Condensed azepines, pharmaceutical composition comprising thereof, method for treatment by using indicated composition

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

 

The scope of the invention

This invention relates to a new class of chemical compounds that act as antagonists of the peptide hormone vasopressin. They reduce the secretion of urine by the kidneys and therefore suitable for the treatment of several human diseases characterized by polyuria. They are also suitable for treating diseases of the urinary incontinence and bleeding.

Background of invention

Vasopressin is a peptide hormone, secretively rear part of the pituitary gland. It acts on the kidneys, increasing water retention, and thus reduces the flow of urine. For this reason, vasopressin alternative known as "antidiuretic hormone". It also acts on the vascular system, where it has a hypertensive effect. Cellular receptors that mediate these two steps, as shown and described, various. Antidiuretic action is mediated vasopressive receptor type-2, commonly called receptors V2. Substances that can interact with V2receptors and activate them the same way as vasopressin, are called agonists receptor V2(or just V2agonists). Such substances will have an antidiuretic effect. If these substances are selectively interact with V2receptors and not to communicate with the t with other subtypes vasopressinergic receptors they will not have a hypertensive effect of vasopressin. It would be of great importance from the point of view of security and makes these materials attractive for the treatment of painful conditions in humans, characterized by polyuria (the term used here to refer to excessive secretion of urine).

Vasopressin

In fact, this substance has already been used in the treatment of people. Desmopressin (or [1 desamino, D-Arg8]vasopressin, MINIRIN™, DDAVP™) is a peptide analogue of vasopressin, which is a selective agonist of the V2the receptors. It is used to treat diabetes insipidus of Central origin, which is a pathological condition resulting from impaired secretion of vasopressin. It is also used in the treatment of bedwetting and it can be also suitable for the treatment of nocturnal polyuria. However, desmopressin is not ideal in all respects by the tool. Even the most modern methods for the synthesis of this substance are long, and desmopressin not be the most convenient cleaning methods, such as crystallization. In the desmopressin is relatively expensive. It has a very low bioavailability when administered orally, and there is some Riposto nstwo this parameter.

Desmopressin

In General, in this case, there is a need in the selective agonist of the receptors of vasopressin V2that is easy to get and clean, and which has a high and predictable bioavailability when administered orally. Such properties are most likely available from ones connection. These considerations have led other groups of researchers to explore ones agonists, vasopressin V2and the results are disclosed, for example, in international patent applications WO 97/22591, WO 99/06403, WO 99/06409, WO 00/46224, WO 00/46224, WO 00/46225, WO 00/46227 and WO 00/46228. The compounds described in these documents, however, are not perfect. In particular, they have poor bioavailability when administered orally, perhaps in part because of their low solubility in water. This invention is compounds with improved solubility and bioavailability.

In addition to its antidiuretic action of desmopressin is used to increase the concentration in the blood clotting proteins, known as factor VIII and von Willebrand factor. In a clinical context it makes desmopressin suitable for the treatment of hemophilia a and von Willebrand disease. Such possible applications will be disclosed in relation to ones agonists of the present invention.

A BRIEF DESCRIPTION FROM THE RETENE

As described herein, this invention relates to certain compounds, which are the ones vasopressin agonists, and which are selective receptor subtype V2. These compounds are described General formula 1

where:

And is a tricyclic azepino derivative selected from the General formulas 2 through 7

And1And4And7and10each independently selected from CH2, And NR8;

And2And3And9And11And13And14and15each independently selected from CH and N;

or And5is a covalent bond, and6is S, or a5represents N=CH, and6is a covalent bond;

And8and12each independently selected from NH and S;

And16and17both represent CH2or one of And16and17is CH2and the other is selected from OH, SOxand NR8,

V1and V2both represent H, OMe or F, or F, or one of V1and V2represents Br, Cl, F, HE, OMe, OBn, OPh, O-acyl, N3, NH2, NHBn, or NH-acyl, and the other represents H, or V1and V2together are =O, -O(CH2)pO - or-S(CH2)pS-;

W1 represents O or S;

X1and X2both represent H or together are =O or =S;

Y is a OR5or NR6R7;

Z represents S or-CH=CH-;

R1, R2, R3and R4independently selected from H, lower alkyl, lower alkoxy, F, Cl and Br;

R5selected from H and lower alkyl;

R6and R7independently selected from H and lower alkyl, or together are -(CH2)n-;

R8represents H or lower alkyl;

n=3, 4, 5 or 6;

p is 2 or 3; and

x is 0, 1 or 2.

This invention also relates to pharmaceutical compositions containing these agonists, vasopressin, and compositions are particularly useful for treatment of diabetes insipidus of Central origin, bedwetting and nocturnal polyuria.

Description of the INVENTION

This invention relates to derivatives of N-benzylcarbamoyl defined by General formula 1.

In this formula a represents a bicyclic or tricyclic azepino group one of the General formulas 2-7.

