Substituted imidazoles, methods for their preparation, pharmaceutical composition and method of treatment

 

(57) Abstract:

This invention provides new compounds of formula I where Y is-CH2- or-CO-; R1Is F, Cl or OH; R2Is H, F or Cl; R3- H, CH3or CH2CH3except 4-(5-chloro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole and 4-(4-chloro-2,3-dihydro-1H-indan-2-yl)-1H-imidazole, and their non-toxic acid additive salts and mixtures thereof. Describes how to obtain these compounds and new pharmaceutical compositions containing at least one of the compounds or their salts. Compounds and their non-toxic salts exhibit valuable pharmacological activity and are also highly selective and long acting antagonists 2-adrenergic receptors. Oral activity is good. Compounds particularly useful in the treatment of disorders of cognitive abilities. 8 C. and 19 C.p. f-crystals, 3 ill., table 2. and

The invention relates to new 4(5)-substituted imidazole derivative and their non-toxic salts, receiving them, pharmaceutical compositions containing them and their use.

Imidazole derivatives of this invention have the General formula

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where Y is-CH2- or-CO-;

R1Is F, Cl or OH;

R2- H, F illor-2,3-dihydro-1H-inden-2-yl)-1H-imidazole and 4-(4-chloro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

The most preferred compounds corresponding to this invention, are compounds in which R1is F, R2is hydrogen or F, especially hydrogen. Preferred are also compounds in which R3is hydrogen or CH2CH3and Y is-CH2-. Specific examples of such preferred compounds are mentioned 4-(2-ethyl-5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole and 4-(5-fluoro - 2,3-dihydro-1H-inden-2-yl)-1H-imidazole. These compounds are also valuable intermediate products to obtain disubstituted indan-imidazole derivatives corresponding to the invention.

The compounds of this invention are highly selective and long-acting antagonists2-adrenergic receptors, they also have good bioavailability when administered orally. These compounds are particularly valuable in the treatment of disorders of cognitive abilities.

Value antagonists2-adrenergic receptors have been described (EP NN 183492, 247764 and 372954). Know the use of some inden-imidazole derivatives, especially atipamezole (atipamezole), for the treatment of age-related memory loss and other disorders of cognitive abilities (PCT N 9 is neither typically have a very short validity period. This does not cause problems, when these compounds are used in clinical treatment methods. However, to obtain sufficient adherence of patients to treatment regimens necessary connections with longer period and good bioavailability when administered orally. Also known indan-imidazole derivative with a long-term period (EP N 372954). However, they are less strong antagonists2-adrenoreceptor than the compounds of this invention.

-Adrenergic receptors can be subdivided from a pharmaceutical point of view on two subclasses,1and2-adrenergic receptors (see, for example, Starke & Dochery, J. Cardiovasc. Pharmacol, I, Suppl. 1, 514-523, 1981).

It is known that while1-adrenergic receptors are distributed postsynaptic,2-adrenergic receptors are located in presinapticheskih nerve endings and postsynaptic, for example, in vascular smooth muscle, platelets, pancreatic cells, fat cells and in the Central nervous system.

Presinapticheskie 2receptors modulate the secretion of norepinephrine through the mechanism of negative feedback. In fact, if presinapticheskie 2-adrenerg receptors 2antagonists, on the contrary, increases the production of norepinephrine. 2-Adrenoretseptory antagonism when presinapticheskih the adrenergic receptors can be used in times of illness that are associated with the lack of receipt of norepinephrine to the postsynaptic adrenergic receptors. These diseases include, for example, endogenous depression, age-related memory disorders and other disorders associated with impaired cognitive abilities, especially Alzheimer's disease.

The most studied pharmacological action of postsynaptic 2-adrenergic receptors, is a reduction in vascular smooth muscle. Blockade of peripheral postsynaptic2-adrenergic receptors in blood vessel can expand the vessel and reduce blood pressure.2-Blockers can, thus, be used as antihypotensive agents.

The metabolism of glucose and lipids is also regulated by inhibitory mechanism, which is involved in2-adrenergic receptors.2Antagonists can, thus, be used in the treatment of diabetes and obesity.

Were tested following compounds of this izobreten-imidazole.

3. 4-(2-Ethyl-5,6-debtor-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

4. 2-Ethyl-6-fluoro-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-it.

5. 6-Chloro-2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-it.

6. 4-(4-Fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

7. 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

8. 2-Ethyl-2-(1H-imidazol-4-yl)-5-indanol.

The pharmacological activity of the compounds of this invention was determined as follows.

1.2-Antagonism in vitro.

2The antagonism was determined by means of dedicated, electrically stimulated drug vessel sperm duct mouse (Marshall et. al., Br. J. Pharmac. 62, 147, 151, 1978). In this model, a2antagonist (detomidine - detomidine) blocks of electrically stimulated muscle contraction and the action2antagonist see introduction before a substance having affinity to the receptor, and determining the magnitude of his pA2. Known2antagonist atipamezole was used as a standard substance.

To obtain data on the selectivity of the antagonist against 1and2receptors its ability to inhibit or stimulate 1receptors on andariego substance use phenylephrine, known1agonist and prazosin (prazocin), known1antagonist. To determine1-antagonistic muscle contraction was induced by phenylephrine, and the value of pA2the emitted compounds was determined as described above. Agonistic action is represented as pD2values (negative logarithm of the molar concentration of compound that causes 50% of the maximum reduction). Examples of results are given in table. 1.

2.2-Adrenoretseptory antagonism in vivo.

It is known that rats2agonists cause pupil dilation (mydriasis), whose action is transmitted through postsynaptic2/receptors in the Central nervous system. Under anesthesia, the rat was introduced intravenously standard dose2-agonist (detomidine). After that increasing doses studied antagonists were injected and observed reverse the mydriasis caused by detomidine. The value of the ED50for antagonist was determined, i.e. the dose that causes 50% reversal. Examples of results are presented in table. 2.

Period2-blocking activity of the compounds defined as follows: antagonists injected on the NYM intravenous dosing of detomidine. Calculate the percent antagonism midriatichesky steps of 0.1 mg/kg of detomidine for each pre-treated groups define the relationship of action and time. This, in turn, allows to determine the time required to reduce the effects of antagonists in half. The results are presented in table. 2.

Relative biological value of antagonists with the introduction of orally was evaluated by comparison of their strength2-blocking activity after oral and parenteral administration. The antagonists are introduced in equipotent doses (0.3 to 3 mg/kg) to groups of rats for an hour before anesthesia and the introduction of detomidine as described above in relation to the definition of time steps. The results are presented in table. 2.

