Substituted imidazole derivatives, method of administration of the pharmaceutical compositions and method of treatment using these compounds

 

(57) Abstract:

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims. These compounds are selective agonists in relation to adrenergic receptor subtype(s) 2B or 2B/2C. Also describes how the introduction of pharmaceutical compositions and method of treatment using these compounds. 12 N. and 74 C.p. f-crystals, 6 PL.

1. The scope of the invention

The present invention relates to a method of treating glaucoma or elevated intraocular pressure and other diseases with significantly reduced cardiovascular or sedative side effects by introducing a mammal, including humans, compounds which are selective agonists only adrenergic receptor subtype 2B or 2B and 2C and which do not have significant activity against receptor subtype 2A. The present invention also relates to new compounds and pharmaceutical compositions adapted for administration of these compounds mammals, including people.

2. A brief description of the prior art

Compounds that have U.S. and foreign patents and scientific publications. It is well known and recognized in the art that adrenergic activity useful in the treatment of animals species of mammals, including humans, for treatment or partial withdrawal symptoms and conditions of numerous diseases and conditions. In other words, in the art recognized that the pharmaceutical composition having as an active ingredient adrenergic(s) compound(I), suitable for the treatment of glaucoma, chronic pain, blockage of the nasal channel, high blood pressure, congestive heart failure and for anesthesia.

In the art, two main families of adrenergic receptors called alpha-adrenergic receptors and beta-adrenergic receptors, and it is known that each of these two families has subtypes that represent letters of the alphabet, such as 2A, 2B (Bylund et al, Pharmacol Rev. 46, pp.121-136 (1994)).

The INVENTION

In accordance with the present invention found that adrenergic compounds that act selectively and preferably even specific as agonists of receptor subtype 2B or 2B/2C (hereafter referred to as 2B or 2B/2C), in preference to receptionarea than one unwanted side effect, such as change in blood pressure or sedative effect. For the purposes of the present invention is determined that the connection is specific or at least selective agonist of the receptor subtype(s) 2B or 2B/2C, if the connection is at least approximately ten times more effective as an agonist receptor or 2B, and 2C, or both subtypes than in receptor subtype 2A, or if the difference in the effectiveness of the compounds in the receptor 2B or 2B/2C relatively receptor 2A is greater than 0.3, and its effectiveness in relation to receptor 2A does not exceed 0,4.

Thus, the present invention relates to methods for treating animals of the class Mammalia, including humans, the pharmaceutical composition comprising as active ingredient one or more than one connection, which is specific or selective adrenergic agonist 2B or 2B/2C, for treatment of many diseases or conditions against which the alpha-adrenergic compounds are used, including, without limitation, glaucoma, increased intraocular pressure, chronic pain, diarrhoea and blockage of the nasal channel. In addition, the compounds of the present invention, PRIV cancellation pain, including neuropathic pain, neurodegenerative diseases, including optic neuropathy, spinal ischemia and stroke, deficits in memory and cognitive abilities, attention deficit, psychoses, including manic disorders, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and obstruction of nasal channel.

The present invention also relates to pharmaceutical compositions used in the above methods of treatment.

The present invention particularly encompasses methods of treating diseases and conditions for which treatment are effective adrenergic compounds, but their use is limited because of their well-known side effects.

DETAILED description of the INVENTION

Compounds that are used in the pharmaceutical compositions and treatment methods of the present invention are selective or specific agonists adrenergic receptor subtype 2B or 2B/2C, in preference to the receptor subtype 2A. In accordance with the present invention, the connection is considered as a selective agonist 2B or 2B/2C, if the difference in the effectiveness of the compounds as alonistioti receptor 2A does not exceed 0,4, and/or connection of at least approximately ten times more effective. Preferably, the compounds used in accordance with the present invention are specific agonists of receptor subtype 2B or 2B/2C. In this regard, specific agonist particularly defined in the sense that specific-adrenergic agonist does not act as an agonist of the receptor subtype 2A in any measurable or biologically significant extent.

Was discovered a number of agents that are functionally selective in relation subtypes 2B or 2B/2C these adrenergic receptors. This preferred activity can be defined in many functional analyses, such as Cyclic AMP Production (production of cyclic adenosine monophosphate) (Shimizu et al., J. Neurochem. 16, pp.1609-1619 (1969)); RSAT (technology selection and amplification of the receptor) (Messier et al., Pharmacol. Toxicol. 76, pp.308-311 (1995)) and cytosensor microphysiometry (Neve et al, J. Biol. Chem. 267, pp.25748-25753 (1992)), using cells in vivo Express individual subtypes or had one of these subtypes. Used cells or recombinant receptors must be human or from a species which, as shown, is similar to the x 2A receptors man (gene C10), receptor 2B rat (gene RNG) and 2C receptors person (C4 gene). It is shown that the receptor 2B rat has pharmacology, which corresponds to the receptor 2B man (Bylund et al., Pharmacol, Rev. 46, pp.127-129 (1994)).

For the treatment in particular of glaucoma can be applied to local introduction. Any local pharmaceutical preparation such as a solution, suspension, gel, ointment or balm and the like, can be applied to eyes with glaucoma and skin for the treatment of other indications. The preparation of such local products are widely known in the field of pharmaceuticals (Remington''s Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania).

If the drug must enter systemically, it can be made in the form of powder, pills, tablets or the like, either in the form of a syrup or elixir for oral administration. For intravenous, intraperitoneal, vnutriobolochechnoe and epidural injection compound is prepared in the form of a solution or suspension, which can be introduced through injection. In some cases it may be useful cooking preparations of these compounds in the form of a suppository or prolonged drug release, including in the form of a skin patch for the Deposit is to be followed, known or discovered, are sensitive to the treatment of adrenergic compounds, is carried out by introducing a therapeutically effective dose of one or more than one compounds of the present invention. Therapeutic concentration is a concentration that causes weakening of the specific state or slows down its development. In some cases, the drug can be applied as a preventive measure to prevent the beginning of a specific state. Introduce therapeutic concentration will vary from state to state and in some cases may vary depending on the severity of the condition being treated, and the susceptibility of the patient to treatment. Accordingly, the insertion of therapeutic concentration is best determined at this time and in this place by routine experimentation. However, they are supposed to treat such as glaucoma drug containing from 0.001 to 5% by weight, preferably approximately from 0.01 to 3%, typically will correspond to a therapeutically effective concentration. When the system introduction a number of from 0.001 to 50 mg/kg, preferably from 0.001 to 10 mg/kg weight is employed in therapeutic result.

As specific selective agonists 2B and 2B/2C not have substantial 2A side effects, the treatment of diseases or conditions such compounds according to the present invention has the advantage, especially when treatment is assigned to a person with cardiovascular problems.

General structure typical of adrenergic compounds representing specific 2B and 2C agonists or selective in regard 2B and 2B/2C agonists, which are used in pharmaceutical compositions and methods of treatment of the present invention represented by the General formula below.

In one aspect of the present invention the compounds having selective agonistic activity against adrenergic receptor subtype(s) 2B or 2B/2C compared to the adrenergic receptor subtype 2A represented by the General formula

where the dotted lines represent possible double bonds;

R represents H or lower alkyl;

X represents S or C(H)R1where R1represents H or lower alkyl, or R1absent when X represents S or when the relationship between X and the ring represented by the formula

where y is an integer from 1 to 3, -CH=CH - or-Y1CH2- where Y1represents O, N or S; x is an integer 1 or 2, and x=1 when R2, R3or R4associated with unsaturated carbon atom, and x=2 when R2, R3or R4linked to a saturated carbon atom;

R2represents H, lower alkyl, halogen, hydroxy, lower alkoxygroup, lower alkenyl, acyl or lower quinil, or R2can represent oxo, when it is attached to a saturated carbon atom;

each of R3and R4represents H, lower alkyl, halogen, lower alkenyl, acyl, lower quinil, aryl, heteroaryl or substituted aryl or heteroaryl, where specified, the Deputy represents halogen, lower alkyl, lower alkoxygroup, lower alkenyl, acyl, lower quinil, nitro, cyano, trifluoromethyl, hydroxy or phenyl, or together they represent-C(R2)x)z-; -Y1(C(R2)x)z’-; -Y1(C(R2)x)yY1-; -(C(R2)x)-Y1-(C(R2)x)-; -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x) and Y1-(C(R2)x)-Y1-(C(R2)x3or R4with the formation of a condensed ring structure

and thus formed ring may be fully unsaturated, partially unsaturated or fully saturated, provided that the carbon ring has a valence of not more than 4, the nitrogen has a valence of not more than 3, and O and S have a valence not more than 2.

In another aspect of the invention, the above compound represented by the formula

where X can be represented as C(H)R1and R1represents N.

In the specified compound of formula II, R2can represent N and

can be farnily radical.

In such furnishing derivatives of the formula II, R3and R4together may represent (CH)4or R3can represent N, and R4can represent tert-butyl, or R3and R4can represent H, or R3can represent N, and R4can represent methyl or ethyl.

Alternatively, the connection formedical.

Alternatively, in the above compounds of formula II, R2can represent N and

can be a thienyl radical.

In such thienyl derivatives of the formula II, R3and R4together may represent (CH2)4or R3can be a phenyl, and R4can represent H, or R3and R4together may represent (CH2)3S, or R3and R4can represent H, or R3and R4together may represent (CH)4or R3can represent N, and R4can represent methyl, or R3can represent bromo, and R4can represent H, or R3can represent hydrogen, and R4can represent chloro, or R3can represent methyl, and R4may represent hydrogen.

Alternatively, compounds of formula II

can be a tsiklogeksilnogo radical.

In such tsiklogeksilnogo derivatives of the formula II, R2can represent hydrogen, and R3and R4together may represent (CH)4
or R2can represent hydrogen or oxo, and R3and R4together may represent (CH)2S, or R2can represent hydrogen, and R3and R4together may represent (CH2)4forming octahydronaphthalene, or R2can represent oxo, and R3and R4together may represent (CH2)4or R2can represent oxo, and R3and R4together may represent (CH2)C(CH3)(SN), or R2can represent hydrogen, and R3and R4together can represent S(CH2)2or R2, R3and R4can represent H, or R2can represent oxo, and R3and R4together may represent (CH)2(OCH3)CH, or R3and R4together may represent-Y1-C(R2)x-C(R2)x-Y1- where Y1represents N, forming tetrahydroquinoxalin, where R2can represent hydrogen or oxo.

Alternatively, compounds of formula II

can be tetrahydroquinoline radical, where31represents N. In such tetrahydroquinoline derivatives (R2)xcan represent hydrogen or oxo; or can be tetrahydroisoquinoline radical, where R3and R4together represent-C(R2)x-Y1-C(R2)x-C(R2)x- where Y1represents N, and (R2)xcan represent hydrogen or oxo.

Alternatively, compounds of formula II

can be cyclopentadienyl radical.

In such cyclopentenone derivatives of the formula II, R2can represent N, and R3and R4together may represent (CH)4or R2can represent oxo, and R3and R4together may represent (CH)4or R2can represent hydrogen, and R3and R4together may represent (CH2)3.

In another aspect of the invention Y is (CH2)3X can represent CH, and R2can represent oxo, or X can be a CH2, R2can represent N, and R3and R4together can predstavnytstvo a CH2C(CR12)2where R1represents hydrogen, or Y can represent a-CH2(IU)-, and R2can represent hydrogen or oxo.

Finally, in compounds of formula II

can be a phenyl radical.

In such phenyl derivatives of formula I, X can represent a CH2, R2can represent N or CH3, R2, R3and R4can represent H, or R3and R4together represent O(CR2)2O, forming 1,4-benzodioxane derived, or alternatively, X can represent S, and R2, R3and R4can represent N.

In another aspect of the invention the specified connection has the formula

where Y represents S or O.

In this connection formula III X can be represented as C(H)R1, R, R1, R2, R3and R4can represent H, and Y can represent O or S.

In another aspect of the invention the specified connection has the formula

and R3and R4together are (CH)4.

In such connected the Oh CH or CH2or one of R2represents hydroxy and the other can represent H, or R2can represent H.

In such compounds of formula IV, Y1can represent S, X may represent a CH2and R2can represent oxo, or R2can represent H, and X can represent CH, and R2can represent oxo.

In another aspect of the invention the compounds having selective activity against adrenergic receptor subtype(s) 2B or 2B and 2C in comparison with the adrenergic receptor subtype 2A, represented by the formula

alternatively, W is a bicyclic radical selected from the group consisting of

where R5, R6, R7and R8selected from the group consisting of H and lower alkyl, provided that at least one of R5and R6or R6and R7represents OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo;

where R10represents H, lower alkali norbornyl, known and declared in assigned simultaneously considering the application 09/003902, filed January 7, 1998, the contents of which in all its fullness are included in this description by reference.

In one aspect of the invention, Z can represent O, and W can be represented as

and R10can be selected from the group consisting of H, phenyl and o-methylphenyl; for example, R10can be an on-were.

In another aspect of the invention, the W can be a

where Z may represent NR, R can be a methyl or hydrogen, one (R9)xcan represent N, and R5can represent H.

Alternatively, W can be a

where R can be an H, and R8can represent methyl.

It is clear that the above reference to the lower alkyl, alkoxygroup, alkenyl or quinil intended to refer to radicals having from one to eight carbon atoms, preferably from one to four carbon atoms. The above reference to the aryl is intended to refer to radicals having from six to four who are respectful of fluorescent and chloro.

The invention is additionally illustrated by the following examples (including the General synthesis schemes), which are the illustration of the various aspects of the invention and are not intended to limit the scope of the invention as defined by the points of the attached claims.

Example

Synthesis of 1-dimethylsulphamoyl-2-tert-butyldimethylsilyl-5-imidazolecarboxaldehyde

Methodology

To 320 ml of benzene was added imidazole (1) (20,0 g, 0.29 mol), triethylamine (41,0 ml, 0.29 mol) and N,N-dimethylsulphamoyl (31,6 ml, 0.29 mol). The reaction mixture was stirred for 48 hours at room temperature (RT), and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude product (~0.5 mm Hg, 115-S) resulted in the receipt of 38.7 g (76%) transparent and colorless oil. Upon cooling, the product was hardened with the formation of white crystals (2). To 430 ml of tetrahydrofuran (THF) was added 1-(dimethylsulphamoyl)imidazole (2) (18,8 g, 0.11 mol). The solution was cooled to-S. In the reaction flask was added dropwise a solution of n-utility (n-BuLi) in hexane (1.6 M, 70,9 ml, 0.11 mol). Upon completion of addition the reaction mixture was stirred for 1 hour is. After the addition, the reaction mixture was slowly heated to CT, and then was stirred for 24 hours. The reaction mixture was diluted with water and the separated organic layer. The organic phase was washed with brine, and then dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane as eluent) yielded a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals (3).

To 100 ml of THF was added 1-dimethylsulphamoyl-2-tert-butyldimethylchlorosilane (3) (5.0 g, 17.3 mmol). The solution was cooled to-20C. In the reaction flask was added dropwise a solution of secondary utility (sec-BuLi) in hexane (1.3 M to 14.6 ml, 19 mmol). Upon completion of addition the reaction mixture was stirred for 1 hour at-20C. To this reaction mixture was added 8 ml of dimethylformamide (DMF), and then stirred at RT for 3.5 hours. The reaction mixture was diluted with water and the separated organic layer. The organic phase was washed with brine, and then dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane receiving yellow crystals of 1-dimethylsulphamoyl-2-tert-butyldimethylsilyl-5-imidazolecarboxaldehyde (4).