And1And4And7and10represent a divalent group selected from methylene (-CH2-), oxygen (-O-) and substituted nitrogen (-NR8-). sup> 2And3And9And11And13And14and15present or nitrogen atom (-N=) or methine group (-CH=). And5can represent a covalent bond, and in this case, And6represents a sulfur atom (-S-), so that the ring, which includes these two groups represents a thiophene ring. An alternative, And5can represent a group-N=CH-, and in this case, And6represents a covalent bond, so that the ring, which includes these two groups is a pyridine ring. And8and12represent or-NH-or a sulfur atom (-S-). And16and17represent a divalent group. Both can be methylene groups (-CH2-), or one represents a methylene group and the other is selected from hydroxymethylene (-CH(OH)-), deformation (-CF2-), oxygen (-O-), substituted nitrogen (-NR8-) and sulfur or oxidized sulfur (-S-, -SO - or-SO2-). V1and V2may both represent hydrogen, methoxy or fluorine, or one may be selected from bromine, chlorine, fluorine, hydroxy, lower alkoxy, benzyloxy, phenoxy, acyloxy, azido, amino, benzylamino, acylamino (Br, Cl, F, HE, O-lower alkyl, OBn, OPh, O-acyl, NH2, NHBn and NH-acyl, provided that the other represents hydrogen, or V1and V2together can represent an oxygen atom, so that the fragment CV1V represents a carbonyl group (C=O). V1and V2may also be ethylene or Propylenediamine or-dithio chain (-O(CH2)2O-, -O(CH2)2O-, -S(CH2)2S-, -S(CH2)3S-), so CV1V2represents 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane or 1,3-diciannove ring.

W1represents either an oxygen atom or a sulfur atom. X1and X2both can represent either hydrogen, or together they can represent an oxygen atom or sulfur, so that the fragment CX1X2represents a carbonyl or thiocarbonyl group (C=O or C=S).

Y represents an or group OR5or the group-NR6R7.

Z represents or sulfur atom, so that the ring, which it includes, is a thiophene ring, or represents the group-CH=CH-, so that the ring is a benzene ring.

R1, R2, R3and R4each independently selected from hydrogen, lower alkyl groups, lower alkoxy groups and Halogens, fluorine, chlorine and bromine.

R5may represent either a hydrogen atom or a lower alkyl group.

R6and R7each independently can represent hydrogen atoms or lower alkyl groups, or together they may form a chain consisting of from 3 to 6 methylene groups, so that together with economista, with which they are connected, they form azetidinone, pyrolidine, piperidine or peligrosamente ring.

R8can be hydrogen or a lower alkyl group.

In the context of this description, the term "lower alkyl"includes alkyl groups of straight and branched chain and cycle alkylene group consisting of from 1 to 6 carbon atoms. For example, methyl, ethyl, isopropyl, tertbutyl, neopentyl and cyclohexyl, all included in the scope of the term lower alkyl. The term "acyl" means a carbonyl group of the lower Akilov, such as acetyl, pivaloyl, cyclopropanecarbonyl etc. Formyl also seen as acyl group.

Some compounds of General formula 1 are capable of forming salts with acids or bases. For example, compounds containing one or more nitrogen atoms, may form a salt accession 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, can form 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 in the morning salt (zwitterion). Because these salts are pharmaceutically acceptable, they are included in the scope of this invention.

Compounds of General formula 1, all have at least one stereogenic center (tetrahedral carbon atom bearing four different substituent) and, therefore, can exist as optical isomers, such as enantiomers and diastereomers. Such isomers and mixtures thereof are all included in the scope of this invention.

In the preferred embodiment of the present invention And represents a group corresponding to General formula 2. In another preferred embodiment of the present invention And represents a group corresponding to General formula 3. In yet another preferred embodiment of the present invention And represents a group corresponding to General formula 4. In yet another preferred embodiment of the present invention And represents a group corresponding to General formula 5. In yet another preferred embodiment of the present invention And represents a group corresponding to General formula 6.

In another preferred embodiment of the present invention And represents a group corresponding to General formula 7. In a more preferred embodiment a represents tetrahydro-1-benzazepin-1-ilen group, i.e. a group corresponding to General formula 1 in which Z is-SNSN men And 16and17are methylene groups.

In another preferred embodiment, one of R1and R2is chlorine or a methyl group and the other is hydrogen, and each R3and R4are hydrogen.

In yet another preferred implementation of one of the V1and V2represents methoxy or benzyloxy, and the other is hydrogen.

In another preferred embodiment X1and X2together represent an oxygen atom, a Y is-NR6R7.

Particularly preferred embodiments of this invention are those which combine two or more of the above preferred features.

Even more preferred embodiment of the present invention is a compound of General formula 8.

In the General formula 8 W1, R5and R6have the values specified above for 1. One of Raand Rbis hydrogen and the other is either chlorine, or methyl group. Rcis either a methyl group or benzyl group.

Even more preferred embodiment is the compound of General formula 8A, the stereochemistry of which is shown below.

Another preferred embodiment of this invention is to connect the work, corresponding to General formula 1, in which V1and V2both represent hydrogen. In a more preferred embodiment X1and X2together are an oxygen atom, a Y represents NR6R7. More preferred is a compound corresponding to the General formula 9.

In the General formula 9 W1, R5and R6have the values specified above for 1. One of R8and R15is hydrogen and the other is either a chlorine or a methyl group.

Even more preferred is a compound corresponding to the General formula (9A), the stereochemistry of which is shown below.

