clinical obesity or disorders caused by excess weight in mammals, including, but not limited to, humans. Compounds in accordance with this invention can be administered orally, sublingual, parenteral, rectal, local path or in the form of transdermal patches. Percutaneous patches distribute medication with controlled speed, releasing the drug for absorption effective way with minimal decomposition of the drug. Usually percutaneous patches include impermeable upper floor, single, pressure-sensitive adhesive layer and a removable protective layer with a disposable seal. Specialist in this field, if necessary, can recognize the methods suitable for producing the desired effective percutaneous patches.

In addition to the neutral forms of the compounds according to the data of the invention, with appropriate addition of an ionisable Deputy, that does not change the specificity of the compound to the receptor can be obtained physiologically acceptable salts of the compounds which are used as therapeutic agents. Different amounts of the compounds in accordance with this invention required to achieve the desired biological effect. The amount depends on various factors such as the particular compound that is intended for use, route of administration and the state of cure of the patient - all of these parameters dispensing well-known specialists in the field of medicine. A typical dose is in the range from 0.001 to 200 mg per kilogram of body weight of the mammal. The unit dose can contain from 1 to 200 mg of the compounds in accordance with this invention and can be administered one or more times per day, separately or in combination.

Pharmaceutical compositions, including, but not limited to, pharmaceutical compositions containing at least one compound in accordance with this invention and/or an acceptable salt or MES (for example, pharmaceutically acceptable salt or MES) as the active ingredient in combination with at least one carrier or excipient (for example, a pharmaceutical carrier or excipient), can the application is taken in the treatment of clinical conditions, which shows agonists NT2Cthe receptor. At least one connection in accordance with this invention can be combined with the carrier either in solid or in liquid form in a single dosage form. The pharmaceutical carrier must be compatible with other ingredients of the composition and must be perceived by the individual patients. Other physiologically active ingredients can be introduced into pharmaceutical compositions in accordance with this invention, if desired, if such ingredients are compatible with other ingredients of the composition. The composition can be obtained by any suitable method, typically homogeneous mixing of the active compounds (compounds) with liquid or powdered solid carriers, or both, in the required proportions, and then, if necessary, to obtain a mixture in the desired form.

Conventional excipients such as binding agents, fillers, acceptable moisturizing agents, tabletiruemye lubricants and disintegrant, can be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oil suspensions, and syrups. Alternative oral drugs may be in the form of dry powders, which can be recovered water and the and other appropriate liquid immediately before use. Additional additives, such as suspendresume or emulsifying agents, non-aqueous media (including edible oils), preservatives, and flavoring and coloring agents, may be added to liquid products. Parenteral dosage forms can be obtained by dissolving the compounds in accordance with this invention in a suitable liquid medium and sterilization by filtration of the solution prior to filling and sealing of suitable vials or ampoules. Presents just a few examples of the many suitable ways to get dosage forms well known in this field.

It is noted that when the agonists NT2Creceptor used as active ingredients in pharmaceutical compositions, they are not designed for use only in humans, and can be used in mammals other than man. In fact, the recent development of the field of animal health suggest that agonists NT2Cthe receptor can be used for the treatment of obesity in domestic animals (e.g. cats and dogs), and agonists NT2Cthe receptor can be used in other domestic animals even in the absence of obvious disease or disorder (e.g., suitable for use in food animals such as cows, chickens, fish etc). Specialist in data the second area will easily find ways of using these compounds for such cases.

Compounds in accordance with this invention can be easily obtained according to different methods of synthesis known to specialists in this field. Example of a General synthesis are presented in the following scheme, I:

Scheme 1

The General reaction scheme

Specialists in this field will understand that according to the scheme I can get a lot of compounds in accordance with this invention. For example, on the basis of appropriately substituted 2-phenylethylenediamine And having any of a variety of substituents R1and R2can be obtained the corresponding 7 - and/or 8-substituted 1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (compound H). N-alkylation may be carried out, for example, by treatment with excess paraformaldehyde (for methylation) or aldehyde of the highest order, with subsequent restoration NaBH3CN according to the General synthesis technique presented in examples 9 and 10 below. Furthermore, starting from an appropriately substituted 1-alkyl-2-phenylethylenediamine And having any of a variety of substituents R1and R2can be obtained the corresponding 7 - and/or 8-substituted 2,5-dialkyl-2,3,4,5-tetrahydro-1H-3-benzazepin.

In the synthesis of many compounds in accordance with this invention may require protective g is uppy to protect various functional groups during the synthesis. Examples of protective groups suitable for a variety of synthetic transformations described in Greene and Wuts, Protective Groups in Organic Synthesis, 2d ed, John Wiley & Sons, New York, 1991, the description of which is presented here by reference in full.

Obviously, there is no need to stage methods in accordance with this invention a certain number of times or in a certain sequence. Additional objects, advantages and new features of this invention will become apparent to the person skilled in the art upon study of the following examples, which are illustrative and do not limit the scope of the present invention.

EXAMPLES

Examples synthesis

Example 1

(R,S) 8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-3-methoxyphenethylamine

A solution of 3-methoxyphenethylamine (10.0 g, 64,0 mmol) in dichloromethane (150 ml) is cooled to a temperature of 0°and treated With pyridine (6.5 ml, 83.5 mmol), followed by adding dropwise triperoxonane anhydride (17.9 g, 83.5 mmol) and the resulting mixture is stirred for 3 hours while heating to a temperature of 20°C. the product Mixture was diluted with EtOAc (500 ml), sequentially washed with 10% aqueous HCl (100 ml), water (100 ml), saturated salt solution (100 ml), dried over Na2SO4and the oxygen is their obtaining to 15.8 g of a yellow oil. 1H-NMR (400 MHz, CDCl3) δ 7,26 (DD, J=8, 8 Hz, 1H), for 6.81 (d, J=8 Hz, 1H), 6,77 (d, J=8 Hz, 1H), 6,72 (s, 1H), 6.30-in (Sirs, 1H), 3,80 (s, 3H), 3,62 (DD, J=7, 7 Hz, 2H), 2,86 (DD, J=7, 7 Hz, 2H). MS calculated for C11H12F3NO2+H: 248, found: 248.

N-TRIFLUOROACETYL-2-iodine-5-methoxyphenethylamine

A solution of N-TRIFLUOROACETYL-3-methoxyphenethylamine (15,8 g, 64 mmol) in methanol (325 ml) cooled to a temperature of -78°and treated CaCO3(14,7 g, 145 mmol) followed by a solution of ICl (29 g, 181 mmol) in methanol (40 ml). The reaction is heated to a temperature of 20°under stirring overnight and then filtered, concentrated, dissolved in EtOAc (200 ml), washed twice with 5% aqueous sodium bisulfite (100 ml), once washed with saturated salt solution (100 ml), dried over Na2SO4and concentrate with the receipt of 23.8 g of a white solid powder.1H-NMR (400 MHz, CDCl3) δ to 7.68 (d, J=9 Hz, 1H), 6,76 (s, 1H), to 6.57 (d, J=9 Hz, 1H), 6.42 per (Sirs, 1H), of 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, found: 374.

N-allyl, N-TRIFLUOROACETYL-2-iodine-5-methoxyphenethylamine

A solution of N-TRIFLUOROACETYL-2-iodine-5-methoxyphenethylamine (23,8 g, to 63.8 mmol) in toluene (425 ml) was sequentially treated To a2CO3(12.4 g, by 89.8 mmol), KOH (11.6 g, 207 mmol), n-Bu4NBr (2.2 g, 6,9 mmol) and allylbromide (10.7 g, by 89.8 mmol). The mixture is stirred at t is mperature 80° C for 3.5 hours, cooled to a temperature of 20°C, acidified with 10% aqueous HCl, separated and the aqueous phase is extracted with simple ether (500 ml). The combined organic phases are washed with saturated salt solution (200 ml), dried over Na2SO4and concentrate to obtain 20.5 g of a brown oil.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ to 7.67 (m, 1H), 6,80 (m, 1H), to 6.57 (m, 1H), 5,9-5,6 (SIRM, 1H), 5,27 (m, 2H), 4,11 (d, J=6 Hz, 0,5H), 3,85 (d, J=6 Hz, 0,5H), of 3.77 (m, 3H), 3,55 (m, 2H), 3,00 (m, 2H). MS calculated for C14H15F3INO2+H: 414, found: 414.

N-TRIFLUOROACETYL-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-allyl, N-TRIFLUOROACETYL-2-iodine-5-methoxyphenethylamine (20.5 g, 50 mmol) in dimethylformamide (250 ml) is treated with COAs (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 a temperature of 90°C. the product Mixture is cooled to a temperature of 20°, filtered, diluted with water (500 ml) and extracted with simple ether (3×500 ml). The combined organic phases are washed with water (100 ml), saturated salt solution (100 ml), dried over Na2SO4and concentrate. Flash chromatography (10% EtOAc in hexane, silica) to give 6.6 g of a yellow oil.1H-NMR (400 MHz, CDCl3) δ 7,26 (d, J=8 Hz, 1H), 6,77 (d, J=8 Hz, 1H), 6,66 (s, 1H), 5,34-5,19 (m, 2H), and 4.40 (m, 2H), 3,83 (m, 2H), 3,80 (s, 3H), of 3.00 (m, 2H) MS calculated for C 14H14F3NO2+H: 285, found: 285.

N-TRIFLUOROACETYL-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (6.6 g, 23.2 mmol) in ethanol (100 ml) is treated with 10% Pd/C (0.75 g, 2.3 mmol) and stirred overnight in a hydrogen atmosphere. The product mixture was filtered through a layer of celite and silicon dioxide and the solvent is removed to obtain 6,27 g of a white solid.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ 7,10 (m, 1H), 6,74 (m, 1H), of 6.68 (m, 1H), 4,1-3,8 (SIRM, 2H), and 3.8 (s, 3H), 3,5 (m, 1,5H), 3,4 (m, 0,5H), 3,2-2,9 (SIRM, 4H), 1,32 (m, 3H). MS calculated for C14H16F3NO2+H: 288, found: 288.

N-TRIFLUOROACETYL-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

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) is treated with N-bromosuccinimide (0,852 g, 4,79 mmol) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with EtOAc (200 ml), washed with saturated aqueous sodium bisulfite (100 ml) and saturated salt solution (100 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) to give 1.55 g of a clear oil.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ 7,34 (s, 1H), 6,65 (m, 1H), a 3.87 (s, 3H), 3,81 (m, 1H), 3,55 (m, 1,3H), 3,37 (m, 0,7H), 3,2-2,9 (width is, 4H), of 1.30 (m, 3H). MS calculated for C14H15BrF3NO2+H: 366, found: 366.

8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.95 g, at 2.59 mmol) in methanol (20 ml) is treated with 15% aqueous NaOH (25 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with water (100 ml), twice extracted with EtOAc (100 ml), the combined organic phases are washed with saturated salt solution (100 ml), dried over Na2SO4and concentrate to obtain 0,687 g of a clear oil.1H-NMR (400 MHz, CDCl3) δ a 7.92 (s, 1H), 6,34 (s, 1H), a 3.87 (s, 3H), of 3.1 and 2.9 (m, 6H), to 2.75 (m, 1H), 2,60 (Sirs, 1H), 1,31 (d, J=7 Hz, 3H). MS calculated for C12H16BrNO+H: 270, found: 270.

Example 2

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

N-TRIFLUOROACETYL-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (to 0.900 g, to 2.67 mmol) in acetonitrile (30 ml) is treated with N-chlorosuccinimide (0,357 g, to 2.67 mmol) and stirred overnight at a temperature of 70°C. the product Mixture was diluted with water (100 ml), twice extracted with EtOAc (100 ml), the combined organic phases are washed with saturated salt solution (100 ml), dried over Na2SO4/sub> and concentrate. Flash chromatography (20% EtOAc in hexane, silica) gives 0,399 g of a clear oil.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ 7,17 (s, 1H), of 6.68 (m, 1H), 3,88 (s, 3H), of 3.78 (m, 1H), 3,6-3,3 (m, 2H), 3,2-a 2.9 (m, 4H), of 1.34 (m, 3H). MS calculated for C14H15ClF3NO2+H: 322, found: 322.

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

A solution of N-TRIFLUOROACETYL-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0,399 g of 1.24 mmol) in methanol (20 ml) is treated with 15% aqueous NaOH (20 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with water (100 ml), twice extracted with EtOAc (100 ml), the combined organic phases are washed with saturated salt solution (100 ml), dried over Na2SO4and concentrate to obtain 0,306 g yellow solid.1H-NMR (400 MHz, CDCl3) δ 7,05 (s, 1H), 6,59 (s, 1H), 3,80 (s, 3H), from 3.0 to 2.8 (m, 6H), 2,62 (m, 1H), 2,16 (Sirs, 1H), 1,24 (d, J=7 Hz, 3H). MS calculated for C12H16ClNO+H: 226, found: 226.

Example 3

(R,S) 8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.50 g, with 5.22 mmol) in methanol (70 ml) is treated CaCO3(1.06 g, 10,44 mmol) followed by treatment of RA is tworoom ICl (1.70 g, 10,44 mmol) in methanol (10 ml), and stirred overnight at a temperature of 20°C. the product Mixture was filtered, concentrated, dissolved in EtOAc (200 ml), extracted twice with 5% aqueous sodium bisulfite (100 ml), once with saturated salt solution (100 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) to give 1.54 g of a white solid.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ at 7.55 (m, 1H), to 6.57 (m, 1H), 3,86 (s, 3H), 3,80 (m, 1H), 3,60-3,30 (m, 2H), 3,20 is 2.80 (m, 4H), of 1.30 (m, 3H). MS calculated for C14H15F3INO2+H: 414, found: 414.