3. Influence on memory.

The influence of atipamezole, MPV-1743 A III (compound 7) and MPV-1730 B III (compound 4) on cognitive ability and memory has been studied on rats in the linear sleeve labyrinth job. Linear sleeve labyrinth is a modified version of the radial sleeve of the labyrinth, which is commonly used to study memory in rats. Atipamezole hydrochloride (0.3 mg/kg subcutaneously), MPV-1730 B III hydrochloride (3 mg/kg orally) and MPV-1743 A III hydrochlo is jaczie were made in a volume of 1 ml/kg

Hardware: the labyrinth is a wooden platform in the form of two junctions, one after another. The barrel (first sleeve) with a length of 90 cm and a width of 12 see Five other sleeves (sleeves gate) had a length of 50 cm and a width of 12 see Four of the portal sleeve were located perpendicular to the trunk and to the fifth sleeve, which is placed in front of the barrel. On each side of the barrel and sleeve edges were of a height of 2.0, see the end of the portal sleeve is a hole with a depth of 1 cm to 3 cm in diameter, which serves as a Cup for food. The original platform (20x20 cm) was separated from the trunk halatnoe door. The door was with a height of 12 cm and a width of 7 cm Door to the building was a height of 20 cm and a width of 20 see the Maze was raised to 31 cm above the floor and located in slaboosveshchennoj room for trials in which there were other items as well as equipment for testing. The hole in the end of the portal sleeve were fitted with baits on three pellets prize food (45 mg pellets Bio Serve. In.)

Methods: two days before the test, animals were placed in an isolation cell with deprivation of food, which reduced their weight by up to 90% of the initial weight. During these days the rats were accustomed to the hands (three times a day), to the room for the experience and food prize. On WTA for 10 minutes. On the third day in the portal sleeves were placed bait, and was held a training test each rat. The rat received medication or distilled water and after 60 minutes after it was placed on the starting platform. After ten seconds the door opened and the rat was allowed to explore the maze until then, until all baits were not detected. The time spent on finding all of the bait and return to already visited sleeves were recorded. It is time for each rat was allowed to be in the maze at least for five minutes. The next day began testing the correctness of memory and learning ability, which lasted for four days of tests 1-4). Rats were given eight attempts, two in a day. The time interval between attempts was 50 minutes. Medications or distilled water was administered 30 minutes before the first attempt of the day. In other words, experimental attempts were identical to the training attempt. All observations were made blindly, so that the experimental solutions were coded envelopes.

Statistical analysis: results were presented as the value of time/attempt/day (seconds) and the average znati drugs and testing learning ability and memory.

Results: the impact of atipamezole, MPV-1743 A III (= connection # 7) and MPV-1730 B III (= connection # 4) on the learning ability and memory shown in Fig. 1, 2 and 3, respectively. All tested drugs reduced the number of errors, i.e., repeated occurrences in sleeves, has already visited during this attempt. This shows the effect on working memory. All drugs also reduced the time required to solve the problem. This is considered as the effect on cognitive ability and speed make the right decision. The number of errors and time was also decreased day by day in the control group, which is an indicator of learning ability during the test. It was found that the drug effect is not dependent on the day of testing. These results confirm that atipamezol, MPV-1743 A III and MPV-1730 B III have the effect of increasing learning ability and memory in adult rats.

The compounds of this invention interact with organic and inorganic acids with the formation of a variety of pharmaceutically usable acid additive salts, for example chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formate, tartratami, malatov, nitrage.

Compounds and their non-toxic, pharmaceutically acceptable acid additive salts can be administered orally, parenterally or intravenously. In the treatment of disorders of cognitive abilities preferred compounds are compounds, administered orally at a daily dose of from 0.1 to 10 mg/kg, preferably from 0.2 to 1 mg/kg

Pharmaceutical carriers normally used with the compound of the invention may be solid or liquid and are generally chosen based on the intended method of administration. Selection of auxiliary ingredients for the composition corresponds to the established order, well-known experts in this field. Suitable solvents are gelling ingredients, dispersing agents, dyes, etc.

Acute toxicity (LD50compounds of this invention for the mouse does not exceed 50 mg/kg (oral). For example, LD504-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole (compound 7) is 100 mg/kg (oral).

The compounds of formula I receive in accordance with the following methods.

The compound of formula II

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where R3takes the values defined above,

nitrous strong nitrous agent, JV is the presence of sulfuric acid, obtaining mainly of compounds of formula III

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as well as small amounts of the compounds of formula IV, which may not necessarily be separated

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The nitro-group of compounds III or IV then reduced to the corresponding amino group, for example, catalytic hydrogenation using molecular hydrogen. The preferred catalysts are, for example, PtO2or Pd/C. Aminosilane compounds thus obtained can be separated from each other.

Aminotoluene connection

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and

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transformed into their corresponding diazonium salts with nitrous acid, which is formed in the presence of amine (V or VI) under the action of mineral acid, preferably forborne acid (HBF4), sodium nitrite at low temperature, preferably at a temperature of approximately 0oC. the thus Obtained forbert the page can be thermally decomposed to obtain fluoride (VII or VIII), boron TRIFLUORIDE and nitrogen.

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where X represents f

The corresponding chlorine substituted compounds can be obtained by the interaction of the amine (V or VI) from hydrochloric acid and nitrite intothree the tion chloride copper (I) in concentrated hydrochloric acid at elevated temperature.

Mnogoelektronnoe compound of formula VII

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where X represents F or Cl,

may be further nitride by reacting, for example, with nitrate of urea to sulfuric acid to obtain compound IX

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where the nitro-group can be substituted by halogen through the intermediate amino group, as described above, to obtain compounds of formula I, where R1and R2both are halogen.

The compounds of formula I, where Y is CO, R1are F or Cl in position 6

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(X = F or Cl) can be obtained by narisovanie starting compound of the formula XI

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for example, nitrate of urea to sulfuric acid and substitution of the nitro group by the amino group, followed by substitution of halogen in accordance with the method described above. Another halogen atom may be further introduced in the 4 position of the aromatic ring of the compound (X) by nitration of compounds, such as nitrate of urea to sulfuric acid, the hydrogenation of the nitro group to the amino group and, finally, by the substitution of the amino group by a halogen according to the method described above.

