Bicyclic agonists of vasopressin

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

 

The scope of the invention

The present invention relates to a new class of chemicals that act as agonists of the peptide hormone vasopressin. They reduce the production of urine by the kidneys and, thus, can be used in the treatment of certain human diseases characterized by polyuria. They can also be used to treat urinary incontinence and diseases associated with blood coagulation disorders.

Background of the invention

Vasopressin is a peptide hormone, secretively posterior pituitary. It acts on the kidneys, increasing water retention and, thus, reducing the production of urine. Therefore, vasopressin otherwise known as "antidiuretic hormone". It also acts on vascular smooth muscle, causing a hypertensive effect. Cellular receptors that mediate these two impacts were characterized and it was shown that they are different. Antidiuretic action is mediated by the vasopressin receptor type 2, commonly called V2the receptor. Agents that can interact with V2the receptor and activate it in the same way as vasopressin, are called agonists V2receptor (or simply V2agonists). Such agents will have an antidiuretic effect. If these agents selectively interact the V 2receptor and do not interact with other subtypes of receptor vasopressin, they will not have the hypertensive action of vasopressin. This could be important when considering security and makes them attractive agents for the treatment of pathological conditions of a person characterized by polyuria (by which we mean excessive urine production).

Indeed, this matter has already been applied in the treatment of people. Desmopressin (another name [1 desamino, D-Agde8]vasopressin, Minirin™, DDAVP™) is a peptide analogue of vasopressin, which is a selective agonist of the V2the receptor. It is used in the treatment of diabetes insipidus of Central origin, resulting from insufficient secretion of vasopressin. It is also used to treat nocturnal enuresis and can also be used for the treatment of nocturia. However, desmopressin is not ideal in all respects by the tool. Even the best currently synthesis agent takes a long time, and desmopressin non-cleanable most convenient method, such as crystallization. So desmopressin relatively expensive. It has a very low bioavailability when administered orally, and this option is somewhat fickle.

Thus, there is a need in the electoral agonist V2receptor vasopressin, which can be easily obtained and a clear and which has a high and predictable bioavailability when administered orally. Such properties are most likely when getting ones connection. These findings led other research groups to study ones V2agonists of vasopressin, and their results are described for example in international patent applications WO 97/22591, WO 99/06403, WO 99/06409, WO 00/46224, WO 00/46225, WO 00/46227 and WO 00/46228. The compounds described in these documents, however, cannot be considered ideal. In particular, they have poor bioavailability when administered orally, probably because of its poor solubility in water. The present invention relates to compounds with improved solubility and bioavailability.

In addition to the antidiuretic action of desmopressin is used to increase the concentration in the blood coagulation protein known as factor VIII and the factor a background of Villebranda. In the clinical aspect of this fact makes desmopressin useful in the treatment of hemophilia a and disease von Willebrand's disease. This way you could use ones agonists of the present invention.

Brief description of the invention

As described herein, the present invention relative to the Xia to the group of compounds which ones are the antagonists of vasopressin and are selective against subtype V2receptor vasopressin. Compounds are described General formula 1

where V is a covalent bond or NH,

X is selected from CH2, And N-alkyl,

Z represents S or-CH=CH-,

R1and R2independently selected from H, F, Cl, Br and alkyl,

R3selected from HE, O-alkyl and NR4R5,

R4and R5each independently represent H or alkyl, or both represent -(CH2)q-,

p is 0, 1, 2, 3 or 4 and

q is 4 or 5.

The invention also relates to pharmaceutical compositions containing vasopressin agonists, which, in particular, can be used in the treatment of diabetes insipidus of Central origin, nocturnal enuresis, and nocturia.

Description of the invention

The present invention includes derivatives of N-allterrain defined General formula 1

In this formula, V represents NH-group or covalent bond. X represents a special methylene group (-CH2-), oxygen atom (O) or N-alkyl. Z represents a sulfur atom (S) or the group-CH=CH-.

R1and R2each independently selected from H, F, CL, Br and alkyl groups.

R3you are the wounds from IT, O-alkyl and NR4R5.

R4and R5each independently selected from H and alkyl groups. Alternatively, both may represent -(CH2)q-where q is 4 or 5, so that together with the nitrogen atom to which they are attached, they may form pyrolidine or piperidino ring.

The integer R can take values 0, 1, 2, 3 and 4. When p is 0, covalent bond is between V and group COR3. When p is 0 and V is a covalent bond, then a single covalent bond is between two carbonyl groups.

As is used herein, "alkyl" includes saturated hydrocarbon residues, linear or branched, containing up to six carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, neopentyl and n-hexyl.

Some compounds of General formula 1 are capable of forming salts with acids or bases. For example, compounds containing a basic nitrogen atom, may form a salt of the added acid with mineral and organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, triperoxonane acid, methanesulfonate acid, citric acid and benzoic acid. Compounds containing acid groups may images is their salts with bases. Examples of such salts include salts of sodium, potassium, calcium, triethylamine and tetraethylammonium. In addition, compounds which have both acidic and basic groups can form internal salts (zwitterions). If these salts are pharmaceutically acceptable, they are included in the scope of the invention.

In the preferred embodiment of the invention, the group Z represents-CH=CH-.

In another preferred embodiment of the invention Z is S.

In another preferred embodiment of the invention X represents a methylene group CH2.

In another preferred embodiment of the invention R1represents a hydrogen atom and R2represents a methyl group or a chlorine atom.

In another preferred embodiment of the invention R1represents a methyl group or chlorine atom and R2represents a hydrogen atom.

In another preferred embodiment of the invention R3represents O-alkyl.

In a particularly preferred compounds within the invention the combined strengths of these preferred embodiments.