8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0,600 g, 1,45 mmol) in methanol (20 ml) is treated with 15% aqueous NaOH (20 ml) and stirred for 3 hours at a temperature of 50°C. the product Mixture was diluted with water (100 ml), twice extracted with EtOAc (100 ml), the combined organic phases are washed with saturated salt solution (100 ml), dried over Na2SO4and concentrate to obtain 0,425 g yellow solid.1H-NMR (400 MHz, CDCl3) δ 7,52 (s, 1H), to 6.57 (s, 1H), 3,86 (s, 3H), 3,12-of 3.06 (m, 4H), 2.95 and (m, 2H), 2,75 (m, 1H), 2,43 (Sirs, 1H), 1,33 (d, J=8 Hz, 3H). MS calculated for C12H16INO+H: 318, found: 318.

Example 4

(R,S) 8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1 is-3-benzazepin

N-TRIFLUOROACETYL-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.50 g, 4,10 mmol) in dichloromethane (80 ml) dropwise treated with BBr3(9.4 ml of a 1.0 M solution in CH2Cl2, 9.4 mmol) and the mixture is stirred overnight while heating to a temperature of 20°C. Excess BBr3removed by adding water dropwise, the mixture is diluted with simple ether (200 ml), washed with Na2CO3(100 ml) and saturated salt solution (100 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) to give 1.25 g of a white solid foam.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ to 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-benzazepin

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) is treated with 15% aqueous NaOH (20 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with water (100 ml), twice extracted with EtOAc (100 ml), the combined organic phases are washed with saturated salt solution (100 ml), dried over Na2SO4and concentrate to obtain 0,460 g of a clear oil.1H-NMR (400 MHz, DMSO-d6) ´ 7,11 (s, 1H), 6,65 (s, 1H), 2,90 (m, 1H), 2,73 (m, 5H), to 2.55 (m, 1H), 1,19 (d, J=7 Hz, 3H). MS calculated for C11H14BrNO+H: 256, found: 256.

Example 5

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

N-TRIFLUOROACETYL-7-allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

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) is treated with allylbromide (0,155 g, 1.28 mmol) and DBU (of € 0.195 g, 1.28 mmol) and the mixture is stirred for 2 hours at a temperature of 20°C. the product Mixture was diluted with EtOAc (50 ml), washed with 5% aqueous HCl (20 ml), saturated salt solution (20 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) gives 0,149 g of a clear oil.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ 7,34 (s, 1H), 6,65 (m, 1H), 6,04 (m, 1H), vs. 5.47 (d, J=17 Hz, 1H), and 5.30 (d, J=9 Hz, 1H), 4,59 (s, 2H), 3,80 (m, 1H), 3,6-3,3 (m, 3H), of 3.2 to 2.8 (m, 4H), to 1.31 (m, 3H). MS calculated for C16H17BrF3NO2+H: 392, found: 392.

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

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) is treated with 15% aqueous NaOH (35 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with water (200 ml), dwai the s extracted with EtOAc (200 ml), the combined organic phases are washed with saturated salt solution (100 ml), dried over Na2SO4and concentrate to obtain 0,880 g of a clear oil.1H-NMR (400 MHz, CDCl3) δ 7,29 (s, 1H), 6,63 (s, 1H), 6,04 (m, 1H), vs. 5.47 (d, J=17 Hz, 1H), from 5.29 (d, J=11 Hz, 1H), 4,58 (s, 2H), 3,01 (m, 3H), 2,89 (m, 3H), of 2.75 (m, 1H), 1,31 (d, J=7 Hz, 3H). MS calculated for C14H18BrNO+H: 296, found: 296.

Example 6

(R,S) 7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

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) is treated with benzylbromide (0,072 g, 0.64 mmol), DBU (0,100 g, 0.64 mmol) and stirred for 2 hours at a temperature of 20°C. the product Mixture was diluted with EtOAc (50 ml), washed with 5% aqueous HCl (20 ml), saturated salt solution (20 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) network of 0.081 g of a clear oil. MS calculated for C20H19BrF3NO2+H: 442, found: 442.

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

A solution of N-TRIFLUOROACETYL-7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0,81 g and 1.83 mmol) in methanol (20 ml) is treated with 15% aqueous NaOH (20 ml) and paramashiva the t overnight at a temperature of 20° C. the product Mixture was diluted with water (200 ml), twice extracted with EtOAc (200 ml), the combined organic phases are washed with saturated salt solution (100 ml), dried over Na2SO4and concentrate to obtain 0,412 g of a clear oil.1H-NMR (400 MHz, CDCl3) δ 7,38 (d, J=8 Hz, 2H), 7,30 (DD, J=7, 8 Hz, 2H), 7.23 percent (m, 2H), is 6.61 (s, 1H), to 5.03 (s, 2H), 2,94 (m, 3H), of 2.81 (m, 3H), 2,62 (m, 1H), 2,30 (Sirs, 1H), 1,24 (d, J=7 Hz, 3H). MS calculated for C18H20BrNO+H: 346, found: 346.

Example 7

(R,S) 8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

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) is treated with ethyliodide (0,016 g is 0.102 mmol), DBU (0,016 g is 0.102 mmol) and stirred for 2 hours at a temperature of 20°C. the product Mixture was diluted with EtOAc (10 ml), washed with 5% aqueous HCl (5 ml), saturated salt solution (5 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) gives 0,010 g of a clear oil.

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

A solution of N-TRIFLUOROACETYL-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0,010 g, was 0.026 mmol) in methanol (1 ml) is treated with 15% aqueous NaOH (1 ml) and stirred for n is Chi at a temperature of 20° C. the product Mixture was diluted with water (3 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (3 ml), dried over Na2SO4and concentrate to obtain 0,007 g of a clear oil.1H-NMR (400 MHz, CDCl3) δ 7,29 (s, 1H), 6,63 (s, 1H), 4,07 (kV, J=6 Hz, 2H), 3,03 (m, 3H), 2.91 in (m, 3H), 2,73 (m, 1H), 2.26 and (Sirs, 1H), 1,46 (t, J=6 Hz, 3H), 1,32 (d, J=7Hz,3H). MS calculated for C15H17BrF3NO2+H: 380, found: 380.

Example 8

(R,S) 8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.035 g, 0,099 mmol) in dichloromethane (1 ml) is treated with Isopropylamine (0.037 g, 0,297 mmol), DBU (0,048 g, 0,205 mmol) and stirred for 2 hours at a temperature of 20°C. the product Mixture was diluted with EtOAc (10 ml), washed with 5% aqueous HCl (5 ml), saturated salt solution (5 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) network of 0.014 g of a clear oil. MS calculated for C16H19BrF3NO2+H: 394, found: 394.

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

A solution of N-TRIFLUOROACETYL-8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetr the hydro-1H-3-benzazepine (0,014 g, 0.035 mmol) in methanol (1 ml) is treated with 15% aqueous NaOH (1 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with water (3 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (3 ml), dried over Na2SO4and concentrate to obtain 0.008 g of a clear oil.1H-NMR (400 MHz, CDCl3) δ from 7.24 (s, 1H), only 6.64 (s, 1H), 4,48 (m, 1H), 2,98 (m, 3H), 2,87 (m, 3H), of 1.36 (m, 6H), of 1.30 (d, J=7 Hz, 3H). MS calculated for C14H20BrNO+H: 298 found: 298.

Example 9

(R,S) N-methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of 8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (6 mg, of 0.022 mmol) in methanol (1 ml) is treated with excess paraformaldehyde, 1.0 M HCl in a simple ether (0,004 ml of 0.004 mmol), NaBH3CN (1.0 mg, of 0.013 mmol) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with 5% aqueous NaOH (5 ml), extracted three times CH2Cl2(5 ml each), the combined organic phases are dried over Na2SO4and concentrate. Flash chromatography (10% MeOH in CH2Cl2, silica) 5 mg of a clear oil.1H-NMR (400 MHz, CDCl3) δ 7,31 (s, 1H), 6,66 (s, 1H), a 3.87 (s, 3H), 3,26 (SIRM, 2H), 3,01 (Sirs, 1H), 2,85 (m, 2H), of 2.45 (s, 3H), 2,45 was 2.25 (m, 2H), 1,36 (d, J=7 Hz, 3H). MS calculated for C13H18BrNO+H: 284, Nai is prohibited: 284.

Example 10

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

A solution of 8-bromo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine (6 mg, of 0.022 mmol) in methanol (1 ml) is treated with Propionaldehyde (5.0 mg, 0,067 mmol), 1.0 M HCl in a simple ether (0,004 ml of 0.004 mmol), NaBH3CN (1.0 mg, of 0.013 mmol) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with 5% aqueous NaOH (5 ml), extracted three times CH2Cl2(5 ml each), the combined organic phases are dried over Na2SO4and concentrate. Flash chromatography (10% MeOH in CH2Cl2, silicon dioxide) to give 4 mg of a clear oil.1H-NMR (400 MHz, CD3OD) δ 7,33 (c, 1H), 6.87 in (c, 1H), 3,84 (s, 3H), of 3.25 (m, 2H), 3,11 (m, 2H), 2,97 (m, 1H), 2,78 (SIRM, 2H), 2.63 in (SIRM, 2H), 1,67 (m, 2H), 1,38 (d, J=7 Hz, 3H), of 0.96 (t, J=7 Hz, 3H). MS calculated for C15H22BrNO+H: 312, found: 312.

Example 11

(R,S) 7-hydroxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-7-hydroxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (80 mg, 0,19 mmol) in dichloromethane (3 ml) is treated with BBr3(and 0.40 ml of 1.0 M solution in CH2Cl2, 0.40 mmol) and the mixture is stirred overnight at a temperature of 20°C. Excess BBrsub> 3remove the addition of water, the mixture is diluted with simple ether (20 ml), washed with Na2CO3(10 ml) and saturated salt solution (10 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) to give 74 g of a white solid. MS calculated for C13H13F3INO2+H: 400 found: 400.

7-hydroxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-hydroxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (25 mg, 0,063 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with water (5 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (5 ml), dried over Na2SO4and concentrate to obtain 13 mg of a white solid.1H-NMR (400 MHz, CD3OD) δ 7,46 (s, 1H), only 6.64 (s, 1H), and 3.16 (m, 3H), 2,94 (m, 3H), of 2.81 (m, 1H), 1,35 (d, J=7 Hz, 3H). MS calculated for C11H14INO+H: 304, found: 304.

Example 12

(R,S) 7-allyloxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-7-allyloxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-hydroxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (30 mg, of 0.075 mmol) in dichloromethane (2 ml) is treated and what lilromeo (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred for 2 hours at a temperature of 20°C. the product Mixture was diluted with EtOAc (10 ml), washed with 5% aqueous HCl (5 ml), saturated salt solution (5 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) to give 23 mg of a clear oil. MS calculated for C16H17F3INO2+H: 440, found: 440.

7 allyloxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-allyloxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (23 mg, 0,058 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with water (5 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (5 ml), dried over Na2SO4and concentrate to obtain 18 mg of a white solid. MS calculated for C14H18INO+H: 344, found: 344.

Example 13

(R,S) 3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-Aza-Cycloheptane

N-TRIFLUOROACETYL-3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-Aza-Cycloheptane

A solution of N-TRIFLUOROACETYL-7-allyloxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (158 mg, 0,360 mmol) in dimethylformamide (4 ml) is treated with COAs (106 mg, of 1.08 mmol), n-Bu4NBr (116 mg, 0,360 mm is l), PPh3(13 mg, being 0.036 mmol), Pd(OAc)2(4 mg, 0.018 mmol) and stirred overnight at a temperature of 100°C. the product Mixture was filtered, add water (10 ml) and then twice extracted with EtOAc (10 ml). The combined organic phases are washed with saturated salt solution (10 ml), dried over Na2SO4and concentrate. Flash chromatography (5% EtOAc in hexane, silica) to give 15 mg of a clear oil. MS calculated for C16H16F3NO2+H: 312, found: 312.

3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-Aza-Cycloheptane

A solution of N-TRIFLUOROACETYL-3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-Aza-cycloheptadiene (15 mg, 0,048 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with water (5 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (5 ml), dried over Na2SO4and concentrate to obtain 10 mg of a white solid.1H-NMR (400 MHz, CDCl3) δ to 7.25 (s, 1H), 7,12 (s, 1H), to 7.09 (s, 1H), 3,12 (m, 1H), 2,97 (m, 4H), 2,85 (m, 1H), 2,64 (SIRM, 1H), 2,15 (s, 3H), of 1.34 (d, J=8 Hz, 3H). MS calculated for C14H17NO+H: 216, found: 216.

Example 14

(R,S) 7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetr the hydro-1H-3-benzazepin

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) is treated with BBr3(0,30 ml of 1.0 M solution in CH2Cl2, 0.30 mmol) and stirred overnight at a temperature of 20°C. Excess BBr3remove the addition of water, the mixture was diluted with simple ether (20 ml), washed with Na2CO3(10 ml) and saturated salt solution (10 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) to give 24 mg of a white solid. MS calculated for C13H13ClF3NO2+H: 308, found: 308.

N-TRIFLUOROACETYL-7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

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) is treated with allylbromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred for 2 hours at a temperature of 20°C. the product Mixture was diluted with EtOAc (10 ml), washed with 5% aqueous HCl (5 ml), saturated salt solution (5 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) to give 23 mg of a white solid. MS calculated for C16H17ClF3NO2+H: 348, found: 348.