The compound of formula XII

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can be obtained by the coupling of compounds of formula (V), for example, with sodium nitrite in the presence of con is in the compounds of formula XII.

In addition, the compounds of this invention can be obtained analogously to the methods described in EP-A-183492.

In the examples below, where the above changes1H and13C spectra of nuclear magnetic resonance, NMR spectra were obtained on brand spectrometer Bruker AC 300 P when used as an internal standard connection tetramethylsilane from which these chemical shifts were measured. Abbreviations s, d, a, K, m was used to refer to singlet, doublet, triplet, Quartet or multiplet, respectively. In this regard, the number of hydrogen atoms have also been recorded. Spectra of compounds in the form of the Foundation were recorded in deuterated methanol or deuterated chloroform, while the spectra of hydrochloride were recorded in deuterated methanol. Massspectra were recorded on masspectrometry brand Kratos MS 80 RF Antoconsole.

Example 1. 4-(2-Ethyl-5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

4-(2-Ethyl-2,3-dihydro-5-nitro-1H-inden-2-yl)-1H-imidazole.

4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole obtained according to the U.S. patent N 468933 (3.00 g, 0,0141 mole), is added to 15 ml of concentrated sulfuric acid at a temperature of 0oC. Nitrate urea (1,74 g, 0,0141 mo is deliciuous sodium hydroxide and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated. The result 3,59 g (99%) of 4-(2-ethyl-2,3-dihydro-5-nitro-1H-inden-2-yl)-1H-imidazole. Chloride-hydrogen salt of this product is obtained in the dry hydrochloride in ethyl acetate.

MS: 257 (22, M+), 228 (100, M-CH2CH3), 182, (27, 228 - NO2).

Chloride-hydrogen salt,1H NMR (300 MH, CD3OD): of 0.82 (3H, t, J=7 Hz, CH2CH3), of 1.97 (2H, K, J=7 Hz, CH2CH3), 3,31, and to 3.41 (4H, AB, JAB=17 Hz, indianby cycle H2-1 and H2-3), 7,44 (1H, s, im-5), 7,46 (1H, d, H-7), with 8.05 (1H, d, J=8 Hz, H-6), 8,10 (1H, s, H-4), of 8.92 (1H, s, im-2).

4-(5-Amino-2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

A solution of 4-(2-ethyl-2,3-dihydro-5-nitro-1H-inden-2-yl)-1H-imidazole (of 10.25 g, 0,03988 mol) in ethanol (150 ml) hydronaut over PtO2(1 g) under a pressure of 3 ATM. When the absorption of hydrogen ceases, the reaction mixture is filtered and evaporated to dryness to obtain 4-(5-amino-2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole (8.2 g, 91%).

The product was then purified by thin-layer chromatography, elwira a mixture of methylene chloride methanol (9,6 : 0,5). Chloride-hydrogen salt of the product obtained by reaction with dry hydrogen chloride in dry ethyl acetate; so pl. 145 - 152oC.

MC: 227 (50, M+), 212 (15, M-CH3), to 1.87 (2H, K, J= 7 Hz, CH2CH3), 2,96, and the 3.11 (2H, AB, JAB=15 Hz, indianby cycle H2-1 or H2-3), 2,98, and of 3.13 (2H, AB, JAB=16 Hz, indianby cycle H2-1 or H2-3), 6,48 (1H, DD, J=8 Hz,4J=2 Hz, H-6), is 6.54 (1H, ush. s, H-4), was 6.73 (1H, s, im-5), to 6.95 (1H, d,3J= 8 Hz, H-7), of 7.48 (1H, s, im-2).

Chloride-hydrogen salt,13C NMR (CD3OD): 9,82 (K), 33,35 (t), 44,15 (t), 44,53 (t), 48,92 (C), 117,34 (d), 120,47 (d), 122,64 (d), 127,12 (d), 130,63 (C), 135,67 (d), 140,69 (C), 143,71 (C), 144,97 ().

4-(2-Ethyl-5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

The flask containing forborne acid (48 wt.% the solution in water, 25 ml) and 5.63 g (0,0248 mole) of 4-(5-amino-2-ethyl-2,3-dihydro - 1H-inden-2-yl)-1H-imidazole, placed in a bath with ice cold brine and cooled to 0oC. Maintaining the temperature of the reaction mass to 0oC, slowly poured a solution of 2.6 g (0,0377 mole) of sodium nitrite in 5 l of water. After the addition the reaction mixture is stirred for one hour at a temperature of 0oC, and then for one hour at room temperature. The reaction mixture is twice evaporated to the dry state with toluene.

Thermal decomposition is carried out in a flask equipped with elektrokabeljnoj net. When the selection of white smoke boron TRIFLUORIDE is stopped, the heating is stopped.

MC: 230 (27, M+), 201 (100, M-CH2CH3), 133 (14), 100 (15).

Chloride-hydrogen salt,1H NMR (300 MHz, CD3OD): 0,80 (3H, t, J=7 Hz, CH2CH3), of 1.93 (2H, K, J=7 Hz, CH2CH3), approximately 3,11 - 3,30 (4H, m, indianby cycle H2-1 and H2-3), 6,87 (1H, m, H-6), of 6.96 (1H, DD,3JHF= 9 Hz4JHH= 2 Hz, H-4), 7,18 (1H, DD,3JHH= 8 Hz,4JHH= 5 Hz, H-7), 7,37 (1H, d, J= 1 Hz, im-5), 8,87 (1H, d, J= 1 Hz, im-2).

Chloride-hydrogen salt,13C NMR (CD3OD): 9,87 (CH3) 33,45 (CH2CH3), 43,99 (C-1), 44,74 (4JCCCCF= 2 Hz, C-3), 49,14 (C-2), 112,14 (2JCCF= 23 Hz, C-4), 114,55 (2JCCF= 23 Hz, C-6), 117,28 (mi-5), 126,78 (3JCCCF= 9 Hz, C-7), 135,60 (im-2), 137,93 (4JCCCCF= 3 Hz, C-7a), 141,15 (im-4), 144,72 (3JCCCF= 8 Hz, C-3a), 163,75 (JCF= 242 Hz, C-5).

Example 2. 4-(5-fluoro-2,3-dihydro-2-methyl-1H-inden-2-yl)-1H-imidazole.

The procedure of example 1 is used for the synthesis of 4-(5-fluoro-2,3-dihydro-2-methyl-1H-inden-2-yl)-1H-imidazole and its intermediate products of 4-(2,3-dihydro-2-methyl-1H-inden-2-yl)-1H - imidazole (Karjalainen, A. J. et. al., USA 4689339).

