The method of obtaining substituted imidazole


(57) Abstract:

New imidazole derivative f-ly I, where R1and R2that may be the same or equal, each H CH3C2H5, OCH3or halogen; R is H or the radical of f-crystals II, where R3it H R4is H and R5this is H or HE, or R4and R5together form a bond and X is a bond or C1-C2- alkylen with normal circuit receive when interacting Olkiluoto ether 4(5) imidazolinone acid f-ly III, where R above, and R represents alkyl, with the reagent Greenacre f-ly IV where R1and R2above, and 1 halogen followed, if necessary, by dehydration of the product and, optionally, hydrogenation, further optionally, the interaction with a strong base and then with benzylchloride f-ly R3-C6H4-CH2Hal and further if desired, the hydrogenation, the compound obtained is optionally transferred to acid-additive non-toxic pharmacologically acceptable salt applied in the new pharmaceutical compositio. The structure of the compounds f-ly I, II, III, IV:

The invention relates to methods of producing substituted imidazole derivatives and their non-toxic pharmaceutically when the B>2-CHR where R1and R2that may be different or identical, represent H, CH3C2H5, OCH3or halogen; R1represents N or

-CHR3where R3represents N, CH3or halogen; R4is a N; R5represents H or IT; or R4and R5together form a bond; X is a bond or C1-C2-alkylen with normal chains.

Non-toxic pharmaceutically acceptable acid additive salts of these compounds are also included in the scope of the invention.

The compounds of formula I form acid additive salts with organic and inorganic acids. Thus, they can form a variety of pharmaceutically acceptable acid additive salts, such as chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formats, tartratami, maleate, citrates, benzoate, salicylates, ascorbates etc.

In the scope of the invention also includes pharmaceutical compositions that include at least some of the compounds of formula I or their non-toxic pharmaceutically acceptable salt and a compatible pharmaceutically acceptable carrier.


4-[3,3-bis(4-chlorophenyl)-3-hydroxyprop - MPI] -1H-imidazole; 4-[3,3 - bis(2-were)-3-hydroxypropyl] -1H-imidazole; 4-[3,3-bis(3 - were)-3-hydroxypropyl] 1H-imidazole; 4-(3,3-diphenylpropane - 2-yl)-1H-imidazole; 4-[3,3-bis(4-chlorophenyl)propen-2-yl] -1H - imidazole; 4-[3,3-bis(2 - methyl-phenyl)propen-2-yl] -1H-imidazole; 4-[3,3-bis(3-were)propen-2-yl]-1H-them - Gasol; 4-(3,3-diphenylpropyl)-1H-imidazole; 4-[3,3-bis(2-were) propyl] -1H-imidazole; 1-benzyl-5-[3,3-bis(4-chlorophenyl)-3 - hydroxypropyl] -1H-imidazole; 1-benzyl-5-[5-(2,6-dimetilfenil)-3 - hydroxy-3-(2,6-dimethylpentyl)-pentyl] 1H-imidazole; 1-benzyl-5- [3,3-bis(4-chlorophenyl)propen-2-yl]-1H-imidazole; 4-[3-(4-chlorophenyl) -3-hydroxy-3-phenylpropyl]-1H-imidazole; 1-benzyl-4-(3,3 - diphenylpropyl)-1H-imidazole; 1-benzyl-5-(3,3-diphenylpropyl)-1H - imidazole; 4-[5-(2,6 - dimetilfenil)-3-(2,6-dimethylpentyl)- pentyl]-1H-imidazole; 4-[3,3-bis(3-were)propyl] -1H-imida - angry; 1-(4-Chlorobenzyl)-4-(3,3-diphenylpropyl)-1H-imidazole; 1-(4-Chlorobenzyl)-5-(3,3-diphenylpropyl)-1H-imidazole; 4-[5-(2,6-di - were)-3-hydroxy-3-(2,6-dimethyle - niatel)- pentyl]-1H-imidazole; 4-[3,3-bis(3-forfinal)propen-2-yl]-1H-imida evil; 4-[3,3-bis(3-forfinal)propyl] -1H-imidazole 4-[3,3-bis(3, 5dimethylphenyl)Pro - MPI] -1H-imidazole; 1-benzyl-5-(3,3-diphenylpropane-2-yl)-1H-imidazole; 1-benzyl-5-[3,3-bis(3, 5dimethylphenyl)-3-hydroxy - ol the EN-2-yl] 1H-imidazole; 1-benzyl-5-[3,3-bis(3-methoxyphenyl)propene-2-yl] -1H-imidazole; 1 - benzyl-5-[3,3-bis(4-methoxyphenyl)propene-2-yl] -1H-imidazole; 1-benzyl-5-[3,3-bis(4-methoxyphenyl)propene-2-yl] 1H-imidazole; 1-benzyl-5-[3,3-bis(2,3-dimetilfenil)propen-2-yl]-1H-imidazole; 1-benzyl-5-[3,3-bis(2-were)propen-2-yl] -1H-imidazole; 1-benzyl-5-[3,3-bis(3-were)propen-2-yl]-1H-imidazole;

1-benzyl-5-[3,3-bis(4-were)Pro - pen-2-yl]-1H-imidazole; 1-benzyl-5-[3,3-bis(3, 5dimethylphenyl)propyl] -1H-imida-angry; 1-benzyl-5-[3,3-bis(3-methoxyphenyl)propyl] -1H-imidazole; 4-[3,3-bis(3, 5dimethylphenyl)propyl]-1H-imidazole;

4-[3,3-bis(2,3-dimetilfenil)propyl] -1H-imidazole; 4-[3,3-bis(2 - methoxyphenyl)propyl]-1H-imidazole; 4-[3,3-bis(3-methoxyphenyl) propyl]-1H-imidazole;

4-[3,3-bis(4-methoxyphenyl)propyl] -1H - imidazole; 4-[3,3-bis(4 - were)propyl]-1H-imidazole.