Individual preferred compounds within the scope of the invention include (but are not limited to) the following connections:

1-(4-[N-(4-methoxy-4-oxobutanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-Benzes the pin,

1-(4-[N-(2-methoxy-2-oxoethyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-hydroxy-2-oxetanyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(5-methoxy-5-oxopentanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-ethoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-hydroxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(3-methyl-4-[N-(2-methylamino-2-oxoethylidene)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-dimethylamino-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-methoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-amino-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

4-(3-chloro-4-[N-(4-methoxy-4-oxobutanoic)aminomethyl]benzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin,

5-(4-[N-(4-methoxy-4-oxobutanoic)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1,5-benzoxazepin,

1-(4-[N-(2-ethoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine,

1-(4-[N-(3-methoxy-3-oxopropanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(3-ethoxy-3-oxopropanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-those whom rehydro-1H-1-benzazepin,

1-(4-[N-(3-hydroxy-3-oxopropanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(4-hydroxy-4-oxobutanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(5-hydroxy-5-oxopentanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(3-methoxy-3-oxopropanoic)aminomethyl]-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(N'-ethoxycarbonylmethyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-ethoxy-2-oxoethylidene)aminomethyl]-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-isopropoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-tert-butoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(3-chloro-4-[N-(2-dimethylamino-2-oxoethylidene)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(3-methyl-4-[N-(2-(1-piperidino)-2-oxoethylidene)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(3-methyl-4-[N-(2-(1-pyrrolidino)-2-oxoethylidene)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(3-ethoxy-3-oxopropanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin and

1-(4-[N-(3-hydroxy-3-oxopropylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin.

Join this izobreteny may be obtained by methods widely known in this field. Compounds of General formula 1 can be viewed as consisting of three related parts (a-C).

Three fragments are usually obtained separately and then in the later stages of the synthesis unite. Individual cases of different groups (especially R3and X) may be incompatible with such an organization and therefore require the use of protective groups. The use of protective groups is well known in the art (see, for example, "Protective Groups in Organic Synthesis", T.W.Greene, Wiley-Interscience, 1981). Specific groups who may require protection are amines (protected as amides or carbamates) and carboxylic acid (protected in the form of esters). For the purposes of this study it is assumed that such protective groups, if required, are available.

Fragments a, b and C can be combined in accordance with the two strategies produce compounds of formula 1. First, the fragments a and b are associated with obtaining a fragment corresponding to AB, which is then combined with the fragment of S. secondly, fragments b and C are associated with obtaining the fragment corresponding to the aircraft, which then combine with fragment A. the Chemistry of condensation of the fragment And In and condensation of the fragment In the fragment With the same, regardless of strategy.

Education fragm the NTA AV

The nature of the reaction, forming the link a-b depends on the type V.

V=covalent bond

Here {} and {} are part of the structures of the fragments a and b, respectively. The formation of amides by reacting acid chlorides of the acids with primary amines is well known. Typically, the amine and the acid chloride of the acid are mixed in an aprotic solvent such as dichloromethane or dimethylformamide, in the presence of a tertiary amine such as triethylamine.

V=NH

The formation of ureas by reacting isocyanate and a primary amine is widely known. Typically, amine and isocyanate are mixed in an aprotic solvent such as dichloromethane or dimethylformamide. The presence of a tertiary amine such as triethylamine, can be useful, but usually not necessary.

Education fragment SU

The formation of amide linkages between fragments b and C can be most easily achieved by reacting the carboxylic acid corresponding to the fragment, with a secondary amine, which is part of azepino ring fragment C. the Reaction is carried out in an aprotic solvent in the presence of a tertiary amine base. Depending on the specific nature of the two fragments to achieve a satisfactory output is Yes product for the reaction may take more or less time. Alternatively, the carboxylic acid corresponding to the fragment, can be condensed with azepino, using one of a variety of reagents known in this area for the implementation of the formation of the amide bond.

In General, for the synthesis of compounds of the present invention requires the following intermediate compounds.

The anhydrides of the acids are widely known. Many are commercially available or described in the literature. If necessary, the acid chloride of the acid is unknown connection, you usually get one-step reaction of the corresponding carboxylic acid. Isocyanates are also widely known. Usually, they can be obtained from the corresponding primary amine interaction with phosgene or an equivalent reagent.

ii) For a fragment

Since the primary amine and chloranhydride group incompatible, they must be obtained separately and protected. The acid chloride of the acid can be obtained from the corresponding carboxylic acid, which is easy to defend in the form of a methyl ester. The primary amine can be obtained from the corresponding nitrile (recovery) or alcohol (by nucleophilic substitution with nitrogen). The best way will depend on the nature of the substituents R1 and R2.

iii) For a fragment With

Condensed azepine of this type receive in accordance with the methods described in the literature.

The present invention also includes pharmaceutical compositions that include at least one connection in accordance with the following description as an active component. The composition can also include a second pharmacological agent, such as spasmolysant or blocker of potassium channels, these agents are known in this area as improving bladder function. Preferably the composition contains only one active ingredient. The composition comprises excipients selected from linking agents, agents that increase the volume, dispersing agents, solvents, stabilizing agents and the like, such excipients generally well known in the field.

Used excipients will depend on the proposed nature of the drug, which, in turn, depends on the proposed route of administration.

The administration can be oral, through the mucous (sublingual, buccal, intranasal, vaginal and rectal), transdermal, or by injection (subcutaneously, intramuscularly and intravenously). Oral administration is generally preferred. For Perea inogo administration of the drug can be in the form of tablets or capsules. Other drugs include dry powders, solutions, suspensions, suppositories and the like.