Example B-1

The method of obtaining hydrochloride 4(5)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole:

Methodology

To an 8.5 ml of 40% aqueous solution of sulfuric acid was added 7-methoxy-1-tetralone (1) (1.5 g, 8.5 mmol) and 1-dimethylsulphamoyl-2-tert-butyldimethylsilyl-5-imidazolecarboxaldehyde (2) (2.7 g, 8.5 mmol). The reaction mixture was heated for 24 hours at 900C. After cooling to CT the reaction mixture was made basic with an excess of concentrated ammonium hydroxide. The mixture twice was extracted with THF. The organic layers were combined and washed with brine. The organic layer was separated and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.7 g of a yellow solid substance (3) containing 3-(3H-imidazol-4(5)ylmethylene)-7-methoxypropan-4-one. This crude product is suspended in 100 ml of ethanol was added palladium catalyst on carbon (10%, 0.27 g). The mixture was shaken in hydrogenator Parra at hydrogen pressure of 40 psi (275,8 kPa). After 19 hours the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Column chromatography using 7% methanol in chloroform]-7-methoxy-3,4-dihydro-2H-naphthalene-1-he (4) (B-1A). (4) (0.5 g, of 1.95 mol) was added to 20 ml of methanol. To the solution was added borohydride sodium (74 mg, 1,95 mol). After stirring for 2.5 hours at RT, the reaction mixture was extinguished with water. Then the reaction mixture two times were extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was separated and dried over sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure to obtain 0.5 g of a white solid substance (5) containing 2-[3H-imidazol-4(5)-ylmethyl]-7-methoxy-3,4-dihydro-2H-naphthalene-1-ol. This crude product was dissolved in 26 ml of dichloromethane. Added triethylsilane (2.5 ml, 15.6 mol) and triperoxonane acid (4.8 ml, of 62.3 mol), and this reaction mixture was stirred at RT for 22 hours. The reaction mixture was made basic 2 N. NaOH, and the organic layer was separated and washed with brine. The solution was dried over sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure. Column chromatography using 7% methanol in chloroform resulted in the receipt of 0.39 g (83%) of a yellowish-brown oil (6). The product was dissolved in methanol and was added an excess of hydrogen chloride (HCl) in the air. The solution was concentrated under reduced pressure to get hloroform, after recrystallization from a mixture of acetone and methanol, resulted in the receipt of 0.25 g (46%) of the hydrochloride of 4(5)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole (B-1) in the form of white crystals (7).

1H NMR (300 MHz, CD3OD) 8.83 (s, 1H), 7.38 (s, 1H), 6.95 (d, 1H, J = 8.5 Hz), 6.66 (d, 1H, J=8.4 Hz), 6.57 (s, 1H), 3.73 (s, 3H), 2.71-2.81 (m, 5H), 2.43-2.52 (m, 1H), 1.90-2.14 (m, 2H), 1.40-1.51 (m, 1H).

Following the procedure of Example B-1, various condensed cyclic compound is subjected to interaction with obtaining derivatives of imidazole, listed below.

Example B-2 (a-g)

4-chromanone (2A) 3-(3H-imidazol-4(5)-ylmethylene)chroman-4-one

(2B) 3-(3H-imidazol-4(5)-ylmethyl)chroman-4-one

(2B) 3-(3H-imidazol-4(5)-ylmethyl)chroman-4-ol

(2G) 4(5)-chroman-3-ylmethyl-1H-imidazol

Example B-3 (a-b)

1-tetralone (3A) 2-(3H-imidazol-4(5)-ylmethyl)-3,4-dihydro-2H-naphthalene-1-he

(3b) 4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazol

Example B-4 (a-b)

4-methyl-1-tetralone (4A) 4(5)-(4-methyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazol

(4B) 2-(3H-imidazol-4(5)-ylmethyl)-4-methyl-3,4-dihydro-2H-naphthalene-1-he

Example B-5 (a-b)

thiochroman (5A) 3-(3H-imidazol-4(5)-ylmethylene)thiochroman-4-one

(5B) 3-(3H-it in accordance with stage 5 the method of Example B-1, above.

thiochroman 4(5)-thiochroman-3-ylmethyl-1H-imidazol

Example B-7 (a-b)

1-indanone (7a) 2-(3H-imidazol-4(5)-ylmethylene)indan-1-he

(7b) 2-(3H-imidazol-4(5)-ylmethyl)indan-1-he

(7b) 4(5)-indan-2-ylmethyl-1H-imidazol

Example B-8 (a-b)

7-methyl-1-tetralone (8A) 2-(3H-imidazol-4(5)-ylmethyl)-7-methyl-3,4-dihydro-2H-naphthalene-1-he

(8b) 4(5)-(7-methyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazol

The hydrochloride of this compound is produced by the method of Example B-6.

Example B-9 (a-b)

4-keto-4,5,6,7-tetrahydrothieno (9a) 4(5)-(4,5,6,7-tetrahydrobenzo[b]thiophene-5-ylmethyl)-1H-imidazo

The hydrochloride of this compound is produced by the method of Example B-6.

(9b) 5-(3H-imidazol-4(5)-ylmethyl)-6,7-dihydro-5H-benzo[b]thiophene-4-one

The hydrochloride of this compound is produced by the method of Example B-6.

(9b) 5-(octahedrons[b]thiophene-5-ylmethyl)-1H-imidazol

Example B-10

4,4-dimethyl-1-tetralone 4(5)-(4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazol

Example B-11 (a-b)

1-benzocycloheptene (11) 4(5)-(6,7,8,9-tetrahydro-5H-benzocycloheptene-6-ylmethyl)-1H-imidazol

(11b) 6-(1H-imidazol-4(5)-ylmethylene)-(6,7,8,9-Tetra is:

Methodology

1-(Dimethylsulphamoyl)imidazole (1) (2.0 g, to 11.4 mmol) transferred to 42 ml of anhydrous THF and cooled to-S. To a solution of (1) are added dropwise n-BuLi (6.6 ml, 10.6 mmol). The resulting solution was stirred at-S within 30 minutes. To the reaction mixture of tert-butyldimethylsilyloxy (TBSH) (1.6 g, 10.6 mmol) in 8 ml THF. The reaction mixture is heated to CT and stirred over night. The next day the reaction mixture is cooled to-20C and added 7.3 ml (11.6 mmol) of n-BuLi. After stirring at-20C for 45 minutes to the reaction mixture add 3-thiophenecarboxaldehyde (2) (1.0 ml, 11.6 mmol). Then the reaction mixture is heated to CT and stirred over night. The next day the reaction is quenched with water and diluted with ethyl acetate.

The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography (2:5 ethyl acetate/hexane) leads to obtain 3.0 g (7.5 mmol) of dimethylamine 2-(tert-butyldimethylsilyl)-5-(hydroxythiophene-2-ylmethyl)imidazole-1-sulfonic acid (3). (3) (1.5 g, 3,74 mmol) is transferred into a 37 ml of THF. To a solution of (3) is added dropwise a 1 M solution of Tetra-n-butylammonium fluoride (TBAF) in THF (4,1 Em the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Allocate 0,94 g (3.3 mmol) of dimethylamine 5-(hydroxythiophene-2-ylmethyl)imidazole-1-sulfonic acid (4). (4) (0.5 g, of 1.74 mmol) is transferred to a 23 ml of dichloromethane, to the solution was added 2.2 ml (a 13.9 mmol) of triethylsilane and 4.3 ml (55,7 mmol) triperoxonane acid. The reaction mixture was stirred at RT overnight and then quenched with water and neutralized with solid sodium bicarbonate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography using mixtures of ethyl acetate and hexane (1:1) results of 0.42 g (1.55 mmol) of dimethylamine 5-(thiophene-2-ylmethyl)imidazole-1-sulfonic acid (5). (5) (0,42 g, 1.55 mmol) is transferred into 10 ml of 1.5 n HCl solution and heated under reflux for 3 hours and then stirred at RT overnight. The reaction mixture was diluted with ethyl acetate, neutralized with solid sodium bicarbonate, and then make the primary 2n. NaOH. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and ponizhennoi to obtain 0.17 g (1.0 mmol) 4(5)-thiophene-3-ylmethyl-1H-imidazole (6) (B-1).

1H NMR (300 MHz, CD3OD) 7.52 (s, 1H), 7.25-7.27 (m, 1H), 6.96-7.01 (m, 2H), 6.77 (s, 1H), 3.98 (s, 2H).

Example b-2

In the method of Example B-1 3-thiophenecarboxaldehyde replace the isomer 2-carboxaldehyde with obtaining 4(5)-thiophene-2-ylmethyl-1H-imidazole.

Example b-3

In the method of Example B-1 3-thiophenecarboxaldehyde replace 5-methyl-2-thiophenecarboxaldehyde obtaining 4(5)-(5-methylthiophene-2-ylmethyl)-1H-imidazole.

Example b-4

In the method of Example B-1 3-thiophenecarboxaldehyde replace 5-chloro-2-thiophenecarboxaldehyde obtaining 4(5)-(5-chlorothiophene-2-ylmethyl)-1H-imidazole.

Example B-5

In the method of Example B-1 are replacing 2-furancarboxaldehyde obtaining 4(5)-furan-2-ylmethyl-1H-imidazole.

Example B-6

In the method of Example B-1 are replaced by 3-furancarboxaldehyde obtaining 4(5)-furan-3-ylmethyl-1H-imidazole.

Example B-7

In the method of Example B-1 are replaced by 5-methyl-2-furancarboxaldehyde obtaining 4(5)-(5-methylfuran-2-ylmethyl)-1H-imidazole.

Example B-8

In the method of Example B-1 are replacing the benzaldehyde with obtaining 4(5)-benzyl-1H-imidazole.

Example B-9

In a way is desola.

Example B-10

In the method of Example B-1 are replacing 2-benzofurazanyl obtaining 4(5)-benzofuran-2-ylmethyl-1H-imidazole.

Example B-11

In the method of Example B-1 are replaced by 5-ethyl-2-furancarboxaldehyde obtaining 4(5)-(5-ethylfuran-2-ylmethyl)-1H-imidazole.

Example b-12

In the method of Example B-1 are replacing 4-bromo-2-thiophenecarboxaldehyde obtaining 4(5)-(4-bromothiophene-2-ylmethyl)-1H-imidazole.

Example b-13

In the method of Example B-1 are replacing 4-phenyl-2-thiophenecarboxaldehyde obtaining 4(5)-(4-phenylthiophene-2-ylmethyl)-1H-imidazole.

Example B-14

In the method of Example B-1 are replacing 4-methyl-2-thiophenecarboxaldehyde obtaining hydrochloride 4(5)-(4-methylthiophene-2-ylmethyl)-1H-imidazole.

Example D-1

The method of obtaining oxazolidin-2-ilidene-(3-Panevezio[2.2.1]hept-2-yl)amine:

Methodology

Endo Exo relative stereochemistry of compounds obtained by education-nitrostyrene as shown above. Processing methanolic solution of benzaldehyde (10 g, was 94.3 mmol) nitromethane (51 ml, 943 mmol) in the presence of sodium hydroxide (3 n solution in botki the acid chloride methanesulfonic acid (of 3.56 g, of 31.1 mmol) and then triethylamine (6.3 g, 62,2 mmol) in dichloromethane (35 ml) with 97% yield. Cleaning compounds performed Kugelrohr distillation. Creating skeleton bicyclo[2.2.1]heptane was carried out in one stage. The reaction of the Diels-alder reaction was performed by heating nitrostyrene (4.5 g, 30.2 mmol) with cyclopentadiene (3.98 g, 60,4 mmol) in 1,2-dichloroethane (10 ml). The reaction of the Diels-alder reaction proceeds at nitrosotoluene endo:Exo approximately 3:1. Ratio and relative stereochemistry shows x-ray analysis. Recovery as the nitro group and the olefin was carried out in an atmosphere of hydrogen in the presence of 10% by weight palladium on coal. Separation of isomers was performed at this stage using flash chromatography using 5% saturated ammonia methanol in dichloromethane. Amine (0.7 g, 3,74 mmol) was treated chlorotriazine (0,38 ml of 4.49 mmol) in obtaining chloramination, which was then heated in the presence of aqueous NaHCO3getting oxazolidin-2-ilidene-(3-Panevezio[2.2.1]hept-2-yl)amine (G-1) with 51% yield.

1H NMR (300 MHz, CDCl3) d 1.36-1.80 (m, 6H), 2.14 (d, 1H, J=4.40 Hz), 2.37 (s, 1H), 2.65 (s, 1H), 3.71-3.78 (m, 2H), 3.95-3.98 (m, 1H), 4.19-4.25 (t, 2H, J=17.15 Hz, J=8.36 Hz), 7.17-7.29 (m, 5H).

Example D-2

Received the roll.

Example D-3

Get bicyclo[2.2.1]hept-2-yl-oxazolidin-2-ylideneamino, by the way G-1 replacement on nitrogen.

Example D-1

The method of obtaining imidazolidin-2-ilidene-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)amine:

Methodology

To 2-amino-4-NITROPHENOL (1) (4,00 g, 25,95 mmol), triethylamine (15,20 ml, 109,0 mmol) and 4-dimethylaminopyridine (0,063 g, 0.52 mmol) suspended in anhydrous CH2Cl2(250 ml) at 0 C in an argon atmosphere by means of a syringe was added the acid chloride Chloroacetic acid (2,27 ml, 28,55 mmol). After heating under reflux for 72 hours of pure product was filtered and washed with water. The mother solution was sequentially washed with phosphoric acid (0.5 M), saturated sodium bicarbonate, water, brine, and then dried over MgSO4. This solution was applied onto silica and purified flash chromatography on silica, using a mixture of hexane and ethyl acetate (4:6), with an additional product. The combined solids were dried in vacuum to obtain pure 6-nitro-4H-benzo[1,4]oxazin-3-one (2) (4.12 g) in 82% yield. To a suspension of (2) (1,49 g of 7.65 mmol) in anhydrous THF (40 ml) in dvuhholos round bottom flask, Sabines was heated under reflux until while the results of TLC starting material was no longer detected (2 hours). The reaction mixture was cooled to CT and carefully extinguished, adding dropwise methanol. Then the obtained mixture was heated under reflux for an additional 10 minutes. The crude reaction mixture was concentrated in vacuo, and purified flash chromatography on silica, using a mixture of hexane and ethyl acetate (8:2), to obtain pure 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (3) (1,36 g) as an orange solid with 99% yield. (3) (0,032 g, 0,178 mmol) and formalin (37% in N2Oh, 0,20 ml, to 2.67 mmol) in anhydrous acetonitrile (1.5 ml) at ambient temperature was added cyanoborohydride sodium (0,034 g, 0,534 mmol). Before adding glacial acetic acid (to 0.032 ml, 0,534 mmol), the solution was stirred for 30 minutes. The resulting mixture was stirred for additional 16 hours. Organic matter carried in diethyl ether and then washed with NaOH (2 BC) and brine, dried over MgSO4and concentrated in vacuum. The obtained solid substance was purified flash chromatography on silica, using a mixture of hexane and ethyl acetate (7:3), to obtain pure 4-methyl - g, 10 wt.%) in an atmosphere of argon was added methanol (Meon) (30 ml), and then THF (30 ml). Through the resulting suspension was barbotirovany hydrogen, while the results of thin layer chromatography (2 h) (4) remains visible. Added celite, and the mixture was filtered through a layer of celite, and then washed Meon. The resulting solution was concentrated in vacuum to obtain pure 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamine (5) (1.86 g) as a pale purple oil with 100% output, which is further used without additional purification. (5) (1.86 g, 11,34 mmol) and imidazolin-2-sulfonic acid (1.84 g, 12,24 mmol) in anhydrous acetonitrile (50 ml) in an argon atmosphere at 0 C was added triethylamine (3,26 ml, 23,36 mmol). This solution was slowly heated to ambient temperature and was stirred for additional 16 hours. Added additional amount imidazolin-2-sulfonic acid (0,86 g, 5,55 mmol) and the resulting mixture was stirred for another 5 hours. This solution was concentrated in vacuo, and the residue was transferred into a H2O. the Organic matter was extracted with CH2Cl2and washed twice with NaOH, then brine, dried over MgSO4and concentrated in vacuum. The resulting mixture was purified flash chromatography on dioxan-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)amine (6) (D-1) (0,905 g) with 34% yield.

1H NMR (CDCl3): 2.81 (s, 3H); 3.26 (t, J=8.9 Hz, 2H); 3.60 (s, 4H); 4.26 (m, 2H); 4.60 (vbrs, 2H); 6.34 (dd, J=8.2 Hz, J=2.4 Hz, 1H); 6.39 (d, J=2.4 Hz, 1H); 6.68 (d, J=8.2 Hz, 1H).