Found that the compounds of the invention inhibit the production of aromatase and therefore are valuable in the treatment of estrogenzawisimy diseases, such as breast cancer. Found also antifungal properties.

In accordance with the invention the compounds of formula I are obtained by implementation of a number of reactions involving Grignard reaction, alkylboron ether 4(5)-imidazolinone acid (II) or 1-benzyl derivative R> In formulas II-IV R represents alkyl; R3represents N, CH3or halogen, R1and R2may be the same or different and represent N, CH3WITH2H5THE CO3or HaL (HaL is halogen). The first stage of the reaction, Grignard reaction, leads to the following compounds of formula I



In this reaction derived arylalkylamine may be, for example, a derivative of arylalkylamine, which is obtained by reaction of the corresponding derived arylalkylamine with magnesium. Suitable reaction solvents include various ethers, preferably tetrahydrofuran.

Derived arylalkylamine receive the usual way, by adding the derived arylalkylamine in an appropriate solvent, for example tetrahydrofuran, is added dropwise to magnesium turnings covered with tetrahydrofuran, at the boiling temperature of the reaction mixture. When magnesium turnings propagare, the mixture is carefully cooled and to it add alkilany ether 4(5)-imidazolinone acid or its 1-benzylamino derived small portions in solid form or dropwise as a solution in tetrahydrofuran is Ola does not react. The reaction time ranges from 1 to 5 o'clock

Further in accordance with the invention the compounds of formula I in which R4and R5both represent hydrogen or together form a bond, obtained by dehydration of compounds of formula I in which R5is HE and by the catalytic addition of hydrogen in the second stage. Water drains the usual ways, for example by heating with concentrated hydrochloric acid or by heating with anhydrous potassium bisulfate. Unsaturated derivatives (V) (compounds of formula (I), where R4and R5together form a bond), is isolated and then hydronaut. Alternative, you can directly gidrirovanii in the acidic environment without prior selection. The hydrogenation is usually carried out at room temperature with thorough stirring in alcohol, for example ethanol, in the presence of a catalyst and in an atmosphere of hydrogen. Suitable catalysts include platinum oxide, palladium on charcoal or catalyst of Raney. The scheme of these reactions can be represented as follows.



If R' represents a substituted or unsubstituted benzyl, then this group can also be removed by hydrogenation. In this case, gidrirovanie the Scheme such hydrogenation reactions, which leads to the production of the compounds of formula I, where R4and R5both represent hydrogen, can be shown as follows:



The compounds of formula I can also be obtained directly from compounds of formula V by simultaneous hydrogenation of the double bond and the protective benzyl group.

Another method of preparing compounds of formula I, where R' is a benzyl, includes benzylidene the corresponding compounds where R' is hydrogen. The original connection is first treated with a strong base, such as sodium hydroxide solution in water or hydrate of sodium in an appropriate solvent, e.g. dimethylformamide, resulting in a gain of alkali-metal salt of imidazole, and the second stage in this mixture add halogenic. The scheme of this reaction can be represented as follows:


< / BR>
In the described method, the esters of 4(5)-imidazolinone acid (II) and (III) can be obtained, for example from 1-benzyl-5 - imidazolecarboxaldehyde and malonic acids that work together to condense and get 5-(1-benzylimidazole)acrylic acid. When this connection hydronaut in acidic medium at elevated temperatures (70-80about(C) in the mouth, for example methanol, in the presence of anhydrous hydrochloric acid get alkilany ether 4-imidazolinone acid, which is used as the source material for the Grignard reaction.

< / BR>
When 5-(1-benzylimidazole)acrylic acid (benzyl group can be substituted not substituted) hydronaut at room temperature in the alcohol, then get a 1-benzyl-5-imidazolinone acid. Subsequent treatment with an alcohol in the presence of anhydrous hydrochloric acid at elevated temperature gives a different starting material for the Grignard reaction, namely, alkilany ester of 1-benzyl-5-imidazolinone acid. Described stages of the reaction can also be done in reverse order. The scheme of reactions can be prestiti as follows:

< / BR>
To apply the compounds of formula I and non-toxic pharmaceutically acceptable acid salts or mixtures thereof can be parenteral, intravenous or oral. Typically, an effective amount of a derivative is combined with a suitable pharmaceutical carrier. The term "effective amount" includes the amount which gives the desired effect and do not cause unwanted side effects. A certain number of connections, which are used in concr the cure, etc. and, of course, derived from the structure.