In another aspect, the present invention relates to a method for the treatment or regulation of some physiological dysfunction in humans. This method comprises the administration to a subject in need of such treatment, an effective amount of a pharmaceutical composition, which contains as an active ingredient the compound described above. The effect of compounds reduces rochevilaine, and thus the method according to the invention can be used in all States in which the increase rochevilaine is a contributory factor. Connections also increase the production of coagulation proteins in the blood, known as factor VIII and the factor a background of Villebranda and thus can be carried out treatment of disorders associated with bleeding disorders.

In the preferred embodiment of the condition being treated is diabetes insipidus. This condition is caused by inability of the body to produce and secrete physiologically active vasopressin, resulting in reabsorption of water is greatly reduced and produce large volumes of urine.

In another preferred embodiment the condition for treatment is nocturnal enuresis. It is defined as the release of the bladder well what womam during sleep. This condition is more vulnerable children, and the etiology is associated with a large number of factors.

In another preferred embodiment the condition for treatment is nocturia. It is defined as the production of a sufficient amount of urine at night, required to ensure that the individual woke up to empty their bladder. Again, this condition may be the result of many factors.

In another preferred embodiment the condition for treatment is incontinence. This condition is characterized, in particular, reduction of bladder capacity and, thus, control that leads to unintended urinate when the bladder is often not emptied. Matenadarani is divided into two States, matenadarani associated with stress and forced incontinence. I believe that included many etiological factors. The treatment according to the invention is particularly useful for deferral is necessary to release the bladder (urinary retention)to allow the subject with urinary incontinence is dry for several hours (for example, up to four hours). This urine may be useful for people with incontinence, for example for people who are forced to be at the meeting for a long time.

In another preferred embodiment the condition that the machining is to provide treatment, is hemophilia a or disease von Willebrand's disease. These States, which decreases the synthesis of factor VIII or factor a background of Villebranda and the individual suffers from prolonged bleeding.

In another preferred embodiment the composition is administered before surgery (including dental surgery)to increase the coagulability of the blood and thus reduce blood loss during surgery.

The introduction of the compositions of the present invention is usually carried out under the supervision of a physician. The attending physician determines the number of input composition and schedule, prinimaya into consideration the physical condition of the patient and the goals of therapy. For the adult patient with diabetes insipidus, the usual dose may be from 50 mg to 1 g of active compound per day, taken as one tablet, or up to four tablets per day. For routes of administration other than oral, the number of connections can be reduced, as non-oral route of administration are more effective for the delivery of therapeutic agents into the bloodstream. For the treatment of hemophilia a and disease von Willebrand's disease the number of connections may require more than in the treatment of diabetes.

The preceding General description will now be additionally proillyustriroval what about the next non-limiting examples.

EXAMPLES

Abbreviations

We used the following abbreviations:

AIBNAzo-bis-(isobutyronitrile)
VOStert-Butyloxycarbonyl
(VOS)2AboutDi-tert-BUTYLCARBAMATE
DIADiisopropylethylamine
DMFDimethylformamide
EtOAcThe ethyl acetate
IPAIsopropanol
M.S.Mass spectrometry
NBSN-Bromosuccinimide
NMRSpectrometry nuclear magnetic resonance
Peter. etherpatriliny ether fraction boiling at 60-80°
Rougher®Bromo-Tris-(pyrrolidino)fosfodiesterasa
THFTetrahydrofuran
WSCDIWater-soluble carbodiimide

Obtaining intermediates

Reagents corresponding to the fragment a and C, were commercially available or were obtained in accordance with published methods, except as described in the specific examples.

The Regents, corresponding to the fragment were obtained, as described below.

Note the R And

4-(tert-Butyloxycarbonyl)-3-chlorbenzene acid

A1. Methyl-4-methyl bromide-3-chlorobenzoate

To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27,1 mmol) in carbon tetrachloride (50 ml) was added NBS (5.8 g, 32,0 mmol) and AIBN (0,442 g, 2,70 mmol). The mixture was stirred while boiling under reflux for 18 hours the Mixture was left to cool to room temperature and then concentrated in vacuum. The residue was purified using flash chromatography on silica gel (eluent EtOAc:petrify 0:100-5:95); exit 5,96 g (84%).

A2. 4-(tert-Butyloxycarbonyl)-3-chlorbenzene acid

To a saturated solution of ammonia in ethanol (170 ml) was added methyl-4-methyl bromide-3-chlorobenzoate from example A1 (5.5 g, to 20.9 mmol). The mixture was stirred at room temperature for 1 h and then concentrated in vacuum. The residue was treated with diethyl ether and the resulting white crystals were filtered and washed again with diethyl ether. To a solution of this solid in water (100 ml) was added solutions (VOS)2O (5.0 g, 23,0 mmol) in dioxane (100 ml) and sodium hydroxide (1.86 g, 46,0 mmol) in water (100 ml). The mixture was stirred at room temperature for 18 h and then concentrated in vacuum. The aqueous residue was acidified with citric acid and was extracted with chloroform/IPA. The organic layer was washed in the water, dried over MgSO4and concentrated in vacuum to obtain a white solid product; yield 2.8 g (67%).

The example In

4-Cyano-3-methylbenzoic acid

To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at -78°C in an atmosphere of nitrogen was added dropwise a 2.5 M solution of n-utility (4,48 ml, and 11.2 mmol). The mixture was stirred at -78°C for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was left to warm to room temperature. Was added water (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by adding concentrated Hcl and was extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4and concentrated in vacuum to obtain a white solid product; yield 1.2 g (73%).

The example

4-Cyano-2-methylbenzoic acid

4-Bromo-3-methylbenzonitrile (2.0 g, 10.2 mmol) was subjected to interaction by way of example, obtaining a yellow solid product, which was treated with hexane and filtered; yield 0.96 g (59%).