Example E and W

Method for producing 6-(imidazolidin-2-ylideneamino)-5-methyl-4H-benzo[1,4]oxazin-3-one (E) and imidazolidin-2-ilidene-(5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)amine (G):

Methodology

To 2-amino-3-METHYLPHENOL (1) (14,72 g, 0,120 mol), triethylamine (35,0 ml, 0,251 mol) and 4-dimethylaminopyridine (0.29 grams, 2,39 mmol) in anhydrous CH2Cl2(100 ml) at 0 C in an argon atmosphere by means of a syringe was added dropwise to the acid chloride Chloroacetic acid (10.0 ml, 0,126 mol). After adding the resulting solution was heated under reflux for 24 hours. Organic matter then washed with phosphoric acid (0.5 M), saturated sodium bicarbonate, water and brine and then dried over MgSO4. The resulting solution was concentrated and transferred in THF, to which was added ether. The obtained crystals were filtered to obtain pure 5-methyl-4H-benzo[1,4]oxazin-3-one (2) (12,30 g) with 63% yield. (2) (14,64 g, 89,72 mmol) dissolved in concentrated H2SO4(65 ml) at-10C was added 70% concentrated HNO3(8,08 g, 89,72 IMO the I which the internal temperature was maintained below-5C. At the end of the addition the mixture was poured on crushed ice (500 ml) and the resulting solid was filtered and suspended in cold water (300 ml) while adding NaOH sufficient to establish a pH of 7. The obtained yellow powder was dissolved in THF, was applied onto silica and purified flash chromatography using a mixture of 60% hexane and ethyl acetate, to obtain microproduct in the form of a mixture of two regioisomers, i.e. the target 6-substituted aromatic substances, representing 6-nitro-5-methyl-4H-benzo[1,4]oxazin-3-one (3) (55%), and 8-substituted side product, representing 8-nitro-5-methyl-4H-benzo[1,4]oxazin-3-one (4) (22%). At the moment, these isomers are difficult to separate, and they were sent to the next stage in the mixture. To a mixture of (3) (1,93 g, 9,27 mmol) and (4) (0,48 g, 2.32 mmol), dissolved in solution Meon (300 ml) and THF (300 ml) in an argon atmosphere was added 10% palladium on coal (1.20 g). The resulting solution was subjected to N2at a pressure equal to 1 atmosphere. After 16 hours, the catalyst was filtered, and the resulting solution was concentrated in vacuo, and purified flash chromatography on silica, using a mixture of 50% hexane and ethyl acetate to obtain 6-amino-5-methyl-4H-benzo[1,4]ox is l), imidazolin-2-sulfonic acid (2,02 g, 13,48 mmol) and triethylamine (2.35 ml, 16,85 mmol) was heated under reflux in anhydrous acetonitrile (50 ml) in an argon atmosphere for 48 hours. Added additional amount imidazolin-2-sulfonic acid (1.01 g, 6,74 mmol) and triethylamine (1,41 ml, 10,12 mmol) and the resulting mixture was stirred for additional 24 hours. This solution was concentrated in vacuo, and the residue was transferred into a solution CHCl3/isopropyl alcohol (3:1) and then washed with NaOH (1N.) and brine, dried over MgSO4and concentrated in vacuum. The resulting foam was purified flash chromatography on silica using 20% methanol (saturated with ammonia) in chloroform, to obtain 6-(imidazolidin-2-ylideneamino)-5-methyl-4H-benzo[1,4]oxazin-3-one (7) (0,42 g) in the form of foam with 27% yield along with a 55% return of the original substance. HCl salt was recrystallized from a mixture of ethanol and diethyl ether (EtOH/Et2(O) obtaining a thin white needles.

1H NMR (DMSO): 2.10 (s, 3H); 3.59 (s, 4H); 4.53 (s, 2H); 6.83 (d, J=8.6 Hz, 1H); 6.90 (d, J=8.6 Hz, 1H); 8.07 (brs, 2H); 10.15 (vbrs, 1H); 10.42 (s, 1H).

(6) (0,222 g, 1.35 mmol), imidazoline-2-sulfonic acid (0,223 g, 1,49 mmol) and triethylamine (0,415 ml, 2,98 mmol) was heated at S in beswt the sulfonic acid (0,112 g, 0.75 mmol) and the reaction was continued for another 16 hours. This solution was concentrated in vacuo, and the residue was transferred into a solution CHCl3/isopropyl alcohol (3:1) and then washed with NaOH (2 BC) and brine, dried (MgSO4) and concentrated in vacuum. The resulting oil was recrystallized from CHCl3to obtain pure 6-(imidazolidin-2-ylideneamino)-5-methyl-4H-benzo[1,4]oxazin-3-one (8) (E) (0,048 g) as a white powder (15% yield together with a 35% return of the original substance. To the suspension (8) (0.08 g, 0,321 mmol) in anhydrous THF (50 ml) in a three-neck round-bottom flask, equipped with reflux condenser, an argon atmosphere was added a complex of borane-dimethyl sulfide (of 0.48 ml, 0,936 mmol). The mixture was heated under reflux until starting material until the results of thin-layer chromatography was no longer detected (3 h). The reaction mixture was cooled to room temperature and carefully extinguished, adding dropwise methanol. The crude reaction mixture was concentrated in vacuo, and purified flash chromatography on silica using 20% methanol (saturated with ammonia) in chloroform to obtain imidazolidin-2-ilidene-(5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)amine (9) (G) (0.03 g) as an HCl salt .44 (d, J=8.0 Hz, 1H); 6.57 (d, J=8.0 Hz, 1H).

Example C

Method for producing 4(5)-phenylsulfanyl-1H-imidazole:

Methodology

1-(N,N-dimethylsulphamoyl)imidazole (1.5 g, 8.6 mmol) was transferred in 28 ml of THF. The solution was cooled to-S and through syringe was added dropwise n-BuLi (5,4 ml, 8.6 mmol). After stirring at C for 1 hour was added TBSH (1.3 g, 8,56 mmol) in 10 ml of THF. Bath was removed and the reaction mixture was left to warm to CT. The reaction mixture was stirred over night. The reaction mixture was cooled to-20 ° C was added n-BuLi (5,4 ml, 8.6 mmol). After 45 minutes was added phenoldisulfonic (1.9 g, 8.6 mmol) in 8 ml THF. The reaction mixture was stirred at RT for 48 hours. The reaction mixture was extinguished with saturated ammonium chloride and was extracted with ethyl acetate. The organic layer was collected and washed with water and then brine. The solution was dried over sodium sulfate, and under reduced pressure, the solvent was removed. Flash chromatography (2.5% of EtOAc/hexane) yielded 2.8 g (7.0 mmol) of dimethylamine 2-(tert-butyldimethylsilyl)-5-phenylalaninamide-1-sulfonic acid (1) in the form of a yellow oil. Connection (1) (2.8 g, 7.0 mmol) was dissolved in THF, and this solution was cooled to 0C. To the solution was added dropwise T the th and were extracted with ethyl acetate. The organic layer was washed with water and then brine. The solution was dried over sodium sulfate, and under reduced pressure, the solvent was removed. Flash chromatography (50% EtOAc/hexane) resulted in 474 mg dimethylamide 5-phenylalaninamide-1-sulfonic acid (2) and 290 mg of 5-phenylsulfanyl-1H-imidazole (3) (C). 478 g (2) was added to 2 N. HCl, and the solution was heated under reflux for 2 hours. The reaction mixture was made basic with 2 N. NaOH and was extracted with ethyl acetate. The organic layer was washed with water and then brine. The solution was dried over sodium sulfate and under reduced pressure, the solvent was removed. Flash chromatography (EtOAc) resulted in (3) as a white crystalline solid. The amount allocated 360 mg (2.0 mmol) of (3).

1H NMR (300 MHz, CD3OD) 7.91 (s, 1H), 7.37 (s, 1H), 7.19-7.23 (m, 2H), 7.07-7.11 (m, 3H).

Example

The method of obtaining methansulfonate 4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4,5-dihydro-1H-imidazole:

Methodology

mmol in anhydrous THF (250 ml) at 20 ° C in argon atmosphere by means of a syringe was added 3,26 ml (32,90 mmol) of the complex of borane-dimethyl sulfide (BH3-Me2S). After stirring for 16 hours doba is in Seeley Et2O and then washed with 2 M phosphoric acid, saturated sodium bicarbonate, water and brine, and then dried over MgSO4and again concentrated. The resulting oil was purified by Kugelrohr distillation under high vacuum and 150C to obtain pure alcohol (1,2,3,4-tetrahydronaphthalen-2-yl)methanol) (2) (4.09 g) in 93% yield. To triphenylphosphine (10,179 g, 38,809 mmol) and imidazole (2.64 g, 38,809 mmol) in anhydrous benzene (175 ml) with rapid stirring, was added iodine (at 8.60 g, 33,865 mmol) in benzene (75 ml), and then (2) in benzene (50 ml). After 3 hours, the solids were filtered off, the filtrate was reduced under vacuum to a volume of 50 ml, to which was added hexane (200 ml). The obtained solid substance was filtered, the filtrate is then washed with water and brine, dried over MgSO4and concentrated in vacuum. The resulting oil was purified flash chromatography on silica using hexane, to obtain pure 2-iodomethyl-1,2,3,4-tetrahydronaphthalene (3) (6,239 g) with 90% yield. (3) (10,02 g, eur36, 85 mmol) and Cul (1,41 g, 7,37 mmol) in anhydrous THF (50 ml) at-C in argon atmosphere was slowly added vinylmania (1 M solution in THF, 73,70 ml, 73,70 mmol) at a rate at which there was no appearance of color. This solution of the and carefully adding 2 M phosphoric acid (35 ml). This solution was diluted with 100 ml water and was extracted with hexane. The organic fraction was sequentially washed with water and brine, dried over MgSO4and concentrated in vacuum. The resulting oil was purified flash chromatography on silica using hexane, to obtain the 2-allyl-1,2,3,4-tetrahydronaphthalene (4) (5,618 g) with 88% yield. (4) (5,615 g 32,645 mmol) and meta-chlormadinone acid (m-HNBK) (14,08 g, 81,613 mmol) was stirred in anhydrous methylene chloride (50 ml) for 16 hours. The solids were filtered and added potassium fluoride (KF) (5,11 g, 88,142 mmol) and the mixture was stirred for another hour. The solids were filtered off and the reaction mixture was concentrated in vacuum. The resulting oil was purified flash chromatography on silica, using a mixture of 5% ethyl acetate and hexane, to obtain 2-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)oxirane (5) (5,41 g) with 88% yield. (5) (1,626 g 8,649 mmol) in acetone solution (20 ml) and water (5 ml) was added sodium azide (1.97 g, 30,271 mmol). This solution was heated to 850C and was stirred for 48 hours. The solution was concentrated in vacuo, and the residue was transferred into CHCl3and then washed with water and brine, with Omnia, using a mixture of 30% ethyl acetate and hexane, to obtain pure 1-azido-3-(1,2,3,4-tetrahydronaphthalen-2-yl)propan-2-ol (6) (1,762 g) with 88% yield. The mixture (6) (1.88 g, 8,140 mmol), triphenylphosphine (2.67 g, 10,173 mmol), phthalimide (1.50 g, 10,173 mmol), diethylazodicarboxylate (DAADC) (1.77 g, 10,173 mmol) was stirred in anhydrous THF (50 ml) for 4 hours. This solution was concentrated in vacuum, transferred into a solution of hexane (25 ml) and ether (25 ml) and was stirred for 16 hours. The solids were filtered off and the filtrate was concentrated in vacuum. The resulting oil was purified flash chromatography on silica, using a mixture of 20% ethyl acetate and hexane, to obtain 2-[1-azidomethyl-2-(1,2,3,4-tetrahydronaphthalen-2-yl)ethyl]isoindole-1,3-dione (7) (2,487 g) contaminated with a small amount of impurity, which was used without further purification. The mixture (7) (3,93 g 10,917 mmol) and hydrazine (0,680 ml, 21,833 mmol) was heated under reflux in ethanol (60 ml) for 16 hours. The solids were filtered off and the filtrate was concentrated in vacuum. The residue was purified flash chromatography on silica using 5% Meon in CH2Cl2pick 1-azidomethyl-2-(1,2,3,4-tetrahydronaphthalen-2-yl)ethylamine (8) (2.057 g) with 88% yield. The mixture (8) (2,056 is for 16 hours. The solids were filtered off and the filtrate was concentrated in vacuum. The residue was purified flash chromatography on silica using 10% Meon, saturated with ammonia, CH2Cl2pick 3-(1,2,3,4-tetrahydronaphthalen-2-yl)propane-1,2-dione (9) (1,557 g) with 85% yield. The mixture (9) (0,590 g 2,892 mmol) and methanesulfonic acid (0,980 ml, 14,460 mmol) was heated in triethylorthoformate (10 ml) at 1050C for 3 hours. The reaction mixture was concentrated in vacuo, and the solids were filtered off. Subsequent recrystallization of these solids from a mixture of the Meon and ether gave pure methanesulfonate 4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4,5-dihydro-1H-imidazole (I) (0,435 g) in 48% yield.

1H NMR (CDCl3): 1.37-1.56 (m, 1H); 1.56-1.70 (m, 1H); 1.80-2.02 (m, 2H); 2.32-2.55 (m, 2H); 2.72 (s, 3H); 2.75-2.95 (m, 3H); 3.48-3.59 (m, 1H); 3.93-4.08 (m, 1H); 4.31-4.47 (m, 1H); 7.00-7.20 (m, 4H); 8.46 (s, 1H); 10.04 (s, 1H); 10.35 (brs, 1H).

Example K-1

Method for producing 4(5)-cyclohexylmethyl-1H-imidazole:

Methodology

2-Tert-butyldimethylsilyl-1-dimethylsuberimidate (1) (4.1 g, of 14.2 mmol) is transferred in 47 ml of anhydrous THF and cooled to-20C. To a solution of (1) are added dropwise n-BuLi (8,9 ml of 14.2 mmol). The resulting solution was stirred at-20C during the nnuu the mixture is heated to CT and stirred over night. The next day the reaction is quenched with saturated ammonium chloride and diluted with water. The mixture is extracted with ethyl acetate (3100 ml). The organic layers are combined and washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography (4:1 ethyl acetate/hexane) results of 2.26 g (5.6 mmol) of 5-cyclohexylmethyl-2-tert-butyldimethylsilyl-1-dimethylsuberimidate (3). (3) (of 2.26 g, 5.6 mmol) is transferred in 56 ml of THF and cooled to 0C. To a solution of (3) is added dropwise a 1 M solution TBAF in THF (5.6 ml, 5.6 mmol). The reaction mixture is heated to CT and stirred over night. The next day the reaction mixture was quenched with water then extracted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography (1:1 ethyl acetate/hexane) leads to obtain 1.2 g (4,42 mmol) 5-cyclohexylmethyl-1-dimethylsuberimidate (4). (4) (1.2 g, was 4.42 mmol) is transferred into 25 ml of 1.5 n HCl solution and heated under reflux for 2 hours. The reaction mixture is cooled to room temperature and diluted with ethyl acetate. 2 N. NaOH bring the pH of the mixture to 13, and the organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography (9:1 chloroform/methanol) leads to obtain 700 mg (4,27 mmol) 4(5)-cyclohexylmethyl-1H-imidazole (5) (K-1).

1H NMR (CDCl3): 0.92-1.00 (m, 2H); 1.16-1.26 (m, 3H); 1.57-1.73 (m, 6H); 2.48 (d, J=6.9 Hz, 2H); 6.77 (s, 1H); 7.56 (s, 1H).

Example K-2

In the method of Example K-1 are replacing (S)-2-iodomethyl-1,2,3,4-tetrahydronaphthalen with receipt (S)-4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole. (S)-2-iodomethyl-1,2,3,4-tetrahydronaphthalen received from (S)-1,2,3,4-tetrahydro-2-naphthoic acid. (S)-1,2,3,4-tetrahydro-2-naphthoic acid obtained by dividing 1,2,3,4-tetrahydro-2-naphthoic acid (J. Med. Chem. 1983, 26, 328-334).