Pharmaceutical carriers used derivative according to the invention can be solid or liquid and are usually chosen based on the intended method of application. So, for example, solid carriers include lactose, sucrose, gelatin and agar, liquid carriers include water, syrup, walnut or olive oil. Other carriers are well known to the specialists-pharmacists. The combination of derived and media can be presented in different acceptable forms, such as tablets, capsules, suppositories, up solutions, emulsions and powders.

Compounds according to the invention are particularly valuable as suppressing the production of aromatase drugs and therefore useful in the treatment estrogenzawisimy diseases such as breast cancer.

Extrogen are required steroids physiology and functioning in the normal development of the mammary gland and genital organs in women. On the other hand, it is known that extrogen stimulate the growth estrogenzawisimy cancers, in particular breast cancer, and endometrial cancers, and they increase the risk of developing breast cancer if they are introduced in pharmacological doses in the course of the disease gormonzavisimykh bodies. The importance of estrogen as stimulants and/or growth regulators of cancer is confirmed by the fact that antiestrogens took the main place in the treatment rich in estrogen receptors breast cancers. Antiestrogens act by binding to the estrogen receptor and thus inhibit the biological action of estrogen. Another approach to blocking the action of estrogen is the suppression of the synthesis of estrogen. This clinic is achieved by nonspecific steroid synthesis inhibitor aminoglutethimide. Synthesis of estrogen can specifically block by inhibiting the production of aromatase, which is a key enzyme in the biochemical synthesis of estrogen. Suppression of generation aromatase is very mnogoobeschayuschem way, as some tumors in the mammary glands produce estradiol and estrone in place and are therefore constant growth stimulants (Alan Lipton et. al. 59:779-782, 1987).

The ability of compounds according to the invention to suppress the production of aromatase investigated in vitro by the method of M. Pasanen, Biological Research in Pregnancy 6, No. 2, 1985 (pp. 94-99). Used aromatase person. The enzyme was prepared from human placenta, rich in this enzyme. With the preliminary cleanup. Test compounds were added together with 100000 dpm 1,23 H/-androsten-3,17-dione and generating NADPH system. The concentration of the test compounds were of 0.001, 0.01, 0.1, and 1.0 mm. Incubation was carried out at a temperature of 37aboutC for 40 minutes. The introduction of 1.23 N/a-androsten-3,17-dione resulted in the recovery of 3H2O. Saturated with tritium water and the substrate is easily separated using miniology Sep-Pak, which adsorbs steroids, but ignores the free water. Radioactivity was determined using liquid scintillation counter. Suppression of generation aromatase assessed by comparing 3H2About radioactivity inhibitor-treated samples with control samples that did not contain the inhibitor. IR-10, IR-50 IR-90 this drug concentrations that inhibit the enzyme activity by 10% to 50% and 90%, respectively. These concentrations are presented in table.1.

Test the connection.

1) 4-[5-(2,6-dimetilfenil)-3-hydroxy-3-(2,6-dimethylphenylamine) pentyl] -1H-imidazole;

2) 4-[3,3-bis(4-chlorophenyl)-3-hydroxypropyl]-1H-imidazole;

3) 4-(3,3-diphenyl-3-hydroxypropyl)-1H-imidazole;

4) 4-(3,3-diphenylpropane-2-yl)-1H-imidazole;

5) 4-(3,3-diphenylpropyl)-1H-imidazole;

6) 4-[3,3-bis(2-were)-3-hydroxypropyl]-ol;

9) 4-[3,3-bis(2-were)propyl]-1H-imidazole;

10) 1-benzyl-5-(3,3-diphenylpropyl)-1H-imidazole;

11) 4-[3,3-bis(3-were)propyl]-1H-imidazole;

12) 4-[3,3-bis(3-were)propen-2-yl]-1H-imidazole;

13) 4-[3,3-bis(3-methoxyphenyl)propyl]-1H-imidazole;

14) 4-[3,3-bis(2,3-dimetilfenil)propyl]-1H-imidazole;

15) 1-benzyl-5-[3,3-bis(3-methoxyphenyl)propyl]-1H-imidazole;

16) 1-benzyl-5-[3,3-bis(3-methoxyphenyl)propene-2-yl]-1H-imidazole;

17) 4-[3,3-bis(3, 5dimethylphenyl)propyl]-1H-imidazole;

18) 4-[3,3-bis(4-methoxyphenyl)propyl]-1H-imidazole;

19) 4-[3,3-bis(3-forfinal)propyl]-1H-imidazole;

20) 1-benzyl-5-(3,3-diphenylpropane-2-yl)-1H-imidazole;

Daily dose of the drug to one patient ranges from 20 to 200 mg.