4-(2,3-Dihydro-2-methyl-5-nitro-1H-inden-2-yl)-1H-imidazole.

MC: 243 (5>
), 3.05, and 3,44 (4H, AB, JAB= 16 Hz, H2-1 and H2-3), 6,79 (1H, d, J= 1 Hz, im-5), of 7.36 (1H, d, J= 9 Hz, H-7), 7,56 (1H, d, J= 1 Hz, im-2), of 8.04 (1H, d, J= 9 Hz, H-6), of 8.06 (1H, s, H-4).

4-(5-Amino-2,3-dihydro-2-methyl-1H-inden-2-yl)-1H-imidazole.

MC: 213 (90, M+), 198 (100, M-CH3).

Basis1H NMR (300 MHz, CDCl3+ CD3OD): to 1.42 (3H, s, CH3), 2,87, and 3.21 (2H, AB, JAB= 16 Hz, indianby cycle H2-1 or H2-3), 2,86, and 3,18 (2H, AB, JAB= 15 Hz, indianby cycle H2-1 or H2-3), 6,51 (1H, DD,3J= 8 Hz,4J= 2 Hz, H-6), 6,55 (1H, d, J= 2 Hz, H-4), 6,74 (1H, d, J= 1 Hz, im-5), 6,98 (1H, d,3J= 8 Hz, H-7), 7,52 (1H, J=1 Hz, im-2).

4-(5-fluoro-2,3-dihydro-2-methyl-1H-inden-2-yl)-1H-imidazole.

Chloride-hydrogen Sol: so pl. 188 - 190oC.

MC: 216 (50, M+), 201 (100, M-CH3), 133 (18).

Chloride-hydrogen salt,1H NMR (300 MHz, CD3OD): 1,51 (3H, s, CH3), 3,03 - 3,12 and 3.26 - to 3.36 (4H, H2-1 and H2-3), 6,87 - 6,99 (2H, m, H-4 and H-6), 7,20 (1H, m, H-7), 7,38 (1H, s, im-5), cent to 8.85 (1H, J=1 Hz, im-2).

Example 3. 2-Ethyl-2-(1H-imidazol-4-yl)-5-indanol.

In the flask is charged 0,76 g (0,00334 mole) of 4-(5-amino-2-ethyl-2,3 - Ligero-1H-inden-2-yl)-1H-imidazole, and 2.7 ml of water and 0,76 ml of concentrated sulfuric acid. The solution is cooled to 0oC and a solution of 0.47 g (0,00681 mole) of the nitrite nallah 0 - 5oC. Stirring is continued for one more time at a temperature of 0 to 5oC.

While the diazotization proceeds, 2,28 ml of concentrated sulfuric acid is added to 1.9 ml of water in the flask and the solution heated to boiling (160oC). Then a solution of diazotization add with such speed, that the acid mixture continues to boil. Boiling is maintained for one hour. The cooled mixture is poured the water. The pH was adjusted to a value of 7 - 8 and precipitated impurities filtered. The aqueous solution is extracted with several portions of ethyl acetate, the combined organic layers washed with water, dried with sodium sulfate and evaporated to dryness. The output product is 0.6 g (79%).

Cleaning is carried out by thin layer chromatography (eluent: methylene chloride/methanol in the ratio of 9.5:0.5 to). Chloride-hydrogen salt get in ethyl acetate; so pl. 193 - 196oC.

MC: 228 (38, M+.), 213 (12, M-CH3), 199 (100, M-CH2CH3).

Chloride-hydrogen salt,1H NMR (300 MHz, CD3OD): of 0.79 (3H, t, J=7 Hz, CH2CH3), at 1.91 (2H, K, J= 7 Hz, CH2CH3), 3,06 and 3.15 (2H, AB, JAB= 15 Hz, indianby cycle H2-1 or H2-3), 3,09 and outstanding 3.18 (2H, AB, JAB= 15 Hz, indianby Hz, H-7), 7,31 (1H, d, J= 1 Hz, im-5), 8,80 (1H, s, im-2).

Example 4. 2-Ethyl-6-fluoro-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-it.

2-Ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-6-nitro-1H-inden-1-it.

Nitro-derivatives of 2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-1H - inden-1-she (U.S. patent N 4689339) produced by the method described in example 1. The output is 100%, so pl. chloride-hydrogen salt of the product 226 - 228oC.

MC: 271 (33, M+.), 256 (12, M-CH3), 242 (100, M-CH2CH3), 196 (32, 242-NO2).

Chloride-hydrogen salt, 1H NMR (300 MHz, CD3OD): of 0.87 (3H, t, J= 7 Hz, CH2CH3), 1,96 - of 2.20 (2H, m, CH2CH3), 3,66 and of 3.78 (2H, AB, JAB= 19 Hz, indianby cycle H2-3), the 7.65 (1H, d, J= 1 Hz, im-5), to $ 7.91 (1H, d,3J= 9 Hz, H-4), and 8.5 (1H, d,4J= 2 Hz, H-7), 8,58 (1H, DD,3J= 9 Hz,4J= 2 Hz, H-5), 8,98 (1H, d, J= 1 Hz, im-2).

6-Amino-2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-it.

To 7.20 g (0,0265 mole) 2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-6-nitro-1H-inden-1-she dissolved in 70 ml of ethanol, add 0.7 g of 10% palladium on carbon and the mixture is shaken in an atmosphere of hydrogen at room temperature. After the reaction proceeded, the catalyst is removed. The filtrate is evaporated to obtain 6-amino-2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-it is the ratio of 9.5:0.5 in.

MS: 241 (36%, M+.), 212 (100%, M-CH2CH3).

Basis1H NMR (300 MHz, CDCl3): 0,81 (3H, T., J= 7 Hz, CH2CH3), 1,84-2,04 (2H, m, CH2CH3), 3,20 and 3,55 (2H, AB, JAB= 17 Hz, indianby cycle H2-3), 6,92 (1H, s, im-5), approximately 6,9 (1H, m, H-5), 6,97 (1H, s, H-7), 7,25 (1H, d,3J 10Hz, H-4), 7,51 (1H, s, im-2).

Basis31C NMR (CD3OD): 9,42 (K), 31,85 (t), 38,88 (t), 55,15 (C), 108,77 (d), 117,39 (d), 125,28 (d), 127,90 (d), 136,48 (d), 137,67 (C), 140,37 (C), 144,48 (C), 149,07 (C), 188,78 ().