Example D

4-(tert-Butyloxycarbonyl)-2-Formentera acid

D1. 2-Fluoro-4-methylbenzoic acid

4-Bromo-3-vtortola (8,33 g, 44,07 mmol) experience and interaction in accordance with the method of example In obtaining a white solid product; 4,89 g (72%).

D2. Methyl 2-fluoro-4-methylbenzoate

To a solution of 2-fluoro-4-methylbenzoic acid in example D1 (6,04 g, 39,18 mmol) in toluene (80 ml) was added thionyl chloride (6.5 ml, 89,11 mmol). The mixture was heated at the boil under reflux for 2.5 h, cooled and concentrated in vacuum. The residue was dissolved in dichloromethane (50 ml) was added methanol (50 ml). The mixture was stirred at room temperature for 2.5 h and then concentrated in vacuum. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and saturated saline solution, dried over MgSO4and concentrated in vacuo to obtain a yellow-brown solid product; output 5,07 g (77%).

D3. Methyl 4-methyl bromide-2-perbenzoate

Methyl 2-fluoro-4-methylbenzoate for example D2 (5,07 g, 30,16 mmol) was subjected to interaction in accordance with the method of example A1. The product was purified using flash chromatography on silica gel (eluent EtOAc:Petefi 20:80); yield 5.9 g (80%).

D4. 4-(tert-Butyloxycarbonyl)-2-Formentera acid

Methyl 4-methyl bromide-2-perbenzoate for example D3 (5.9 g, 24,13 mmol) was subjected to interaction in accordance with the method of example A2. The product was recrystallized from dioxane/petrifier to obtain white crystals; yield of 2.46 g (38%).

Reagents corresponding to the fragments a, b and C, combined with the receipt of the special examples described below.

Example 1

1-(4-[N-(4-Methoxy-4-oxobutanamide]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

1A. 1-(4-Cyano-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

To a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (0,80 g, 5,44 mmol) in dichloromethane (40 ml) was added 4-cyano-3-methylbenzoic acid for example (0.96 g, 5,95 mmol), triethylamine (0,76 g, 5,44 mmol), 4-(dimethylamino)pyridine (0.66 g, 5,44 mmol) and WSCDI (2.17 g, 10,88 mmol). The mixture was stirred while boiling under reflux for 18 h, cooled and evaporated in vacuum. The residue was distributed between EtOAc and 1 M KHSO4. The organic layer was washed with saturated sodium bicarbonate solution and saturated saline solution, dried over gSO4and concentrated in vacuum. The residue was purified using flash chromatography on silica gel (eluent EtOAc:Petefi 30:70); yield 1.10 g (70%).

1B. Hydrochloride of 1-(4-[aminomethyl-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

To a degassed solution cyanobenzylidene in example 1A (1.10 g, with 3.79 mmol) in methanol (40 ml) was added concentrated hydrochloric acid (0,98 ml, 11.3 mmol) and 10% palladium on coal (0,80 g). The mixture barbotirovany hydrogen gas for 5 hours at room temperature. The catalyst was removed by filtration through a layer of cellite and the filtrate was evaporated the vacuum to obtain the product as Hcl salt; the output of 1.23 g (98%).

1C. 1-(4-[N-(4-Methoxy-4-oxobutanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

To a solution of amine from example 1B (0.10 g, 0.30 mmol) in dichloromethane (10 ml) was added triethylamine (0,061 ml, 0.90 mmol) and 3-carbomethoxyamino (0,046 g, 0.90 mmol). The mixture was stirred at room temperature for 18 hours and then washed with 1 M KHSO4(3 times), water and saturated saline solution, dried over Na2SO4and concentrated in vacuum to obtain a white solid product; yield 0.10 g (81%).

1H-NMR: δ 1,40-1,60 (1H, m), 1,84-of 2.20 (3H, m), of 2.15 (3H, s), 2,40-of 2.54 (2H, m), 2,58 of 2.92 (4H, m), 2,94-3,10 (1H, m), the 3.65 (3H, s), 4,30 (2H, d, J=5.6 Hz), 4,99 (1H, d, J=12,6 Hz), 5,90 (1H, s), 6,62 (1H, d, J=7.9 Hz), 6,78-of 6.96 (3H, m), 7,00-7,16 (2H, m), 7,21 (1H, m) ppm

M.S.: calculated m/e=408; found [M+H]+=409.

Example 2

1-(4-[N-(2-Methoxy-2-oxoethyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

The amine hydrochloride from example 1B (0.10 g, 0.30 mmol) was subjected to interaction with methylacetylene (0.037 g, 0.30 mmol) according to the method of example 1C to obtain a white solid product; the output of 0.085 g (76%).

1H-NMR: δ 1,48 is 1.70 (1H, m), 1,96-of 2.16 (3H, m), and 2.26 (3H, s), 2,78-3,18 (3H, m), 3,98 (3H, s), 4,50 (2H, d, J=6.8 Hz), to 5.08 (1H, d, J=a 12.7 Hz), 6,72 (1H, d, J=7,6 Hz), 6,88-7,06 (3H, m), 7,18 (1H, d, J=7,6 Hz), 7,22 and 7.36 (2H, m) ppm

M.S.: calculated m/e=380; found [M+H]+=31.

Example 3

1-(4-[N-(2-Hydroxy-2-oxetanyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

To a solution of methyl ester from example 2 (0,045 g, amount of 0.118 mmol) in THF (10 ml) and water (5 ml) was added monohydrate of lithium hydroxide (0,010 g, 0.23 mmol). The mixture was stirred at room temperature for 2 h, acidified to pH 1 by adding 1 M Hcl and was extracted with EtOAc (3 times). The combined organic extracts were washed with saturated brine, dried over Na2SO4and concentrated in vacuum to obtain a white solid product; output 0,034 g (76%).