Toxicity imidazole derivatives of the present invention was studied on rats. In each gruppe were 5 female rats who were given the drug for 8 days. The drug was injected into his mouth in a dose of 10 mg/kg/day. Experienced 4-(3,3-diphenylpropane-2-yl)- 1H-imidazole, 4-(3,3-diphenylpropyl)-1H-imidazole, 4-[3,3-bis(2 - were)propyl] -1H-imidazole, 1-benzyl-5-(3,3 - diphenylpropyl)-1H-imidazole and 1-benzyl-5-(3,3-diphenylpropane-2-yl)- 1H-imidazole. Animals were monitored daily. They were weighed before and after a period of administration. The bodies of all who had. Weight in all groups was normal. In those groups where animals received 4-(3,3 - diphenylpropane-2-yl)-1H-imidazole and 1-benzyl-5- (3,3-diphenylpropane - 2-yl)-1H-imidazole, there was a slight lifting of the coat, probably as a result of the pharmacological effects of drugs. No caused by drugs deviations in the weight of organs and microscopic pathology were observed. So, all tested compounds were tolerant.

P R I m e R 1. 4-(3,3-Diphenyl-3-hydroxypropyl)-1H-imidazol

a) 5-(1-benzylimidazole)acrylic acid.

In the test tube is placed to 18.6 g of 5-(1-benzylimidazole)-carbaldehyde, 10.4 g of malonic acid and 4.8 ml of pyridine. The mixture was heated on a water bath for 16 hours Then cooled and diluted with water. The precipitate, which was the target product was filtered and washed with water. The outlet 15, So pl. 221-226aboutC.

1H NMR: 5,15 (s, 1H), 5,64 (s, 2H), return of 6.58 (d, 1H) 7.3 to 7.4 (m, 5H), TO 7.61 G(d, 1H), 8,08 (s, 1H), 9,07 (s, 1H)

b) ethyl ester of 4(5)-imidazolinone acid.

5-(1-benzylimidazole)acrylic acid (15 g) was dissolved in 50 ml of 4n. of hydrochloric acid. Added 60 mg of 10% Pd/C and the mixture was intensively stirred in hydrogen atmosphere at 85aboutWith up until the hydrogen has not ceased spending the and, after the solution was purged with dry hydrogen chloride for 4 h, the mixture was maintained at the temperature of reflux distilled and mixed. The mixture is then boiled away the dryness and the obtained oily residue, which was a dry product used in the subsequent edition of the Grignard.

1H NMR: 1,237 (t, 3H), 2,656 (t, 2H), 2,936 (t, 2H), 4,137 (K, 2N), 6,804 (s, 1H), 7,559 (s, 1H).

C) 4-(3,3-diphenyl-3-hydroxypropyl)-1H-imidazole.

3,3 g of magnesium shavings covered 100 ml of dry tetrahydrofuran. This mixture is then added dropwise a solution of 21.8 g of bromine benzol in 30 ml of dry tetrahydrofuran with such speed that was supported by a smooth reaction. After complete addition, the reaction MESI was delegirovali for one additional hour and cooled to room temperature. After this the reaction mixture was dropwise added to a solution of ethyl ester 4(5) imidazolinone acid (7.8 g) in 50 ml of tetrahydrofuran at room temperature. After complete addition, the reaction mixture was stirred 1 h at 40-50aboutC. the Mixture was then cooled and poured into cold water. The tetrahydrofuran was evaporated and the solution was added concentrated hydrochloric acid (20 ml). The solution was cooled and the precipitate, Koth etc. 189-191aboutC.

1H NMR: 1,703 (s, 4H), 4,578 (s, 3H), 7,214-7,429 (m, 11N), 8,457 (s, 1H).

Similarly, when using the Grignard reaction starting from the ethyl ester 4(5) imidazolinone acid and the corresponding substituted brombenzene, you can also obtain other compounds of the present invention. For example, the following substituted derivatives:

4-[3,3-bis(4-chlorophenyl)-3-hydroxyprop - MPI] -1H-imidazole. Similar hydrochloride 85-89aboutC.

4-[3,3-bis(2-were)-3-hydroxy - propyl]-1H-imidazole. Similar hydrochloride 211-213aboutC.

4-[3,3-bis(3-were)-3-hydroxy - propyl]-1H-imidazole. Similar hydrochloride 170-172aboutC.

P R I m m e R 2. 4-(3,3-diphenylpropane-2-yl)-1H-imidazole.

2.0 g of the hydrochloride of 4-(3,3-diphenyl-4-hydroxypropyl)-1H-imidazole was mixed with 20 g of anhydrous potassium bisulfate and the mixture was heated on an oil bath at 150-155aboutWith 4 hours the mixture is Then cooled and added with 20 ml water. The mixture was podslushivaet sodium hydroxide solution and cooled. The residue, representing the product was filtered, washed with water and obezbedili. The output of 1.25, After recrystallization from a mixture of water-ethanol, the product melted at 124 to 128aboutC.

1H NMR: 3,42 (d, 2H), 4,756 (s, 1H), 6,284 (t, 1H), 6,768 (s, 1H), 7,2-7,4 (m, 10H),data:

4-[3,3-bis(4-chlorophenyl)propen-2-yl] 1H-imidazolidinone.

Etc., 158-163aboutC.


Etc., 195-198aboutC.


Etc., 115-118aboutC.


So square hydrochloride 125-128aboutC.

P R I m e R 3. 4-(3,3-Diphenylpropyl)-1H-imidazole.