2-Ethyl-6-fluoro-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-it.

2-Ethyl-6-fluoro-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-it is produced by a method described in example 1. The product was then purified by thin-layer chromatography (eluent: a mixture of methylene chloride/methanol in the ratio of 9.5:0.5 to). Exit after cleanup is 75%. Chloride-hydrogen salt of the product is obtained in ethyl acetate; so pl. 167-168oC.

MC: 244 (27, M+.), 215 (100, M-CH2CH3), 187 (10), 149 (14), 133 (18), 107 (12), 85 (14), 71 (12), 69 (10), 57 (24).

Chloride-hydrogen salt,1H NMR (300 MHz, CD3OD): of 0.85 (3H, t, J= 7 Hz, CH2CH3), 1,93-of 2.20 (2H, m, CH2CH3), 3,48, and of 3.60 (2H, AB, JAB= 17 Hz, indianby cycle H2-3), the 7.43 (1H, DD,3JHF= 8 Hz,4JHH= 3 Hz, H-7), 7,53 (1H, m4JHH= Chloride-hydrogen salt,13C NMR (CD3OD): TO 9.32 (CH2CH3), 32,35 (CH2CH3), 37,91 (C-3), 54,18 (C-2), 110,89 (2JCCF= 22 Hz, C-7), 117,83 (mi-5), 124,83 (2JCCF= 24 Hz, C-5), 129,97 (3JCCCF= 8 Hz, C-4), 135,38 (im-4), 136,24 (im-2), 137,30 (3JCCCF= 7 Hz, C-7a), 149,57 (4JCCCCF= 2 Hz, C-3a), 164,12 (JCF= 248 Hz, C-6), 193,93 (C=O).

Example 5. 6-Fluoro-2,3-dihydro-2-(1H-imidazol-4-yl)-2-methyl-1H-inden-1-it.

6-Fluoro-2,3-dihydro-2-(1H-imidazol-4-yl)-2-methyl-1H-inden-1-he and his intermediate products are synthesized from 2,3-dihydro-2-(1H-imidazol-4-yl)-2-methyl-1H-inden-1-she (U.S. patent N 4689339) in accordance with the methodology described in example 4.

2,3-Dihydro-2-(1H-imidazol-4-yl)-2-methyl-6-nitro-1H-inden-1-it.

MC: 257 (100, M+.), 242 (98, M-CH3), 228 (65).

Basis1H NMR (300 MHz, CDCl3+CD3OD): of 1.62 (3H, s, CH3), 3,32, and of 3.94 (2H, AB, JAB= 18 Hz, H2-3), of 6.96 (1H, s, im-5), 7,52 (1H, s, im-2), of 7.70 (1H, d, 9= Hz, H-5), 8,51 (1H, DD,3J= 9 Hz, 2H, H-5), at 8.60 (1H, d, J= 2 Hz, H-7).

6-Amino-2,3-dihydro-2-(1H-imidazol-4-yl)-2-methyl-1H-inden-1-it.

MC: 227 (100, M+.), 212 (85, M-CH3), 198 (50).

Basis1H NMR (300 MHz, CD3OD): of 1.52 (3H, s), 3,07 and to 3.52 (2H, AB, K, JAB= 17 Hz, H2-3), 6,93 (1H, s, im-5), 6,98 (1H, d, J= 2 Hz, H-7), 7,03 (1H, DD,3J= 8 Hz,4J= 2 Hz, H-5), the IMS-hydrogen Sol: so pl. 164-167oC.

MC: 230 (100, M+.), 215 (95, M,-CH3), 201 (80), 187 (25), 174 (25), 133 (25).

Chloride-hydrogen salt,1H NMR (300 MHz, CD3OD): 1,65 (3H, s, CH3), 3,38, and the 3.65 (2H, AB, JAB= 17 Hz, H2-3), 7,45-7,66 (3H, m, H-4, H-5, H-7), 7,54 (1H, s, im-5), cent to 8.85 (1H, s, im-2).

Example 6. 6-Chloro-2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-it.

In the flask is charged 2,95 g (0,0122 mole) of 6-amino-2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-it, 4,5 ml and 4.5 ml of concentrated hydrochloric acid. This solution is cooled to 0oC, and thereto is added slowly a solution of 0.84 g (0,0122 mole) of sodium nitrite in 3 ml of water so that the temperature of the reaction mixture did not exceed 5oC. After the addition the mixture is stirred for one hour at a temperature of 0oC.

In another flask of 1.46 g (0,0147 mole) chloride copper (I) dissolved in a mixture of water (6 ml) and concentrated hydrochloric acid (4.5 ml) and the resulting solution cooled in an ice bath.

The frozen solution, page added under stirring to a solution of copper chloride (I), keeping the temperature at 0oC. After the addition stirring is continued for thirty minutes at a temperature of 0oC. Then the temperature is allowed to rise to on the mixture is cooled, add water and the solution is alkalinized. The product is extracted with ethyl acetate, washed with water and evaporated. Technical product was then purified by thin-layer chromatography (eluent: methylene chloride/methanol in the ratio of 9.5:0.5 to). Khloristogo salt of 6-chloro-2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)- 1H-inden-1-get it in etilatsetate; so pl. 198-201oC.

MC: 260 and 262 (22 and 8, M+.), 231, and 233 (100 and 34, M-CH2CH3).

Chloride-hydrogen salt, 1H NMR (300 MHz, CD3OD): 0,84 (3H, t, J= 7 Hz, CH2CH3), 1,93-2,19 (2H, m, CH2CH3), 3,48, and of 3.60 (2H, AB, JAB= 18 Hz, indianby cycle H2-3), EUR 7.57 (1H, d, Hz, im-5), of 7.64 (1H, distorted d, J=8 Hz, H-4), 7,73 (14, s, H-7), 7,74 (1H, distorted, d, H-5), of 8.90 (1H, s, im-2).

Example 7. 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

4-(2,3-Dihydro-5-nitro-1H-inden-2-yl)-1H-imidazole.