1H-NMR: δ 1,40-of 1.62 (1H, m), 1,84-of 2.24 (3H, m), 2,17 (3H, s), 2,70-3,10 (3H, m), and 4.40 (2H, d, J=5,9 Hz), 4,99 (1H, d, J=12.9 Hz), 6,63 (1H, d, J=7,6 Hz), 6,80-6,98 (3H, m), 7,02-7,28 (3H, m), 7,38 (1H, user. C) ppm

M.S.: calculated m/e=366; found [M+H]+=367.

Example 4

1-(4-[N-(5-Methoxy-5-oxopentanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

The amine hydrochloride from example 1B (0.10 g, 0.30 mmol) was subjected to interaction with methyl-4-(chloroformyl)butyrate (0,050 g, 0.30 mmol) according to the method of example 1C to obtain a white solid product; output 0,061 g (48%).

1H-NMR: δ 1,42-of 1.62 (1H, m), 1,84-2,28 (8H, m), 2,30-of 2.50 (4H, m), 2,70-to 2.94 (1H, m), 2,96-of 3.12 (1H, m), the 3.65 (3H, s), or 4.31 (2H, d, J=5.3 Hz), 4,99 (1H, d, J=a 13.9 Hz), of 5.75 (1H, user. C)6,63 (1H, d, J=7,6 Hz), 6,78-6,98 3H, m), 7,02-7,16 (2H, m), 7,21 (1H, d, J=6.6 Hz) ppm

M.S.: calculated m/e=422; found [M+H]+=423.

Example 5

1-(4-[N-(2-Ethoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

To a solution of amine from example 1B (0.10 g, 0.30 mmol) in dichloromethane (10 ml) was added triethylamine (0,061 ml, 0.90 mmol) and utilizationfocused (0,059 g, 0.45 mmol). The mixture was stirred at room temperature for 18 h and then washed with 1 M SO4(3 times), water and saturated saline solution, dried over Na2SO4and concentrated in vacuum to obtain a white solid product; yield 0.10 g (81%).

1H-NMR: δ of 1.18 (3H, t, J=7,3 Hz), 1,38-of 1.55 (1H, m), 1,80-2,10 (3H, m), of 1.95 (3H, s), 2,60 are 2.98 (3H, m), a-3.84 (2H, s), Android 4.04 (2H, s)4,07 (2H, q, J=7,3 Hz), 4,78 to 4.92 (1H, m), 5,73 (2H, user. C)6,50 (1H, d, J=7,3 Hz), 6,63-6,97 (5H, m), 7,11 (1H, d, J=7,3 Hz) ppm

M.S.: calculated m/e=423; found [M+H]+=424.

Example 6

1-(4-[N-(Carboximetilkrahmal)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

To a solution of ethyl ester from example 5 (0,050 g, 0.10 mmol) in THF (20 ml) and water (5 ml) was added monohydrate of lithium hydroxide (0,020 g, 0.45 mmol). The mixture was stirred at room temperature for 4 h the Mixture was concentrated in vacuo and the residue was diluted with water, then washed with diethyl ether. The aqueous layer was acidified to p is 1 with 1 M Hcl and was extracted with EtOAc (3 times). The combined organic extracts were washed with saturated brine, dried over Na2SO4and concentrated in vacuum to obtain a white solid product; output 0,046 g (99%).

1H-NMR: δ 1,30-1,50 (1H, m), 1,75-2,05 (3H, m), of 1.94 (3H, s), 2,60 are 2.98 (3H, m)and 3.59 (2H, user. C)to 4.01 (2H, user. s), 4.80 to around 4.85 (1H, m), equal to 6.05 (2H, user. C)6,53 (1H, d, J=7,2 Hz), 6.75 in-6,99 (5H, m), 7,11 (1H, d, J=7.2 Hz) ppm

M.S.: calculated m/e=395; found [M+H]+=396.

Example 7

1-(4-[N-(2-Methylamino-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

To a solution of carboxylic acid from example 6 (0.10 g, 0.25 mmol) in dichloromethane (25 ml) was added DIEA (0,221 ml of 1.26 mmol) and(0,129 g, 0,278 mmol). The mixture was stirred at room temperature for 10 minutes and then was added methylamine hydrochloride (of 0.085 g of 1.26 mmol). Stirring is continued for another 3 hours the Mixture was then washed with 1 M KHSO4(3 times), saturated sodium bicarbonate solution (3 times) and saturated saline solution, dried over Na2SO4and concentrated in vacuum. The residue was purified using flash chromatography on silica gel (eluent dichloromethane:methanol 96:4) to give a white solid product; output 0,018 g (17%).

1H-NMR: δ 1,40-1,60 (1H, m), 1,80-2,00 (2H, m), 2.00 in of 2.20 (3H, s), 2,60 (3H, d, J=4.0 Hz), 2,65 was 3.05 (3H, m), 3,60 (2H, d, J=4.0 Hz), 4,15 (2H, d, J=4.0 Hz), 4,98-5,0 (1H, m), 6,10-6,30 (2H, m), 6,60 (1H, d, J=8.0 Hz), 6,70-7,20 (8H, m) ppm

M.S.: calculated m/e=408; found [M+H]+=409.

Example 8

1-(4-[N-(2-Dimethylamino-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

Carboxylic acid from example 6 (0.07 g, 0.18 mmol) was subjected to interaction with dimethylaminohydrolase (0,072 g, 0.88 mmol) in accordance with the method of example 7. The product was purified using flash chromatography on silica gel (eluent chloroform:methanol:acetic acid 98:1:1) to obtain white solid; yield 0.08 g (11%).