4-(3,3-Diphenylpropane-2-yl-1H-imida evil (0.7 g) was dissolved in ethanol and added a catalytic amount of Pd/C (10%). The reaction mixture was strongly stirred at room temperature in a hydrogen atmosphere until stopped absorption of hydrogen. The mixture was filtered and the filter was evaporated to dryness. The residue was recrystallization from water-ethanol mixture. Yield 0.4 g so pl. 115-117aboutC.

1H NMR: of 2.3-2.5 (m, 4H), 3,919 (t, 1H), of 4.752 (s, 1H), 6,708 (s, 1H), 7,1-7,3 (m, 10H), 7,532 (s, 1H).

In accordance with the same procedure, for example, the following substituted derivatives:

4-[3,3-bis(2-were)propyl]-1H - imidazole, hydrochloride. So pl. 84-87aboutC.

4-[3,3-bis(3-were)propyl]-1H - imidazole. So pl. 111-114aboutC.

1H NMR (as base).

2,272 (C, 6N), 2,2-2,5 AK HCl).

2,3-2,8 (m, 4H), 4,060 (t, 1H), 4,784 (s, 2H), 6,7-of 7.4 (m, N), 8,743 (s, 1H).

P R I m e R 4. 1-Benzyl-5-[3,3-bis(4-chlorophenyl)-3-hydroxypropyl] 1H-imidazole.

a) Methyl ester of 1-benzyl-5-imidazolinone acid.

Into the flask was placed 12.0 g of 5-(1-benzylimidazole)acrylic acid (obtained in example 1), 70 ml of methanol and within 4 hours the solution was passed dry gaseous hydrogen chloride, during this process the reaction mixture is maintained at the temperature of reflux distilled. The mixture was then evaporated to dryness and the residue dissolved in cold water. The solution is made alkaline with sodium carbonate and the precipitate, representing the product was filtered, washed with water and obezbedili. Yield 12.2 g, so pl. 137-139aboutC.

1H NMR: 3,781 (s, 3H), 5,490 (s, 2H), 6,452 (d, 1H), 7,2-7,5 (m, 5H), 7,493 (d, 1H), 7,710 (s, 1H), 8,083 (s, 1H).

b) 1-benzyl-5-imidazolidinedione acid methyl ester.

The double bond of the side chain was hydrogenosomal in absolute ethanole, using as the catalyst is Pd/C. When the absorption of hydrogen has ceased, the reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in methylene chloride, which was washed with water. Phase methylene chloride then obezbedili and steamed up is SUP>H NMR: Aliphatic hydrocarbons found in the following parts per million: 19, 374, 32, 573 48, 466 51, 675; aromatic hydrocarbons are found in the following parts per million: 126, 569, 128, 022 128, 748 128, 960 130, 474 136, 074 137, 88 and the carbonyl at 172, 522.


The Grignard reagent obtained from 2.4 g of magnesium shavings and of 19.1 g of p-chlorpromazine in tetrahydrofuran as described in example 1C.

Methyl ester of 1-benzyl-5-imidazolinone acid (6.4 g) in tetrahydrofuran was heated to 60aboutAnd it was added dropwise prepared above methyl p-chloraniline. After complete addition, the reaction mixture was delegirovali further 3 hours, cooled and poured into cold water. The tetrahydrofuran was evaporated, added toluene and the mixture was acidified with hydrochloric acid. The precipitated product was filtered, washed with ether and obezbedili. Yield 12.2 g, etc., 210-213aboutS. T. pl. nitrate 157-160about(Obtained in a mixture of water-simple ether). So square hydrochloride (from ethyl acetate) 178-187aboutC.

1H NMR: 2,985 (s, 4H), 4,854 (s, 2H), 5,330 (s, 2H), 7,06-7,46 (m, 14N), 8,993 (s, 1H).

Similarly, also received other 1-benzylamine derivatives. For example, 1-benzyl-5-[5-(2,6-dimethylphenyl methyl-2-(2,6-dimetilfenil)etermine. The melting point of the hydrochloride 67-71aboutC.

P R I m e R 5. 1-Benzyl-5-[3,3-bis(4-chlorophenyl)propen-2-yl]-1H - imidazol

4.1 g of 1-benzyl-5-[3,3-bis(4-chlorophenyl)-3-hydroxypropyl]-1H - imidazole and 22.0 anhydrous potassium bisulfate was heated to 150aboutWith 4 hours the Mixture was cooled, added 100 ml of ethanol to dissolve the product. The mixture then was filtered and the filtrate was evaporated to a small volume. Added water and the mixture is made alkaline using sodium hydroxide. The residue, representing the product was filtered, washed with water and obezbedili. Product recrystallization from water-ethanol. The output of 2.3, Nitrate obtained in water by means of nitric acid.

1H NMR: 3,923 (d, 2H), 5,287 (s, 1H), 6,010 (t, 1H), from 6.9 to 7.4 (m, 14N), 9,330 (s, 1H).

P R I m e R 6. 1-Benzyl-4-(3,3-diphenylpropyl)-1H-imidazole and 1-benzyl-5-(3,3-diphenylpropyl)-1H-imidazole.