Concentrated sulfuric acid cooled to -10oC, and then added at a temperature of -10oC mixture of 4-(2,3-dihydro-1H - inden-2-yl)-1H-imidazole hydrochloride (U.S. patent N 4689339)(2.70 g, 0,0122 mol) and nitrate urea (1.50 g, 0,0122 mol) in small portions. Upon completion the reaction mixture was poured into ice. The solution is alkalinized and extracted three times with ethyl acetate. The organic extracts are combined, the NO2), 182 (61, 288-NO2), 168 (14), 153 (13), 154 (16), 129 (10), 128 (18), 127 (16), 115 (16), 91 (12), 77 (12), 68 (19).

Basis1H NMR (300 MHz, CDCl3+ one drop CD3OD): 3,18 (2H, DD, Jgem= 16 Hz, Jvis= 8 Hz, indianby cycle one H-1 and one H-3), 3,39 (2H, DD, Jgem= 16 Hz, Jvis= 8 Hz, indianby cycle another H-1 and one H-3), 3,80 (1H, quintet, J=8 Hz, indianby cycle H-2), to 6.80 (1H, s, im-5), 7,34 (1H, d, J= 8 Hz, H-7), EUR 7.57 (1H, s, im-2), with 8.05 (1H, d, J= 8 Hz, H-6), of 8.06 (1H, s, H-4).

4-(5-Amino-2,3-dihydro-1H-inden-2-yl)-1H-imidazol

Recovery of 4-(2,3-dihydro-5-nitro-1H-inden-2-yl)-1H - imidazole 4-(5-amino-2,3-dihydro-1H-inden-2-yl)-1H-imidazole carried out by the method described in example 4. The yield is 94%. Purification of the product is carried out by thin layer chromatography (eluent: a mixture of methylene chloride/methanol in the ratio of 9.5:0.5 to).

MC: 199 (100, M+.), 198 (34, M-H), 184 (32), 171 (12), 157 (12), 149 (21), 131 (21), 130 (25), 99 (14), 98 (14), 77 (10), 69 (18).

Basis1H NMR (300 MHz, CD3OD): 2,85-2,96 (2H, m, one of H-1 and one H-3), 3,09-3,18 (2H, m, one of H-1 and one H-3), of 3.57 (1H, quintet, J= 8 Hz, H-2), is 6.54 (1H, DD,3J 8 Hz,4J= 2 Hz, H-6), 6,63 (1H, s, H-4), is 6.78 (1H, s, im-5), to 5.93 (1H, d, J= 8 Hz, H-7), EUR 7.57 (1H, s, im-2).

4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazol recip is 99%. The product is purified by thin layer chromatography (eluent: a mixture of methylene chloride/methanol in the ratio of 9.5:0.5 to). Chloride-hydrogen salt get in ethyl acetate; so pl. 189-191oC

MC: 202 (100, M+.), 201 (64, M-H), 187 (51), 174 (25), 160 (16), 147 (14), 146 (17), 133 (32), 132 (16), 100 (10).

Chloride-hydrogen salt,1H-NMR (300 MHz, CD3OD): 3,01-3,14 (2H, m, one of H-1 and one H-3), 3,34 is-3.45 (2H, m, one of H-1 and one H-3), a-3.84 (1H, quintet, J= 8 Hz, H-2), of 6.90 (1H, m, H-6), of 6.99 (1H, d, 3JHF= 9 Hz, H-4), from 7.24 (1H, DD,3JHH= 8 Hz,4JHF= 5 Hz, H-7), 7,37 (1H, s, im-5), 8,83 (1H, s, im-2).

Chloride-hydrogen salt, 13C NMR (CD3OD): 37,37 (C-2), UP 38.94 (C-1), 39,75 (4JCCCCF=2 Hz, C-3), 112,42 (2JCCF= 23 Hz, C-4), 114,65 (2JCCF= 23 Hz, C-6), 116,18 (mi-5), 126,63 (3JCCCF= 9 Hz, C-7), 135,15 (im-2), 138,27 (4JCCCCF= 2 Hz, C-7a), 138,47 (im-4), 145, (3JCCCF= 8 Hz, C-3a), 163,80 (2JCF= 242 Hz, C-5).

Example 8. 4-(4-Fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

4-(4-Amino-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

When the nitration of 4-(2,3-dihydro-1H-inden-2-yl)-1H-imidazole (example 7) is formed of a small amount of 4-(2,3-dihydro-4 - nitro-1H-Eden-2-yl)-1H-imidazole. After catalytic hydrogenation of 4-aminoester and allocate ), 130 (28), 69 (20).

4-(4-Fluoro-2,3-dihydro-1H-inden-1-yl)-1H-imidazole.

4-(4-Fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazol receive in accordance with the method of fluorination as described in example 1. The product was then purified by thin-layer chromatography (eluent: methylene chloride/methanol in the ratio of 9.5: 0.5 to). Chloride-hydrogen salt of the product is obtained in ethyl acetate: so pl. 180-183oC.

MC: 202 (100, M+.), 201 (72, M-H), 187 (38), 174 (24), 160 (12), 147 (12), 146 (16), 134 (15), 133 (27), 100 (11), 68 (12).

Chloride-hydrogen salt,1H NMR (300 MHz, CD3OD): 3.04 from-3,18 (2H, m, one of H-1 and one H-3), 3,56-of 3.53 (2H, m, one of H-1 and one H-3), 3,86 (1H, quintet, J= 8 Hz, H-2), 6,91 (1H, t,3JHH= 9 Hz, H-6), to 7.09 (1H, d,3JHH= 9 Hz, H-7), 7,18-of 7.25 (1H, m, H-5), 7,39 (1H, s, im-5), 8,83 (1H, s, im-2).

Example 9. 4-(2-Ethyl-5,6-debtor-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

4-(4-Ethyl-5-fluoro-2,3-dihydro-6-nitro-1H-inden-2-yl)-1H-imidazole.

4-(2-Ethyl-5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole (4,56 g, 0,0198 mole) are added to 24 ml of concentrated sulfuric acid at a temperature of -10oC. Nitrate urea (2,44 g, 0,1098 mole) are added to the mixture in small portions at a temperature of -10oC. After the reaction solution was poured into ice. Then the solution is alkalinized and extrn2CH3), 200 (34, 246 - NO2), 199 (11).

Basis1H NMR (300 MHz, CDCl3): of 0.77 (3H, t, J=7 Hz, CH2CH3), 1,90 (2H, K, J= 7 Hz, CH2CH3), is 3.08 and of 3.32 (2H, AB, JAB=16 Hz, H2-1 or H2-1 or H2-3), 3,11 and 3.38 (2H, AB, JAB=17 Hz, H2-1 or H2-3), 6,76 (1H, s, im-5), 7,07 (1H, d,3JHF=11 Hz, H-4), a 7.62 (1H, s, im-2), to 7.84 (1H, d,4JHF=7 Hz, H-7).