Specific preferred compounds in this invention include (but are not limited to) the following:

1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide,

(4R)-4-hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide,

(4R)-1-(3-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-Proline-N,N-dimethylamide,

(4R)-1-(2-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-Proline-N,N-dimethylamide,

(4R)-4-benzyloxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benicar mail)-L-Proline-N,N-dimethylamide,

(4R)-4-methoxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide,

(4R)-4-methoxy-1-(3-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide,

(4R)-1-(2-chloro-4-(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-Proline-N,N-dimethylamide,

(4R)-1-(4-(10,11-dihydro-5H-pyrrolo[2,1-C](1,4)benzodiazepine-10-ylcarbonyl)-2-methylbenzylamino)-4-methoxy-L-Proline-N,N-dimethylamide,

(4R)-1-(2-chloro-4-(10,11-dihydro-5H-pyrrolo[2,1-C](1,4)-benzodiazepine-10-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-Proline-N,N-dimethylamide and

(4R)-1-(4-(10,11-dihydro-5H-pyrrolo[2,1-C](1,4)benzodiazepine-10-ylcarbonyl)-2-methylbenzylamino)-4-methoxy-L-Proline-N,N-dimethylthieno.

The compounds of this invention can be obtained using methods commonly known to specialists in this field. Compounds of General formula 1 can be considered as formed of three related parts (a-C).

These three fragments are usually obtained separately and then combined in the final stages of the synthesis. Some representatives of the different groups (R1-R4, V1, V2X1X2and so on) may be incompatible in this connection, and therefore will require the use of protective groups. The use of protective groups is well known for the experts (see, for example, "Protective Groups in Organic Synthesis", .W.Green, Wiley-Interscience, 1981). Specific groups that may be in need of protection, are amines (protected as amides or carbamates), alcohols (protected as esters or ethers and carboxylic acid (protected in the form of esters). For the purposes of this discussion it will be assumed that such protecting groups, when necessary, are in place.

Fragments a, b and C can be connected in accordance with the two strategies to obtain compounds of formula 1. First, the fragments a and b connected with obtaining fragment corresponding to AB, which is then combined with a fragment of S. secondly, fragments b and C connected with obtaining the fragment corresponding to the SU, which is then combined with fragment A. Chemical group involved in the condensation of the fragment And In, and participating in condensation of the fragment In the fragment, will be the same, whatever the strategy nor followed. Discovered that the first strategy is more flexible when working in small scale and for receiving the selected compounds. However, it is possible that the second strategy would have advantages for obtaining selected compounds on a large scale.

The formation of fragment AB

Here {} and {} are part of the structure of the fragments and In accordance with the public. The formation of amides by condensation of carboxylic acids with amines is well known. In General, the acid and amine are mixed in an aprotic solvent such as dichloromethane or dimethylformamide, in the presence of a condensing agent, such as carbodiimide (e.g., "water-soluble carbodiimide", which is

N-ethyl-N-(3-dimethylaminopropyl)carbodiimide) or a reactive derivative of phosphorus (for example, "BOP", which is a (benzotriazol-1 yloxy)Tris(dimethylamino)fosfodiesterasa). The reaction may optionally be kataliziruetsa tertiary amine such as triethylamine or 4-dimethylaminopyridine. Alternatively, the carboxylic acid can be converted into a more reactive derivative such as acid chloride acid. This derivative can then interact with the amine, as described above, but without the need for condensing agent.

Education fragment SU

The formation of urea or timesaving communication between fragments b and C can be most easily achieved by bringing primary amine corresponding to the fragment, in the interaction with the carboxylic acid derivative such as phosgene (where LG, above, represents chlorine) or carbonyldiimidazole (where LG represents 1-imidazolyl) with the formation temporarily the CSOs derived carbamino acid. When W1is grey, not oxygen, is used thiophosgene or thiocarbonyldiimidazole. The reaction is conveniently carried out in an aprotic solvent such as dichloromethane or dimethylformamide, in the presence of a tertiary amine such as triethylamine or N,N-diisopropylethylamine. After providing sufficient time for the formation of intermediate compounds in the reaction mixture, you can add a secondary amine corresponding to the fragment of the S. there is No need to allocate intermediate urethane derivative.

As a variation on this process, it is possible to change the order of addition of amines corresponding to the fragments b and C, so that the urethane derivative is derived from a secondary amine, and then add a primary amine.

Mainly for the synthesis of compounds of the present invention, the following intermediate compounds.

i) For a fragment And

Condensed azepine these General formulas, can be obtained by the methods described in the literature. See, for example, Aranapakam et al., Bioorg. Med. Chem. Lett. 1993, 1733; Artico et al., Farmaco, Ed. Sci. 24, 1969, 276; Artico et al., Farmaco, Ed. Sci. 32, 1977, 339; Chakrabarti et al., J. Med. Chem. 23, 1980, 878; Chakrabarti et al., J. Med. Chem. 23, 1980, 884; Chakrabarti et al., J. Med. Chem. 32, 1989, 2573; Chimirri et al., Heterocycles 36, 1993, 601; Grunewald et al., J. Med. Chem. 39, 1996, 3539; Klunder et al., J. Med. Chem. 35, 1992. 1887; Liegeois et al., J. Med. Chem. 37, 1994, 519; Olagbemio et al., J. Het. Chem. 19, 1982, 1501; Wright et al., J. Med. Chem. 23, 1980, 462; Yamamoto et al., Tet. Lett. 24, 1983, 4711; and international patent application, publication number WO 99/06403.

Some of them are commercial products.

ii) For a fragment

Because groups are primary amine groups and carboxylic acids are incompatible, they must be formed separately and secured. Substituted benzoic acid are well known, and carboxylic acids are usually protected in the form of their methyl ester. The primary amine can be obtained from the corresponding nitrile (by recovery) or alcohol (by replacement with nitrogen nucleophile). The best method will depend on the nature of the substituents R1-R4.

iii) For a fragment With

Pyrolidine derivatives of this type to be made by methods described in the literature. See, for example, Dugave et al., Tet. Lett. 39, 1998, 1169; Petrillo et al., J. Med. Chem. 31, 1998, 1148 and Smith et al., J. Med. Chem. 31, 1988, 875.