1H-NMR: δ 1,39 of 1.50 (1H, m), 1,86 is 2.10 (3H, m)2,07 (3H, s), to 2.57 (3H, s), 2,60-of 3.00 (3H, m), 2,85 (3H, s), 3,95 (2H, d, J=4.0 Hz), 4,16 (2H, d, J=5.6 Hz), 4,90-5,00 (1H, m), 5,74 (1H, user. C)6,11 (1H, user. C)is 6.54 (1H, d, J=7,6 Hz), 6,78-7,18 (6N, m) ppm

M.S.: calculated m/e=422; found [M+H]+=423.

Example 9

1-(4-[N-(2-Methoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

To a solution of carboxylic acid from example 6 (0,080 g, 0.20 mmol) under nitrogen atmosphere in dichloromethane (25 ml) at 0°With added DMF (20 ml) and oxacillin (31 mg, 0.24 mmol). The mixture was stirred at 0°C to room temperature for 2 h and then concentrated in vacuum. The residue was dissolved in methanol (4 ml) and dichloromethane (16 ml) and the mixture was stirred at room temperature is over 16 PM The mixture was then washed with 1 M KHSO4(3 times), saturated sodium bicarbonate solution (3 times) and saturated saline solution, dried over Na2SO4and concentrated in vacuum. The residue was purified using flash chromatography on silica gel (eluent dichloromethane:methanol 96:4) to give a white solid product; output 0,049 g (60%).

1H-NMR: δ 1,38 of 1.50 (1H, m), 1,80-2,00 (3H, m), from 2.00 (3H, s), 2,60-of 3.00 (3H, m)to 3.64 (3H, s), 3,90 (2H, s), 4,10 (2H, s), 4,85-of 4.95 (1H, m), of 6.52 (1H, d, J=7,2 Hz), 6,67-7,02 (7H, m), 7,13 (1H, d, J=6.2 Hz) ppm

M.S.: calculated m/e=409; found [M+H]+=410.

Example 10

1-(4-[N-(2-Amino-2-oxoethylidene)aminomethyl]-3-

methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

To a solution of carboxylic acid from example 6 (0.10 g, 0.25 mmol) in dichloromethane (20 ml) was added hydroxybenzotriazole (34 mg, 0.25 mmol) and WSCDI (51 mg, 0.25 mmol). The mixture was stirred at room temperature for 10 minutes Then add the 880 ammonia (0.5 ml) and continued stirring for another 16 hours. The mixture was concentrated in vacuo and the residue was purified using flash chromatography on silica gel (eluent ethyl acetate) to give the white solid product; output 0.008 g (8%).

1H-NMR: δ 1,40 to 1.76 (2H, m), 1,84-of 2.16 (2H, m)to 2.29 (3H, s), 2,66-3,10 (3H, s), of 3.95 (2H, s), 4,56 (2H, s), 4,99 (1H, d, J=a 13.9 Hz), 5,59 (1H, user. C)6,63 (1H, d, J=7.9 Hz), 6,80-6,98 (3H, m), 7,00 for 7.12 (2H, m), 7,20 (1H, d, J=7,3 Hz) ppm

M.S.: calculated /e=394; found [M+H]+=395.

Example 11

4-(4-[N-(4-Methoxy-4-oxobutanoic)aminomethyl]-3-chlorobenzoyl)-5,6,7,8-tetrahydro-4H-triene[3,2-b]azepin

11A. The hydrochloride of 4-(4-[N-(tert-butyloxycarbonyl)aminomethyl]-3-chlorobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine

Carboxylic acid (example A2 (0,60 g, 2.10 mmol) was subjected to interaction with 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine (0.28 g, of 1.80 mmol) according to example 1A. The product was purified using flash chromatography on silica gel (eluent tO:petrify 40:60) to give a yellow solid product.

11. The hydrochloride of 4-(4-[aminomethyl-3-chlorobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine

The BOC-amine from 11A was dissolved in 4 BC HCl/dioxane (30 ml). The mixture was stirred at room temperature for 40 minutes, then concentrated in vacuo to obtain a solid product; the yield of 0.41 g (63%in stage 2).

11S. 4-(4-[N-(4-Methoxy-4-oxobutanoic)aminomethyl)-3-chlorobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin

To a solution of amine from example 11B (0,032 g, 0.08 mmol) in dichloromethane (10 ml) was added triethylamine (of 0.025 ml, 0.18 mmol) and 3-carbomethoxyamino (0,014 g, 0.08 mmol).

The mixture was stirred at room temperature for 18 h and then washed with 1 M KHSO4(3 times), water and saturated saline solution, dried over Na2SO4and concentrated in vacuum. About the ADOC was purified using flash chromatography on silica gel (eluent EtOAc: pet. ether 50:50 to 90:10); the output of 0.022 g (56%).

1H-NMR: δ 1,70 is 1.86 (3H, m), 1,96-of 2.08 (2H, m), 2,44-of 2.56 (2H, s), 2,60-of 2.72 (2H, m), 2,86 are 2.98 (2H, m), 3,67 (ZN, C), 3,85 (1H, user. C)of 4.44 (2H, d, J=5,9 Hz), 6,18 (1H, d, J=5.3 Hz), 6,28 (1H, user. C)of 6.68 (1H, d, J=5.3 Hz), 7,03 (1H, d, J=7,6 Hz), to 7.15 (1H, d, J=7,6 Hz) ppm

M.S.: calculated m/e=434; found [M+H]+35=Cl=435.

Examples 12-28

The following compounds in table 1 were obtained by methods similar to those described above.