4-(5-Amino-2-ethyl-6-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

4-(2-Ethyl-5-fluoro-2,3-dihydro-6-nitro-1H-inden-2-yl)-1H-imidazol hydronaut to 4-(5-amino--2-ethyl-6-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole by the method described in example 4. The output product is 85%. Cleaning is performed by thin layer chromatography (eluent: methylene chloride/methanol in the ratio of 9.5:0.5 to).

MC: 245 (49, M+.), 230 (12, M-CH3), 216 (100, M-CH2CH3), 148 (20), 107 (18).

Basis1H NMR (300 MHz, CDCl3): to 0.73 (3H, t, J=7 Hz, CH2CH3) and 1.83 (2H, K, J=7 Hz, CH2CH3), 2,90, and is 3.10 (2H, AB, JAB=16 Hz, H2-1 or H2-3), 2,92, and the 3.11 (2H, AB, JAB= 15 Hz, H2-1 or E2H2-3), 6,56 (1H, d,4JHF=9 Hz, H-4), of 6.71 (1H, s, im-5), 6,76 (1H, d,3JHF=11 Hz, H-7), of 7.48 (1H, s, im-2).

4-(2-Ethyl-5,6-debtor-2,3-dihydro-1H-inden-2-and the m described in example 1.

MC: 248 (16, M+.), 219 (100, M+.).

Chloride-hydrogen salt .1H NMR (300 MHz, CD3OD): 0,80 (3H, t, J=7 Hz, CH2CH3), of 1.93 (2H, K, J=7 Hz, CH2CH3), and 3.16 and 3.25 (4H, AB, JAB=16 Hz, H2-1 and H2-3), 7,12 (2H, DD, 3JHF=4JHF=9 Hz, H-4 and H-7), 7,39 (1H, d, J=1 Hz, im-5), 8,87 (1H, d, J=1 Hz, im-2).

Example 10. 4-(5,6-dichloro-2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

4-(5-Chloro-2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole is obtained by diazotization of 4-(5-amino-2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole by the method described in example 6. The procedure of example 9 is used for the synthesis of nitro and amino derivatives of 4-(5-chloro-2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The chlorination is conducted in the manner described in example 6.

4-(5-chloro-2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazol

Chloride-hydrogen Sol: so pl. 147-149oC.

MS: 246(248) 28 (9, M+.), 217/219 (100/33), 183 (11), 182 (16), 181 (19).

Chlorotoluron salt,1H NMR (300 MHz, CD3OD): 0,80 (3H, t, J=7 Hz, CH2CH3), of 1.93 (2H, K, J=7 Hz, CH2CH3), and 3.16 and 3.25 (2H, AB, JAB=16 Hz, indianby cycle H2-1 or H2-3), 3,18 and of 3.28 (2H, AB, JAB= 16 Hz, indianby cycle H2-1 or H2-3), 7,12-of 7.23 (3H, angry.

MS: 291/293 (22/7, M+.), 262/264 (100/33), 216/218 (28/9), 181 (10).

Basis1H NMR (300 MHz, CDCl3+ CD3OD): 0,74 (3H, t, J=7 Hz, CH2CH3), to 1.87 (2H, K, J=7 Hz, CH2CH3), is 3.08 and 3,29 (2H, AB, J=16 Hz, indianby cycle H2-1 or H2-3), 3,09 and of 3.32 (2H, AB, J=17 Hz, indianby cycle H2-1 or H2-3), 6,72 (1H, s, im-5), 7,34 (1H, s, H-4), 7,56 (1H, s, im-2), of 7.69 (1H, s, H-7).

4-(5-Amino-6-chloro-2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

MS: 261/263 (60/24, M+.), 232/234 (100/35), 196 (53).

Basis 1H NMR (300 MHz, CD3OD): of 0.71 (3H, t, J=7 Hz, CH2CH3), is 1.81 (2H, K, J=7 Hz, CH2CH3), and 2.91 in 3,10 (4H, AB, J=15 Hz, indianby cycle H2-1 and H2-3), of 6.68 (1H, s, H-4), 6,76 (1H, d, J=1 Hz, im-5), 6,998 (1H, s, H-7), to 7.61 (1H, J=1 Hz, im-2).

4-(5,6-dichloro-2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

MS: 280/282/284 (22/14/2, M+.), 251/253/255 (100/64/11).

Basis 1H NMR (300 MHz, CD3OD): to 0.72 (3H, t, J=7 Hz, CH2CH3), 1,84 (K, 2H, J= 7 Hz; CH2CH3), 2,99, and 3.21 (4H, AB, J=16 Hz, indianby cycle H2-1 and H2-3), to 6.80 (1H, s, im-5), 7,26 (2H, s, ArH), to 7.61 (1H, s, im-2).

Example 11. 4-(5-chloro-2-ethyl-6-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.

Chlorination of 4-(5-amino-2-ethyl-6-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole (example 9) is carried out in accordance H NMR (300 MHz, CD3OD): to 0.72 (3H, t, J=7 Hz, CH2CH3), of 1.85 (2H, K, J=7 Hz, CH2CH3), 3.00 and only 3.20 (2H, AB, J=16 Hz, indianby cycle H2-1 or H2-3), to 3.02 and 3.22 (2H, AB, J=16 Hz, Indonesia cycle H2-1 or H2-3), to 6.80 (1H, s, im-5), 7,02 (1H, d,3JHF=9 Hz, H-4), 7,22 (1H, d,4JHF=7 Hz, H-7), a 7.62 (1H, s, im-2).

1. Substituted imidazoles of General formula I

< / BR>
where Y represents-CH2- or-CO-;

R1represents F, Cl or OH;

R2Is H, F or Cl;

R3-H, CH3or CH2CH3,

with the exception of 4-(5-chloro-2,3-dihydro-1H-inden-2 - yl)-1H-imidazole and 4-(4-chloro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole or its pharmaceutically acceptable salt.

2. Connection on p. 1, where R1is fluorine and R2is hydrogen or fluorine.

3. Connection on p. 2, where R2is hydrogen.

4. Connection on p. 1, where R3is hydrogen or CH2CH3.

5. Connection on p. 1, where Y is-CH2-.

6. Connection on p. 1, where the compound is 4-(2-ethyl - 5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole or its pharmaceutically acceptable non-toxic salt.