Prolinnova and hydroxyproline derivatives particular stereochemistry are commercial products, and as such are convenient starting materials.

This invention also relates to pharmaceutical compositions that include at least one compound corresponding to the preceding description, as active com is Ananta. The composition may also include a second pharmacological agent, such as spasmolysant or blocker of potassium channels, and it is known that these agents improve the condition of bladder dysfunction. Preferably, the composition includes only one active component. The composition will include excipients selected from linking agents, fillers, dispersing agents, solvents, stabilizing agents and the like, and such excipients generally known to experts.

Used excipients will depend on the kind of formulation that will, in turn, depend on the intended route of administration. The administration can be oral, through the mucous membranes (sublingual, cheek, intranasal, vaginal, or rectal), transdermal, or by injection (such as subcutaneous, intramuscular and intravenous). Basically, it is preferable to oral administration. For oral administration, new form will be in the form of tablets or capsules. Other preparative forms include dry powders, solutions, suspensions, suppositories and the like.

In an additional aspect, the invention relates to a method of treatment or control of some physiological dysfunction in humans. This method includes the introduction of the person needing such Leche is NII, the effective amount of the pharmaceutical composition which contains a compound described above as an active ingredient. These compounds act in a way that decreases urine output, and thus, the method of the present invention can be used in all pathological conditions in which increased diuresis he is a contributing factor. These compounds also increase the production of proteins of blood clotting, known as factor VIII and von Willebrand factor, and, therefore, can be carried out treatment of diseases associated with bleeding.

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

In another preferred embodiment of the pathological condition being treated, is bedwetting. It is characterized as the emptying of the bladder at the time when the individual is sleeping. This disease is a pathological condition that mainly occurs in children, and its etiology may involve a number of factors.

In another site Cetelem embodiment of the pathological condition, which heal is nocturnal polyuria. It is characterized by the product of the amount of urine during the night is sufficient for the individual was required to get up and empty your bladder. And again, the pathological condition may be the result of several factors.

In another preferred embodiment of the pathological condition being treated, is incontinence. This pathological condition is characterized, in part, reduced bladder capacity and the kind of regulation that is involuntary urination, if the bladder is not emptied often. Incontinence was divided into two pathological conditions, stress incontinence and Callsign incontinence. Believed to be involved in a number of etiological factors. Treatment in accordance with this invention is particularly suitable for postponing the necessity of emptying the bladder ("delayed discharge")to give the subject with incontinence opportunities dry period of several hours (such as up to four hours). This delay emptying may also be useful for people without incontinence, for example, for people who are obliged to remain at the meetings for extended periods.

In yet another preferred embodiment of the pathological condition, Ketorolac is hemophilia a or von Willebrand disease. These diseases are pathological States in which the production of factor VIII or von Willebrand factor is reduced, and the individual suffers prolonged bleeding.

In another preferred embodiment the composition is administered before surgery (including dental surgery) to improve blood clotting and reducing, thus, the blood loss during the operation.

The introduction of the compositions of this invention will typically be under the supervision of a physician. The doctor will determine the amount of songs that you want to enter, and the dosage given physical condition of the patient and therapeutic purposes. For the adult patient with diabetes insipidus, the usual dose may be in the range of 50 mg to 1 g of active compound per day taken as a single pill or in the form of up to four tablets per day. As for other routes of administration, except for oral, amount of substance will be reduced, so as not oral route of administration tend to be more effective in delivering therapeutic agents into the systemic circulation. As for the treatment of hemophilia a and von Willebrand disease, it may be necessary that the number of connections was higher than for the treatment of diabetes.

The preceding General description below extra is niteline illustrated by the use of some non-limiting examples.

EXAMPLES

Abbreviations

We used the following abbreviations.

AUAcetyl
AEBNAzo-bis-(isobutyronitrile)
BnBenzil
SIDE (EAST)tert-butyloxycarbonyl
(VOS)2ODi-tert-BUTYLCARBAMATE
DMFDimethylformamide
EtEthyl
EtOAcThe ethyl acetate
IPA (IPA)Isopropanol
IPrIsopropyl
MCMass spectrometry
MeMethyl
NC (NBS)N-Bromosuccinimide
pet. etherpetroleum ether fraction, boiling at 60-80°
PhPhenyl
TButert-Butyl
THFTetrahydrofuran
WRKDYWater-soluble carbodiimide

The intermediate compounds

Reagents corresponding to fragments a and C were purchased or received on the published methods, except that specified in the specific examples. Reagents, appropriate is rahmanto, were obtained, as described below.

Example

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 NC (5.8 g, 32,0 mmol) and AIBN (0,422 g, 2,70 mmol). The mixture was stirred at reflux for 18 hours. The mixture was allowed to cool to room temperature, and then concentrated in vacuum. The residue was purified flash chromatography on silica (eluent: EtOAc: pet. ether 0:100 to 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 hour and then concentrated in vacuum. The residue is triturated with diethyl ether and the resulting white crystals were filtered and optionally washed with diethyl ether. To a solution of this solid in water (100 ml) was added solutions (VOS)2Oh (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 hours and then concentrated in vacuum. The aqueous residue was acidified lemon is Oh acid and was extracted with chloroform/IPA. The organic layer was washed with water, dried over MgSO4and concentrated in vacuum to obtain a white solid; 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 nitrogen atmosphere drops) was added a 2.5 M solution of n-utility (4,48 ml, and 11.2 mmol). The mixture was stirred at -78°C for 1 hour and then poured onto solid carbon oxide (5 g) in THF (50 ml). The mixture was allowed 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; yield 1.2 g (73%).