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

A solution of N-Tr is peracetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin (23 mg, of 0.066 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with water (5 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (5 ml), dried over Na2SO4and concentrate to obtain 19 mg of a white solid.1H-NMR (400 MHz, CD3OD) δ for 7.12 (s, 1H), for 6.81 (s, 1H), 6,03 (m, 1H), 5,43 (d, J=17 Hz, 1H), 5,24 (d, J=10 Hz, 1H), 4,57 (d, J=5 Hz, 2H), 3,1 and 2.9 (m, 5H), of 2.81 (m, 1H), 2.63 in (m, 1H), 1,30 (d, J=7 Hz, 3H).

Example 15

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

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

A solution of N-TRIFLUOROACETYL-8-bromo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine (51 mg, 0.14 mmol) in 1,4-dioxane (2 ml) was treated with thiophene-2-Bronevoy 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 a temperature of 100°C. the product Mixture was diluted with EtOAc, filtered, adsorb on silica and purified flash chromatography (10% EtOAc in hexane, silica) to give 28 mg of yellow solid. MS calculated for C18H18F3NO2S+H: 370, found: 370.

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

A solution of N-TRIFLUOROACETYL-7-methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (28 mg, 0,076 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred for 0.5 hour at a temperature of 50°C. the product Mixture was diluted with water (5 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (5 ml), dried over Na2SO4and concentrate to obtain 18 mg of yellow oil.1H-NMR (400 MHz, CDCl3) δ was 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), of 6.71 (s, 1H), 3,90 (s, 3H), of 3.1 and 2.9 (m, 6H), 2,80 (m, 1H), 2,22 (Sirs, 1H), 1,38 (d, J=7 Hz, 3H). MS calculated for C16H19NOS+H: 274, found: 274.

Example 16

(R,S) 8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (18 mg, 0.05 mmol) in dimethylformamide (1 ml) is treated with CuCN (20 mg, 0.24 mmol) and the mixture is treated with microwaves at a temperature of 200°C for 0.5 hour. The product mixture was diluted with water (5 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (5 ml), dried over Na2SO4and concentrate. Flash chromatography (35% EtOAc in hexane, silica) 10 mg pet is ajnogo oil. MS calculated for C15H15F3N2O2+H: 313, found: 313.

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

A solution of N-TRIFLUOROACETYL-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (10 mg, to 0.032 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred for 1 hour at a temperature of 50°C. the product Mixture was diluted with water (5 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (5 ml), dried over Na2SO4and concentrate to obtain 6.0 mg of a white solid.1H-NMR (400 MHz, CD3OD) δ 7,33 (s, 1H), 6,93 (s, 1H), 3,91 (s, 3H), 3,18-of 2.97 (m, 5H), 2,80 (m, 1H), 2,60 (m, 1H), 1,33 (d, J=8 Hz, 3H). MS calculated for C13H16N2O+H: 217, found: 217.

Example 17

(R,S) 8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of diethyl zinc (1 ml, 1 M in hexane) in dichloromethane (1 ml) at a temperature of 0°With handle triperoxonane acid in dichloromethane (0.5 ml) and the mixture is stirred for 15 minutes. Then add diameter (0,280 g, 1.0 mmol) in dichloromethane (0.5 ml) and stirred for 15 minutes. Add N-TRIFLUOROACETYL-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepin (0.075 g, 0.26 of the mol) in dichloromethane (1 ml), and the mixture is stirred for 30 minutes at a temperature of 0°C, then for 2 hours at a temperature of 20°C. the product Mixture quenched with saturated aqueous NH4Cl (5 ml), twice extracted with CH2Cl2(20 ml), washed with saturated aqueous NaHCO3(10 ml), washed with H2About (10 ml) and concentrated. Flash chromatography (7% EtOAc in hexane, silica) gives 0,050 g of a white solid. MS calculated for C15H16F3NO2+H: 300 found: 300.

N-TRIFLUOROACETYL-8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.025 g, 0.08 mmol) in acetonitrile (1 ml) is treated with N-bromosuccinimide (0,032 g, 0.18 mmol) and stirred for 2 hours at a temperature of 50°C. the product Mixture concentrated and purified flash chromatography (10% EtOAc in hexane, silica) with the receipt of 0.014 g of a white solid. MS calculated for C15H15BrF3NO2+H: 378, found: 378.

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

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) is treated with 15% aqueous NaOH (1 ml) and stirred for 2 hours at a temperature of 50°C. the product Mixture was diluted with saturated salt solution (10 is l), twice extracted with EtOAc (10 ml), dried over MgSO4and concentrate to obtain 0.008 g of a clear oil.1H-NMR (400 MHz, CD3OD) δ 7,26 (s, 1H), 6,78 (s, 1H), 3,83 (s, 3H), to 3.02 (m, 2H), 2,92 (m, 2H), to 2.67 (s, 2H), of 0.91 (m, 2H), 0,85 (m, 2H). MS calculated for C13H16BrNO+H: 282 found: 282.

Example 18

(R,S) 8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A 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) is treated with a complex BH3-THF (0,36 ml, 1 M in THF) and stirred for 30 minutes at a temperature of 20°C. Successively added water (0.5 ml), saturated aqueous NaHCO3(0.5 ml) and 30% H2About2(0.2 ml) and the reaction mixture is stirred for 30 minutes at a temperature of 20°C. the product Mixture was diluted with EtOAc (10 ml), washed with saturated salt solution (10 ml) and concentrated. Flash chromatography (33% EtOAc in hexane, silica) to give 0.035 g of a clear oil. MS calculated for C14H16F3NO3+H: 304, found: 304.

N-TRIFLUOROACETYL-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.035 g, 0.12 mmol)in acetonitrile (1 ml) is treated with N-bromosuccinimide (0.025 g, 0.14 mmol) and stirred for 30 minutes at a temperature of 20°C. the product Mixture concentrated and purified flash chromatography (33% EtOAc in hexane, silica) gives 0,019 g of a clear oil. MS calculated for C14H15BrF3NO3+H: 382, found: 382.

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

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) is treated with 15% aqueous NaOH (1 ml) and stirred for 1 hour at a temperature of 50°C. the product Mixture was diluted with saturated salt solution (5 ml), twice extracted with EtOAc (5 ml), dried over MgSO4and concentrate to obtain 0,006 g of a clear oil.1H-NMR (400 MHz, CD3OD) δ 7,28 (s, 1H), 6,79 (s, 1H), 3,84 (m, 2H), from 3.0 to 2.8 (m, 7H). MS calculated for C12H16BrNO2+H: 286, found: 286.

Example 19

(R,S) 8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

N-crotyl, N-TRIFLUOROACETYL-2-iodine-5-methoxyphenethylamine

A solution of N-TRIFLUOROACETYL-2-iodine-5-methoxyphenethylamine (of 6.68 g of 17.9 mmol) in toluene (100 ml) is treated To a2CO3(3,22 g, with 23.3 mmol), KOH (3,01 g of 53.7 mmol), n-Bu4NBr (0,580 g of 1.80 mmol) and crotylboration (3,15 g, with 23.3 mmol). The mixture is stirred at a temperature of 75°C for 16 hours, cooled to a tempera the URS 20° C, diluted with Et2O (500 ml), washed with 10% aqueous HCl (500 ml) and concentrated. Flash chromatography (10% EtOAc in hexane, silica) gives with 5.22 g of a clear oil. MS calculated for C15H17F3INO2+H: 428, found: 428.

N-TRIFLUOROACETYL-1-ethylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-crotyl, N-TRIFLUOROACETYL-2-iodine-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 a temperature of 90°C. the product Mixture is cooled to a temperature of 20°, filtered, diluted with water (200 ml), extracted twice with simple ether (500 ml), the combined organic phases are washed twice with saturated salt solution (200 ml) and concentrated. Flash chromatography (10% EtOAc in hexane, silica) gives to 2.29 g of a clear oil which contains a mixture of olefin isomers. MS calculated for C15H16F3NO2+H: 300 found: 300.

N-TRIFLUOROACETYL-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-1-ethylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (to 2.29 g of 7.65 mmol) in methanol (100 ml) is treated with 10% Pd/C (4.0 g, 0.77 mmol)and stirred overnight in a hydrogen atmosphere. The product mixture was filtered through a layer of cellite and TLD is Kari silicon, the solvent is removed to obtain 2.14 g of a clear oil. MS calculated for C15H18F3NO2+H: 302 found: 302.

N-TRIFLUOROACETYL-8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0,710 g, 2.36 mmol) in acetonitrile (20 ml) is treated with N-bromosuccinimide (0,504 g, and 2.83 mmol) and stirred overnight at a temperature of 20°C. the product Mixture is concentrated and diluted with EtOAc (100 ml), washed with water (50 ml) and saturated salt solution (50 ml), dried over Na2SO4and concentrate. Flash chromatography (10% EtOAc in hexane, silica) gives 0,561 g of a clear oil. MS calculated for C15H17BrF3NO2+H: 380, found: 380.

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

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) is treated with 15% aqueous NaOH (30 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with saturated salt solution (100 ml), twice extracted with EtOAc (200 ml), dried over MgSO4and concentrate to obtain 0,412 g of a clear oil.1H-NMR (400 MHz, CD3OD) δ from 7.24 (s, 1H), 6,76 (s, 1H), 3,83 (s, 3H), to 3.02 (m, 3H), 2.91 in (s, 1H), 2,85 was 2.76 (m, 3H), 2.63 in (m, 1H), 1,78 (m, 1H), 1,72 (m, 1H), 0,94 (DD, J=8, 8 Hz, 3H). MS calculated for C13H8 BrNO+H: 284, found: 284.

Example 20

(R,S) - 8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0,600 g, 1,99 mmol) in acetonitrile (20 ml) is treated with N-chlorosuccinimide (0,057 g, 0.32 mmol) and stirred overnight at a temperature of 60°C. the product Mixture is concentrated and diluted with EtOAc (100 ml), washed with water (50 ml) and saturated salt solution (50 ml), dried over Na2SO4and concentrate. Flash chromatography (10% EtOAc in hexane, silica) gives 0,421 g of a clear oil. MS calculated for C15H17ClF3NO2+H: 336, found: 336.

8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

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) is treated with 15% aqueous NaOH (30 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with saturated salt solution (100 ml), twice extracted with EtOAc (200 ml), dried over MgSO4and concentrate to obtain 0,241 g of a clear oil.1H-NMR (400 MHz, CD3OD) δ 7,05 (s, 1H), 6,79 (s, 1H), 3,84 (s, 3H), 3,03 (m, 3H), 2.91 in (s, 1H), 2,86 was 2.76 (m, 3H), of 2.64 (m, 1H), is 1.81 (m, 1H), 1,72 (m, 1H), 0,93 (DD, J=8, 8 Hz, 3H). MS calculated for C1 H18ClNO+H: 240 found: 240.

Example 21

(R,S) 8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

N-(3-methylbut-2-enyl), N-TRIFLUOROACETYL-2-iodine-5-methoxyphenethylamine

A solution of N-TRIFLUOROACETYL-2-iodine-5-methoxyphenethylamine (0,700 g, 1.88 mmol) in toluene (25 ml) is treated To a2CO3(0,340 g, 2.4 mmol), KOH (0,210 g, 3,76 mmol), n-Bu4NBr (to 0.060 g, 0,19 mmol) and 4-bromo-2-methyl-2-butene (0,364 g of 2.44 mmol). The mixture is stirred at a temperature of 80°C for 3 hours, cooled to a temperature of 20°C, diluted with simple ether (100 ml), washed with 10% aqueous HCl (50 ml) and concentrated. Flash chromatography (10% EtOAc in hexane, silica) gives 0,272 g of a clear oil.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ the 7.65 (m, 1H), 6.75 in (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), to 3.02 (m, 2H), of 1.75 (m, 3H), of 1.66 (m, 3H).

N-TRIFLUOROACETYL-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-(3-methylbut-2-enyl), N-TRIFLUOROACETYL-2-iodine-5-methoxyphenethylamine (0,272 g of 0.62 mmol) in dimethylformamide (12 ml) was treated with KOAc (0,183 g of 1.86 mmol), n-Bu4NBr (0,200 g 0,062 mmol), PPh3(0,016 g 0,062 mmol), Pd(OAc)2(0,183 g of 1.86 mmol) and stirred overnight at a temperature of 90°C. the product Mixture is cooled to a temperature of 20°, filtered, diluted with water (50 ml), twice extrag the shape of simple ether (50 ml), the combined organic phases are washed twice with saturated salt solution (50 ml) and concentrated. Flash chromatography (10% EtOAc in hexane, silica) gives 0,096 g of a clear oil. MS calculated for C16H18F3NO2+H: 314, found: 314.

N-TRIFLUOROACETYL-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0,096 g, 0.31 mmol) in ethanol (2 ml) is treated with 10% Pd/C (0,033 g 0,031 mmol)and stirred overnight in a hydrogen atmosphere. The product mixture was filtered through a layer of cellite and silicon dioxide, the solvent is removed to obtain 0,091 g of a clear oil. MS calculated for C16H20F3NO2+H: 316, found: 316.

N-TRIFLUOROACETYL-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0,091 g, 0.29 mmol) in acetonitrile (3 ml) is treated with N-bromosuccinimide (0,057 g, 0.32 mmol) and stirred overnight at a temperature of 20°C. After removal of the solvent, flash chromatography (10% EtOAc in hexane, silica) gives 0,056 g of a clear oil. MS calculated for C16H19BrF3NO2+H: 394, found: 394.