Example K-3

In the method of Example K-1 are replacing (R)-2-iodomethyl-1,2,3,4-tetrahydronaphthalen obtaining (R)-4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole. (R)-2-iodomethyl-1,2,3,4-tetrahydronaphthalen received from (R)-1,2,3,4-tetrahydro-2-naphthoic acid. (R)-1,2,3,4-tetrahydro-2-naphthoic acid obtained by dividing 1,2,3,4-tetrahydro-2-naphthoic acid (J. Med. Chem. 1983, 26, 328-334).

Example L-1

Method for producing 4(5)-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-ylmethyl)-1H-imidazole:

Methodology

4,5,6,7-tetrabasic n-BuLi (6.0 ml, 15 mmol). The resulting solution was stirred at-C within 60 minutes. To the reaction mixture was added 1-dimethylsulphamoyl-2-tert-butyldimethylsilyl-5-imidazolecarboxaldehyde (2) (4.8 g, 15 mmol) in 25 ml THF. The reaction mixture is heated to CT and stirred for 2 hours and then quenched with water and diluted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography (1:3 ethyl acetate/hexane) results of 5.2 g (11 mmol) of dimethylamine 2-(tert-butyldimethylsilyl)-5-[hydroxy-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)methyl]imidazole-1-sulfonic acid (3). (3) (5,2 g, 11.3 mmol) is transferred in 57 ml of THF. To a solution of (3) is added dropwise a 1 M solution of fluoride, Tetra-n-butylamine (TBAF) in THF (11.3 ml, 11.3 mmol). Before quenching the reaction with water, and then extracted with ethyl acetate, the reaction mixture is stirred for 1 hour and 15 minutes. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Recrystallization from hexane/ethyl acetate yields dimethylamide 5-[hydroxy-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)methyl] (4) (2.0 g, 5.9 mmol) is transferred in 78 ml of dichloromethane, to the solution was added 7.5 ml (46,9 mmol) of triethylsilane and 14.4 ml (0,19 mol) triperoxonane acid. The reaction mixture was stirred at RT overnight and then quenched with water and neutralized 2 N. NaOH. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography using mixtures of ethyl acetate and hexane (1:1) leads to obtain 0.75 g (2.3 mmol) of dimethylamine 5-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-ylmethyl)imidazole-1-sulfonic acid (5). (5) (0,42 g, 1.55 mmol) is transferred into 15 ml of 1.5 n HCl solution and heated under reflux for 2 hours and then stirred at RT overnight. The reaction mixture was diluted with ethyl acetate, neutralized 2 N. NaOH. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. The crude product is dissolved in methanol and add an excess of HCl in ether. The solvent is removed under reduced pressure to obtain 0.6 g (2.3 mmol) 4(5)-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-ylmethyl)-1H-imidazole (6) (L-1).

1H NMR (CD3OD): 8.80 (s, 1H); 7.34 (s, 1H); 6.57 (s, 1H); 4.18 (s, 2H);-(tert-butyl)furan with obtaining 4(5)-(5-tert-butylfuran-2-ylmethyl)-1H-imidazole.

Example L-3

In the method of Example L-1 are replacing 5,6-dihydro-4H-thieno[2,3-b]thiopyran obtaining 4(5)-(5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-ylmethyl)-1H-imidazole.

Example M

Method for producing 4(5)-(1-furan-2-retil)-1H-imidazole:

Methodology

2-(Tert-butyldimethylsilyl)-1-(dimethylsulphamoyl)imidazole (1) (3.3 grams, or 11.4 mmol) is transferred into 38 ml of anhydrous THF and cooled to-S. To a solution of (1) are added dropwise n-BuLi (7.2 ml of 11.4 mmol). The resulting solution was stirred at-S within 30 minutes. To the reaction mixture are added 2-furfural (2) (0,94 ml of 11.4 mmol). The reaction mixture is heated to CT and stirred over night. The next day the reaction is quenched with saturated ammonium chloride, and the reaction mixture is diluted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography (4:1 ethyl acetate/hexane) results 4.4 g to (11.4 mmol) of dimethylamine 2-(tert-butyldimethylsilyl)-5-(furan-2-elgeroctober)imidazole-1-sulfonic acid (3). (3) (4.4 g, to 11.4 mmol) is transferred in 110 ml of THF and cooled to 0C. To a solution of (3) is added dropwise a 1 M solution of fluoride, Tetra-n-butylammonium quenched with water, and the reaction mixture was then extracted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Gain of 3.9 g of the crude dimethylamide 5-(furan-2-elgeroctober)imidazole-1-sulfonic acid (4). (4) (1.0 g, 3.7 mmol) is transferred into a 37 ml of dichloromethane, to the solution was added 1.6 g (18.5 mmol) of manganese dioxide. The reaction mixture was stirred at RT overnight, and then filtered through celite. Eluent is collected, and under reduced pressure to remove the solvent. Flash chromatography using mixtures of ethyl acetate and hexane (1:1) results 0,69 g (2.6 mmol) of dimethylamine 5-(furan-2-ylcarbonyl)imidazole-1-sulfonic acid (5). (5) (0,69 g, 2.6 mmol) is transferred in 26 ml of THF. The solution is cooled to-S. Add 1.7 ml (5.1 mmol) of 3 M solution of methylmagnesium. After stirring at C for 1.5 hours the reaction mixture is heated to CT and stirred for additional 1 hour. The reaction is quenched with water, and the reaction mixture was then extracted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Crystal)imidazole-1-sulfonic acid (6). Get additional 0,19 g (6). (6) (0,58 g, 2.0 mmol) is transferred into 27 ml of dichloromethane, to the solution was added to 2.6 ml (16.3 mmol) of triethylsilane and 5.5 ml (71,4 mmol) triperoxonane acid. The reaction mixture was stirred at RT overnight and then quenched with water and neutralized with solid sodium bicarbonate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography using mixtures of ethyl acetate and hexane (2:1) results of 0.53 g (2.0 mmol) of dimethylamine 5-(1-furan-2-retil)imidazole-1-sulfonic acid (7). (7) (0.34 g, 1.3 mmol) is transferred into 10 ml of 1.5 n HCl solution and heated under reflux for 30 minutes and then stirred at RT overnight. The reaction mixture was diluted with ethyl acetate, and then made basic with 2 N. NaOH. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography (10:1 chloroform/methanol) yields a 0.1 g (of 0.62 mmol) 4(5)-(1-furan-2-retil)-1H-imidazole (8) (M).

1H NMR (300 MHz, CDCl3) 7.56 (m, 1H), 7.33-7.34 (m, 1H), 6.81 (m, 1H), 6.29-6.31 (m, 1H), 6.06-6.07 (m, 1H), 4.22 (methyl)-4-methyl-1H-imidazole:

Methodology

4-Methyl-1-(dimethylsulphamoyl)imidazole (1) (2.0 g, 10.6 mmol) is transferred in 42 ml of anhydrous THF and cooled to-S. To a solution of (1) are added dropwise n-BuLi (6.6 ml, 10.6 mmol). The resulting solution was stirred at-S within 30 minutes. To the reaction mixture of tert-butyldimethylsilyloxy (NBDMSCL) (1.6 g, 10.6 mmol) in 10 ml of THF. The reaction mixture is heated to CT and stirred over night. The next day the reaction mixture is cooled to-20C and added 7.3 ml (11.6 mmol) of n-BuLi. After stirring at-20C for 30 minutes to the reaction mixture of 1,4-benzodioxan-6-carboxaldehyde (2) (1.92 g, 11.7 mmol) in 10 ml of THF. Then the reaction mixture is heated to CT and stirred for 3 hours. The reaction is quenched with water and the reaction mixture is diluted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography (1:2 ethyl acetate/hexane) results of 3.9 g (8.4 mmol) of dimethylamine 2-(tert-butyldimethylsilyl)-5-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydroxymethyl]-4-Mei-1-sulfonic acid (3). (3) (1.0 g, 2.14 mmol) is transferred in 21 ml of THF. To a solution of (3) are added dropwise 1 M dissolve the ri CT. The reaction is quenched with water, and the reaction mixture was then extracted with ethyl acetate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography using ethyl acetate as eluent results in 0.75 g (2,12 mmol) dimethylamide 5-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydroxymethyl]-4-Mei-1-sulfonic acid (4). (4) (0.75 g, 2,12 mmol) is transferred in 28 ml of dichloromethane, to the solution was added to 2.7 ml (17,0 mmol) of triethylsilane and 5.2 ml (67.8 mmol) triperoxonane acid. The reaction mixture was stirred at RT overnight and then quenched with water and neutralized with solid sodium bicarbonate. The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate, and under reduced pressure to remove the solvent. Flash chromatography using mixtures of ethyl acetate and hexane (3:1) results 0,63 g (of 1.87 mmol) dimethylamide 5-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-Mei-1-sulfonic acid (5). (5) (0,63 g of 1.87 mmol) is transferred into 10 ml of 1.5 n HCl solution and heated under reflux for. The reaction mixture was diluted with ethyl acetate, neutralized solid bicarb the rija, and under reduced pressure to remove the solvent. Crystallization from a mixture of ether and hexane leads to obtain 0.33 g (1,43 mmol) 4(5)-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-methyl-1H-imidazole (6) (H).

1H NMR (300 MHz, acetone-d6) 7.37 (s, 1H), 6.66-6.67 (m, 3H), 4.18 (s, 4H), 3.73 (s, 1H), 2.13 (s, 3H).

Example OF

Method for producing 2-(3H-imidazol-4(5)-ylmethyl)-3,4,5,6,7,8-hexahydro-2H-naphthalene-1-it-1), 4(5)-2,3,4,4 and,5,6,7,8-octahydronaphthalene-2-ylmethyl)-1H-imidazole (O-2) and 4(5)-(1,2,3,4,5,6,7,8-octahydronaphthalene-2-ylmethyl)-1H-imidazole (3):

Methodology

1-Decalin (10.0 g, 66 mmol) and 4(5)-imidazolecarboxaldehyde (6.3 g, 66 mmol) was added to 100 ml of ethanol. To the solution was added NaOH (5,2 g, 130 mmol) in 20 ml of water. The reaction mixture was heated under reflux for 5 days. The reaction mixture was cooled to CT and made basic with an aqueous solution of HCl. The solution was extracted with THF/ethyl acetate. The organic layers were combined and washed with brine. The organic phase was dried over magnesium sulfate, and under reduced pressure, the solvent was removed to obtain the crude product. This crude product was heated under reflux in 40% H2SO4within 1 day. The reaction mixture was cooled to CT and did the OS is washed with brine. The organic phase was dried over magnesium sulfate, and under reduced pressure, the solvent was removed. Purification with flash chromatography (15:1 CH3Cl/MeOH) resulted in O-1 (4.9 g, yield 32%).

1H NMR: 7.55 (s, 1H), 6.77 (s, 1H), 3.08-3.14 (m, 2H), 1.52-2.46 (m, 13H).

Hydrochloride O-1 was treated with NaOH to obtain the free base (3.0 g, 11 mmol), which was then added to diethylene glycol (100 ml). To the solution was added hydrazinehydrate (3.2 ml, 100 mmol) and the reaction mixture was left to mix overnight at RT. Was added NaOH (3.1 g, 77 mol) and the solution was heated under reflux for 5 days. The reaction mixture was cooled to CT and was diluted with water. The solution was extracted with THF/ethyl acetate. The organic layers were combined and washed with brine. The organic phase was dried over magnesium sulfate, and under reduced pressure, the solvent was removed. Purification with flash chromatography (8:1 CH3Cl/MeOH) resulted in O-2 (0.64 g, yield 27%).

1H NMR: 7.58 (s, 1H), 6.76 (s, 1H), 5.24 (d, J=4.3 Hz, 1H), 0.91-2.58 (m, 16H).

O-2 (1.0 g, 4.6 mmol) was added to 10 ml of concentrated HCl. The solution was stirred at RT for 30 minutes and then neutralized K2CO3. The solution was extracted with THF/ethyl acetate. The organic layers obli solvent. Purification with flash chromatography (15:1 CH3Cl/MeOH) resulted in O-3.

1H NMR: 7.54 (s, 1H), 6.74 (s, 1H), 2.45-2.52 (m, 3H), 1.46-1.97 (m, 14H).

Example N

The method of obtaining hydrochloride 4(5)-octahydrophenanthrene-2-ylmethyl)-1H-imidazole:

Methodology

A. In the flask dried by the fire and cooled to 0C in an argon atmosphere, was added ether (10 ml) (White and Whitesell synthesis, Synthesis, pp. 602-3 (1975)). Then was added n-utility (35 ml of 2.5 M solution in hexane, 2.2 equiv.) and then slowly added Diisopropylamine (14 ml, 2.5 equiv.) and the mixture was left to mix for 30 minutes at 0C. To this resulting solution of diisopropylamide lithium was added oxide cyclooctene (5.0 g, 1.0 EQ.). The mixture was stirred at RT for one day, and then was heated to a temperature of education phlegmy in argon atmosphere for 2 days. The reaction was suppressed by adding NH4Cl. The solution was extracted with THF/EtOAc. The organic extracts were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuum to obtain a yellow-brown oil, which was a 1-hydroxyacetophenone. The connection used in the next stage without additional purification.

B. thus Obtained F.), and the mixture was stirred at RT for one day. Then the solution was filtered through a short column of SiO2using diethyl ether as eluent. The resulting solution was concentrated in vacuum to obtain oil pale greenish-yellow color, which is used in the next stage without additional purification.

Century. Octahydro-pentalen-1-he (5.0 g, 1.0 EQ.) above the stage was added to 4(5)-imidazolecarboxaldehyde (3.8 g, 1.0 EQ.) and 40% H2SO4(20 ml), and the mixture was stirred at 90 ° C for 3 days. Then the reaction was suppressed by adding ammonium hydroxide, and the reaction mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate. The resulting aqueous layer was neutralized with HCl/NH4Cl. The aqueous layer was re-extracted as described above, and the combined organic fractions were concentrated in vacuum to obtain an orange solid.

Was This orange solid was dissolved in ethanol, to which was added palladium on coal (0.5 g). The reaction flask was placed in an atmosphere of hydrogen under a pressure of 40 psi (275,8 kPa) for one day. The reaction solution Phil who was tribali in vacuum to obtain a yellow-brown oil. Purification of column chromatography using a mixture of chloroform and methanol (17:1) led to a ketone containing some impurities.

D. Ketone functional group was then removed by adding the product of the above stage (8,2 g, 1.0 EQ.) to diethylene glycol (80 ml) and hydrazinehydrate (13,0 g, 1.0 EQ.). This mixture was stirred overnight, then was added potassium hydroxide (11,0 g, 5.0 EQ.), and the solution was stirred under reflux for one day. The reaction solution was cooled to CT and washed with water. The solution was extracted with THF/EtOAc and the combined fractions were washed with brine, dried over magnesium sulfate and concentrated in vacuum to obtain a yellow oil. By dissolving this oil in anhydrous ethanol saturated with HCl, and heated received monohydrochloride.

Example R

Method for producing 7-(3H-imidazol-4(5)-ylmethyl)-6,7-dihydro-5H-isoquinoline-8-it (P-1) and 7-(3H-imidazol-4(5)-ylmethyl)-5,6,7,8-tetrahydroisoquinoline (R-2):

Method:

A. 3,4-lutidine (21,4 g, 1 EQ.) was dissolved in 200 ml of water at 20 ° C and during 5 days in portions of 6,32 g twice daily was added potassium permanganate (a total of 63.2 g, 2 EQ.). After 5 days, the solution was placed in storage in morosely to 90 ° C on a rotary evaporator until until he got a white solid. This solid is recrystallized from 5 N. HCl obtaining of 9.56 g of white crystals. Analysis by NMR showed a mixture of two regioisomers, and the desired isomer was the major product.

B. These crystals were heated under reflux in anhydrous ethanol saturated with gaseous HCl, in an argon atmosphere for 6 hours. Then on a rotary evaporator from the solution, ethanol was removed, the residue was transferred into 100 ml of water, and solid sodium bicarbonate was established pH between 7 and 8. The aqueous phase was extracted with diethyl ether (3x) and the combined organic fractions were washed with brine, dried over magnesium sulfate, and then filtered and concentrated to obtain a colorless oil (of 3.56 g, yield 10.8 per cent).