4-(3,3-Diphenylpropyl)-1H-imidazole (2.6 g) was dissolved in 6 ml of dry dimethylformamide. Under stirring for 0.5 h was added at room temperature, 0.5 g of NaH (60%). After the addition the reaction mixture was stirred for another 1 h At room temperature dropwise then added 1.7 g of benzylbromide and stirring continued for 4 h, the Reaction mixture was poured into cold water (30 ml) and the mixture extrag the Wallpaper mix of products, purified and separated for cleaning isomers column chromatography (methylene chloride/methanol) 9,5/0,5).

1H NMR products:

One of the isomers: to 2.57 (m, 4H), 3,52 (1H, 3,877 (t, 1H), 5,362 (s, 2H), 6,531 (s, 1H), 7,05-7,40 (m, 15 NM), 9,567 (s, 1H).

The other isomer: 2,375 (m, 4H), 3,858 (t, 1H), 5,253 (s, 2H), 7,01 and 7.36 (m, N), 9,441 (s, 1H).

P R I m e R 7. 1-(4-Chlorobenzyl)-4-(3,3-diphenylpropyl)-1H-imidazole and 1-(4-Chlorobenzyl)-5-(3,3-diphenylpropyl)-1H-imidazole.

Connection received similar compounds in example 6 from 4-(3,3-diphenylpropyl)-1H-imidazole and 4-chlorobenzylchloride - Yes.

1H NMR products. One isomer: 2,48 (m, 4H), 3,934 (t, 1H), 4,999 (s, 2H), 6,514 (s, 1H), 7,0-to 7.3 (m, 14N), 7,517 (s, 1H).

The other isomer: 2,33 (m, 4H), 3,887 (t, 1H), 4,852 (s, 2H), 6,7-7,5 (m, N).

P R I m e R 8. 4-[5-(2,6-Dimetilfenil)-3-(2,6-dimethylphenylamine) pentyl] -1H-imidazole.

4.0 g of the hydrochloride of 1-benzyl-5-[5-(2,6-dimetilfenil)-3-hydroxy-3- (2,6-dimethylphenylamine)pentyl] -1H-imidazole and 20 g of potassium bisulfate combined and the mixture was heated for 6 hours at 150aboutC. was Added ethanol (40 ml) and the mixture was filtered. Added 20 ml of concentrated hydrochloric acid and the mixture was hydrogenosomal using a catalyst of palladium on coal (10%) until the uptake of hydrogen ceased. Reaction Aravali in toluene, washed with water and evaporated to dryness. The remainder, which is the product base, converted to nitrate by means of nitric acid in water. Etc., 147-150aboutC.

P R I m e R 9. 4-[3,3-bis(3, 5dimethylphenyl)propyl]-1H-imidazol

a) 1-benzyl-5-[3,3-bis(3, 5dimethylphenyl)-3-hydroxypropyl]-1H - imidazole.

1.06 g of magnesium shavings covered 30 ml of dry tetrahydrofuran. The mixture was then added dropwise a solution of 5-bromo - acid (8,14 g) in 10 ml dry tetrahydrofuran at this rate, which was supported by the smooth reaction. After the addition, the reaction mixture was delegirovali 1 h and cooled to room temperature. Then the reaction mixture was dropwise added to a solution of ethyl ester of 1-benzyl-5-imidazolinone acid (5.0 g) in 40 ml of tetrahydrofuran at 60aboutC. After complete addition, the reaction mixture was delegirovali 2 h, cooled and poured into cold water. The tetrahydrofuran was evaporated and the solution was added concentrated hydrochloric acid. The solution was cooled, added the same ether and the precipitate, which contains the product in the form of a hydrochloric salt was removed by filtration, washed and obezbedili. The output of 4.1, So pl. 120-124aboutC.

b) 1-benzyl-5-[3,3-bis(3, 5dimethylphenyl)propen-2-yl]-1H and the La and added 2 ml of concentrated hydrochloric acid. The reaction mixture was then delegirovali 4 hours and evaporated to dryness. The remainder, which is the product, recrystallization of ethyl acetate. Output 3.1 g So pl. 170-176aboutC.

In accordance with the procedure outlined in example procedure received the following substituted derivatives:

1-Benzyl-5-(3,3-diphenylpropane-2-yl)-1H-imidazole, hydrochloride. So pl. 173-175aboutC.

1-benzyl-5-[3,3-bis(2-methoxyphenyl) propene-2-yl] -1H-imidazole, hydrochloride. So pl. 191-194aboutC; 1-benzyl-5-[3,3-bis(3-methoxyphenyl) propene-2-yl]-1H-imidazole, hydrochloride. So pl. 132-135aboutC; 1-benzyl-5-[3,3 - bis(4-methoxyphenyl)propene-2-yl] -1H-them - Gasol hydrochloride. So pl. 157-163aboutC; 1-benzyl-5-[3,3-bis(2,3 - dimetilfenil)propen-2-yl]-1H-imidazole, hydrochloride.

1H NMR (as base)

2,055 (s, 3H), 2,159 (s, 3H), 2,251 (C, 6N), 3,467 (d, 2H), 4,781 (s, 1H), 5,281 (s, 2H), 5,761 (t, 1H), 6,8-7,4 (m, N), becomes 9.97 (s, 1H).