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

A solution of N-TRIFLUOROACETYL-8-bromo-1-from the propyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0,013 g, 0.03 mmol) in methanol (0.5 ml) is treated with 15% aqueous NaOH (0.5 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with saturated salt solution (5 ml), twice extracted with EtOAc (5 ml), dried over MgSO4and concentrate to obtain 0.10 g of a clear oil.1H-NMR (400 MHz, CD3OD) δ was 7.08 (s, 1H), only 6.64 (s, 1H), and 3.72 (s, 3H), 3,2-3,10 (m, 3H), 2,7-2,5 (m, 3H), 2,3-2,1 (m, 2H), of 0.96 (d, 3H), 0,63 (d, 3H). MS calculated for C14H20BrNO+H: 298 found: 298.

Example 22

(R,S) 8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine level (0.041 g, 0.10 mmol) in dichloromethane (1 ml) is treated with BBr3(0,32 ml, 1.0 M solution in CH2Cl2) and the mixture is stirred overnight at a temperature of 20°C. Excess BBr3remove the added water and the mixture is diluted with simple ether (50 ml), washed twice with saturated aqueous Na2CO3(20 ml) and concentrated. Flash chromatography (20% EtOAc in hexane, silica) to give 0.037 g of a clear oil. MS calculated for C15H17BrF3NO2+H: 380, found: 380.

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

A solution of N-TRIFLUOROACETYL-8-bromo-7-Ki-the Roxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0,018 g, 0,047 mmol) in methanol (1 ml) is treated with 15% aqueous NaOH (1 ml) and stirred for 3 hours at a temperature of 50°C. the product Mixture was adjusted to pH 7-8 with 10% aqueous HCl, three times extracted with EtOAc (50 ml), dried over MgSO4and concentrate to obtain 0,013 g of a white solid.1H-NMR (400 MHz, CD3OD) δ 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), of 1.05 (d, 3H), to 0.73 (d, 3H). MS calculated for C13H18BrNO+H: 284, found: 284.

Example 23

(R,S) 7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepin

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) is treated with N'-tert-butyl-N,N,N',N',N",N"-hexamethylphosphoramide triamide (0,016 g, 0,068 mmol), allylbromide (to 0.011 g, 0.09 mmol) and stirred for 3 hours at a temperature of 20°C. the product Mixture was diluted with 10% aqueous HCl, extracted twice with dichloromethane (20 ml) and concentrated. Flash chromatography (10% EtOAc in hexane, silica) gives to 0.011 g of a clear oil. MS calculated for C18H21BrF3NO2+H: 420, found: 420.

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

A solution of N-TRIFLUOROACETYL-7-allyloxy-8-brough the-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepin (0,011 g, it was 0.026 mmol) in methanol (0.5 ml) is treated with 15% aqueous NaOH (0.5 ml) and stirred for 3 hours at a temperature of 50°C. the product Mixture was diluted with saturated salt solution (5 ml), twice extracted with EtOAc (5 ml), dried over MgSO4and concentrate to obtain 0,010 g of a clear oil.1H-NMR (400 MHz, CD3OD) δ to 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 (SIRM, 2H), 2,3-2,1 (m, 2H), of 0.95 (d, 3H), 0,63 (d, 3H). MS calculated for C16H22BrNO+H: 324, found: 324.

Example 24

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

N-TRIFLUOROACETYL-1-(3-methoxyphenyl)-2-Propylamine

A solution of 1-(3-methoxyphenyl)-2-Propylamine (3,59 g, and 21.7 mmol) in dichloromethane (75 ml) at a temperature of 0°treated With pyridine (2.1 ml, of 28.2 mmol), triperoxonane anhydride (5.9 g, of 28.2 mmol) and then stirred for 3 hours while heating to a temperature of 20°C. the product Mixture was diluted with EtOAc (300 ml), washed sequentially with 10% aqueous HCl (100 ml), water (100 ml), saturated salt solution (100 ml), dried over Na2SO4and concentrate. Flash chromatography (20% EtOAc in hexane, silica) gives the 4.29 g of yellow solid.1H-NMR (400 MHz, CD3OD) δ 7,17 (DD, J=8, 8 Hz, 1H), 6,76 (m, 3H), 4,19 (m, 1H), of 3.77 (s, 3H), 2,78 (m, 2H), 1,21 (d, J=7 Hz, 2H).

N-triptorelin-(2-iodine-5-methoxyphenyl)-2-Propylamine

A solution of N-TRIFLUOROACETYL-1-(3-methoxyphenyl)-2-Propylamine (4,29 g, 15.7 mmol) in methanol (100 ml) cooled to a temperature of -78aboutWith and treated CaCO3(3,17 g of 31.4 mmol) followed by treatment with a solution of ICl (6,37 g, and 39.9 mmol) in methanol (50 ml). The reaction mixture is heated to a temperature of 20°under stirring overnight. The product mixture was filtered, concentrated, dissolved in EtOAc (200 ml), washed twice with 5% aqueous sodium bisulfite (100 ml), once with saturated salt solution (100 ml), dried over Na2SO4and concentrate to obtain 6,72 g of white solid powder. MS calculated for C12H13F3INO2+H: 388, found: 388.

N-allyl, N-TRIFLUOROACETYL-1-(2-iodine-5-methoxyphenyl)-2-Propylamine

A solution of N-TRIFLUOROACETYL-1-(2-iodine-5-methoxyphenyl)-2-Propylamine (6,09 g, 15.7 mmol) in toluene (450 ml) is treated To a2CO3(2,82 g of 20.4 mmol), KOH (2,45 g of 47.1 mmol), n-Bu4NBr (0,506 g, 1.57 mmol) and allylbromide (2,47 g of 20.4 mmol) and stirred overnight at a temperature of 80°C. the product Mixture acidified with 10% aqueous HCl, separated, the aqueous phase is extracted with simple ether (500 ml), the combined organic phases are washed with saturated salt solution (200 ml), dried over Na2SO4and concentrate with the receipt of 4.45 g of brown oil.

N-TRIFLUOROACETYL-7-methoxy-4-methyl-1-methylene-2,3,4,5-tetrahydro-1H-3-Benzes the pin

A solution of N-allyl, N-TRIFLUOROACETYL-1-(2-iodine-5-methoxyphenyl)-2-Propylamine (4,45 g to 10.8 mmol) in dimethylformamide (120 ml) is treated with COAs (3,17 g, and 32.3 mmol), n-Bu4NBr (3,47 g to 10.8 mmol), PPh3(0,283 g at 1.08 mmol), Pd(OAc)2(0,242 g at 1.08 mmol) and stirred overnight at a temperature of 80°C. the product Mixture is cooled to a temperature of 20°, filtered, diluted with water (200 ml) and extracted with simple ether (3×200 ml), the combined organic phases are washed with water (100 ml), saturated salt solution (100 ml), dried over Na2SO4and concentrate. Flash chromatography (10% EtOAc in hexane, silica) to give 1.39 g of a yellow oil.

N-TRIFLUOROACETYL-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-methoxy-4-methyl-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (1.39 g, with 4.64 mmol) in ethanol (40 ml) is treated with 10% Pd/C (0,49 g, 0.46 mmol) and stirred overnight in a hydrogen atmosphere. The product mixture was filtered through a layer of cellite and silica and concentrated. Flash chromatography (20% EtOAc in hexane, silica) network of 0.77 g of a clear oil.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ 7,06 (m, 1H), of 6.71 (m, 1H), 6,63 (m, 1H), to 4.38 (SIRM, 1H), and 3.8 (s, 3H), 3,6 (m, 1H), 3,25 (m, 1H), 3,18 (SIRM, 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-benzazepin

A solution of N-drift reatil-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0,452 g, 1.50 mmol) in acetonitrile (20 ml) is treated with N-bromosuccinimide (0,294 g of 1.65 mmol) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with EtOAc (100 ml), washed with saturated aqueous sodium bisulfite (50 ml) and saturated salt solution (50 ml), dried over Na2SO4and concentrate. Flash chromatography (20% EtOAc in hexane, silica) to give a clear oil.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ to 7.32 (s, 1H), 6,62 (m, 1H), 4,37 (m, 1H), a 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-benzazepin

A solution of N-TRIFLUOROACETYL-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (21 mg, by 0.055 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred overnight at a temperature of 20°C. the product Mixture was diluted with water (5 ml), twice extracted with EtOAc (10 ml), the combined organic phases are washed with saturated salt solution (10 ml), dried over Na2SO4and concentrate to obtain 11 mg of a clear oil.1H-NMR (400 MHz, CDCl3) δ 7,29 (s, 1H), only 6.64 (s, 1H), 3,88 (s, 3H), to 3.02 (m, 2H), 2,89 (DD, J=9, 14 Hz, 1H), 2,80 (m, 1H), to 2.67 (d, J=14 Hz, 1H), 2,53 (DD, J=10, 13 Hz, 1H), 1,30 (d, J=7 Hz, 3H), 1,19 (d, J=6 Hz, 3H). MS calculated for C13H18BrNO+H: 284, found: 284.

Example 25

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

N-TRIFLUOROACETYL-8-bromo-1,4-dimethyl-7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0,383 g, 1.01 mmol) in dichloromethane (30 ml) is treated with BBr3(2.35 ml, 1.0 M solution in CH2Cl2, 2,35 mmol) and the mixture is stirred overnight while heating to a temperature of 20°C. Excess BBr3remove the added water and the mixture is diluted with simple ether (100 ml), washed with saturated aqueous Na2CO3(50 ml) and saturated salt solution (50 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) gives 0,302 g of a white solid.1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ 7,22 (m, 1H), 6,77 (m, 1H), of 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-benzazepin

A solution of N-TRIFLUOROACETYL-8-bromo-1,4-dimethyl-7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0,030 g, 0,082 mmol) in dichloromethane (2 ml) is treated with allylbromide (0,030 g, 0,246 mmol), DBU (0.037 g, 0,246 mmol) and stirred for 2 hours at a temperature of 20°C. the product Mixture was diluted with EtOAc (10 ml), washed with 5% aqueous HCl (2 ml), saturated salt solution (5 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, co kr is mnia) gives 0,028 g of a clear oil. 1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ to 7.32 (s, 1H), 6,62 (m, 1H), 6,02 (m, 1H), the 5.45 (d, J=17 Hz, 1H), and 5.30 (d, J=11 Hz, 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=10 Hz, 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-benzazepin

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) is treated with 15% aqueous NaOH (2 ml) and stirred for 3 hours at a temperature of 20°C. the product Mixture was diluted with water (10 ml)and twice extracted with EtOAc (10 ml), the combined organic phases are washed with saturated salt solution (10 ml), dried over Na2SO4and concentrate to obtain 0,020 g of a clear oil.1H-NMR (400 MHz, CDCl3) δ 7,30 (s, 1H), only 6.64 (s, 1H), the 6.06 (m, 1H), vs. 5.47 (d, J=17 Hz, 1H), and 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=14 Hz, 1H), 2,55 (DD, J=10, 14 Hz, 1H), 1.77 in (Sirs, 1H), 1,30 (d, J=7 Hz, 3H), 1,20 (d, J=6 Hz, 3H).

Example 26

(R,S) - 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-4-chlorophenethylamine

A solution of 4-chlorophenethylamine (1.0 g, 6.4 mmol) in dichloromethane (20 ml) cooled to a temperature of 0°and treated With pyridine (1.0 ml, 12.8 mmol), triperoxonane anhydride (1.6 g, 7.7 mmol) and then stirred for 1 hour while heating to a temperature of 20°C. a Mixture of products is and diluted with EtOAc (100 ml), sequentially washed with 10% aqueous HCl (50 ml), water (50 ml), saturated salt solution (50 ml), dried over Na2SO4and concentrate to obtain 1.6 g of a white solid.

N-TRIFLUOROACETYL-2-iodine-4-chlorophenethylamine

A solution of N-TRIFLUOROACETYL-4-chlorophenethylamine (1.6 g, 6.4 mmol) in dichloromethane (20 ml) is treated with tetrafluoroborate bis(pyridine)iodone(I) (2.6 g, 7.0 mmol), CF3SO3H (2.1 g, 14.1 mmol) and stirred overnight at a temperature of 20°C. the product Mixture is concentrated and dissolved in EtOAc (100 ml), washed twice with 5% aqueous sodium bisulfite (50 ml), washed twice with saturated aqueous NaHCO3(50 ml), once washed with saturated salt solution (50 ml), dried over Na2SO4and concentrate with the receipt of 0.94 g of a clear oil. MS calculated for C10H8ClF3INO+H: 378, found: 378.

N-allyl, N-TRIFLUOROACETYL-2-iodine-4-chlorophenethylamine

A solution of N-TRIFLUOROACETYL-2-iodine-4-chlorophenethylamine (0,94 g, 2.4 mmol) in toluene (25 ml) was sequentially treated To a2CO3(0,43 g of 3.12 mmol), KOH (0.40 g, 7.2 mmol), n-Bu4NBr (0,077 g, 0.24 mmol) and allylbromide (of 0.43 g, 3.6 mmol). The mixture is stirred at a temperature of 80°C for 3.5 hours, cooled to a temperature of 20°C, acidified with 10% aqueous HCl. The phases are separated, the aqueous phase is extracted with simple ether (100 ml), the combined organic Gazpromviet saturated salt solution (50 ml), dried over Na2SO4and concentrate to obtain 0,76 g of a clear oil. MS calculated for C13H12ClF3INO+H: 418, found: 418.