Century For the education of diisopropylamide lithium in situ Diisopropylamine (2,84 g, 1.3 EQ.) through syringe was added n-BuLi (11,21 ml, 1.3 EQ.) in 100 ml of anhydrous THF in an argon atmosphere at-S. To this solution via a syringe was added to the above product B (of 3.56 g, 1 EQ.) in 20 ml of tetrahydrofuran, and the mixture was stirred at-C for 20 minutes. At the same time via cannula dropwise added methyl acrylate (4,85 ml, 2.5 EQ.) in 20 ml of tetrahydrofuran. The solution PDO 20C, and then concentrated on a rotary evaporator. Water balance of three times was extracted with chloroform. Combined fractions were washed with brine and dried over magnesium sulfate, filtered and concentrated to a black solid, which was kept under high vacuum. Chromatography on silica gel using mixtures of hexane/ethyl acetate (7/36/4) resulted to 2.41 g (58.2 per cent) of the target product, which was used in the next stage without additional purification.

Was the Substance from the stage (of 0.48 g, 1 EQ.) was dissolved in 1 ml of 6 M HCl solution and heated at 105C for 16 hours and then the solution was concentrated on a rotary evaporator at 80 ° C to solid state. The residue was transferred into 2 ml of water and neutralized with solid sodium bicarbonate. The neutralized solution was extracted with chloroform (3x) and the combined fractions were washed with brine, dried over magnesium sulfate and concentrated to a colorless oil (0,456 g, 93,4%).

D. Isoquinoline (1,91 g, 1 EQ.), obtained in the above stage G, was heated with 4(5)-imidazolecarboxaldehyde (1,25 g, 1 EQ.) when 110S in 15 ml of 40% sulfuric acid for 30 hours. The reaction mixture is kept for several days at 0 C in an argon atmosphere. Then the solution rasb the NYM vacuum. The product was a yellow solid (2,81 g, 96.1 per cent), containing a mixture of both isomers position when activaloe connection.

That is, the above-Mentioned product D was dissolved in 150 ml of methanol and to this solution was added Pd/C (0,412 g, 0.15 in EQ. wt.). Then a methanol solution saturated H2by repeating the steps of degassing and the saturation of H2. The solution was stirred at a pressure of H2equal to 1 ATM for 20 hours up until TLC showed the absence of unsaturated educt. The solution was filtered through celite and concentrated to oil. The result chromatography on silica using dichloromethane and methanol (9/1) received net product (1,853 g, 65,04%) as a white foam. The foam was transferred to methanol, which was added fumaric acid (0,4817 g, 1.5 EQ.) when heated to dissolve the solids. The solution was slowly cooled to obtain off-white crystals (0,826 g, 74%), which represent a combination of R-1. R-2 received recovery using hydrazine as described in stage D of example II, above.

Example

Method for producing (Z)-6-(3H-imidazol-4(5)-ylmethylene)-7,8-dihydro-6N-quinoline-5-it (P-1), (E)-6-(3H-imides lorida 6-(3H-imidazol-4(5)-ylmethyl)-5,6,7,8-tetrahydroquinoline (C-4) and 6-(3H-imidazol-4(5)-ylmethyl)-5,6,7,8-octahedrally-5-it (p-5).

Method:

A. the Reactive azido-reagent from the first stage were formed in situ by adding monochloride iodine (67,6 g, 1.15 EQ.) in 50 ml of acetonitrile is added dropwise via addition funnel to a stirred suspension of sodium azide (58,84 g, 2.5 EQ.) in 350 ml of anhydrous acetonitrile at-10 ° C in argon atmosphere. The addition was completed after 30 minutes, the mixture was stirred for another 30 minutes, and by means of a syringe was added cyclohexene (34,81 g, 1.0 EQ.), and then was stirred at 20 ° C for a further 20 hours. The mixture is then poured into one liter of water and was extracted with three portions of diethyl ether in 200 ml. of combined fractions were washed with 5% sodium thiosulfate solution, and then brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum at 20C. The residue was transferred into 1 l of DMSO at 0C was added in the second portion NaN3and the mixture was stirred until then, until it warms to ambient temperature. Then the mixture was diluted with 2.5 l of ice water and was extracted ten times with dichloromethane (10250 ml). The combined organic fractions were concentrated on a rotary evaporator to a volume of ~1 l, and this concentrate three times was extracted with 250 ml of water, and then rasmalai on the silicon dioxide, using a mixture of hexane:ethyl acetate (9/1 to 8/2). Provided two isomers, the first sidegroups in position to the keto functional group in the amount of 13,22 g (yield of 26.6%). -isomer was obtained in the amount of 15,825 g 32,0% output.

B. Triphenylphosphine were dissolved in 20 ml dichloromethane and placed in an argon atmosphere at 20 ° C. To the mixed solution through a cannula was added-isomer obtained as described above and kept at 200C for 2 hours. As the reaction of the solution was released nitrogen, and after 2 hours, TLC showed no starting material. The solution was concentrated and passed through a column of silica gel using a mixture of dichloromethane and methanol (pure dichloromethane to 95/5) as eluent. Aminophosphonate intermediate compound obtained in the amount of 2,139 g with 65.1% yield.

Century Aminophosphonate was dissolved in 100 ml of anhydrous o-xylene, and then with stirring, was added 10% Pd/C. Then, to the mixture via a syringe was added freshly acrolein and heated to a temperature of education phlegmy for 4 hours, then added the rest of acrolein, and the reflux was continued for 44 hours in argon atmosphere. At this point TLC pok the VA was heated to a temperature of education phlegmy for another 8 hours. The mixture was cooled to CT, filtered and concentrated on a rotary evaporator to remove excess acrolein until then, until all that was left approximately 100 ml of o-xylene solution. This solution was cooled by adding ice, and three times was extracted with 1 N. HCl. The combined aqueous fractions were extracted 3 Et2O. Then the aqueous phase was cooled to 0C and concentrated NaOH solution was established pH ~10. The aqueous phase then was extracted 5 times with portions of chloroform, 100 ml of combined fractions of chloroform was washed with water and then brine and dried over magnesium sulfate, filtered and finally concentrated to obtain 3.51 g of the oil from 84.4% yield 7,8-dihydro-6N-quinoline-5-it.

, 4(5)-imidazolecarboxaldehyde are condensed with Hinayana, as described in Stage D of Example R and received both C-1 and C-2.

D. Then activelow communication was restored palladium on coal, as described in Stage E of Example R above, up to two products which were separated by chromatography to obtain p-3 and .

E. Ketogroup was removed by the method of reduction with hydrazine, as described in Stage D of Example Paragraph above, to obtain the C-4.

J. Product p-5, which is a completely restored quinoline, Xili NH4OH, gradual heating to evaporation of NH3).

Example T-1

Method for producing (E)-6-(3H-imidazol-4(5)-ylmethylene)-7,8-dihydro-6N-cinoxacin-5-it

Method:

A. a Mixture of 5,6,7,8-tetrahydroquinoxaline-holding (23.75 g, 1 EQ.), benzaldehyde (19,81 ml, 1.1 EQ.) and acetic anhydride (33,4 ml, 2.0 EQ.) was stirred at 150 C in argon atmosphere for 15 hours, after which TLC showed the presence of mainly the desired product with some residual amount of the original substance. The initial substance was removed by vacuum distillation using a column in the Game when S. Then VAT residue was subjected to Kugelrohr distillation at a temperature of 170-220C. The first fraction was slightly contaminated source materials (4.71 g). The second fraction was clean (18,93 g). After applying high vacuum first fraction crystallized. After combining the fractions obtained 20,11 g, 51%.

B. the Product from step a above, was dissolved in 100 ml of methanol and slightly heated, and then cooled to -35 -40 ° C, and after the solution was barbotirovany ozone. After a few minutes of starting material began to crystallize from the solution, the solution was heated and added to 200 ml of methanol, after which the reaction vozobnovlyali nitrogen, then the solution was injected metilsulfate (3.5 ml), after which the solution was stirred for a further 30 minutes at-35C, then left to warm to ambient temperature with stirring. After approximately 48 hours at 20 ° C and the mixture was distilled with steam to remove the solvent to obtain a residue of 8.4 g of a yellow-brown oil. This residue was transferred into diethyl ether and 3 times were extracted portions 1 N. HCl and 25 ml of the combined aqueous fractions were washed with diethyl ether three times. The aqueous solution was gradually podslushivaet to pH 8 with concentrated NaOH. Then from the aqueous phase with chloroform (3x) was extracted with free amine. The combined chloroform extracts twice washed with brine, dried MgSO4and concentrated to a yellow oil (3,01 g). After exposure to high vacuum for 1 hour left, 2,97, the residue was recrystallized from diethyl ether to obtain 2.35 g of bright yellow solid. The yield of 67.5%.

Century 7,8-Dihydroquinoxaline-5-Oh and 4(5)-imidazolecarboxaldehyde (Aldrich Chemicals) suspended in 75 ml of anhydrous tetrahydrofuran at 20 ° C in an argon atmosphere followed by the addition of piperidine, and then acetic acid. The mixture was stirred for 16 hours at aniem and washed with a small amount of tetrahydrofuran, and then chloroform. The solid was dried under strong vacuum with getting 6,85 g T-1. The yield of 90.3%.

Example T-2 and T-3

Just as received T-1, 5,6,7,8-tetrahydroisoquinoline (5,42 g, 1 EQ., Aldrich) was mixed with benzaldehyde (at 5,182 g, 1.2 EQ.) and acetic anhydride (6,309 g, 2.0 EQ.), then the mixture was subjected to vacuum distillation and used in the next stage without additional purification. Yield (crude): 8,28,

The crude product (of 7.96 g) above the stage was subjected to ozonolysis as described in Stage B above. After processing and chromatography got 5,18 g of pale oil. Yield: 97.8 per cent, implying a net initial substance.

Received 7,8-dihydro-6N-isoquinoline-5-he (1,692 g, 1 EQ.) are condensed with 4(5)-imidazolecarboxaldehyde, as described in the Stage above, with the receipt of 2.23 g of unsaturated compounds, similar to the T-1 on the map above, from 92.8% yield. This product is for recovery activaloe communication was treated with palladium on coal, as described in Stage E of Example R, to obtain 6-(3H-imidazol-4(5)-ylmethyl)-7,8-dihydro-6N-isoquinoline-5-it (T-2) with 52% yield.

Ketone, mentioned above, was restored with the use of hydrazine and was converted into fumarate, organizations: 30.4% of 6-(3H-imidazol-4(5)-ylmethyl)-5,6,7,8-tetrahydroisoquinoline (T-3).

Example

The method of obtaining salt 4(5)-(4A-methyl-2,3,4,4 a,5,6,7,8-octahydronaphthalene-2-ylmethyl)-1H-imidazole booth-2-endeavou acid:

Methodology

Bromide methyltriphenylphosphonium (2,75 g of 7.70 mmol) was suspendable in 50 ml of diethyl ether. At-10C was added n-BuLi (is 3.08 ml of 7.70 mmol, 2.5 M solution in a mixture of hexanol). Before cooled to-70C this mixture was stirred for 35 minutes. Through syringe solution was added (R)-(+)-4,4 and,5,6,7,8 hexahydro-4A-methyl-2(3H)-naftalina (1) (1.0 g, 6,09 mmol) in 15 ml of ether. This mixture was heated to 0C for 30 minutes and was stirred at RT for another 30 minutes. The solution was washed with brine (220 ml), dried over MgSO4was filtered and solvent was removed.

Chromatography on SiO2using hexanol gave 0,82 g (83%) of diene 2 in the form of a colorless transparent oil.

This technique hydroporinae adheres to known methods (Brown, H. C. et. al., J. Am. Chem. Soc. 1969, 91, 2144). To a solution of diene 2 (750 mg, 4,63 mmol) in 20 ml THF at 0 C was added 9-BBN (11.8 ml, 5.9 mmol 0.5 M solution in THF). After 30 minutes the mixture was heated to CT and left to react at RT for 1 hour. To obtain LiAlH(OMe)3to a stirred solution of LiAlH4(5,04 ml, 5,04 mmol, 1.0 M in ether) was added dry Meon (3 the ut CT through the solution for 20 minutes was barbotirovany carbon monoxide. Added phosphate buffer (25 ml, pH 7.0), and then H2O2(10 ml, 30% solution) and stirred for 30 minutes. After a typical process of extraction of oil was purified by chromatography on SiO2the mixture is from 5 to 10% EtOAc:Hx obtaining colorless aldehyde 3 as the major product (455 mg, 51%).

This procedure of obtaining corresponds to a known Protocol (Horn, D. A.; Yakushijin, K.; , G. Heterocycles, 1994, 39, 139). A solution of the above aldehyde 3 (450 mg, 2.34 mmol) in EtOH (8 ml) was treated with toiletrieschoice (TosMIC) (430 mg, 220 mmol) and NaCN (~15 mg, cat.) at RT for 20 minutes. The solvent was removed in vacuo, and the residue was dissolved in Meon, saturated NH3(10 ml). The solution was heated in a sealed tube at 110S in 6-12 hours. The substance was concentrated and purified by chromatography on SiO2using a mixture of 5% Meon (saturated NH3):CH2Cl2with the receipt of imidazole in the form of a viscous glassy substance (193 mg, 36%).

Further, the imidazole was purified by stirring in THF or Meon with equimolar amount of fumaric acid at RT for 10 minutes. The solvent was removed, and the salt was recrystallized by adding in THF and rubbing with a mixture of ether and hexanol, emitting 70-80% of net fumarata (4) ((m, 2H), 2.30 (brs, 1H), 2.12 (brs, 1H), 1.91-1.88 (m, 1H), 1.73-1.71 (m, 1H), 1.56-1.46 (m, 5H), 1.30-1.09 (several m, 4H), 1.01 (s, 3H).

13(125 MHz, DMSO-d6, Rel. TMS): 167.0, 143.5, 134.8, 134.5, 128.7, 123.7, 118.2, 42.3, 36.7, 35.0, 32.8, 32.5 (2C), 28.4, 25.9, 24.4, 22.3.

Example f-1

The method of obtaining salt 4(5)-(3-methyl-cyclohex-2-animetal)-1H-imidazole booth-2-indicolite:

Methodology

A solution of 3-methyl-2-cyclohexen-1-it (1) (5 g, to 45.4 mmol) in 25 ml of ether is added dropwise through an addition funnel was added to a solution of LiAlH4(45 ml, 1 M solution in THF) in ether (100 ml) at-10C. After 1 hour the mixture gently extinguished NH4Cl (10 ml) and was treated with 10% HCl (7 ml). The organic layer was extracted with ether (370 ml), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography, elwira 20% EtOAc:Hx with getting 2 as a clear, colorless alcohol, 4,46 g (88%).

A solution of alcohol 2 (1.68 g, 15 mmol) in ethylvanillin ether (38 ml) was treated with Hg(OAc)2(3.2 g, 10 mmol) and NaOAc (410 mg, 5 mmol) at 35C for 4 hours. The mixture was poured into a 5% solution of KOH (15 ml), diluted with ether and extracted with hexane. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was used in the next stage without additional purification.

4, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on SiO2with EtOAc:Hx or according to the Protocol ,as described above, concerning education imidazol-fumarata 5 (8% from 6 to free base 5).

1H NMR (500 MHz, d6-DMSO, Rel. TMS): 7.71 (s, 1H), 6.82 (s, 1H), 6.61 (s, 2H), 5.27 (s, 1H), 2.46-2.32 (range, 3H), 1.85 (brs, 2H), 1.60 (s, 3H); 1.35-0.86 (several m, 4H).

13(125 MHz, DMSO-d6, Rel. TMS): 167.3, 134.9, 134.5, 125.5, 118.1, 35.5, 32.6, 30.1, 28.5, 24.0, 21.4.

Example f-2

But-2-entiat 4(5)-(3,5,5-trimethyl-cyclohex-2-animetal)-1H-imidazole get through in the way that f-1 replacement for isophorone.

Example f-3

But-2-entiat 4(5)-(3-methyl-cyclopent-2-animetal)-1H-imidazole get through in the way that f-1 replace 3-methyl-2-cyclopenten-1-it.