7. Connection on p. 1, where the compound is 4-(5-fluoro - 2,3-dihydro-2-METI, where the compound is 4-(2-ethyl-5,6 - debtor-2,3-dihydro-1H-inden-2-yl)-1H-imidazole or its pharmaceutically acceptable non-toxic salt.

9. Connection on p. 1, where the compound is 2-ethyl-6-fluoro - 2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-one or its pharmaceutically acceptable non-toxic salt.

10. Connection on p. 1, where the compound is 6-chloro-2-ethyl - 2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-one or its pharmaceutically acceptable non-toxic salt.

11. Connection on p. 1, where the compound is 4-(4-fluoro-2,3 - dihydro-1H-inden-2-yl)-1H-imidazole or its pharmaceutically acceptable non-toxic salt.

12. Connection on p. 1, where the compound is 4-(5-fluoro-2,3 - dihydro-1H-inden-2-yl)-1H-imidazole or its pharmaceutically acceptable non-toxic salt.

13. Connection on p. 1, where the compound is 2-ethyl-2-(1H - imidazol-4-yl)-5-indanol or its pharmaceutically acceptable non-toxic salt.

14. Connection on p. 1, where the compound is 4-(5,6 - dichloro-2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole or its pharmaceutically acceptable non-toxic salt.

15. Connection on p. 1, where the compound is 4-(5-chloro-2 - ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole or its pharmaceutical is- -CH2-;

R1Is F or Cl;

R2- H;

R3- H, CH3or CH2CH3,

characterized in that the compound of formula II

< / BR>
where R3takes the values defined above

nitrous obtaining compounds of formulas III and IV

< / BR>
< / BR>
which, if necessary, share and then restore to the appropriate aminosilane compounds of formulas V and VI

< / BR>
< / BR>
which, if necessary, share and turn in their corresponding diazonium salts, after which the diazonium group is replaced by the corresponding halide with obtaining compounds of formula VII and VIII

< / BR>
< / BR>
where X Is F or Cl.

17. The method according to p. 16, wherein in formulas VII and VIII X is fluorine.

18. The method according to p. 17, characterized in that the said diazonium salts obtained by interaction of the amine of the formula V and/or VI with a mineral acid and sodium nitrite at low temperature.

19. The method according to p. 16, wherein in formulas VII and VIII and X is chlorine.

20. The method according to p. 19, characterized in that the said diazonium salts obtained by interaction of the amine of formula V or VI with hydrochloric acid and sodium nitrite at low Cl;

X2Is F or Cl3;

R3- H, CH3or CH2CH3,

characterized in that the compound of formula VII

< / BR>
where X is F or Cl and R3takes the values defined above,

nitrous with obtaining the compounds of formula IX

< / BR>
where X and R3have the above values,

and the nitro-group is then reduced to the corresponding amino group to obtain compounds of General formula

< / BR>
where X, Y and R3have the above values,

then the amino group is transformed into the corresponding diazonium group which is converted into the corresponding halide compound.

22. The method of obtaining compounds of General formula X

< / BR>
where X is F or Cl;

R3- H, CH3or CH2CH3,

characterized in that the compound of formula XI

< / BR>
where R3takes the values defined above, nitrous obtaining compounds of General formula

< / BR>
and the nitro-group is reduced to the corresponding amino group to obtain compounds of General formula

< / BR>
where R3have the above values,

which then transformed into a diazonium group, and then turn to the appropriate/SUB> Is F or Cl;

R3- H, CH3or CH2CH3,

characterized in that the compound of the formula

< / BR>
where X1and R3take the values defined above,

nitrous with obtaining the compounds of formula

< / BR>
and the nitro-group is reduced to amino group to obtain the compounds of formula

< / BR>
then the amino group is transformed into the corresponding diazonium group, and the diazonium group is transformed into the corresponding halide compound.

24. The method of obtaining compounds of General formula XII

< / BR>
where R3- H, CH3or CH2CH3,

characterized in that the compound of General formula V

< / BR>
where R3takes the values defined above,

reacts with sodium nitrite in the presence of concentrated sulfuric acid at low temperature and thus obtained Sol, page decomposes with obtaining the compounds of formula XII.

25. Composition for oral administration of increasing cognitive ability, containing the active ingredient and pharmaceutically acceptable carrier or excipient, wherein the active ingredient is used, the imidazole of the General formula I

< / BR>
where Y is automatic acceptable salt in an effective amount.

26. Substituted imidazoles under item 1 of General formula I

< / BR>
where Y is-CH2- or-CO;

R1Is F, Cl or OH;

R2Is H, F or Cl;

R3- H,

or their pharmaceutically acceptable salts, showing the properties of antagonists of adrenergic receptors.

27. A method of treatment of disorders of cognitive abilities, including introduction to the subject of the medicinal product, wherein the administered effective amount of a substituted imidazole of the General formula

< / BR>
where Y is-CH2- or-CO-

R1Is F, Cl or OH;

R2Is H, F or Cl;

R3- H,

or its pharmaceutically acceptable salt.

 

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z represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, a process for the preparation of these compounds and insecticides containing as active components of these compounds

The invention relates to the field of medicine and is intended for the treatment of various fungal infections of the skin and mucous membranes, increases the efficiency of releasing the drug reduces allergenic and sensitizing effect

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to new substituted phenylimidazoline, to a method for their production and to their use in pharmaceutical compositions

The invention relates to new derivatives of pyrazolo/4,3-d/pyrimidine-7-it formula I, where R1- H, CH3C2H5, R2- CH3CH2OH, CH2OCH3or n - C3H7, R3- C2H5CH2= CH - CH2, R4together with the nitrogen atom to which it is attached is 4-(R5)-piperidino - or 4-N (R6)-piperazino group, R5- H, N(CH3)2, CONH2, R6- H, CH3i - C3H7CH2CH2OH, CSNH2C(NH)NHCH3or C(NH)S CH3and their pharmaceutically acceptable salts, pharmaceutical compositions showing inhibitory activity against cyclic guanosin-31,51-monophosphatase (CGMP), which contains 1-400 mg per single dose of the compounds of formula (I) in a mixture with a pharmaceutically acceptable diluent or carrier; the method of treatment or prevention of conditions caused by the activity of CGMP, the essence of which consists in assigning to the person an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or above compositions
The invention relates to the field of veterinary medicine, namely to helminthology

The invention relates to medicine

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

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