N-TRIFLUOROACETYL-8-chloro-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-allyl, N-TRIFLUOROACETYL-2-iodine-4-chlorophenethylamine (0,76 g, 1.8 mmol) in dimethylformamide (20 ml) is treated with COAs (0,53 g, 5.4 mmol), n-Bu4NBr (of 0.58 g, 1.8 mmol), PPh3(0,047 g, 0.18 mmol), Pd(OAc)2level (0.041 g, 0.18 mmol) and stirred overnight at a temperature of 105°C. the product Mixture is cooled to a temperature of 20°, filtered, diluted with water (100 ml) and extracted with simple ether (3×100 ml), the combined organic phases are washed with water (100 ml), saturated salt solution (100 ml), dried over Na2SO4and concentrate. Flash chromatography (10% EtOAc in hexane, silica) gives 0,228 g of a clear oil.1H-NMR (400 MHz, CDCl3) δ 7,29 (s, 1H), 7,18 (m, 1H),? 7.04 baby mortality (m, 1H), 5,38 (m, 2H), of 5.40 (d, J=16 Hz, 2H), 3,80 (m, 2H), 3,00 (m, 2H). MS calculated for C13H11ClF3NO+H: 290, found: 290.

N-TRIFLUOROACETYL-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-8-chloro-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (0.16 g, 0.55 mmol) in methanol (10 ml) is treated with 10% Pd/C (0.02 g) and stirred for 30 minutes in a hydrogen atmosphere. The product mixture was filtered, concentrated and purified flash chromatography the th (5% EtOAc in hexane, silicon dioxide) obtaining 0,057 mg of a white solid. MS calculated for C13H13ClF3NO+H: 292, found: 292.

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

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) is treated with 15% aqueous NaOH (2 ml) and stirred for 3.5 hours at a temperature of 60°C. the product Mixture is concentrated and extracted 3 times CH2Cl2(5 ml), dried over Na2SO4and concentrate to obtain 35 mg of a clear oil.1H-NMR (400 MHz, CDCl3) δ 7,11 (c, 1H), 7,05 (d, J=8 Hz, 1H), 6,98 (d, J=8 Hz, 1H), 3,1 and 2.9 (m, 6H), 2,71 (m, 1H), 2,68 (Sirs, 1H), 1,32 (d, J=8 Hz, 3H). MS calculated for C11H14ClN+H: 196, found: 196.

Example 27

(R,S) 7-(2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0,506 g of 1.76 mmol) in dichloromethane (20 ml) is treated with BBr3with 4.1 ml, 1.0 M solution in CH2Cl2, 4.1 mmol) and stirred overnight while heating to a temperature of 20°C. Excess BBr3remove the addition of water, the mixture is diluted with simple ether (200 ml), washed with Na2CO3(100 ml) and saturated salt solution (100 ml), dried on the Na 2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) gives 0,460 g of white solid foam. MS calculated for C13H14F3NO2+H: 274, found: 274.

N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin, triftorbyenzola

A solution of N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (460 mg, of 1.76 mmol) in dichloromethane (15 ml) is treated with pyridine (417 mg, at 5.27 mmol), triftormetilfullerenov anhydride (991 mg, to 3.52 mmol) and stirred for 1.5 hours at a temperature of 20°C. the product Mixture was diluted with dichloromethane (100 ml), washed with water (50 ml), 5% aqueous HCl (50 ml), saturated aqueous NaHCO3(50 ml), saturated salt solution (50 ml), dried over Na2SO4and concentrate. Flash chromatography (15% EtOAc in hexane, silica) to give 658 mg of a clear oil. MS calculated for C14H13F6NO4S+H: 406, found: 406.

N-TRIFLUOROACETYL-7-(2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, triftoratsetata (100 mg, 0.25 mmol) in dimethylformamide (2 ml) is treated with (2-methyl-2H-pyrazole-3-yl)-tri-n-botulinum (138 mg, and 0.37 mmol), LiCl (21 mg, 0.50 mmol), Pd(PPh3)2Cl2(35 mg, 0.05 mmol) and stirred for 4 hours at a temperature of 100&x000B0; C. the product Mixture was diluted with EtOAc (20 ml), washed twice with water (10 ml), once washed with saturated salt solution (10 ml), dried over Na2SO4and concentrate. Flash chromatography (30% EtOAc in hexane, silica) to give 80 mg of a clear oil. MS calculated for C17H18F3N3O+H: 338, found: 338.

7-(2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-(2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (48 mg, 0.14 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred overnight at a temperature of 20°C. the product Mixture is concentrated and extracted 3 times CH2Cl2(5 ml), dried over Na2SO4and the solvent is evaporated. Flash chromatography (0-15% MeOH in CH2Cl2, silicon dioxide) to give 30 mg of a clear oil.1H-NMR (400 MHz, CDCl3) δ of 7.48 (s, 1H), 7,21 (m, 2H), 7,13 (s, 1H), 6,27 (s, 1H), with 3.89 (s, 3H), 3,3-2,9 (m, 9H), and 2.79 (DD, J=7, 14 Hz, 1H), 1,40 (d, J=8 Hz, 3H). MS calculated for C15H19N3+H: 242, found: 242.

Example 28

(R,S) 7-(4-bromo-2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-7-(4-bromo-2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-(2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (3 mg, 0,082 mmol) in dichloromethane (1 ml) is treated with N-bromosuccinimide (15.3 mg, 0,086 mmol) and stirred overnight at a temperature of 20°C. a Mixture of the product absorb on silica and purified flash chromatography (2-5% MeOH in CH2Cl2, silica) to give 37 mg of a white crystalline solid. MS calculated for C17H17BrF3N3O+H: 416, found: 416.

7-(4-bromo-2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-(4-bromo-2-methyl-2H-pyrazole-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (37 mg, 0,089 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred overnight at a temperature of 20°C. the product Mixture is concentrated and extracted 3 times CH2Cl2(5 ml), dried over Na2SO4and the solvent is evaporated. Flash chromatography (0-15% MeOH in CH2Cl2, silicon dioxide) to give 28 mg of a clear oil.1H-NMR (400 MHz, CDCl3) δ to 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 and 2.9 (m, 8H), 2,80 (DD, J=7, 13 Hz, 1H), 2,48 (Sirs, 1H), 1,40 (d, J=8 Hz, 3H). MS calculated for C15H18BrN3+H: 320, found: 320.

Example 29

(R,S) 7-(3-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, Tr is formeasurement (50 mg, 0,123 mmol) in 1,4-dioxane (1.5 ml) is treated with 2-by-Chlorfenvinphos acid (39 mg, 0,243 mmol), CsF (56 mg, and 0.37 mmol), water (50 mg, 2,78 mmol), Pd(PPh3)4(29 mg, of 0.025 mmol) and stirred overnight at a temperature of 75°C. the product Mixture was diluted with EtOAc (20 ml), washed with water (10 ml), saturated salt solution (10 ml), dried over Na2SO4and concentrate. Flash chromatography (10-20% EtOAc in hexane, silica) to give 45 mg of a clear oil. MS calculated for C19H17ClF3NO+H: 368, found: 368.

The product (27 mg, 0,073 mmol) dissolved in methanol (2 ml), treated with 15% aqueous NaOH (2 ml) and stirred overnight at a temperature of 20°C. the product Mixture is concentrated and extracted 3 times CH2Cl2(5 ml), dried over Na2SO4and the solvent is evaporated to obtain 18 mg of a clear oil.1H-NMR (400 MHz, CDCl3) δ 7,54 (s, 1H), 7,42 (d, J=6 Hz, 1H), 7,35-7,21 (m, 5H), 3,14 (m, 1H), 3,1 and 2.9 (m, 8H), 2,80 (SIRM, 2H), 1,38 (d, J=8 Hz, 3H). MS calculated for C17H18ClN3+H: 272, found: 272.

Example 30

(R,S) 7-(2-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, triftoratsetata (50 mg, 0,123 mmol) in 1,4-dioxane (1.5 ml) is treated with 2-by-Chlorfenvinphos acid (39 mg, 0,243 mmol), CsF (56 mg, 0,37 mm is l), water (50 mg, 2,78 mmol), Pd(PPh3)4(29 mg, of 0.025 mmol) and stirred overnight at a temperature of 75°C. the product Mixture was diluted with EtOAc (20 ml), washed with water (10 ml), saturated salt solution (10 ml), dried over Na2SO4and concentrate. Flash chromatography (10-20% EtOAc in hexane, silica) to give 36 mg of a clear oil. MS calculated for C19H17ClF3NO+H: 368, found: 368.

The product (27 mg, 0,073 mmol) dissolved in methanol (2 ml), treated with 15% aqueous NaOH (2 ml) and stirred overnight at a temperature of 20°C. the product Mixture is concentrated and extracted 3 times CH2Cl2(5 ml), dried over Na2SO4and the solvent is evaporated to obtain 24 mg of a clear oil.1H-NMR (400 MHz, CDCl3) δ 7,44 (d, J=8 Hz, 1H), 7,35-7,22 (m, 5H), to 7.15 (s, 1H), 3,14 (m, 1H), 3,1 and 2.9 (m, 8H), 2,80 (DD, J=13 Hz, 1H), of 2.51 (Sirs, 1H), 1,38 (d, J=8 Hz, 3H). MS calculated for C17H18ClN3+H: 272, found: 272.

Example 31

(R,S) - 8-chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-8-chloro-1-oxo-3,4,5-trihydro-1H-3-benzazepin

A 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 a temperature of -78°C, treated with ozone until then, until the solution becomes blue (about 20 minutes), we use the t PPh 3(0.21 g, 0.80 mmol) and the resulting solution was stirred for 90 minutes at temperatures up to 20°C. the product Mixture concentrated and purified flash chromatography (30% EtOAc in hexane, silica) to give the 0,215 g of a white solid. MS calculated for C12H9ClF3NO2+H: 292, found: 292.

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

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 NaBH4and the resulting mixture is stirred for 16 hours at a temperature of 20°C. the White solid product is collected by filtration, washed with water and dried to obtain 30 mg of a white solid.1H-NMR (400 MHz, CD3OD) δ 7,39 (s, 1H), 7,12 (d, J=8 Hz, 1H), 7,06 (d, J=8 Hz, 1H), 4,74 (d, J=8 Hz, 1H), 3,1-2,7 (m, 6H). MS calculated for C10H12ClNO+H: 198, found: 198.

Example 32

(R,S) 8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 26 to obtain (R,S) 8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of 4-bromophenethylamine, in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ 7,27 (s, 1H), 7,22 (d, J=8 Hz, 1H), 6,94 (d, J=8 Hz, 1H), 3,1-to 2.85 (m, 6H), of 2.72 (m, 1H), 2,25 (Sirs, 1H), 1,33 (d, J=7 Hz, 3H). MS calculated for C11H14BrN+H: 240 found: 240.

Example 33

(R,S) - 8-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-Ben is azepin

According to the method of example 26 to obtain (R,S) - 8-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of 4-fortunetelling, in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ 7,00 (DD, J=8, 10 Hz, 1H), 6,86 (d, J=10 Hz, 1H), 6,76 (d, J=8 Hz, 1H), is 3.08-of 2.56 (m, 7H), 1,85 (Sirs, 1H), 1,31 (d, J=7 Hz, 3H). MS calculated for C11H14FN+H: 180, found: 180.

Example 34

(R,S) 7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 26 to obtain (R,S) 7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin from 3-fortunetelling, in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ to 7.09 (DD, J=6, 8 Hz, 1H), 6,85-of 6.78 (m, 2H), 3,10-2,89 (m, 6H), 2,71 (DD, J=7, 13 Hz, 1H), 1.91 a (Sirs, 1H), 1,33 (d, J=7 Hz, 3H). MS calculated for C11H14FN+H: 180, found: 180.

Example 35

(R,S) 7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 26 to obtain (R,S) 7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin from 3-chlorophenethylamine, in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ 7,10 (d, J=8 Hz, 1H), 7,06 (m, 2H), 3,1 and 2.9 (m, 6H), 2,70 (DD, J=13, 7 Hz, 1H), 1,89 (Sirs, 1H), 1,31 (d, J=7 Hz, 3H). MS calculated for C11H14ClN+H: 196, found: 196.

Example 36

(R,S) 7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 26 to obtain (R,S) 7,8-di the ENT-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of 3,4-dichlorophenylamino, in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ 7,20 (c, 1H), 7,16 (s, 1H), 3,05-of 2.86 (m, 6H), 2,71 (DD, J=7, 13 Hz, 1H), 1,83 (Sirs, 1H), 1,33 (d, J=7 Hz, 3H). MS calculated for C11H13Cl2N+H: 230, found: 230.

Example 37

(R,S) N-methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 9 receive (R,S) N-methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of (R,S) - 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, in the form of a colorless oil. MS calculated for C12H16ClN+H: 210, found: 210.

Example 38

(R,S) 1-methyl-7-triptoreline-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 26 to obtain (R,S) 1-methyl-7-triptoreline-2,3,4,5-tetrahydro-1H-3-benzazepin from 3-triphtalocyaninine in the form of a colorless oil.1H-NMR (400 MHz, CD3OD) δ 7,39 (d, J=8 Hz, 1H), 7,19 (m, 1H), 3.46 in (m, 2H), 3,38 (d, J=13 Hz, 1H), 3,29 (m, 1H), and 3.16 (m, 2H), 3,05 (DD, J=13, 9 Hz, 1H), 1,50 (d, J=8 Hz, 3H). MS calculated for C12H14F3NO+H: 246, found: 246.

Example 39

(R,S) 8-iodine-1-methyl-7-triptoreline-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 3 to obtain (R,S) 8-iodine-1-methyl-7-triptoreline-2,3,4,5-tetrahydro-1H-3-benzazepin of N-TRIFLUOROACETYL-1-methyl-7-triptoreline-2,3,4,5-tetrahydro-1H-3-benzazepine in the form of colorless mA is La. 1H-NMR (400 MHz, CD3OD) δ 7,79 (c, 1H), 7,25 (c, 1H), 3.46 in is 3.40 (m, 3H), 3,28-of 3.12 (m, 3H), of 3.07 (DD, J=13, 9 Hz, 1H), 1,47 (d, J=7 Hz, 3H). MS calculated for C12H14F3INO+H: 372, found: 372.