Example X-1

Method for producing buta-2-indioate 4(5)-cyclohex-2-animetal-1H-imidazole:

Methodology

The solution cyclohexenone (1) (2,88 g, 30 mmol) in hexano at C was treated with DIBAL (30 ml, 1.0 M solution in cyclohexane). After 25 minutes, was added Meon (7 ml), and the mixture was heated the Yali, dried over MgSO4, filtered and concentrated under vacuum. The product was purified by chromatography on SiO2using 20% EtOAc:Hx with obtaining a clear, colorless alcohol 2, 2.0 g (68%).

A solution of the above alcohol 2 (2.0 g, with 20.4 mmol) in 1,1,1-triethoxysilane (30 ml) and propionic acid (~0,025 ml, cat.) was heated to remove ethanol. After removal of ethanol heating was continued at C for 1 hour. 1,1,1-triethoxide was removed by simple distillation. After cooling the remainder of the CT product was purified by chromatography on SiO2using a mixture of 5% ether:Hx with the receipt of ester 3 in the form of a colorless transparent oil. 1.08 g (~31%).

A solution of the above-mentioned complex of ethyl ether 3 (1.0 g, 5.9 mmol) was dissolved in hexano (50 ml) and was cooled to-S. Was added dropwise a solution of DIBAL (5.8 ml, 1.0 M solution in cyclohexane). After 15 minutes, was added diethyl ether (50 ml) and the mixture was stirred with a solution of Rochelle salt (25 ml) for 10 minutes. The organic layer was separated, dried and filtered. Chromatography on SiO2using a 7% Et2O:Hx led to the aldehyde as a clear colorless oil, 0.52 g (74%). Aldehyde 4 was subjected to the treatment according to the Protocol , as described enter/SUB>, Rel. TMS): 7.67 (s, 1H), 6.80 (s, 1H), 6.60 (s, 2H), 5.66-5.54 (m, 2H), 2.52-2.42 (m, 2H), 2.34 (brs, 1H), 1.93 (s, 2H), 1.66 (brs, 2H), 1.46-1.43 (m, 1H), 1.22-1.16 (m, 1H).

13(125 MHz, DMSO-d6, Rel. TMS): 166.3, 134.3, 134.2, 131.2, 126.9, 118.1, 96.5, 35.0, 32.5, 28.4, 24.8, 20.7.

Example X-2

But-2-entiat 4(5)-(4-methyl-cyclohex-2-animetal)-1H-imidazole get through in the way that X-1 replacement 6-methyl-2-cyclohexen-1-it.

Example C

Method for producing buta-2-indioate 2-(1H-imidazol-4(5)-ylmethyl)-cyclohexanone:

Methodology

4(5)-imidazolecarboxaldehyde (2,52 g, 26,23 mmol), suspended in cyclohexanone (25,74 g, 262,25 mmol) in an argon atmosphere was added piperidine (0.56 g, 6,56 mmol) and acetic acid (0.52 g, 8,65 mmol). After heating under reflux for 16 hours cyclohexanone was removed ugelrohr by distillation. Chromatography on SiO2with the use of a mixture of 5-10% Meon (saturated NH3):CH2Cl2gave 4,07 g (88%) of unsaturated imidazole 1 in the form of butter.

Unsaturated imidazole 1 (1,02 g of 5.81 mmol) in Meon (40 ml) containing palladium (10 wt.% on charcoal) (0.15 g) was first made at a pressure of H2equal to 1 atmosphere. After 16 hours the palladium was filtered, and the filtrate was concentrated at panicaway acid to the disappearance of all solids, subsequent addition of a small amount of diethyl ether and storage in cold conditions. Specified in the title compound 2 (C) of 0.80 g (48%) was obtained as white crystals.

1H NMR (300 MHz, CDCl3, Rel. TMS): 9.5-6.5 (vbs, 3H), 7.71 (s, 1H), 6.80 (s, 1H), 6.60 (s, 2H), 2.91 (dd, J=14.8 Hz, J=5.4 Hz, 1H), 2.75-2.60 (m, 1H), 2.42-2.28 (m, 2H), 2.27-2.17 (m, 1H), 2.02-1.89 (m, 2H), 1.78-1.68 (m, 1H), 1.68-1.45 (m, 2H); 1.32-1.17 (m, 1H).

13C (75 MHz, DMSO-d6, Rel. TMS): 211.6, 166.6, 134.4, 134.2, 133.8, 117.4, 49.7, 41.4, 33.1, 27.5, 25.8, 24.3.

Example H-1

Method for producing buta-2-indioate 4(5)-(3,4-dimethyl-cyclohex-3-animetal)-1H-imidazole:

Methodology

2,3-Dimethyl-1,3-butadiene (10,16 g, 123,72 mmol), acrylate (11,06 g, 110,47 mmol) and hydroquinone (0.12 g, 1.11 mmol) was heated under stirring at C in a sealed tube for 16 hours, and then when C for an additional 4 hours. Kugelrohr distillation of the obtained residue at 150 and 0.5 Torr gave 14,11 g (70%) complex cyclohexenones ether 1 in the form of oil in the flask at 20 ° C. To a solution of ester 1 (13,62 g, 72,32 mmol) in anhydrous THF (200 ml) at-C in argon atmosphere was added LiAlH4(54,30 ml, 1 M solution in diethyl ether). This mixture was stirred for 1 hour at 20 ° C, and then extinguished at 0C careful serial added the tion was filtered, and under reduced pressure the filtrate was concentrated. Kugelrohr distillation of the obtained residue at 150-180C and 0.5 Torr gave 9,98 g (98%) of alcohol 2 in the form of a colorless volatile oil in the flask at 0C. To a solution of triphenylphosphine (27,13 g, 103,45 mmol) and imidazole (? 7.04 baby mortality g, 103,45 mmol) in anhydrous benzene (450 ml) in an argon atmosphere for 10-minute period with rapid mechanical stirring was added I2(22,75 g, 89,61 mmol) in benzene (170 ml). After 10 additional minutes to a rapidly stirred mixture of 5-minute period was added to the alcohol 2 (9,23 g, 65,89 mmol) in benzene (100 ml). After 2 hours the reaction mixture was diluted with a mixture of hexanol (800 ml) and solids were filtered off. Organic matter was washed with three portions of N2O (800 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The residual solids were filtered off and the resulting oil was purified ugelrohr distilled at 200 C and 0.5 Torr with getting 11,99 g (73%) of iodide 3 as a pale oil in the flask at 0C. To a solution of the previously described 1-N-(dimethylsulphamoyl)-2-tert-butyldimethylchlorosilane (4,34 g, 15.00 mmol) in anhydrous THF (50 ml) at-S in an atmosphere of argon was added n-utility (USD 5.76 ml, 2.5 M solution in a mixture of hexanol). This mixture was stirred for up to-20C. The resulting solution was stirred for 16 hours at 20 ° C, then extinguished with saturated aqueous NaHCO3and concentrated under reduced pressure. The residue was transferred into diethyl ether and then washed with water and brine, dried (MgSO4) and concentrated. Subsequent purification by chromatography on SiO2using a mixture of 5-10% EtOAc:hexane gave 0,89 g (15%) of the imidazole 4 as a pale oil. To a solution of imidazole 4 (0,89 g, 2,17 mmol) in anhydrous THF (25 ml) in an argon atmosphere was added tetrabutylammonium fluoride (2.38 ml, 1 M solution in THF) and the resulting solution was stirred for 1 hour at 20C. The mixture was concentrated under reduced pressure, and the residue was transferred into diethyl ether and then washed with saturated aqueous NaHCO3and brine, dried (MgSO4) and concentrated. The residue was purified by chromatography on SiO2using a blend of 50% EtOAc:hexane to obtain 0.56 g (87%) of the imidazole 5 as a pale oil. To a solution of 5 (0,53 g, 1.77 mmol) in Meon (5 ml) was added aqueous KOH solution (15 ml of a 5 M solution), and the mixture was heated under reflux for 32 hours. The mixture was concentrated under reduced pressure, diluted with H2O (5 ml) and was extracted with CHCl3. The combined organic is nom pressure. The imidazole was recrystallized by stirring in the Meon with equimolar amount of fumaric acid to the disappearance of all solids and then add a small amount of diethyl ether. Specified in the title compound 6 (H-1) 0.27 g (57%) was obtained as white crystals.

1H NMR (300 MHz, DMSO-d6, Rel. TMS): 10.3-8.8 (vbs, 3H), 7.88 (s, 1H), 6.89 (s, 1H), 6.59 (s, 2H), 2.48 (d, J = 6.7 Hz, 2H), 2.00-1.70 (m, 4H), 1.70-1.57 (m, 2H), 1.56 (s, 3H), 1.54 (s, 3H), 1.21-1.04 (m, 1H).

13With NMR (75 MHz, DMSO-d6, Rel. TMS): 166.7, 134.4, 134.1, 133.4, 124.8, 124.3, 117.9, 37.6, 34.1, 32.2, 31.1, 28.7, 19.0, 18.7.

Example H-2

But-2-entiat 4(5)-cyclohex-3-animetal-1H-imidazole get through in the way H-1 replacement 3-cyclohexen-1-methanol.

Example III-1

Method for producing buta-2-indioate 4(5)-(4-methyl-cyclohex-3-animetal)-1H-imidazole:

Methodology

To a suspension of NaH (60% in oil) (6,92 g, 288,28 mmol) in anhydrous THF (1500 ml) at 0 C in an argon atmosphere with vigorous mechanical stirring was added dropwise trimethylphosphate (52,50 g, 288,28 mmol). The mixture was stirred for an additional 30 minutes and then was added dropwise 1,4-cyclohexanediamine-atlantal (40,93 g, 262,07 mmol) in THF (170 ml). Mixture the residue was transferred into diethyl ether (1000 ml) and sequentially washed with N2O and brine, dried (MgSO4), filtered and concentrated to obtain 60,08 g (98%) of unsaturated complex ester 1, which is sent to the next stage without additional purification. To a solution of unsaturated complex ester 1 in EtOAc (500 ml) was added palladium (10 wt.% on charcoal) (2,13 g). The suspension was saturated with H2several times with the vacuum and re-saturation of N2and then was stirred for 16 hours at a pressure of H2equal to 1 atmosphere. To the reaction mixture was added celite (5 g), palladium was filtered, and the filtrate was concentrated under reduced pressure to get 59,45 g (98%) of the saturated ester 2, which is sent to the next stage without additional purification. Unsaturated ester 2 in anhydrous THF (400 ml) with slow flow with vigorous mechanical stirring at-S in argon atmosphere was added to a solution of LiAlH4(200,00 ml, 1 M solution in diethyl ether). After warming to 20 ° C was added an additional amount of THF (600 ml) and the reaction mixture was stirred for 1 hour. The mixture was cooled to 0C and extinguished careful sequential addition of N2On (7,60 ml), NaOH (7,60 ml of 15% aqueous solution) and an additional portion N2using a mixture of 20-50% EtOAc:hexane gave 50,93 g (98%) alcohol 3 as a pale oil. To a solution of the acid chloride oxalic acid (20,65 ml, 41,29 mmol) in anhydrous CH2Cl2(100 ml) at-C in argon atmosphere was added dropwise a solution of DMSO (6,72 g, 86,02 mmol) in CH2Cl2(25 ml). After mechanical stirring for 15 minutes, was added dropwise a solution of alcohol 3 (6,40 g, 34,41 mmol) in CH2Cl2(80 ml) and before the addition of triethylamine (27,85 g, 275,30 mmol), the mixture was stirred for additional 15 minutes at-S. The reaction mixture was stirred for 2 hours at 20 ° C, and then extinguished with saturated aqueous NaHCO3. This mixture was extracted with CH2Cl2, and the combined organic fractions sequentially washed with N2O and brine, dried (MgSO4) and concentrated under reduced pressure. The obtained solid was purified by chromatography on SiO2using a mixture of 20-30% EtOAc:hexane with getting to 5.08 g (79%) of aldehyde 4 as a white solid. A solution of aldehyde 4 (5,08 g, 27,59 mmol) in EtOH (40 ml) was treated at 20 ° C for 3 hours toiletrieschoice (ToSMIC) (5,15 g, 26,27 mmol) and NaCN (0,13 g, 2.68 mmol), and then cooled. After 2 hours of cooling solids officina 3.5 hours. Then the reaction mixture was concentrated under reduced pressure, and the residue was transferred into CHCl3and then washed with saturated aqueous NaHCO3and brine, dried (MgSO4) and concentrated to a red oil. This residue was further purified by chromatography on SiO2using a mixture of 5-10% Meon (saturated NH3):CH2Cl2with the receipt of 1.87 g (31%) of imidazole 5 in the form of oil rose color. A solution of 5 (0.55 g, 2.48 mmol) in acetone (2 ml) containing HCl (5 N., 0.5 ml), was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was transferred into a H2Oh, neutralized to pH 7 with saturated aqueous NaHCO3and was exhaustively extracted with a mixture of CHCl3and isopropyl alcohol (3:1). The combined organic part was sequentially washed N2O and brine, dried (MgSO4) and concentrated. Chromatography on SiO2using a mixture of 5-10% Meon (saturated NH3):CHCl3gave 0,43 g (97%) of the target ketone 6. A solution of 6 (0.20 g, 1.11 mmol) in anhydrous DMF (4 ml) in an argon atmosphere was treated with triethylamine (0.14 g, of 1.33 mmol) and dimethylsulfamoylchloride (0,19 g of 1.33 mmol) and was stirred for 16 hours. The solids were filtered, and the filtrate is and H2O and brine, dried (MgSO4) and concentrated. Chromatography on SiO2using a mixture of 1-5% Meon:CH2Cl2gave 0,22 g (69%) of the target protected imidazole 7 in the form of a mixture of regioisomers, which was sent to the next stage without separation. A solution of 7 (0.18 g, of 0.62 mmol) in anhydrous THF (10 ml) in an argon atmosphere was treated with methylmagnesium (of 0.32 ml, 3.0 M solution in THF) and the resulting mixture was stirred for 16 hours. The reaction mixture was extinguished a small number of Meon, concentrated under reduced pressure, and the residue was transferred into a H2O. the Mixture was acidified by adding dropwise 1 N. HCl until then, until the solution became homogeneous, and then saturated aqueous NaHCO3brought the pH up to 7. Organic substances were extracted in CHCl3, and the combined organic portions sequentially washed with N2O and brine, dried (MgSO4) and concentrated. Chromatography on SiO2using a mixture of 5% Meon:CH2Cl2gave 0.18 g (95%) of alcohol 8 as a mixture of regioisomers, which was sent to the next stage without separation. A solution of 8 (0.14 g, 0.46 mmol) in anhydrous benzene (3 ml) at 0 C in an argon atmosphere was treated with hydroxide (methoxycarbonylamino)treat the mixture was concentrated under reduced pressure, and subsequent purification by chromatography on SiO2using 5% Meon:CH2Cl2gave 0.12 g (92%) alkenes 9 and 10 in the form of mixtures of isomers, which were sent to the next stage without separation. The mixture of isomers 9 and 10 (0.12 g, 0.42 mmol) was heated under reflux in a solution consisting of Meon (2 ml) and KOH (2 ml of a 5 n solution) for 30 hours. The reaction mixture was concentrated under reduced pressure, and the residue was transferred into a H2About and was exhaustively extracted with CHCl3. The combined organic part was sequentially washed2O and brine, dried (MgSO4) and concentrated. Chromatography on SiO2using a mixture of 5-10% Meon (saturated NH3):CH2Cl2gave 0.05 g (67%) alkenes 11 and 12 in the form of a mixture of isomers, which were sent to the next stage without separation.

A mixture of alkenes 11 and 12 (0,045 g, 0.26 mmol) and hydrate p-toluensulfonate acid (0,063 g, 0.32 mmol) was heated under reflux in 1,2-dichloroethane (2 ml) in an argon atmosphere for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on SiO2using a mixture of 10% Meon (saturated NH3):CH2Cl2obtaining free founded the equimolar amount of fumaric acid to the disappearance of all solids, subsequent addition of a small amount of diethyl ether and storage in cold conditions. Specified in the title compound 13 (W-1) 0,040 g (54%) was obtained as white crystals.