1-benzyl-5-[3,3-bis(2-were)Pro - pen-2-yl] -1H-imidazole, hydrochloride. So pl. 84-87aboutC; 1-benzyl-5-[3,3-bis(3-were) propen-2-yl]-1H-imidazole, hydrochloride. So pl. 115-117aboutC; C) 2-benzyl-5-[3,3-bis(3, 5dimethylphenyl)propyl] -1H-imidazole; 1-benzyl-5-[3,3-bis(3, 5dimethylphenyl)propen-2 - yl] -1H-imidazole hydrochloride was dissolved in ethanol and added to the mixture a catalytic amount of Pd/C (10%). Reectometry absorption of hydrogen. The mixture was filtered and the filtrate is boiled away the dryness. The remainder, which represents the target product was purified using the evaporative chromatography, using as eluent a mixture of methylene chloride with methanol.

In the same way received:

1-benzyl-5-[3,3-bis(3-methoxyphenyl) propyl]-1H-imidazole hydrochloride. So pl. 165-167aboutWith 1-benzyl-5-[3,3-diphenylpropyl] 1H-imidazole hydrochloride, T. pl. 160-162aboutC; d) 4-[3,3-bis(3, 5dimethylphenyl)Pro - MPI]-1H-imidazole.

20 g of 1-benzyl-5-[3,3-bis(3, 5dimethylphenyl)propyl]-1H-imidazole hydrochloride was first made in a mixture of 30 ml. of 2n. hydrochloric acid and 10 ml of ethanol at 80aboutWith using Pd/C as catalyst (10%). When the absorption of hydrogen has ceased, the reaction mixture is cooled, filtered and boiled away the dryness. Then added water and Podlachia mixture with caustic soda. The product was then extracted to ethyl acetate, which was washed with water, obezbedili using sodium sulfate and boiled away the dryness. The rest was a target product as a base and it turned into a salt of hydrochloric acid in ethyl acetate, using anhydrous hydrochloric acid. The output of 0.6, So pl. 101-105aboutC.

1H NMR: 2,247 (s, N), 2,2-3,7 (m, 4H), 3,798 (t, 1H), 4788 (s, 2H), 6,8-7, fenil)propyl]-1H-imidazol

1H NMR: (as base)

2,097 (C, 6N), 2,260 (C, 6N), 2,3 (m, 2H), and 2.6 (m, 2H), 4,389 (s, 1H), 6,0 (s, 1H), 6,712 (s, 1H), 7,011 (C, 6N), 7,508 (s, 1H).

4-[3,3-bis(2-methoxyphenyl)propyl] 1H-imidazole, hydrochloride. So pl. 194-196aboutC.


1H NMR (as base):

of 2.5 (m, 4H), 3,747 (C, 6N), 3,862 (t, 1H), of 6.6 to 7.3 (m, N), 7,498 (s, 1H), 8,165 (s, 1H).

4-[5-(2,6-dimetilfenil)-3-hydroxy-3- (2,6-dimethylpentyl)-pentyl] 1H-imidazole, hydrochloride, T. pl. 178-180aboutC.

4-[3,3-bis(4-methoxyphenyl)propyl]-1H - imidazol

1H NMR (as base):

of 2.5 (m, 4H), 3,744 (C, 6N), 3,815 (t, 1H), 6,1 (Shir. band, 1H), 6,732-7,171 (m, N), 7,489 (s, 1H).

4-[3,3-bis(4-were)propyl]-1H - imidazol

1H NMR (as hydrochloride):

2,260 (C, 6N), 2,5 (m, 4H), 3,879 (t, 1H), 4,907 (s, 2H), 6,9-7,2 (m, N), 8,727 (s, 1H).

P R I m e R 10. 4-(3,3-Diphenylpropyl)-1H-imidazole.

1-Benzyl-5-(3,3-phenyl-1-propenyl)-1H - imidazole hydrochloride was dissolved in ethanol and the solution was acidified with concentrated hydrochloric acid. The mixture was first made by the Pd/C catalyst (10%) until such time as not to stop the absorption of hydrogen. The mixture was filtered, added water and the mixture was podslushivaet sodium hydroxide. The precipitate, which is a target Prada/ethanol.

A method of OBTAINING a SUBSTITUTED IMIDAZOLE of the General formula I

< / BR>
where R1and R2the same or different, hydrogen, CH3WITH2H5THE CO3or halogen;

R is hydrogen or

< / BR>
where R3hydrogen;


R5hydrogen or HE or R4and R5together form a bond;

X communication or1WITH2-alkylen with normal chain,

or its non-toxic pharmaceutically acceptable acid salt additive, characterized in that alkilany ether 4(5)-imidazolinone acid of General formula

< / BR>
where R has the above meanings;

R alkyl,

subjected to interaction with the Grignard reagent of General formula

< / BR>
where R1, R2and X have the above meanings;

Hal is halogen,

obtaining compounds of General formula

< / BR>
where R, R1, R2and X have the above values,

and, if necessary, carry out the subsequent dehydration of the resulting product with obtaining compounds of General formula

< / BR>
where R R1, R2and X have the above values,

and optional hydronaut this product with the receipt of: (a) soedineniya General formula

< / BR>
where R1, R2and X have wilhelmenia General formula

< / BR>
where R3and Hal have the above values,

obtaining compounds of General formula

< / BR>
where R1, R2, R3and X have the above values,

or b)compounds of General formula

< / BR>
where R1, R2and X have the above values,

R1benzyl group,

and if you want hydronaut the compound obtained to obtain compounds of General formula

< / BR>
where R1, R2and X have the above values,

and if desired, the compound obtained prevresult its pharmaceutically acceptable acid salt additive.