Example 40

(R,S) - N-propyl-8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 10 to obtain (R,S) - N-propyl-8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of (R,S) 8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the form of a colorless oil. MS calculated for C15H22INO+H: 360, found: 360.

Example 41

(R,S) 1-ethyl-8-iodine-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 19 get (R,S) 1-ethyl-8-iodine-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin of N-TRIFLUOROACETYL-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ 7,47 (s, 1H), is 6.54 (s, 1H), 3,86 (s, 3H), 3,20-of 2.97 (m, 4H), 2.93 which is 2.75 (m, 3H), of 2.64 (m, 1H), 1,78 (m, 2H), 0,95 (DD, J=8, 8 Hz, 3H). MS calculated for C13H18INO+H: 332, found: 332.

Example 42

(R,S) 7-(3-methoxyphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 29 to obtain (R,S) 7-(3-methoxyphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, triftoratsetata in the form of b is izvetnogo oil. 1H-NMR (400 MHz, CDCl3) δ 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), to 7.09 (s, 1H), 6,86 (d, J=8 Hz, 1H), 3,85 (s, 3H), of 3.2 and 2.9 (m, 6H), 2,80 (m, 1H), 2,64 (Sirs, 1H), 1,38 (d, J=7 Hz, 3H). MS calculated for C18H21NO+H: 268, found: 268.

Example 43

(R,S) 7-(2,6-differenl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 29 to obtain (R,S) 7-(2,6-differenl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, triftoratsetata in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ 7,35-7,10 (m, 5H), to 6.95 (DD, J=7, 8 Hz, 1H), 3,2-a 2.9 (m, 6H), and 2.79 (DD, J=8, 13 Hz, 1H), 2,70 (Sirs, 1H), 1,38 (d, J=8 Hz, 3H). MS calculated for C17H17F2N+H: 274, found: 274.

Example 44

(R,S) 7-(2-forfinal)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 29 to obtain (R,S) 7-(2-forfinal)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of N-TRIFLUOROACETYL-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ 7,35-of 7.23 (m, 3H), 7,19-to 7.09 (m, 2H), 7,03 (s, 1H), 3,15-to 2.85 (m, 7H), was 2.76 (DD, J=8, 13 Hz, 1H), 1,36 (d, J=8 Hz, 3H). MS calculated for C17H17ClFN+H: 290, found: 290.

Example 45

(R,S) 7-(2-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 29 to obtain (R,S) 7-(2-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, triftoratsetata in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ 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 in (m, 1H), 3,1 and 2.9 (m, 5H), was 2.76 (DD, J=8, 13 Hz, 1H), 2,37 (Sirs, 1H), 1,38 (d, J=8 Hz, 3H). MS calculated for C18H18F3N+H: 306 found: 306.

Example 46

(R,S) 7-(3-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 29 to obtain (R,S) 7-(3-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, triftoratsetata in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ 7,80 (s, 1H), 7,73 (d, J=8 Hz, 1H), EUR 7.57-of 7.48 (m, 2H), 7,38 (d, J=8 Hz, 1H), 7,30 (s, 1H), 7,24 (d, J=7 Hz, 1H), and 3.16 (m, 1H), 3,1 and 2.9 (m, 6H), and 2.79 (DD, J=8, 13 Hz, 1H), 1,38 (d, J=8 Hz, 3H). MS calculated for C18H18F3N+H: 306 found: 306.

Example 47

(R,S) 7-(4-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 29 to obtain (R,S) 7-(4-triptoreline)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of N-TRIFLUOROACETYL-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-be zotepine, On-triftoratsetata in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ the 7.65 (s, 4H), 7,38 (d, J=8 Hz, 1H), 7,31 (s, 1H), 7,24 (d, J=8 Hz, 1H), 3.15 in (m, 1H), 3,1 and 2.9 (m, 5H), 2,80 (DD, J=8, 13 Hz, 1H), 2,48 (Sirs, 1H), 1,38 (d, J=8 Hz, 3H). MS calculated for C18H18F3N+H: 306 found: 306.

Example 48

(R,S) - 8-(2-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

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) is treated with 2-by-Chlorfenvinphos acid (43 mg, 0,275 mmol), CsF (52 mg, 0.34 mmol), water (70 mg, 2.9 mmol), Pd(PPh3)4(27 mg, is 0.023 mmol) and stirred overnight at a temperature of 75°C. the product Mixture was diluted with EtOAc (20 ml), washed with water (10 ml), saturated salt solution (10 ml), dried over Na2SO4and concentrate. Flash chromatography (10-20% EtOAc in hexane, silica) to give 36 mg of a clear oil. MS calculated for C19H17ClF3NO+H: 368, found: 368.

The product (39 mg, 0,106 mmol) dissolved in methanol (2 ml), treated with 15% aqueous NaOH (2 ml) and stirred overnight at a temperature of 20°C. the product Mixture is concentrated and extracted 3 times CH2Cl2(5 ml), dried over Na2SO4and the solvent is evaporated to obtain 18 mg of a clear oil.1H-NMR (400 MHz, CDCl3) δ 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 and 2.9 (m, 5H), and 2.79 (DD, J=7, 13 Hz, 1H), 2,36 (Sirs, 1H), 1,36 (d, J=7 Hz, 3H). MS calculated for C17H18ClN3+H: 272, found: 272.

Example 49

(R,S) 7-methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-cryptomailer-8-iodine-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) is treated with trifurcation sodium (133 mg, 0,981 mmol), copper iodide (I) (124 mg, 0,654 mmol) and toluene is distilled to remove residual water. The reaction mixture is stirred at a temperature of 155°C for 3.5 hours, diluted with EtOAc, filtered, adsorb on silica and purified flash chromatography (10% EtOAc in hexane, silica) to give 26 mg of a colorless oil. MS calculated for C15H15F6NO2+N: 356, found: 356.

The intermediate compound (26 g, 0,073 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred for 0.5 hour at a temperature of 50°C. the product Mixture was diluted with water (5 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (5 ml), dried over Na2SO4and concentrate to obtain 14 mg of colorless oil.1H-NMR (400 MHz, CDCl3) δ to 7.32 (s, 1H), 6.73 x (s, 1H), with 3.89 (s, 3H), 3,1-2,9 (SIRM, 6H), 2,75 (SIRM, 1H), 2,23 (IRS, 1H), 1,36 (d, J=8 Hz, 3H). MS calculated for C13H16F3NO+H: 260, found: 260.

Example 50

(R,S) 7-methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-cryptomailer-8-iodine-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) is treated with pentafluoropropionate sodium (64 mg, 0,344 mmol), copper iodide (I) (92 mg, 0,484 mmol) and toluene is distilled to remove residual water. The reaction mixture is stirred at a temperature of 160°C for 3.5 hours, diluted with EtOAc, filtered, adsorb on silica and purified flash chromatography (10% EtOAc in hexane, silica) to give 22 mg of colorless oil. MS calculated for C16H15F8NO2+H: 406, found: 406.

The intermediate compound (22 g, 0,054 mmol) in methanol (2 ml) is treated with 15% aqueous NaOH (2 ml) and stirred for 0.5 hour at a temperature of 50°C. the product Mixture was diluted with water (5 ml), twice extracted with EtOAc (5 ml), the combined organic phases are washed with saturated salt solution (5 ml), dried over Na2SO4and concentrate to obtain 14 mg of colorless oil.1H-NMR (400 MHz, CDCl3) δ to 7.25 (s, 1H), 6,74 (s, 1H), 3,85 (s, 3H), 3,1-2,9 (SIRM, 6H), was 2.76 (SIRM, 1H), 2,37 (Sirs, 1H), 1,35 (d, J=8 Hz, 3H). MS calculated for C14H16 F5NO+H: 310, found: 310.

Example 51

(R,S) - 8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

According to the method of example 26 to obtain (R,S) - 8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin of 4-triftormetilfullerenov in the form of a colorless oil.1H-NMR (400 MHz, DMSO) δ at 7.55 (d, J=8 Hz, 1H), 7,49 (s, 1H), 7,43 (d, J=8 Hz, 1H), 3,55-to 3.50 (m, 1H) 3,43 is 3.23 (m, 7H), of 3.13 (DD, J=16, 7 Hz, 1H), 3,0-only 2.91 (m, 2H), 1,36 (d, J=7 Hz, 3H). MS calculated for C12H14F3N+H: 230,19 found: 230,4.

Example 52

(R,S) 8-bromo-1-methoxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin

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) is treated with BOC2O (0,062 g, 0.29 mmol) and stirred overnight at a temperature of 20°C. the Product absorb on silica and purified flash chromatography (33% EtOAc in hexane, silica) to give the 0,034 g of colorless oil. MS calculated for C17H24BrNO4+H: 386, found: 386. BOC-protected intermediate compound is dissolved in dimethylformamide (1 ml)was sequentially treated with an excess of NAH and the excess of iodomethane and then stirred for 1 hour at a temperature of 20°C. the Reaction mixture was quenched with water (5 ml), twice extracted with EtOAc (5 ml), the combined organic is such phases are washed with saturated salt solution (5 ml), dried over Na2SO4and concentrate to obtain 0,019 g of a clear oil. MS calculated for C18H26BrNO4+H: 400 found: 400. N-BOC-protected methyl ester is then treated with 4 M HCl in dioxane (1 ml) and stirred for 2 hours at a temperature of 20°C. Evaporation gives 0,009 g of the desired product as a clear oil.1H-NMR (400 MHz, CD3OD) δ 7,30 (c, 1H), 6,92 (s, 1H), a 3.87 (s, 3H), of 3.65 (s, 3H) 3,5-3,1 (m, 9H). MS calculated for C13H18BrNO2+H: 300 found: 300.

Example 53

(R,S) - 8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-crotyl, N-TRIFLUOROACETYL-2-iodine-4-chlorophenethylamine

A solution of N-TRIFLUOROACETYL-2-iodine-4-chlorophenethylamine (6.2 g, 15.8 mmol) in dimethylformamide (350 ml) was sequentially treated To a2CO3(15,8 g, 114 mmol) and crotylboration (6.0 g, 44 mmol), the mixture is stirred at a temperature of 60°C for 16 hours, then cooled to a temperature of 20°C. the Mixture is diluted with EtOAc (350 ml), washed with water (3×300 ml), dried over Na2SO4and concentrate. Flash chromatography (5-15% EtOAc in hexane) to give 2.5 g of a clear oil. MS calculated for C14H14ClF3INO+H: 432, found: 432.

N-TRIFLUOROACETYL-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-crotyl, N-TRIFLUOROACETYL-2-iodine-4-chlorophenethylamine (2.5 g, 5.8 mmol) in dim is telharmonic (250 ml) was treated with KOAc (1.07 g, 10.9 mmol), n-Bn2Et2NBr (1,33 g of 5.84 mmol), Pd(OAc)2(0,063 g, 0.28 mmol) and stirred overnight at a temperature of 77°C. the product Mixture is cooled to a temperature of 20°, filtered, diluted with water (100 ml), extracted with EtOAc (3×100 ml), the combined organic phases are washed with water (100 ml), saturated salt solution (100 ml), dried over Na2SO4and concentrate. Flash chromatography (2-20% EtOAc in hexane, silica) gives 0,339 g of a clear oil. The product which is considered as a mixture of isomers with double bonds, dissolved in methanol (50 ml), treated with Et3N (0.2 ml), 10% Pd/C (0.10 g) and stirred for 16 hours under a pressure of 100 f/d2of hydrogen. The product mixture was filtered, concentrated and purified flash chromatography (5% EtOAc in hexane, silica) to obtain 0.20 g of a white solid. MS calculated for C14H15ClF3NO+H: 306 found: 306.

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

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) is treated with 15% aqueous NaOH (2 ml) and stirred for 3.5 hours at a temperature of 60°C. the product Mixture is concentrated and extracted 3 times CH2Cl2(5 ml), dried over Na2SO4and concentrate to obtain 35 mg of a clear oil.1H-NMR (400 MHz, DMSO-d6) δ 7,2 (who, 3H), 3,3-3,0 (m, 7H), 1,9-1,6 (m, 2H), of 0.91 (t, J=7 Hz, 3H). MS calculated for C12H16ClN+H: 210, found: 210.

Example 54

(R,S) - 8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

N-TRIFLUOROACETYL-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin

A solution of N-TRIFLUOROACETYL-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 mg, 8.5 mmol) in 1,2-dichloroethane (15 ml) is treated Selectufluor (3.9 g, 11 mmol), triftormetilfullerenov acid (8 ml, 90 mmol) and stirred for 60 hours at a temperature of 75°C. the product Mixture was poured into water (200 ml), extracted with EtOAC (200 ml), the organic phase is washed with saturated aqueous NaHCO3(2×100 ml), saturated salt solution (100 ml), dried over Na2SO4and concentrate. The crude product is purified flash chromatography (6% EtOAc in hexane, silica) to give 1.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, found: 310.

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

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) is treated with 15% aqueous NaOH (2 ml) and stirred for 3.5 hours at a temperature of 25°C. the product Mixture is concentrated and extracted 3 times CH2Cl2(5 ml), dried over Na2SO4and concentrate on the doctrine of 93 mg of a clear oil. 1H-NMR (400 MHz, CDCl3) δ 7,11 (m, 1H), 6,85 (m, 1H), 3,05-2,95 (m, 3H), 2.95 and is 2.80 (m, 3H), 2,68 (m, 1H), 2,38 (SIRM, 1H), 1,31 (m, 3H). MS calculated for C11H13ClFN+H: 214, found: 214.