The example

4-Cyano-2-methylbenzoic acid

4-Bromo-3-methylbenzonitrile (2.0 g, 10.2 mmol) was brought into interaction by the method of example In obtaining yellow solid, which was triturated with hexane and filtered; yield 0.96 g (59%).

Reagents corresponding to the fragments a, b and C, connected with obtaining the compounds of the specific examples, which are described below.

Example 1

1-(2-methyl-4-(,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide

1A. 2-Methyl-4-((2,3,4,5-tetrahydro-1H-benzo[b]azepin)-1-carbonyl)benzonitrile

To a solution of 2,3,4,5-tetrahydro-1H-benzo[b]azepine (0,80 g, 5,44 mmol) in dichloromethane (50 ml) was added 4-cyano-3-methylbenzoic acid (0.96 g, 5,95 mmol), triethylamine (0,60 g, 5,95 mmol), 4-(dimethylamino)pyridine (0.73 g, 5,95 mmol) and WRKDY (1.24 g, 6,48 mmol). The mixture was stirred at reflux for 18 hours, cooled and evaporated in vacuum. The residue was separated between EtOAc and 1M KHSO4. The organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution, dried over MgSO4and concentrated in vacuum. Material raw was purified flash chromatography on silica (eluent EtOAc:pet. ether 30:70); yield 1.10 g (70%).

1B. 1-(4-(Aminomethyl)-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine hydrochloride

To a degassed solution cyanobenzene from example 1A (1.10 g, with 3.79 mmol) in methanol (50 ml) was added concentrated hydrochloric acid (0,98 ml, 11.3 mmol) and 10% palladium on coal (0,80 g). After the mixture was passed hydrogen gas for 5 hours at room temperature. The catalyst was removed by filtration through a layer of celite and the filtrate is evaporated; the output of 1.23 g (98%).

1C. 1-(2-Methyl-4-(2,3,4,5-tetrahydro-1H-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide

To a solution of AMI is and example 1B (0.10 g, 0,302 mmol) in DMF (10 ml) under nitrogen atmosphere was added N,N-diisopropylethylamine (43 mg, of 0.332 mmol) and carbonyldiimidazole (0,074 g, 0,453 mmol). The mixture was stirred at room temperature for 40 minutes. Solution was added Proline-N,N-dimethylamide (0,107 g, 0,756 mmol) in DMF (1 ml). The mixture was stirred at room temperature for another 16 hours. The solvent was removed in vacuum and the crude product was purified flash chromatography on silica (eluent:methanol:dichloromethane 5:95); exit 0,115 g (82%).

1H-NMR (CDCl3) δ ppm: 1.35-1.55 (1H, m), 1.74-2.10 (3H, m), 2.11 (3H, s), 2.17-2.35 (1H, m), 2.60-2.82 (2H, m), 2.86 (3H, s), 2.90-3.14 (2H, m), 3.05 (3H, s), 3.26 (1H, DD, J=14.9 and 7.2 Hz). 3.40-3.53 (1H, m), 3.64-3.84 (1H, m), 4.03-4.19 (1H, m), 4.29-4.42 (1H, m), 4.55-4.68 (1H, m), 4.74-4.81 (1H, m), 4.85-4.98 (1H, m), 6.58 (1H, d, J=7.7 Hz), 6.75-6.89 (2H, m), 6.91-7.06 (3H, m), 7.16 (1H, d, J=6.5 Hz), 7.93-8.03 (1H, m).

MS: calc. m/e=462,26; found [M+H]+=463,2

Example 2

(4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide

2A. L-TRANS-4-Hydroxyproline-N,N-dimethylamide hydrochloride

To a solution of BOC-hydroxyproline (2,99 g, 13,89 mmol) in dichloromethane (100 ml) was added N,N-diisopropylethylamine (3,7 ml, 21,24 mmol), 4-(dimethylamino)pyridine (1,74 g, 14.24 from mmol), dimethylamine hydrochloride (1,72 g, 21,09 mmol) and WRKDY (3,17 g, 16,68 mmol). The mixture was stirred at room temperature for 30 hours the century The mixture was diluted with dichloromethane (100 ml) and washed with 0.3 M KHSO4saturated sodium bicarbonate solution and saturated salt solution, dried over MgSO4and concentrated in vacuum to obtain a colorless resin. This crude material was collected in 4N HCl/dioxane (50 ml) and stirred at room temperature for 1 hour and then concentrated in vacuum. The residue was treated with azeotropic mixture of toluene and diethyl ether to obtain white solid; yield 0.45 g (17%).

2B. (4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide

Amine from example 1B (0.10 g, 0,302 mmol) was brought into interaction with the amine from example 2A (0,153 mg, 0,785 mmol) by the method of example 1C. The product was purified flash chromatography on silica (eluent chloroform:methanol:acetic acid 95:4:1); yield 0.95 g (66%).

1H-NMR (CDCl3) δ ppm: 1.65-1.80 (2H, m), 1.85-2.00 (3H, m), 2.05-2.25 (1H, m), 2.10 (3H, s), 2.80-3.10 (3H, m), 2.85 (3H, s), 3.00 (3H, s), 3.40-3.30 (1H, m), 3.45-3.55 (1H, m), 3.65-3.95 (1H, m), 4.00-4.10 (1H, m), 4.30-4.55 (1H, m), 4.91 (1H, t, J=7.7 Hz), 5.15-5.30 (1H, m), 6.10-6.20 (1H, m), 6.55-6.65 (1H, m), 6.85-7.50 (5H, m).