1H NMR (300 MHz, DMSO, Rel. TMS): 7.65 (s, 1H), 6.78 (s, 1H), 6.60 (s, 2H), 5.31 (s, 1H), 2.44 (d, J=6.7 Hz, 2H), 2.02-1.82 (m, 3H), 1.82-1.60 (m, 3H), 1.59 (s, 3H), 1.26-1.11 (m, 1H).

13With NMR (75 MHz, DMSO-d6, Rel. TMS): 175.0, 165.2, 134.3, 134.1, 133.2, 120.3, 118.3, 33.2, 32.4, 31.2, 29.3, 28.3, 23.4.

Example W-2

But-2-entiat 4(5)-(4-ethyl-cyclohex-3-animetal)-1H-imidazole get through in the way that W-1 replacement for ethylaniline.

Example III-3

But-2-entiat 4(5)-(4-pentyl-cyclohex-3-animetal)-1H-imidazole get through in the way that W-1 replacement for pentylaniline.

Example Y

The way of measuring selectivity-agonist includes analysis of RSAT (technology selection and amplification of the receptor), described in Messier et al., 1995, “High throughput assays of cloned adrenergic, muscarinic, neurokinin and neurotrophin receptors in living mammalian cells”, Pharmacol. Toxicol. 76:308-11 and adapted for application with the use of alpha2the receptors. In this analysis measure receptor - mediated loss of contact inhibition, which leads to selective proliferation of cells containing sootvetstvuyuschego transfected with a marker gene, such as b-galactosidase, whose activity can be easily measured in 96-well pad. Receptors that activate G protein, Gqcause this response. Receptors alpha2that are typically associated with Giactivate RSAT answer, if jointly expressed with hybrid Gqprotein having a domain recognition receptor Gicalled Gq/2i5(Conklin et al. (1993), “Substitution of three amino acids switches receptor specificity of Gqa to that of Gia”, Nature 363:274-6).

Cells NIH-3T3 applied at a density of 2106cells in 15 cm plates and incubated in modified according Dulbecco environment, Needle, supplemented with 10% calf serum. After 1 day, the cells are subjected to joint transfection by precipitation of calcium phosphate expressed in mammalian plasmids encoding p-SV-b-galactosidase (5-10 mg), receptor (1-2 mg) and G protein (1-2 mg). In transfection the mixture can also include 40 mg DNA salmon sperm. The next day, add fresh medium, and after 1-2 days, the cells harvested and frozen in the aliquot of 50 tests. Cells are thawed, and 100 ml added to the aliquot of 100 ml of medicines in different concentrations in three repetitions in 96-well plates. Inquire, -galactosidase enzymatic activity determined by adding 200 ml chromogenic substrate (consisting of 3.5 mm o-nitrophenyl-b-D-galactosidase and 0.5% nonidet the P-40 in saline solution, buffered phosphate), incubating overnight at 30 ° C and measuring optical density at 420 nm. The optical absorption is a measure of the enzymatic activity, which depends on the number of cells and reflects the receptor - mediated cell proliferation. Define EU50and the maximum effect of each drug for each receptor alpha2. Efficiency or characteristic activity is calculated as the ratio of maximum effect of the medicinal product to the maximum effect standard full agonists for each receptor subtype. As standard agonist for receptor alpha2Aand alpha2Buse brimonidine, also called UK14304-18. Oxymetazoline is a standard agonist used for receptor alpha2B.

Table 1 below shows the values of the characteristic activity of the compounds of the above Examples B-W in relation subtypes 2-adrenergic receptors, which defined the firm in respect of 2B or 2B/2C subtype(s). In relation to the 2A subtype compounds of Examples inactive or have low efficiency (0,4). They have significant greater efficacy against subtype 2B and 2C, than for subtype 2A. Therefore, unlike ophthalmic 2-adrenoretseptory compounds, such as clonidine, brimonidine, the compounds of Examples B-W can selectively activate subtypes 2-adrenergic, non-subtype 2A.

Example e

Reduction of intraocular pressure (IOP) and sedative side effect

Measurements of IOP were performed at being fully conscious female cynomolgus monkeys weighing 3-4 kg with sustained elevated intraocular pressure, which was created in his right eye by an Ar laser photocoagulation of the trabecular network of the eye. For experiments used animals ~2 months after surgery. During the experiments, monkeys were sitting on chairs special design (Primate Products, San Francisco) and ate orange).

Before IOP measurements to minimize discomfort of the eyes caused by tonometry, each monkey topically applied 25 ál anesthetic (proparacaine). Did two basic measurements before instillation of drugs, and then held periodic measurement within 6 hours after instillation. The test compounds were injected in one eye one eye drops volume of 50 μl; the other eye received the same volume of saline.

The monkeys were tested many selective in respect of 2B or 2B/2C compounds of examples. It was unexpectedly found that, as shown in table 2, all these different structures of the compounds were reduced IOP in the treated eye.

Simultaneously measured sedative effect and evaluate it according to the following scale: 0 = agility, typical vocalizations, gestures, and so on; 1 = calm, less movements; 2 = mild sedative effect, some vocalization, the response to the stimulation; 3 = a sedative effect, vocalization is missing, some response to stimulation; 4 = sleep.

In addition, the compounds of the present invention did not cause a sedative effect, as opposed to clonidine and brimonidine, which caused a sedative effect.

Example BB

Research in the above Examples e and AA show that therapeutic effect of alpha2-agonists can be separated from the sedative and cardiovascular side effects. This separation is achieved using the compounds, for which the common property is the preferred activity against alpha2In and alpha2/Alpha2With subtypes relative to the alpha2And subtype.

Known from the prior art alpha2-adrene the hypotension and bradycardia which prevents or severely restricts their use to treat diseases and conditions, which, as you know, they facilitate. Such diseases and disorders include muscle spasticity, including hyperactive urination, diarrhea, diuresis, withdrawal symptoms, pain, including neuropathic pain, neurodegenerative disease, including optic neuropathy, spinal ischemia and stroke, deficits in memory and cognitive abilities, attention deficit disorder, psychoses, including manic disorders, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and obstruction of the nasal canal (Hieble et al., “Therapeutic applications of agents interacting with alpha-adrenoceptors, Alpha-adrenoceptors: molecular biology, bbiochemistry and pharmacology”. Prog. Basic Clin. Pharmacol.) Basel, Karger) 8, pp.180-220 (1991)). For example, it was shown that clonidine is clinically effective in relieving post-operative pain, pain associated with cancer, and neurogenic pain. However, for these and other alpha2agonists were really clinically promising, requires the creation of compounds that do not cause sedation, hypotension and bradycardia (Maze MB and Tranquilli, W. “Alpha-2 adrenoceptor agonists: defining the role in clinical anesthesia”. Anesthesiology 74, 581-605 (1991)).

PE is. Therefore, the above-described alpha2connection, which, as was shown above, do not cause sedative and cardiovascular effects, suitable and have the advantage of treating these conditions.

Improvement of neuronal degeneration in glaucoma neuropathy is another example of a new use of compounds according to the invention. Recent studies have shown that in several models of neuronal degeneration in rats clonidine and other alpha2agonists exert a neuroprotective effect against cells of the retina. These models include light-induced degeneration of photoreceptors in rats-albinos (Wen et. al., “Alpha-2 adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage.” J. Neurosc. 16, 5986-5992) and calibrated damage to the optic nerve in rats, leading to secondary loss of ganglion cells of the retina (Yoles et al, “Injury-induced secondary degeneration of rat optic nerve can be attenuated by alpha2-adrenoceptor agonists AGN 191103 and brimonidine”. Invest. Ophthalmol. Vis. Sci. 37, 540, S114). However, unlike the compounds of the present invention, the doses used in these studies is from 0.1 to >1 mg/kg by intraperitoneal or intramuscular injection is also called sedative and cardiovascular equator activation of alpha2receptors in the retina (Wen et. al., above), and the measurement of the induction of bFGF after local injection of alpha2-agonists in the eyes of rats shows that approximately 1% of the dose required to cause a 2-3-fold increase in the levels of bFGF, suggesting nerozumite mediated alpha2-agonist (Wen et. al., above; Lai et. al., “Neuroprotective effect of ocular hypotensive agent brimonidin”, Proceedings of Xith Congress of the European Society of Ophalmology (Bologna, Monduzzi Editore), 439-444). It is known that these local dose of modern alpha2-agonists, such as clonidine, lead to systemic side effects such as sedation and hypotension, which prevents their use as eye neuroprotective agents. In addition, properly assigned and concurrently pending application 08/496292 filed June 28, 1995, disclosed and claimed the use of some selective2-adrenergic agents in the treatment of neuronal damage, and the contents of this application in its entirety is included in this description by reference.

Compounds of the present invention do not cause sedative and cardiovascular effects in monkeys after local injection of doses of at least 3%. Thus, the neuroprotective end, it is shown that the compound of Example B-9(b) is neuroprotective in a model calibrated to damage to the optic nerve in rats (Yoles et. al., above) (see table 4 below).

This level of neurotoxity comparable to the effect observed in previous studies with standard A2-adrenoreceptor agonist, brimonidine, and neuroprotective agent, MK.

Example VV

Relief of pain, including neuropathic pain, is another example of a disorder in which the compounds of the present invention are useful and preferred as pain relief without unwanted side effects. Clonidine, an agonist that activates all three alpha2-receptor, clinically used for the treatment of chronic pain, but its applicability for this indication is limited, as it causes a sedative and cardiovascular side effects. Compounds of the present invention was compared with clonidine and brimonidine in a model of neuropathic pain in rodents, which is known to predict clinical activity (Kim, S. and Chung, J. “An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.” Pain 50 pp. 3550363 (1992)). After ligating the two spinal ie. The ability of alpha2connections to reverse this sensitivity is called allodynia, checking after 30 minutes or intrathecal or intraperitoneal dose. Sedative activity of each compound was measured using a camera activation.

Compounds according to the invention, for example O-1, even at very high doses, can alleviate allodynia without sedative effect, as opposed to clonidine and brimonidine that cause a sedative effect at doses that are slightly above their antiallergenic doses (see table 5 and 6).

The results of these Examples demonstrate that common side effects 2A-adrenoreceptor medicines mediated 2A subtype, and that their effect of lowering eye pressure, and other therapeutic effects may be mediated by subtype different from 2A-subtype. Thus, 2-adrenoretseptory connection unrelated structural classes have in common is that they have low functional activity against 2A-subtype, reduce intraocular pressure (IOP) and cause other therapeutic action without dose-limiting side effects.

Saline solution (0.9% NaCl in water) 98%.

The active compound dissolved in physiological solution and poured into a sterile container.

Although described a specific embodiment of the invention, it should be borne in mind that the invention is, of course, not limited, as there may be many obvious modifications and understood that this invention includes all such modifications that are within the scope of the attached claims.

1. Imidazole derivatives having selective agonistic activity against adrenergic receptor subtype(s) 2B or 2B/2C compared to the adrenergic receptor subtype 2A, represented by the formula

where the dotted lines represent possible double bonds;

R represents H or lower alkyl;

X represents S or C(H)R1where R1represents H or lower alkyl, or R1absent when X represents S or when the relationship between X and the ring represented by the formula

is a double bond;

Y represents O, N, S, (CR1x)2, R3or R4associated with unsaturated carbon atom, and x=2 when R2, R3or R4linked to a saturated carbon atom;

R2represents H, lower alkyl, halogen, hydroxy, lower alkoxygroup, lower alkenyl or lower quinil, or R2can represent oxo, when it is attached to a saturated carbon atom;

each of R3and R4represents H, lower alkyl, halogen, lower alkenyl, lower quinil or phenyl, or together they represent-C(R2)x)z-; -Y1(C(R2)x)z'-; -Y1C(R2x)yY1-; -(C(R2)x)-Y1-(C(R2)x)-; -(C(R2)x-Y1-(C(R2)x)-(C(R2)x) and Y1-(C(R2)x)-Y1-(C(R2)x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4, and x and y are as defined above, and, in addition, either end of each of these divalent groups may be attached either to R3or R4with the formation of a condensed ring structure

and educated therefore and, the carbon ring has a valence of not more than 4, the nitrogen has a valence of not more than 3, and S have a valence not more than 2, and including its enantiomers and pharmaceutically acceptable salts, excluding the compounds in which:

(a) R represents H, X represents-CH2-, Y represents -(CH2)2-, R2represents H, hydroxy, lower alkyl, lower alkoxy, R3and R4together represents -(C(R2)x)z- where x=2 and z=4;

(b) R represents hydrogen, X represents-CH - or-CH2-, Y represents-CH2- or -(CH2)2-; R2represents H, lower alkoxy or oxo, R3and R4together represent a -(C(R2)x)z- where x=2 and z=4;

(C) R represents hydrogen, X represents-CH2or CH(CH3)-; Y is S, R2, R3and R4represent H, lower alkyl or halogen;

(g) R represents hydrogen, X represents-CH2or SN(alkyl)-; Y represents-CH2- or -(CH2)2-; R2represents H, hydroxy, lower alkyl, lower alkoxy or lower alcalase a hydrogen or lower alkyl, X represents-CH2-, Y represents-CH=CH-; R2, R3and R4represent H, lower alkyl, lower alkoxy, hydroxy or halogen.

2. Connection on p. 1, which is represented by the formula

X, Y, R, R2, R3and R4such, as defined in paragraph 1.

3. Connection on p. 2, where X represents a C(H)R1, a, Y, R, R2, R3and R4such, as defined in paragraph 1.

4. Connection on p. 3, where R1represents N.

5. Connection on p. 4, where R2represents N and

represents farnily radical.

6. Connection on p. 5, where R3and R4together are (CH)4.

7. Connection on p. 4, where R2represents N and

represents a thienyl radical.

8. Connection on p. 7, where R3and R4together are (CH2)4.

9. Connection on p. 7, where R3represents phenyl, and R4represents N.

10. Connection on p. 7, where R3and R4together are (CH2)3S.

11. Connection on p. 7, where R3and R

13. Connection on p. 12, where R2represents N, and R3and R4together are (CH)2S.

14. Connection on p. 12, where R2represents N, and R3and R4together are (CH2)4.

15. Connection on p. 12, where R2is a dimethyl, a R3and R4together are (CH)4.

16. Connection on p. 12, where Y represents-CH2CH(CH3)-, R2represents hydrogen or oxo, and R3and R4together are (CH)4.

17. Connection on p. 12, where R2represents oxo or hydrogen, and R3and R4together are S(CH)2or S(CH2)2.

18. Connection on p. 12, where Y represents-CH2C(CH3)2-, R2represents hydrogen or oxo, and R3and R4together are (CH)4.

19. Connection on p. 4, where

represents cyclopentadienyl radical.

20. Connection on p. 19, where R2represents hydrogen, and R3and R4together are (CH2)3.

21. Connection on p. 4, where is ormulu

where Y represents S or O;

X, R, R2, R3and R4such, as defined in paragraph 1.

23. Connection on p. 1, which has the formula

X, Y1, R, R2, R3and R4such, as defined in paragraph 1.

24. Connection on p. 23, where R3and R4together are (CH)4.

25. Connection on p. 24, where Y1represents O.

26. Connection on p. 25, where R2represents oxo.

27. Connection on p. 26, where X represents CH.

28. Connection on p. 26, where X represents CH2.

29. Connection on p. 24, where one of R2represents hydroxy and the other represents N.

30. Connection on p. 25, where R2represents N.

31. Connection on p. 24, where Y1represents S.

32. Connection on p. 31, where X represents CH2.

33. Connection on p. 32, where R2represents oxo.

34. Connection on p. 32, where R2represents N.

35. Connection on p. 31, where X represents CH, and R2represents oxo.

36. Connection on p. 3, where Y t is to place an oxo.

38. Connection on p. 36, where X represents CH2, a R2represents N.

39. Connection on p. 2, where X represents S and

represents phenyl.

40. Connection on p. 3, where R1represents methyl, and

is furanyl.

41. Connection on p. 4, where Y is CH2(CR12)2where R1 represents hydrogen or methyl.

42. Connection on p. 41, where R2represents N.

43. Connection on p. 41, where R2represents oxo.

44. Connection on p. 3, where R represents a CH3,

represents a phenyl radical, and R3and R4together represent O(CR2)2O.

45. Connection on p. 2, where X represents CH,

represents cyclopentadienyl radical, a R2represents oxo.