Example 55

Separation of enantiomers for the selected compounds in accordance with this invention

The following compounds are divided into the corresponding enantiomers by HPLC system Varian ProStar with chiral column 20 mm × 250 mm Chiralcel OD, elwira 0.2% diethylamine in various concentrations of isopropanol (IPA) in hexane, see table 1 below. In some cases, carry out the separation of the intermediate triftoratsetata amines.

Table 1
ExampleEnantiomerThe retention time for the free amine (min)The retention time for trifurcatedConditions
11of 21.95% IPA in hexane
224,510 ml/min
21425% IPA in hexane
2479 ml/min
31 5% IPA in hexane
224,210 ml/min
19134,91% IPA in hexane
239,59 ml/min
26123,815% IPA in hexane
229,227 ml/min
37123,835% IPA in hexane
229,247 ml/min
51118,651% IPA in hexane
221,469 ml/min
53113,775% IPA in hexane
220,2810 ml/min

1The separated enantiomer of trifurcated hydrolyzing to obtain enantiomer 1 connection 26

2The separated enantiomer of trifurcated hydrolyzing with obtaining enantiomers of 2 connections 26

p> 3The separated enantiomer of trifurcated and then hydrolyzing N-was identified in obtaining enantiomers of 1 connection 37

4The separated enantiomer of trifurcated and then hydrolyzing N-was identified in obtaining enantiomers of 2 connections 37

5The separated enantiomer of trifurcated hydrolyzing to obtain enantiomer 1 connection 51

6The separated enantiomer of trifurcated hydrolyzing with obtaining enantiomers of 2 connections 51

7The separated enantiomer of trifurcated hydrolyzing to obtain enantiomer 1 connection 53

8The separated enantiomer of trifurcated hydrolyzing with obtaining enantiomers of 2 connections 53

Example 56

The study of intracellular accumulation IP3

Cells NEC transferout 15 cm sterile cuvette with or without (control) 19 μg cDNA of the human receptor T2Cusing 25 μl of lipofectamine. The cells are then incubated for 3-4 hours at a temperature of 37°C/5% CO2and then Wednesday transfection removed and replaced by 100 μl of DMEM. The cells are then applied to 100 cm sterile plates, the next day, the cells are transferred into a 96-cell title microplate PDL at a density C/0,2 ml After 6 hours, the medium replaced with [3H]Inositol (of 0.25 µci/cell) not containing Inositol DMEM and tablets incubated p and a temperature of 37° C/5% CO2throughout the night. The next day cells aspirinum and in appropriate wells add 200 ál of DMEM containing the test compound, 10 μm of parylene and 10 mm LiCl. Then the tablets incubated at 37°C/5% CO2for three hours, followed by aspiration and add fresh ice-cold stop solution (1 M KOH, 19 mm Na-borate, 3.8 mm EDTU) in each cell. Tablets incubated on ice for 5-10 minutes and cells is neutralized by adding 200 ál of fresh ice-cold neutralization solution (7.5% of HCl). Tablets frozen until further processing, if desired. The lysate is then transferred into 1.5 ml Eppendorf tubes and add 1 ml of chloroform/methanol (1:2) in each tube. The solution is shaken for 15 seconds and the upper phase is applied on the ion-exchange resin Biorad AGl-X8™ (100-200 mesh). First, the resin is washed with water at a 1:1.25 wt./about. and 0.9 ml of the upper phase is loaded into the column. Then the column was washed with 10 ml of 5 mm myo-Inositol and 10 ml of 5 mm Na-borate/60 mm Na-formate. Inititatives elute in scintillation vials containing 10 ml of scintillation mixture with 2 ml of 0.1 M formic acid/1 M ammonium formate. Column recovered by lavage with 10 ml of 0.1 M formic acid/3 M ammonium formate and rinsed twice by addition of N2Oh and stored at a temperature of 4°With in the water.

The biological activity of kotoryj characteristic compounds in the study of accumulation of IP are shown in table 2 below.

Table 2
Connection (example)NT2C(IC50)*The study of the accumulation IP (nm)
14,2
24,5
31,4
42,1
512,1
126,3
1918
265,8
322,1

* the values presented are averages of at least two experiments.

The rest of the compounds of the examples was tested at least once, and the compounds showed activity in the study of accumulation of IP in the range from ˜1,4 nm to ˜5 nm.

Example 57

Inhibition of food intake in deprived of food for rats

Male rats Sprague-Dawley (250-350 g) are deprived of food overnight prior to testing. Before deprivation of food animals are weighed and divided into groups for balancing groups on body weight. On the day of testing, animals are placed in individual cells (without reason) at 9:00 am, at the same time provide easy access to the water. 10:00 a.m. animals injected with the test compound (BP, VB. or P.K.) and then the m give a pre-weighed amount of food on the plate after 60 min (BP) or 30 min (VB. and P.K.) after drug administration. food consumption at different points in time is then determined by weighing the plates with food after 1, 2, 4 and 6 hours after the meal. Thus, food consumption is measured after 2, 3, 5 and 7 hours after administration at P.O. introduction and 1.5, and 2.5, 4.5 and 6.5 hours after administration in VB. and P.K. introduction.

On figa-G shows the effect of seven different compounds on food intake in deprived of food rats. All compounds inhibited food intake depending on the dose. This action is definitely more distinctly within 1 hour after a meal. Some compounds (figa, 1C and 1E) retain inhibitory effect on food intake relative to the control group, treated only by the media even 6 hours after the meal. The compounds are also effective in all the ways, including BP

Assume that each patent application, print publishing, and other published documents mentioned or noted in the description, included here by reference in full.

Specialists in this field will recognize many changes and modifications may be made in the preferred embodiments of this invention, and it is clear that such changes and modifications are within the scope of this invention. So, I think that presents fo the mule of the invention includes all such equivalent variations, responsible entity within the scope of this invention.

1. The compound represented by formula (I)

where R1is N or C1-8by alkyl;

R2is C1-8by alkyl, -CH2-O-C1-8by alkyl, -O-N or CH2IT;

R2ais N;

or R2and R2atogether form-CH2-CH2-;

R3is halogen, perhalogenated, CN, SR5, Other5N(R5)2, aryl or heteroaryl, where specified, the aryl may optionally having up to two substituents selected from C1-8of alkyl, halogen of perhalogenated and alkoxy, and the specified heteroaryl may not necessarily be up to two substituents selected from halogen and C1-8of alkyl;

R4is H, halogen, perhalogenated, CN, OR5, SR5, Other5N(R5)2HE, aryl or heteroaryl, where specified, the aryl may optionally having up to two substituents selected from C1-8of alkyl, halogen, perhalogenated and alkoxy, and the specified heteroaryl may not necessarily be up to two substituents selected from halogen and C1-8of alkyl;

or R3and R4together with the atoms to which they are attached, may form a 5 - or 6-membered heterocyclic ring, have it one atom Of;

each R5independently is C1-8the alkyl, C2-8alkenyl, aryl, heteroaryl, arylalkyl, heteroallyl, perhalogenated, or allyl; and

R6is N or C1-8by alkyl; or their pharmaceutically acceptable salt, solvate or hydrate,

provided that

if R6different from H, R4there can be N;

if R1and R2are the stands, and R4is H, R3there can be other5or N(R5)2;

if R1and R2are the stands and R4is H, R3can't be imidazole, substituted imidazole or imidazole derivative.

2. The compound according to claim 1, in which R1is N.

3. The compound according to claim 1, in which R1is C1-8the alkyl.

4. The compound according to claim 1, in which R1is stands, ethyl or n-propylene.

5. The compound according to claim 1, in which R1is stands.

6. The compound according to any one of claims 1 to 5, in which R2is C1-8the alkyl.

7. The compound according to any one of claims 1 to 5, in which R2is stands, ethyl, n-propylene or isopropyl.

8. The compound according to any one of claims 1 to 5, in which R2is stands or ethyl.

9. The compound according to any one of claims 1 to 5, in which R2and R2atogether form-CH2-CH2.

10. The compound according to any one of claims 1 to 5, in which R3is halogen.

11. The compound according to any one of claims 1 to 5, in which R3is chlorine.

12. The compound according to any one of claims 1 to 5, in which R3is bromine.

13. The compound according to any one of claims 1 to 5, in which R3is perhalogenated.

14. The compound according to any one of claims 1 to 5, in which R3is CF3.

15. The compound according to any one of claims 1 to 5, in which R3is a 5-membered heteroaryl having up to two heteroatoms selected from O, N and S.

16. The compound according to any one of claims 1 to 5, in which R3selected from the group including thienyl, furanyl, pyrrolyl, pyrazolyl and imidazolyl.

17. The compound according to any one of claims 1 to 5, in which R4is perhalogenated.

18. The compound according to any one of claims 1 to 5, in which R4is CF3.

19. The compound according to any one of claims 1 to 5, in which R4is-OR5.

20. The connection according to claim 19, in which R5is stands, ethyl, n-propylene, isopropyl or allyl.

21. The connection according to claim 19, in which R5is stands or allyl.

22. The compound according to any one of claims 1 to 5, in which R4is a 5-membered heteroaryl having up to two heteroatoms selected from O, N and S, and the specified heteroaryl optionally substituted by one or two substituents selected from halogen or C1-8Ala is La.

23. The compound according to any one of claims 1 to 5, in which R4selected from the group including thienyl, furanyl, pyrrolyl, pyrazolyl and imidazolyl, optionally substituted by one or two substituents selected from halogen or methyl.

24. The compound according to any one of claims 1 to 5, in which R4is phenyl, optionally having up to two substituents selected from C1-8of alkyl, halogen and alkoxy.

25. The compound according to any one of claims 1 to 5, in which R3and R4together with the atoms to which they are attached, form a-O-CH=C(CH3)-.

26. The compound according to any one of claims 1 to 5, in which R3is halogen and R4is-OR5where R5is1-8the alkyl.

27. The compound according to any one of claims 1 to 5, in which R3is chlorine and R4is-OR5where R5is1-8the alkyl.

28. The compound according to any one of claims 1 to 5, in which R3is bromine and R4is-OR5where R5is1-8the alkyl.

29. The compound according to any one of claims 1 to 5, in which R3is iodine and R4is-OR5where R5is1-8the alkyl.

30. The compound according to any one of claims 1 to 5, in which R3is halogen and R4is methoxy.

31. The compound according to any one of claims 1 to 5, in which R3is halogen and R4is allyloxy.

32 Connection according to claim 1, in which

R2is stands, ethyl, isopropyl or CH2IT; or R2and R2atogether form-CH2-CH2-;

R3is a halogen, or a 5-membered heteroaryl having up to two heteroatoms selected from O, N and S, and up to two substituents selected from halogen and C1-8of alkyl;

R4is H, C1-8alkoxy, 5-membered heteroaryl having up to two heteroatoms selected from O, N and S, and up to two substituents selected from halogen and C1-8the alkyl, or phenyl, optionally having up to two substituents selected from C1-8of alkyl, halogen and alkoxy;

or R3and R4together with the atoms to which they are attached, form a-CH=C(CH3)-; and

R6is H or stands;

or their pharmaceutically acceptable salt, solvate or hydrate.

33. The compound according to claim 1, in which

R2is stands, ethyl, isopropyl or CH2IT; or R2and R2atogether form-CH2-CH2-;

R3is chlorine, bromine or iodine;

R4is H, C1-8alkoxy, and

R6is H or stands;

or their pharmaceutically acceptable salt, solvate or hydrate.

34. The compound according to claim 1, in which

R1is N;

R2what is the stands;

R3is chlorine, bromine or thiophene;

R4is H, C1-8alkoxy, pyrazole-3-yl or phenyl, where the specified pyrazole-3-Il has up to two substituents selected from halogen and C1-8the alkyl and the phenyl optionally has one halogen Deputy; and

R6is N;

or their pharmaceutically acceptable salt, solvate or hydrate.

35. A compound selected from the group including

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

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

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

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

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

N-propyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

7-hydroxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

7 allyloxy-8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-Aza-Cycloheptane;

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

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

8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin;/p>

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

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

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

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

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

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

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

8-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

N-methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-iodine-1-methyl-7-triptoreline-2,3,4,5-tetrahydro-1H-3-benzazepin;

N-propyl-8-iodine-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

1-ethyl-8-iodine-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin;

7-(2-forfinal)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-(2-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; and

8-bromo-1-methoxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin;

or their pharmaceutically acceptable salt, solvate or hydrate.

36. A compound selected from the group including

8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

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

8-iodine-7-is ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

N-methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

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

8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-iodine-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin;

7-methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepin; and

7-methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

or their pharmaceutically acceptable salt, solvate or hydrate.

37. A compound selected from the group including

8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-iodine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

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

8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-iodine-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

7,8-dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; and

8-chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

or their pharmaceutically acceptable salt, solvate or hydrate.

38. The compound according to claim 1 which is 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Il is its pharmaceutically acceptable salt, the MES or hydrate.

39. Connection § 38, which is the R-enantiomer.

40. Connection § 38, which is the S-enantiomer.

41. Connection § 38, which is a mixture of R and S enantiomers.

42. Pharmaceutical composition for modulation NT2Creceptor containing the compound according to any one of claims 1 to 41 and a pharmaceutically acceptable carrier or excipient.

43. Method of modulating receptor T2Ccomprising contacting a specified receptor with a pharmaceutically effective amount of a compound according to any one of claims 1 to 41.

44. The method according to item 43, where the specified compound is an agonist of a specified receptor.

45. The method of prevention or treatment of disorders of the Central nervous system; damage to the Central nervous system; cardiovascular disorders; gastrointestinal disorders, diabetes insipidus, and sleep apnea, comprising the administration to a patient in need of such prevention or treatment an effective dose of a compound according to any one of claims 1 to 41.