Same patents:

The invention relates to new chemical compounds having valuable pharmacological properties and relates to new pharmacologically active N-substituted derivatives of (3R, 4R)-3-ethyl-4- [(1-methyl-1H-imidazol-5-yl)methyl] -2-Pierre - oligonu that have antiglaucoma action and can find application in medicine

The invention relates to the synthesis of new biologically active chemical compounds, specifically to N-2-(I-R1-5-R2-6-R3-benzimidazolyl)-Succinimidyl acids of General formula I

where (a) R1=n-C4H9, R2=R3=H;

b) R1= CH3, R2= R3=Br, which have neuroleptic, antihypoxic and antiarrhythmic activity, and can find application in medicine

The invention relates to the field of organic chemistry, specifically to an improved method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] 4H-carbazole-4-or its salts or their hydrates, as well as intermediates for their synthesis, which can find application in pharmaceutical industry

The invention relates to new chemical compounds with valuable pharmacological properties, namely, condensed the five-membered heterocycles of General formula

(1) where R1the atom of hydrogen, fluorine, chlorine or bromine, alkyl-, aralkyl-, aryl-, heteroaryl-, R3O-, (R3)2N-, R4CO - NR3-, alkylsulfonyl - NR3-, arylsulfonyl - NR3-, R3S-, R3SO, R3S2O-, or R5group, and R3is a hydrogen atom, an alkyl group containing from 1 to 6 carbon atoms, aryl, heteroaryl, kalkilya, carboxialkilnuyu or alkoxycarbonylmethyl group;

R4a hydrogen atom, alkyl or CNS group containing 1-6 carbon atoms, aryl, heteroaryl or kalkilya group containing 1-6 carbon atoms in the alkyl part;

R5azetidinone, pyrolidine, hexamethyleneimino or heptamethylnonane or piperidino group in which the methylene group in the fourth position may be substituted with oxygen, sulfenyl, sulfinil or sulfonylureas or aminogroups, which can be substituted for R3, R4CO4, alkylsulfonyl - or aryl is

The invention relates to medicine and can find application in practical medicine as a remedy to relieve alcohol withdrawal

The invention relates to derivatives of 4,5,6,7-tetrahydroimidazo General formula I or their salts, which are useful as drugs:

RR6(I) in which groups are represented as follows: R1, R2, R3independently represent a hydrogen atom, hydroxy group, lower alkyl group, which optionally can be substituted by halogen atom, lower alkoxy group, a lower alkylthio group, aralkylated group, aryloxy group, lower alkanoyloxy group, carboxy group, lower alkoxycarbonyl group or nitro group;

R4, R5, R6represent a hydrogen atom or a lower alkyl group;

X represents an oxygen atom or a sulfur atom
The invention relates to medicine, namely to ophthalmology

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to the chemistry and technology of thioesters and amides of carboxylic acids, in particular to an improved process for the preparation of thioesters and amides of carboxylic acids of the General formulas I and II, respectively

(I)< / BR>
(II),whereR is the residue of carboxylic acids, which are used as intermediates in obtaining antibiotics cephalosporin and penicillin ranks as the number of individual substances and mixtures

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

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: veterinary science.

SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.

EFFECT: higher efficiency of therapy.

4 cl,262 ex, 12 tbl

FIELD: medicine, gynecology, anesthesiology.

SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.

EFFECT: improved assistance method.

7 tbl, 4 ex

FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an antifungal gel pharmaceutical composition based on ketoconazole and clotrimazole that are derivatives of imidazole. The composition comprises ketoconazole or clotrimazole as an active component, polyethylene glycol-400 (PEG-400) as a solvent, carboxyvinyl polymer as a gel-forming agent, polyethylene glycol as a gel stabilizing agent, organic amine or inorganic bas as a regulator of pH and water taken in the definite ratio of components. The composition is prepared by dissolving active component in PEG-400, dispersing carboxyvinyl polymer in water, successive addition to dispersion propylene glycol as a stabilizing agent and regulator of pH and combination of prepared solution and gel followed by stirring the mixture up to preparing the gel composition with pH 5-7. Invention provides preparing antifungal composition with reduced adverse effect.

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

2 cl, 1 tbl, 11 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with applying selector as a selenium-containing organic preparation to be introduced for cows and calves monthly intramuscularly at the dosage of 10 mcg/kg body weight. The method provides decreased fodder expenses for the synthesis of the production obtained.

EFFECT: higher productivity in cattle.

2 ex, 7 tbl

FIELD: organic chemistry, medicine, allergology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for treatment of patient suffering with allergic disease. Method involves administration to patient the therapeutically effective dose of pharmaceutical composition comprising compound of the formula (I)

. The compound elicits high effectiveness in treatment of allergy and shows low toxicity also.

EFFECT: improved method for treatment.

9 cl, 2 tbl, 2 dwg, 40 ex