Sampling data1H NMR:

a) 1,17 (6N, d, J=6.3 Hz), 1,20-1,24 (1H, m), 1,80-2,10 (3H, m), 2.00 in (ZN, C), 2,60-3,00 (MN, m), 3,85 (2H, d, J=5.3 Hz), 4,10 (2H, d, J=4.9 Hz), 4,82-is 4.85 (1H, m), 4,96 (1H, sept, J=6.2 Hz), 5,33 (1H, t, J=5,2 Hz), 5,43 (1H, t, J=4.9 Hz), of 6.52 (1H, d, J=7,6 Hz) ppm

b) 1,38-of 1.42 (1H, m), 1,38 (N, C), 1,78 is 2.10 (3H, m), 1.97 of (ZN, C), 2,60-of 3.00 (3H, m), of 3.78 (2H, s)4,07 (2H, s), 4,89-4,94 (1H, m), of 5.50 (2H, user. C)6,51 (1H, d, J=7.9 Hz), 6,64-6,98 (5H, m), 7,12 (1H, d, J=7,7 Hz) ppm

C) 1,38 of 1.50 (1H, m), 1,80 e 2.06 (3H, m), 2,60-of 3.00 (3H, m), 2,70 (3H, s), 2,87 (3H, s), of 3.96 (2H, d, J=4.0 Hz), 4,27 (2H, d, J=6.0 Hz), 4,85-of 4.95 (1H, m), 5,98 (1H, t, J=6.0 Hz), 6,14 (1H, t, J=4.0 Hz), 6,55 (1H, d, J=7,6 Hz), 6,80-7,16 (6N, m) ppm

d) a 1.25 (3H, t, J=7.0 Hz), 1,40-1,60 (1H, m), 1.85 to of 2.20 (3H, m), 2,04 (3H, s), a 2.45 (2H, t, J=6,27 Hz), 2,65-3,10 (3H, m), 3,30-3,50 (2H, m), 4,00-4,20 (4H, m), 4,90-5,00 (1H, m), 5,50-5,70 (2H, m), 6,50-7,20 (7H, m) ppm

e) 1,20-of 1.45 (1H, m), 1,65-2,05 (3H, m), of 1.95 (3H, s), 2.05 is was 2.25 (2H, m), 2,50-3,00 (3H, m)3,00-3,20 (2H, m), 3,85-of 4.05 (2H, m), 4,65-of 4.90 (1H, m), 5,80-of 6.20 (1H, user. C)6,40-7,20 (N, m) ppm

Example 29

Biological characteristics in vitro

Compounds according to the invention are the collective agonists of the receptor V 2. In the standard analysis of the substitution of radioactive ligands all compounds gave values of Kibelow 10 μm for V2the receptor.

Example 30

Biological characteristics in vivo

The Brattleboro rat is a model for the identification of a deficiency of vasopressin (as reference see FD Grant, "Genetic models of vasopressin deficiency = MKD", Exp. Physiol. 85, 203S VEHICLES-209S, 2000). Animals do not secrete vasopressin and, accordingly, produce a large volume of dilute urine. Compounds according to the invention was administered to rats Brattleboro (0,1-10 mg/kg) orally in methylcellulose. Urine was collected hourly and compare the volume with the volume control animals. Animals had free access to food and water throughout the experiment. Sample results are shown in table 2. Results for desmopressina shown for comparison.

Table 2

Connection exampleDose% Inhibition of the urinary tract (for 1 hour)
51 mg/kg74
61 mg/kg38
81 mg/kg45-82 per
251 mg/kg58
Desmopressin0.1 mg/kg37
1 mg/kg100
10 mg/kg100

Example 31

Pharmaceutical composition for tablet

Tablets containing 100 mg of the compound from example 5 as an active agent, produced from the following components:

Connection example 5200,0
Corn starch71,0
Hydroxypropylcellulose18,0
Calcixerollic13,0
Magnesium stearate3,0
Lactose195,0
Only500,0

The substance was ground and then extruded to obtain 2000 tablets 250 mg, each containing 100 mg of the compound of example 5.

The above examples showed that the compounds in the scope of the invention can be easily obtained using standard chemical methods, and that these compounds have biological properties that could be expected for agonists V2the receptor. In particular, the compounds possess antidiuretic properties in animal models with deficiency of vasopressin. Thus, it is clear that they can be used in the treatment of diseases in humans that are currently treated by desmopressina, such as the Central n is diabetes mellitus, nocturnal enuresis and nocturia. In addition, it can be assumed that antidiuretic, such as desmopressin, can be used for certain types of urinary incontinence. These arguments also apply to the compounds of the present invention.

Desmopressin is also used to treat certain coagulation disorders. There is good evidence to suggest that this action also when triggered by the V2receptor (see, for example, J.E. Kaufmann et al. "Vasopressin-induced von Willebrand's factor secretion from endothelial cells involves V2receptors and camp", J. Clin. Invest. 106, 107-116, 2000; Bernat et al. "V2receptor antagonism of DDAVP-induced release of hemostasis factors in conscious dogs", J. Pharmacol. Exp. Ther. 282, 597-602, 1997), and therefore, it can be expected that the compounds of the present invention can be used as procoagulants.

Scope of the present invention is further defined in the following claims.

1. The compound of General formula 1 or its pharmaceutically acceptable salt

where V is a covalent bond or NH;

X is selected from CH2,O, and N-alkyl;

Z represents S or-CH=CH-;

R1and R2independently selected from H, F, Cl, Br and alkyl;

R3selected from HE, O-alkyl and NR4R5;

R4and R5each independently represent H or Alky is, or both represent -(CH2)q-;

p is 0, 1, 2, 3 or 4, and

q is 4 or 5.

2. The compound or salt according to claim 1, where Z represents-CH=CH-

3. The compound or salt according to claim 1, where Z represents S.

4. The compound or salt according to any one of the preceding paragraphs, where X represents CH2.

5. The compound or salt according to any one of the preceding paragraphs, where R1represents N and R2selected from methyl and Cl.