MS: calc. m/e=478,26; found [M+H]+=479,2

Examples 3-116

Additional examples are presented in the following examples were obtained using similar methods.

Example No.R/SV2XY[M+HF]+
3SNH2Ome436.4
4RNH2Ome436.2
5R/SOPh0HE528.3
6R/SOPh0NMe2555.3

Example No.R1R2V1V2XY[M+H]+
7NMeHH0OtBu492.5
8NMeHH0OH436.3
9NMeHOH0OMe466.0
10NMeHOAc0NMe2 521.0
11NMe=00NMe2477.3
12NMeHOH0OEt480.2
13NMeHOCOcC3H50NMe2547.3
14NMeHOMe0NMe2493.5
15NClHH0NMe2483.4
16NMeHHSNMe2479.2
17NMeHH0NMeEt477.2
18NOMeHH0NMe2479.2
19NMeHOMe0OMe480.2
20NMeHH 0OiPr478.2
21NMeHOH0HE452.1
22NMeHOBn0OiPr584.2
23NMeHOH0OiPr494.1
24NMeHOBn0NMe2569.2
25MeHHH0NMe2463.2
26NMeHOMe0HE466.2
27ClHHH0NMe2483.1
28NEtHH0NMe2477.3

Me
Example No.R1R2V1V2XY [M+H]+
29NClHHSNMe2499.2
30NClHOBn0NMe2589.2
31NClHOH0NMe2499.2
32NMeHOEt0NMe2507.3
33NMeBrH0NMe2541.1
34NMeHCl0OMe484.1
35NMeFF0NMe2499.2
36NMeHCl0HE470.1
37NMeHN30NMe2504.3
38NMe HCl0NMe2497.2
39NMeHOtBu0NMe2535.3
40NMeClH0NMe2497.2
41NMeHOPh0OMe542.3
42NMeHF0OMe468.3
43NMeHF0HE454.4
44NMeHF0NMe2481.3
45NMeHNHBn0NMe2568.0
46NMeOMeOMe0OMe510.3
47NMeOMeOMe0HE496.2
48NOMeOMe0NMe2523.3

Example No.R2V2X[M+H]+
49ClH0489.1
50MeH0469.2
51MeOH0485.0
52ClOMe0519.3
53MeOMe0499.3
54ClOMeS535.1

Example No.R3V2W1X[M+H]+
55NNS0479.4
56NOHS0495.0
57NNSS495.1
58MeN00477.2
59NOBnS0585.2
60NOBn0S585.0

Example No.And16And17R2V2[M+H]+
61NEtCH2MeOMe522.4
62NHCH2MeOMe494.3
63CH2NiPrMeOMe536.4
64CH2NHMeOMe494.5
650CH2ClOMe515.2
66CH(OH)CH2MeH479.2

Example No. V2[M+H]+
67H518.0
68H532.2
69H527.0
70H516.1
71H515.0
72H514.6
73H513.7
74H502.1

Example No.AndV2[M+H]+
75H500.7
76OH547.9
77OH517.6
78 OH546.3
79H517.2
80OBn619.2
81OMe543.3
82OMe544.3
83OMe549.2
84OMe548.2

Example No.AndV2[M+H]+
85OMe562.1
86OMe590.2

Example No.V1V2XY[M+H]+
87NNSNMe2 516.2
88NAFP0NMe2606.3
89NHE0NMe2507.3
90NOMe0NMe2530.3
91-Och2CH2O-0OMe545.3
92OMeOMe0Ome547.3
93-Och2CH2O-0NMe2558.3
94-SCH2CH2S-0NMe2590.2

Example No.R2V1V2XY[M+H]+
95MeHHE0NMe2516.1
96MeHHS NMe2516.2
97MeHOMe0NMe2530.4
98Me-OCH2CH2O-0OMe545.3
99Me-OCH2CH2O-0HE531.3
100Me-OCH2CH2O-0NMe2558.3
101ClNH0NMe2551.5
102MeHOMe0Net2558.3
103MeHOMe0570.3
104MeHOMeSNMe2546.2

Example No.And10R2V2X[M+H]+
105 0MeH0519.3
106NMeMeH0532.3

Example No.And10R2V2X[M+H]+
107NMeMeOH0548.1
108NMeMeOBn0638.2
109NMeMeOMe0562.3
1100MeOMe0549.2
111NMeMeCl0566.2
112NMeMeOMeS578.2
1130ClOMe0569.1
1140MeOMeS565.2
1150ClOMeS585.1
116NH OMe0548.2

Example 117

Determination of biological properties in vitro

The compounds of this invention are selective agonists of the V2the receptors. In the standard studies with substitution of the radioactively labelled ligand all connection data gave values of Kibelow 10 μm for receptor V2.

Example 118

Determination of biological properties in vivo

Brattleboro rats are recognized model for deficiency of vasopressin (see review F.D.Grant, "Genetic models of vasopressin deficiency = MKD", Exp. Physiol. 85, 203S VEHICLES-209S, 2000). These animals are not secreted vasopressin and, therefore, responsible for the generation of large amounts of dilute urine. The compounds of this invention was administered to rats Brattleboro (0,1-10 mg/kg orally) in methylcellulose. Urine was collected hourly, and volumes were compared with data for control animals. Animals had free access to food and water throughout the experiment. Typical results are presented in the table. Results for desmopressina are given for comparison.