46. The method according to item 45, wherein the Central nervous system disorders selected from the group including depression, atypical depression, bipolar disorders, anxiety, obsessive-compulsive condition, social phobias or panic States, sleep disorders, sexual dysfunction, psychoses, schizophrenia, epilepsy the Yu, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, drug and alcohol addiction, obesity, bulimia, nervous anorexia and premenstrual syndrome.

47. The method according to item 45, in which the disorder of the Central nervous system is the obesity.

48. The method according to item 45, in which damage to the Central nervous system occurs due to trauma, stroke, neurodegenerative diseases or toxic or infective CNS diseases.

49. The method according to p in which the specified toxic or infectious disease of the Central nervous system is an encephalitis or meningitis.

50. The method according to item 45, in which cardiovascular disease is thrombosis.

51. The method according to item 45, in which the gastrointestinal disorder is a dysfunction of gastrointestinal motility.

52. A method of reducing food intake in a mammal, comprising the administration to a mammal pharmaceutically effective amount of a compound according to any one of claims 1 to 41.

53. Method of inducing satiety in a mammal, comprising the administration to a mammal pharmaceutically effective amount of a compound according to any one of claims 1 to 41.

54. the manual control weight in mammals, includes introduction to the mammal pharmaceutically effective amount of a compound according to any one of claims 1 to 41.

55. A method of preventing or treating obesity, comprising administration to a patient in need of such prevention or treatment, a pharmaceutically effective amount of a compound according to any one of claims 1 to 41.

56. The method according to § 55, further comprising the stage of identification of the patient that a patient is in need of prophylaxis or treatment of obesity, where the specified stage identification is carried out before the introduction of the indicated patient pharmaceutically effective amount of the specified connection.

57. A method of obtaining a composition, comprising combining the compound according to any one of claims 1 to 41 and a pharmaceutically acceptable carrier.

58. The compound according to any one of claims 1 to 5, 32-41, intended for use in the treatment of disorders associated with the activity T2Creceptor, human or animal body by therapy.

59. The compound according to any one of claims 1 to 5, 32-41, intended for use in a method of prevention or treatment of disorders of the Central nervous system; damage to the Central nervous system; cardiovascular disorders; gastrointestinal disorders, diabetes insipidus, and sleep apnea.

60. The compound according to any one of claims 1 to 5, 32-41, intended for use in the method is profilaktiki or treatment of disorders of the Central nervous system, selected from the group including depression, atypical depression, bipolar disorders, anxiety, obsessive-compulsive condition, social phobias or panic States, sleep disorders, sexual dysfunction, psychoses, schizophrenia, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, drug and alcohol addiction, obesity, bulimia, nervous anorexia and premenstrual syndrome.

61. The compound according to any one of claims 1 to 5, 32-41, intended for use in a method of prevention or treatment of obesity.

62. The compound according to any one of claims 1 to 5, 32-41, intended for use in the method of reducing food intake in a mammal.

63. The compound according to any one of claims 1 to 5, 32-41, intended for use in the method of inducing satiety in a mammal.

64. The compound according to any one of claims 1 to 5, 32-41, intended for use in the method of controlling the weight of the mammal.

65. The use of compounds according to any one of claims 1 to 41 for the manufacture of a medicinal product for use in the prevention or treatment of disorders of the Central nervous system; damage to the Central nervous system; CE is Dechen-vascular diseases; gastro-intestinal diseases, diabetes insipidus, and sleep apnea.

66. The use of compounds according to any one of claims 1 to 41 for the manufacture of a medicinal product for use in the prevention or treatment of a disorder selected from the group including depression, atypical depression, bipolar disorders, anxiety, obsessive-compulsive condition, social phobias or panic States, sleep disorders, sexual dysfunction, psychoses, schizophrenia, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, drug and alcohol addiction, obesity, bulimia, nervous anorexia and premenstrual the syndrome.

67. The use of compounds according to any one of claims 1 to 41 for the manufacture of a medicinal product for use in the prevention or treatment of obesity.

68. The use of compounds according to any one of claims 1 to 41 for the manufacture of a medicinal product for use in the method of reducing food intake in a mammal.

69. The use of compounds according to any one of claims 1 to 41 for the manufacture of a medicinal product for use in the method of inducing satiety in a mammal.

70. The use of the is placed according to any one of claims 1 to 41 for the manufacture of a medicinal product for use in a method of weight control in a mammal.



 

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SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

FIELD: organic chemistry, pharmaceuticals.

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EFFECT: compounds with specific bonding to 5-HT6 receptor.

10 cl, 3 tbl, 45 ex

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FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydroxytiazolo[5,4-b]indole of formula useful in liver protection from poisoning with carbon tetrachloride. Said compound has boiling point of 174-175°C (decomposition) and LD50 of 1950±180 mg/kg. Method for production of claimed compound also is disclosed.

EFFECT: new compound for liver protection from poisoning with carbon tetrachloride.

2 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: organic chemistry, medicine, pulmonology.

SUBSTANCE: invention relates to a new chemical compound, namely, 7-bromo-4-acetylthiazolo[5,4-b]indol-2-succinimide of the formula: that is able to protect body against hypoxia and possesses the curative effect in lung toxic edema. The melting point of this compound is 267-269°.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7, cycle A, cycles B, X, Y and Z have values given in the invention claims and in description of the claim, and to their pharmaceutically acceptable salts also. Proposed compound possess an antitumor activity and can be used in treatment of oncological diseases. Also, invention relates to a pharmaceutical composition based on these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

23 cl, 1 tbl, 57 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein (a) each R1 is chosen independently from hydrogen atom and alkoxy-group; (b) R2 represents hydrogen atom; (c) each R3 and R4 is chosen independently of one another from hydrogen atom, alkyl, alkynyl, heteroalkyl group, aryl; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one or more hydroxo-group, carboxyl group, keto-, thioketo-, phenyl group, alkyl, heteroalkyl group, heteroaryl, heterocycloalkyl, spirocycloalkyl and their combinations; (d) each R5 and R6 represents hydrogen atom; or optical isomers, diastereomers and enantiomers represented by above given formula, and their pharmaceutically acceptable salts also. Also, invention describes using compound of the formula (I) for preparing a pharmaceutical composition possessing antibacterial activity and antibacterial pharmaceutical composition containing the safety and effective amount of compound of the formula (I) and a pharmaceutically acceptable carrier. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention relates to compounds of formula I , wherein W is halogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C4-haloalkyl or C1-C4-haloalkoxy; X is hydrogen, halogen, C1-C6-alkyl; Y is hydrogen, halogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-haloalcoxy or cyano; Z is hydrogen, halogen, etc.; G is halogen or nitro; meanings of the other substituents are as defined in specification. Also disclosed are methods for production of said compounds by interaction compounds of formula II with halogenation agents in presence of solvent and optionally of radical initiator of with fumed nitric acid in presence of solvent.

EFFECT: new compounds with insecticide activity.

17 cl, 20 tbl, 114 ex

FIELD: organic synthesis.

SUBSTANCE: invention relates to synthesis of camptotecin analogues from 2'-amino-5'-hydroxypropiophnone corresponding to AB ring portion of camptotecin structure and tricyclic ketone converted into CDE ring portion in camptotecin structure. Preparation of 2'-amino-5'-hydroxypropiophnone comprises following steps: (1) preparing compound (b) by mixing compound (a), benzylation agent, and a base followed by stirring mixture obtained in solvent on heating under reflux; (2) preparing compound (c) by dropwise adding Grignard reagent to compound (b) under an inert gas atmosphere; (3) preparing compound (d) by mixing compound (c) with an oxidant and stirring resulting mixture; and (4) preparing compound (e) via catalytic reduction of compound (d) (see scheme 1 below). Intermediate compounds (c') and (d') are described. Also described is a method for preparing tricyclic ketone to provide efficient complete synthesis of camptotecin serving as starting compound for irinotecan hydrochloride and a various types of camptotecin derivatives as well as for stable preparation of camptotecin and its derivatives. Scheme 1: .

EFFECT: expanded synthetic possibilities in camptotecin derivatives series.

5 cl, 17 tbl, 33 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of noscapine of the general formula (1) or its racemates, optical isomers, or their pharmaceutically acceptable salts and/or hydrates possessing anticarcinogenic activity, and to a pharmaceutical composition as tablets, capsules or injection formulations placed into pharmaceutically acceptable package, ant to methods for their synthesis, and to a method for inhibition of proliferation by their using. In compounds of the formula (1) R1 represents a substitute of amino-group chosen from alkyl; R2 represents a substitute of cyclic system chosen from possibly substituted alkyl wherein substitutes are chosen from possibly substituted amino-group or azaheterocycle comprising possibly oxygen (O), sulfur (S) or nitrogen (N) atoms as an additional heteroatom, and added to alkyl group by nitrogen atom, possibly substituted aryl possibly substituted and possibly condensed heteroaryl comprising at least one heteroatom chosen from nitrogen, sulfur and oxygen atoms, possibly substituted sulfamoyl. Except for, invention relates to 3-(9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 5-(4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-9-carbaldehyde (or -9-carbonitrile, or -9-sulfonyl chloride, or -9-carboxylic acid) and 3-(9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, and method for their synthesis. Also, invention relates to combinatory and focused libraries.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 5 tbl, 9 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides novel condensed furan compounds of general formula I: , wherein circle X represents benzene, pyridine, or the like; Y optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted piperidyl, oxo-substituted pyrrolydyl, or oxo-substituted morpholino group; R3 hydrogen and the like; and R4 is hydrogen, or a pharmaceutically acceptable salt thereof, which are useful as drugs, especially as inhibitor of activated blood coagulation factor A, as well as intermediate compounds.

EFFECT: expanded synthetic possibilities in furan series and increased choice of biologically active compounds.

16 cl, 85 tbl, 481 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 4-phenyl-substituted tetrahydroisoquinolines of the formulae: (IA) , (IB) , (IIA) , (IIB) , (IIIA) and (IIIC) wherein values X and R1-R7 are given in the invention description. Proposed compounds show selective binding of neurotransmitters and therefore they can be used in treatment of different neurological or psychological disorders, for example, ADHD. Also, invention relates to a pharmaceutical composition based on proposed compounds and to a method for treatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

36 cl, 1 dwg, 16 tbl, 131 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

FIELD: organic chemistry of natural compounds, medicine, pharmacy.

SUBSTANCE: invention elates to a novel polymorphous form © of crystalline irinotecan hydrochloride of the formula: This form is characterized by X-ray diffraction picture on a powder with values of angle 2θ about 9.15; about 10.00; about 11.80; about 12.20; about 13.00 and about 13.40 and showing infrared spectrum comprising peaks at 1757, 1712 and 1667 cm-1. The novel polymorphous form © is used in treatment of cancer diseases but as distinct from the known polymorphous form (b) it possesses significantly greater solubility in water that allows its using both oral and parenteral administration.

EFFECT: improved and valuable properties of drug.

19 cl, 2 dwg, 4 tbl, 6 ex

FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to hexacyclic compounds of the formula [1]: wherein Z represents -NH-C(=X)-N(R1)- or -N=C(R2)-N(R1)-; R1 represents hydrogen atom, (C1-C10)-alkyl substituted optionally with one-three groups chosen independently from group consisting of (C1-C5)-alkoxy-, hydroxy-, amino-, mono-(C1-C5)-alkylamino-, di-(C1-C5)-alkylamino-group, (C3-C7)-cycloalkyl, heterocyclic ring chosen from pyridine or morpholine and aryl wherein aryl ring is substituted optionally with one-three groups chosen independently from group consisting of hydroxy-, alkoxy-group and halogen atom; R2 represents hydrogen atom, (C1-C5)-alkyl substituted optionally with one-three groups chosen independently from group consisting of (C1-C5)-alkoxy-, hydroxy-group, halogen atom and amino-group, (C1-C5)-alkoxy-, (C1-C5)-alkylthio-, amino-, mono-(C1-C5)-alkylamino- and di-(C1-C5)-alkylamino-group; each R3 and R4 represents independently hydrogen atom or (C1-C5)-alkyl; X represents oxygen atom or sulfur atom, and its pharmaceutically acceptable salts. Hexacyclic compounds of the formula [1] possess antitumor activity. Indicated compounds are used in preparing medicinal agents in treatment of cellular proliferative disorders, pharmaceutical composition and in treatment of cellular proliferative disorder. Also, invention relates to methods for synthesis of hexacyclic compounds. Invention provides synthesis of hexacyclic compounds possessing the strong antitumor activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

31 cl, 1 tbl, 114 ex

FIELD: medicine, pharmaceuticals.

SUBSTANCE: invention relates to compound of general formula I having structure of triazole[4,5-d]pyrimidine derivatives, or pharmaceutically acceptable salts, or prodrugs thereof. Disclosed is method for application of said compound or pharmaceutically acceptable salt thereof to produce pharmaceutical for treatment and prophylaxis of conditions ameliorated with blockage of adenosine A2A receptors. Also disclosed are pharmaceutical composition including compound of formula I, or pharmaceutically acceptable salt, or prodrug thereof in combination with pharmaceutically acceptable carrier or excipient. Said pharmaceutical compositions may be administered to subject by peroral, rectal, parantheral, transdermal, subdermal, etc. methods. Pharmaceutical of present invention are useful in treatment of Parkinson's disease, depression, cognitive or mental disturbances, acute or chronic pain, narcolepsy, etc.

EFFECT: composition of improved neuroprotective characteristics.

50 cl, 3 tbl

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