6. The compound or salt according to any one of claims 1 to 4, where R1selected from methyl and Cl and R2represent N.

7. The compound or salt according to any one of the preceding paragraphs, where R3represents O-alkyl.

8. The compound according to claim 1, selected from the following:

1-(4-[N-(4-methoxy-4-oxobutanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-methoxy-2-oxoethyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-hydroxy-2-oxetanyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(5-methoxy-5-oxopentanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-ethoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-hydroxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(3-IU the Il-4-[N-(2-methylamino-2-oxoethylidene)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-dimethylamino-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-methoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-amino-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

4-(3-chloro-4-[N-(4-methoxy-4-oxobutanoic)aminomethyl]-benzoyl)-5,b,7,8-tetrahydro-4H-thieno[3,2-b]azepin,

5-(4-[N-(4-methoxy-4-oxobutanoic)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1,5-benzoxazepin,

1-(4-[N-(2-ethoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine,

1-(4-[N-(3-methoxy-3-oxopropanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(3-ethoxy-3-oxopropanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(3-hydroxy-3-oxopropanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(4-hydroxy-4-oxobutanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(5-hydroxy-5-oxopentanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(3-methoxy-3-oxopropanoic)aminomethyl]-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(N'-ethoxycarbonylmethyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-ethoxy-2-oxoethylidene)aminomethyl]-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-isopropoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(2-tert-butoxy-2-oxoethylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(3-chloro-4-[N-(2-dimethylamino-2-oxoethylidene)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(3-methyl-4-[N-(2-(1-piperidino)-2-oxoethylidene)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(3-methyl-4-[N-(2-(1-pyrrolidino)-2-oxoethylidene)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin,

1-(4-[N-(3-ethoxy-3-oxopropanoic)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin and

1-(4-[N-(3-hydroxy-3-oxopropylidene)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin

or its salt.

9. Pharmaceutical composition having agonistic activity against receptor V2containing an active agent selected from the compounds and pharmaceutically acceptable salts listed in any of the preceding paragraphs.

10. The pharmaceutical composition according to claim 9, where the composition may be used to treat polyuria.

11. The pharmaceutical composition according to claim 9, where the composition may be used for the treatment of naderian the urine.

12. The pharmaceutical composition according to claim 9, where the composition may be used for urinary retention.

13. The pharmaceutical composition according to claim 9, where the composition may be used for the treatment of diseases associated with bleeding disorders.

14. A method of treating nocturnal enuresis, nocturia and diabetes insipidus, which includes an introduction to the subject in need of such treatment, an effective amount of a composition according to claim 9.

15. Method of controlling urinary incontinence, which includes an introduction to the subject in need of such treatment, an effective amount of a composition according to claim 9.

16. The method according to clause 15, where the treatment is retention of urine.

17. A method of treating diseases associated with bleeding disorders, which includes an introduction to the subject in need of such treatment, an effective amount of a composition according to claim 9.



 

Same patents:

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

The invention relates to compounds of the formula I

in which

R1, R2in each case, independently of one another represent H, A, HE, OA or Hal,

X is R4, R5or R6, monosubstituted R7,

R4is unbranched or branched alkylene with 1-10 atoms, in which one or two CH2groups can be substituted by a group-CH=CH-,

R5is cycloalkyl or cycloalkylation containing 5-12 With atoms

R6is phenyl or vinylmation,

R7is COOH, cooa, CONH2, CONHA, CON(A)2or CN,

And is alkyl having from 1 to 6 atoms

Hal represents F, Cl, Br or I,

where at least one of the radicals R1or R2HE is a,

and their pharmaceutically acceptable salts

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of thienopyrimidine formula (I) or its salts, which have a significant GnRH antagonistic activity and can be used for prophylaxis or treatment of hormone-dependent diseases

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to new biologically active chemical substances of some heterocyclic compounds of formulas I-III

I R=COOH, X=H; II, R=COOK, X=H; III R=COOC2H5X=Cl,

showing property to activate the germination of wheat seeds

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

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

SUBSTANCE: invention relates to new derivatives of piperazinylalkylthiopyrimidine of the formula (I): wherein R1 represents hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkanoyl or di-(C1-C4-alkyl)-amino-(C1-C4-alkyl); R2 means hydrogen atom or benzyl substituted with 1-3 substitutes taken among the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy-group, di-(C1-C4-alkyl)-amino-group, hydroxyl group and halogen atom; n = 2, 3 or 4, and to its pharmaceutically acceptable acid addition salt. Also, invention describes a method for preparing compounds and pharmaceutical composition based on thereof. Compounds are useful for treatment of diseases arising as result of the central nervous system injury.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 3 tbl, 26 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to substituted cyclic aminoven compounds of formula (I)

< / BR>
where Ar represents thienyl, substituted pyridine, phenyl unsubstituted or substituted with halogen, hydroxy, alkoxy, C1-C4the alkyl, phenyloxy, NO2or phenyl; R1is NHOR2where R2is hydrogen; W is one or more hydrogen atoms; Y is independently one or more members of the group consisting of hydroxy, SR3, alkoxy, NR6R7where R6and R7independently selected from hydrogen, alkyl, pyridylethyl, SO2R8, COR9or R6and R7can be combined with the formation of the ring containing the nitrogen to which they relate, formulas

< / BR>
where Y' is CH2OH , SO2; R3represents hydrogen, alkyl, aryl, benzothiazolyl, pyrazinyl, N-methylimidazole; R8represents C1-C4alkyl, phenyl; R9represents hydrogen, alkyl, phenyl; Z is hydrogen; n = 1, and its optical isomer, diastereoisomer, or enantiomer, or its pharmaceutically acceptable salt

The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

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