The compound of exampleDose% suppression of urine output (for 1 hour)
11 mg/kg82
141 mg/kg84
521 mg/to the 90
541 mg/kg68
851 mg/kg63
901 mg/kg60
1011 mg/kg74
1041 mg/kg81
1091 mg/kg73
1101 mg/kg80
1121 mg/kg75
1141 mg/kg85
1151 mg/kg88


Desmopressin
0.1 mg/kg37
1 mg/kg100
10 mg/kg100

Example 119

Pharmaceutical composition for tablets

Tablets containing 100 mg of the compound of example 1 as the active substance, obtained as follows.

Table
Connection example 1200,0 g
Corn starch71,0 g
Hydroxypropylcellulose18.0 g
Calcixerollic13,0 g
Magnesium stearate3.0 g/td>
Lactose195, 0 g
Only500.0 g

Substances are mixed and then pressed to obtain 2000 tablets of 250 mg each contain 100 mg of the compound of example 1.

The preceding examples show that the compounds included in the scope of the present invention, it is easy to obtain using standard chemical techniques, and that these compounds possess biological properties that would be required for agonist V2the receptors. In particular, the connections are strong antidiuretic on animal models with deficiency of vasopressin. Thus, it is clear that they can be useful in the treatment of human diseases that are currently treated by desmopressina, such as diabetes insipidus of Central origin, bedwetting and nocturnal polyuria. In addition, it is assumed that antidiuretic, such as desmopressin, can be useful in some types of urinary incontinence. These arguments should also apply to the compounds of this invention.

Desmopressin is also used to treat some disorders of coagulation. Convincing evidence for the assumption that this action is also mediated by a receptor V2(see, for example, J.E. Kaufmann et al., "Vasopressin-induced von Willebrand's factor secretion from endotelial cells involves V receptors and cAMP", J.Clin. Invest. 106, 107-116, 2000; A.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 should be expected that the compounds of this invention should be suitable as a means of promoting coagulation (procoagulants).

1. Condensed azepine General formula 1

where a represents a bicyclic or tricyclic againby radical of the General formula 2, 3, 5, 6 or 7

where a1means of CH2or NR8;

And4means of CH2, O or NR8;

And10means O or NR8where R8means H or lower alkyl;

And2and3independently denote CH or N;

And11And13And14and15mean SN;

And5is a covalent bond, and6is S, or a5is N=CH, and6is a covalent bond;

And12means S;

And16and17both represent CH2or one of the A16and17means of CH2and the other is selected from CH(OH), O, or NR8where R8has the above meaning;

V1and V2both represent H, or one of V1and V2represents the N, OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NHBn, and the other represents H, or V1and V2together are =O or-O(CH2)pO-;

W1means O or S;

X1and X2both denote H or together are =O or=S;

Y is a OR5or NR6R7;

Z means S or-CH=CH-;

R1means H, lower alkyl, F, Cl or Br;

R2means H, lower alkyl, lower alkoxy, F, Cl or Br;

R3and R5independently mean H, lower alkyl;

R4means N;

R6and R7independently denote a lower alkyl, or together form - (CH2)n-;

n is 3, 4, 5 or 6;

p is 2 or 3;

or their pharmaceutically acceptable salts.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where a represents a group corresponding to General formula 2.

3. The compound according to claim 1 or its pharmaceutically acceptable salt, where a is a group of the General formula 3.

4. The compound according to claim 1 or its pharmaceutically acceptable salt, where a is a group corresponding to General formula 5.

5. The compound according to claim 1 or its pharmaceutically acceptable salt, where a is a group corresponding to General formula 6.

6. The compound according to claim 1 or its pharmaceutically priemel who may salt, where a is a group of the General formula 7.

7. The compound according to claim 1 or 6, or its pharmaceutically acceptable salt, where a is a group of the General formula 7, Z represents-CH=CH-, and both And16and17represent-CH2-.

8. The compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt, where one of R1and R2is Cl or Me, and the other is H, and both R3and R4are N.

9. The compound according to any one of claims 1 to 8, or its pharmaceutically acceptable salt, where one of the V1and V2represents OMe, or OBn, a other is N.

10. The compound according to any one of claims 1 to 9, or its pharmaceutically acceptable salt, and X1and X2together represent =O, and Y represents NR6R7.

11. The compound according to any one of claims 1 or 6-8, or its pharmaceutically acceptable salt, which is a

where W1represents O or S;

one of Raand Rbis Cl or methyl and the other is N;

Rcrepresents methyl or benzyl;

R6and R7independently denote a lower alkyl, or together form - (CH2)n-;

n is 3, 4, 5 or 6.

12. The compound according to any one of claims 1 or 6-11, or its pharmaceutically acceptable salt, to the which is a

where W1represents O or S;

one of Raand Rbis Cl or methyl and the other is N;

Rcrepresents methyl or benzyl;

R6and R7independently denote a lower alkyl, or together form - (CH2)n-;

n is 3, 4, 5 or 6.

13. The compound according to any one of claim 1 to 8, or its pharmaceutically acceptable salt, where V1and V2both represent N.

14. The connection 13 or its pharmaceutically acceptable salt, where X1and X2together are =O and Y represents NR6R7.

15. The compound according to any one of claims 1 or 6 to 8, or 13, or 14, or its pharmaceutically acceptable salt, which is a

where W1represents O or S;

one of Raand Rbis Cl or methyl and the other is N;

R6and R7independently denote a lower alkyl, or together form - (CH2)n-;

n is 3, 4, 5 or 6.

16. The compound according to any one of claims 1 or 6-8, or 13-15, or its pharmaceutically acceptable salt, which is a

where W1represents O or S;

one of R3and R6is Cl or methyl and the other is the;

R6and R7independently denote a lower alkyl, or together form - (CH2)n-;

n is 3, 4, 5 or 6.

17. The compound according to any one of the preceding paragraphs, which is selected from

1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide,

(4R)-4-hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide,

(4R)-1-(3-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-Proline-N,N-dimethylamide,

(4R)-1-(2-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-Proline-N,N-dimethylamide,

(4R)-4-benzyloxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide,

(4R)-4-methoxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide,

(4R)-4-methoxy-1-(3-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide,

(4R)-1-(2-chloro-4-(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-Proline-N,N-dimethylamide,

(4R)-1-(4-(10,11-dihydro-5H-pyrrolo[2,1-C](1,4)benzodiazepine-10-ylcarbonyl)-2-methylbenzylamino)-4-methoxy-L-Proline-N,N-dimethylamide,

(4R)-1-(2-chloro-4-(10,11-dihydro-5H-pyrrolo[2,1-C](1,4)-benzodiazepine-alkarsani)benzylcarbamoyl)-4-methoxy-L-Proline-N,N-dimethylamide; and

(4R)-1-(4-(10,11-dihydro-5H-pyrrolo[2,1-C](1,4)benzodiazepine-10-ylcarbonyl)-2-methylbenzylamino)-4-methoxy-L-Proline-N,N-dimethylthieno

or its pharmaceutically acceptable salt.

18. The compound according to any one of claims 1 to 17 or its pharmaceutically acceptable salt as a component of the pharmaceutical composition.

19. The compound according to any one of claims 1 to 17 or its pharmaceutically acceptable salt as a therapeutic agent for the treatment of bedwetting, nocturnal polyuria, polyuria resulting from diabetes insipidus of Central origin, incontinence and diseases with bleeding.

20. Pharmaceutical composition having an agonist action of vasopressin-containing compounds and their pharmaceutically acceptable salts according to any one of claims 1 to 17 as an active agent.

21. The pharmaceutical composition according to claim 20, which is intended for the treatment of polyuria.

22. The pharmaceutical composition according to claim 20, which is intended for the treatment of urinary incontinence.

23. The pharmaceutical composition according to claim 20, which is designed to delay emptying of the bladder.

24. The pharmaceutical composition according to claim 20, which is intended for the treatment of diseases with bleeding.

25. A method for the treatment of bedwetting, nocturnal polyuria, diabetes insipidus of Central origin is, incontinence of urine or diseases with bleeding, which includes the introduction of the person needing such treatment, an effective amount of a composition according to claim 20.



 

Same patents:

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to the field of organic chemistry, namely to new individual compounds of class benzoxazines that exhibit fluorescent properties and can be used as starting products for the synthesis of new heterocyclic systems, as well as substances for sample labeling and additives for reflective paints

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

The invention relates to new physiologically active substituted oxazolo[4,5-d]pyridazine General formula (1), (2) or (3) and combinatorial library designed to search among them physiologically active substances, compounds leaders and candidates (drug-candidates) on the basis of screening

The invention relates to new cyclic diamine compounds of the formula I, where

< / BR>
represents an optionally substituted divalent residue of benzene, where the substituents are selected from unsubstituted lower alkyl groups, unsubstituted lower alkoxygroup, unsubstituted lower acyl group, a lower allylthiourea, lower alkylsulfonyl group, halogen atom, etc. or unsubstituted pyridine; Ar represents a phenyl group which may be substituted by one to four groups selected from unsubstituted lower alkyl group, the unsubstituted alkoxygroup, low allylthiourea, lower alkylsulfonyl group, and so on, optional substituted amino group, alkylenedioxy; X is-NH-, oxygen atom or sulfur atom; Y is a sulfur atom, sulfoxide or sulfon; Z represents a single bond or-NR2-; R2- the atom of hydrogen or unsubstituted lower alkyl group; l = 2 or 3; m = 2 or 3; n = 1, 2, or 3, or their salts, or their solvate

The invention relates to new heterocyclic o-dicarbonitrile formula (I), where

< / BR>
The compounds obtained can be used to obtain hexatriene-fluorophores

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

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

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new oxathiepino[6,5-b]dihydropyridines of the formula (I):

wherein: (a) R1, R2, R3, R4 and R5 are taken independently among group consisting of hydrogen atom (H), halogen atom, nitro-group (NO2); (b) R6 is taken among group consisting of unbranched or branched (C1-C5)-alkyl wherein indicated alkyl can be substituted with phenylacetyloxy-, hydroxy- carboalkoxy-group or group NR'R'' wherein R' and R'' are taken independently among group consisting of hydrogen atom (H), unbranched or branched (C1-C8)-alkyl, benzyl; (c) R7 is taken among group consisting of hydrogen atom (H), alkyl; (d) R9 represents oxygen atom; (e) n is a whole number from 1 to 2, or its pharmaceutically acceptable salt. Compounds are useful as antagonists of calcium channels and elicit cardiovascular, anti-asthmatic and anti-bronchoconstricting activity. Also, invention describes the pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

28 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

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

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

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

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