46. The compound represented by the formula

47. Connection on p. 1, represented by formula

where Y is (CR1x)2, R3+R4represents (C(R2)1and R2such, as defined in paragraph 1.

48. Connection on p. 47, which is represented by the formula

where (R2)xrepresents hydrogen or oxo.

49. Connection on p. 47, the structure of which is a

50. Connection on p. 47, where the structure is a

51. Connection on p. 2, where R represents hydrogen, R3and R4represent-C(R2)x)-N-(C(R2)x)-(C(R2)x)-, and X represents CHR1as represented by the formula

moreover, the group CHR1attached in one of two positions of the ring, indicated with a wavy line, and the remaining position is hydrogen, and provided that two double bonds cannot be one and the same atom of ring, and R1and R2such, as defined in paragraph 1.

52. Connection on p. 51, which has the formula

(R2)xrepresents hydrogen or oxo.

53. Connection on p. 51, which has the formula

(R2)xrepresents in the(C(R2)x)-(C(R2)x)-Y1and Y1-(C(R2)x)-(C(R2)x)-(C(R2)x)-, and Y1represents N, or O, or S, as represented by the formula

where X and X' is selected from the group consisting of N, O and S, and at least one of X and X' represents N, and R1and R2such, as defined in paragraph 1.

55. Connection on p. 54, which is represented by the formula

where (R2)xrepresents hydrogen or oxo.

56. Connection on p. 54, which is represented by the formula

where (R2)xrepresents hydrogen or oxo.

57. The compounds having selective agonistic activity against adrenergic receptor subtype(s) 2B or 2B/2C compared to the adrenergic receptor subtype 2A, represented by the formula

and its pharmaceutically acceptable salts.

58. Method introduction the mammalian host, including a human, a pharmaceutical composition containing an effective dose of an active compound, which is selected from the group consisting of compounds having the formula

where the dotted line represents S or C(H)R1where R1represents H or lower alkyl, or R1absent when X represents S or when the relationship between X and the ring represented by the formula

is a double bond;

Y represents O, N, S, (CR1x)ywhere y is an integer from 1 to 3, CH=CH - or-Y1CH2- where Y1represents O, N or S; x is an integer 1 or 2, and x=1 when R2, R3or R4associated with unsaturated carbon atom, and x=2 when R2, R3or R4linked to a saturated carbon atom;

R2represents H, lower alkyl, halogen, hydroxy or lower alkoxygroup, or R2can represent oxo, when it is attached to a saturated carbon atom;

each of R3and R4represents H, lower alkyl, hydroxy, lower alkoxygroup or phenyl, or together they represent-C(R2)x)z-; -Y1(C(R2)x)z'-; -Y1C(R2x)yY1-; -(C(R2)x)-Y1-(C(R2)x)-; -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x) and Y1-(C(R2)x)-Y1-(C( as defined above, and besides, any end of each of these divalent groups may be attached either to R3or R4with the formation of a condensed ring structure

and thus formed ring may be fully unsaturated, partially unsaturated or fully saturated, provided that the carbon ring has a valence of not more than 4, the nitrogen has a valence of not more than 3, and S have a valence not more than 2; or from compounds having the formula

where W is a bicyclic radical selected from the group consisting of

where R5, R6, R7and R8selected from the group consisting of H and lower alkyl, provided that at least one of R5and R6or R6and R7represents OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo and R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted lower alkyl, a Z represents O or NH,

for related connection has adrenergic activity and is a selective agonist of adrenergic receptor subtype 2B or adrenoreceptor subtype(s) 2B/2C, in preference to the adrenoreceptor subtype 2A.

59. The method according to p. 58, where the active compound has the efficiency relative to standard full agonist, which is at least approximately 0.3 more in respect adrenoreceptor subtype 2B or 2C than adrenoreceptor subtype 2A, and its effectiveness against adrenoreceptor subtype 2A does not exceed 0,4.

60. The method according to p. 58, where the active compound is at least ten times more effective against adrenoreceptor subtype 2B or 2C than adrenoreceptor subtype 2A.

61. The method according to p. 60, wherein the mammal host locally administered approximately 0.001 to 5% by weight of active compound in a daily or twice daily dose.

62. The method according to p. 61, wherein the mammal host locally injected about 0.01 to 3% by weight of active compound in a daily or twice daily dose.

63. The method according to p. 58, where the specified connection does not have activity against adrenoreceptor subtype 2A.

64. The method according to p. 58, where the specified connection does not have activity against adrenoreceptor subtypes 2A and 2C.

65. The method introduced is active compounds which are selected from the group consisting of compounds having the formula

where the dotted lines represent possible double bonds;

R represents H or lower alkyl;

X represents S or C(H)R1where R1represents H or lower alkyl, or R1absent when X represents S or when the relationship between X and the ring represented by the formula

is a double bond;

Y represents O, N, S, (CR1x)ywhere y is an integer from 1 to 3, CH=CH - or-Y1CH2- where Y1represents O, N or S; x is an integer 1 or 2, and x=1 when R2, R3or R4associated with unsaturated carbon atom, and x=2 when R2, R3or R4linked to a saturated carbon atom;

R2represents H, lower alkyl, halogen, hydroxy or lower alkoxygroup, or R2can represent oxo, when it is attached to a saturated carbon atom;

each of R3and R4represents H, lower alkyl, hydroxy, lower alkoxygroup or phenyl, or together they represent-C(R2)x
)-Y1-(C(R2)x)-; -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x) and Y1-(C(R2)x)-Y1-(C(R2)x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4, and x and y are as defined above, and, in addition, either end of each of these divalent groups may be attached either to R3or R4with the formation of a condensed ring structure

and thus formed ring may be fully unsaturated, partially unsaturated or fully saturated, provided that the carbon ring has a valence of not more than 4, the nitrogen has a valence of not more than 3, and S have a valence not more than 2; or from compounds having the formula

where W is a bicyclic radical selected from the group consisting of

where R5, R6, R7and R8selected from the group consisting of H and lower alkyl, provided that at least one of R5and R6or R6and R7represents OC(R9)C(R9)N(R) forming a condensed ring with

where R9prestiz

where R10represents H, lower alkyl, phenyl or phenyl substituted lower alkyl, a Z represents O or NH,

for the treatment of elevated intraocular pressure without sedative and cardiovascular side effects, with the specified connection has adrenergic activity and is a selective agonist of adrenergic receptor subtype(s) 2B or 2B/2C, in preference to the adrenoreceptor subtype 2A.

66. The method according to p. 65, where the active compound has the efficiency relative to standard full agonist of at least about 0.3 more in respect adrenoreceptor subtype 2B or 2C than adrenoreceptor subtype 2A, and its effectiveness against adrenoreceptor subtype 2A does not exceed 0,4.

67. The method according to p. 66, wherein the mammal host locally administered approximately 0.001 to 5% by weight of active compound in a daily or twice daily dose.

68. The method according to p. 67, wherein the mammal host locally injected about 0.01 to 3.0 percent by weight of active compound in a daily or twice daily dose.

69. The method according to p. 65, where the specified connection does not possess possesses activity against adrenoreceptor subtypes 2A and 2C.

71. A method of treating a mammal to reduce intraocular pressure without cardiovascular and sedative side effects, which is administered an effective amount of a compound that is chosen from the group consisting of compounds having the formula

where the dotted lines represent possible double bonds;

R represents H or lower alkyl;

X represents S or C(H)R1where R1represents H or lower alkyl, or R1absent when X represents S or when the relationship between X and the ring represented by the formula

is a double bond;

Y represents O, N, S, (CR1x)ywhere y is an integer from 1 to 3, CH=CH - or-Y1CH2- where Y1represents O, N or S; x is an integer 1 or 2, and x=1 when R2, R3or R4associated with unsaturated carbon atom, and x=2 when R2, R3or R4linked to a saturated carbon atom;

R2represents H, lower alkyl, halogen, hydroxy or lower alkoxygroup, or R2can represent oxo, when he joined the feast upon issue alkoxygroup or phenyl, or together they represent-C(R2)x)z-; -Y1(CR2)x)z'-; -Y1C(R2x)yY1-; -(C(R2)x)-Y1-(C(R2)x)-; -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x) and Y1-(C(R2)x)-Y1-(C(R2)x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4, and x and y are as defined above, and, in addition, either end of each of these divalent groups may be attached either to R3or R4with the formation of a condensed ring structure

and thus formed ring may be fully unsaturated, partially unsaturated or fully saturated, provided that the carbon ring has a valence of not more than 4, the nitrogen has a valence of not more than 3, and S have a valence not more than 2; or from compounds having the formula

where W is a bicyclic radical selected from the group consisting of

where R5, R6, R7and R8selected from the group consisting of H and lower alkyl, provided that at least one of R5and R

where R represents H, lower alkyl or oxo, a R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted lower alkyl, a Z represents O or NH,

and have a selective agonistic action on the adrenergic receptor subtype 2B or adrenergic receptor subtype(s) 2B/2C, in preference to the adrenoreceptor subtype 2A.

72. The method of selective ionizatsii adrenoreceptor subtype AV or adrenoreceptor subtypes 2B/2C without ionizatsii adrenoreceptor subtype 2A, which is administered a therapeutically effective amount of a selective(s) agonist(s) - receptor subtype 2B or 2B/2C which is selected from the group consisting of compounds having the formula

where the dotted lines represent possible double bonds;

R represents H or lower alkyl;

X represents S or C(H)R1where R1represents H or lower alkyl, or R1absent when X represents S or when the relationship between X and the ring represented by the formula

the C is from 1 to 3, CH=CH - or-Y1CH2- where Y1represents O, N or S; x is an integer 1 or 2, and x=1 when R2, R3or R4associated with unsaturated carbon atom, and x=2 when R2, R3or R4linked to a saturated carbon atom;

R2represents H, lower alkyl, halogen, hydroxy or lower alkoxygroup, or R2can represent oxo, when it is attached to a saturated carbon atom;

each of R3and R4represents H, lower alkyl, hydroxy, lower alkoxygroup or phenyl, or together they represent-C(R2)x)z-; -Y1(C(R2)x)z'-; -Y1C(R2x)yY1-; -(C(R2)x)-Y1-(C(R2)x)-; -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x) and Y1-(C(R2)x)-Y1-(C(R2)x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4, and x and y are as defined above, and, in addition, either end of each of these divalent groups may be attached either to R3or R4with the formation of a condensed ring structure

where W is a bicyclic radical selected from the group consisting of

where R5, R6, R7and R8selected from the group consisting of H and lower alkyl, provided that at least one of R5and R6or R6and R7represents OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo and R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted lower alkyl, a Z represents O or NH.

73. The use of compounds of the formula I

where (a) R represents H, X represents-CH2-, Y represents -(CH2)2-, R2represents H, hydroxy, lower alkyl, lower alkoxy, R3and R4together represent a -(C(R2)x)z- where x=2 and z=4;

(b) R of t )2-; R2represents H, lower alkoxy or oxo, R3and R4together represent- ((R2)x)z; where x=2 and z=4;

(C) R represents hydrogen, X represents-CH2or CH(CH3)-; Y is S, R2, R3and R4represent H, lower alkyl or halogen;

(g) R represents hydrogen, X represents-CH2or SN(alkyl)-; Y represents-CH2- or -(CH2)2-; R2represents H, hydroxy, lower alkyl, lower alkoxy or lower alkenyl, R3and R4together represent a -(C(R2)x)z- where x=2 and z=4; and

(e) R represents hydrogen or lower alkyl, X represents-CH2-, Y represents-CH=CH-; R2, R3and R4represent H, lower alkyl, lower alkoxy, hydroxy or halogen,

or compounds of the formula

where W is a bicyclic radical of the formula

where R5, R6, R7and R8selected from the group consisting of H and lower alkyl, provided that R5and R6or R6and R7represents OC(R

R represents H;

Z represents NH,

as selective agonists adrenergic receptor subtype 2 or subtype(s) 2B/2C in preference adrenergic receptor subtype 2A.

74. Method introduction the mammalian host, including a human, a pharmaceutical composition containing an effective dose of active compound having adrenergic activity, which is selected from the group consisting of compounds having the formula

where the dotted lines represent possible double bonds;

R represents H or lower alkyl;

X represents S or C(H)R1where R1represents H or lower alkyl, or R1absent when X represents S or when the relationship between X and the ring represented by the formula

is a double bond;

Y represents O, N, S, (CR1x)ywhere y is an integer from 1 to 3, CH=CH - or-Y1CH2- where Y1represents O, N or S; x is an integer 1 or 2, and x=1 when R2, R3or R4associated with unsaturated carbon atom, and x=2 when R2, R WHO, halogen, hydroxy or lower alkoxygroup, or R2can represent oxo, when it is attached to a saturated carbon atom;

each of R3and R4represents H, lower alkyl, hydroxy, lower alkoxygroup or phenyl, or together they represent-C(R2)x)z-; -Y1(C(R2)x)z'-; -Y1C(R2x)yY1-; -(C(R2)x)-Y1-(C(R2)x)-; -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x) and Y1-(C(R2)x)-Y1-(C(R2)x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4, and x and y are as defined above, and, in addition, either end of each of these divalent groups may be attached either to R3or R4with the formation of a condensed ring structure

and thus formed ring may be fully unsaturated, partially unsaturated or fully saturated, provided that the carbon ring has a valence of not more than 4, the nitrogen has a valence of not more than 3, and S have a valence not more than 2; or from compounds having the formula

where R5, R6, R7and R8selected from the group consisting of H and lower alkyl, provided that at least one of R5and R6or R6and R7represents OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo and R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted lower alkyl, a Z represents O or NH,

for the treatment or prevention of glaucoma, with the active compound has the biological property, such that the compound is a selective agonist of the receptor subtype(s) 2B or 2B/2C, in preference to the receptor subtype 2A, and the selectivity measured in the analysis using cells in vivo Express individual subtypes 2 or had one of these subtypes, and the receptor is a human or a species which, as shown, has similar pharmacology, and in this analysis, we measured that the effectiveness of active connections relative to the more than the effectiveness of the active compounds relative to the standard connections in the receptor subtype 2A, and its effectiveness receptor subtype 2A does not exceed 0.4, and/or the active compound is at least approximately ten times more potent receptor subtype 2B or 2C than in receptor subtype 2A.

75. The method according to p. 74, wherein the mammal host locally administered approximately 0.001 to 5% by weight of active compound per day.

76. Method introduction the mammalian host, including a human, a pharmaceutical composition containing an effective dose of an active compound, which is selected from the group consisting of compounds having the formula

where the dotted lines represent possible double bonds;

R represents H or lower alkyl;

X represents S or C(H)R1where R1represents H or lower alkyl, or R1absent when X represents S or when the relationship between X and the ring represented by the formula

is a double bond;

Y represents O, N, S, (CR1x)ywhere is the integer is 1 or 2, and x=1 when R2, R3or R4associated with unsaturated carbon atom, and x=2 when R2, R3or R4linked to a saturated carbon atom;

R2represents H, lower alkyl, halogen, hydroxy or lower alkoxygroup, or R2can represent oxo, when it is attached to a saturated carbon atom;

each of R3and R4represents H, lower alkyl, hydroxy, lower alkoxygroup or phenyl, or together they represent-C(R2)x)z-; -Y1(C(R2)x)z'-; -Y1C(R2x)yY1-; -(C(R2)x)-Y1-(C(R2)x)-; -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x) and Y1-(C(R2)x)-Y1-(C(R2)x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4, and x and y are as defined above, and, in addition, either end of each of these divalent groups may be attached either to R3or R4with the formation of a condensed ring structure

and thus formed ring may be fully unsaturated, partially Renacimiento not more than 3, and S have a valence not more than 2; or from compounds having the formula

where W is a bicyclic radical selected from the group consisting of

where R5, R6, R7and R8selected from the group consisting of H and lower alkyl, provided that at least one of R5and R6or R6and R7represents OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo and R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted lower alkyl, a Z represents O or NH,

for treating or preventing muscle spasticity, including overactive bladder, diarrhea, diuresis, withdrawal symptoms, pain, including neuropathic pain, neurodegenerative diseases, including optic neuropathy, spinal ischemia and stroke, deficits in memory and cognitive abilities, attention deficit, psychoses, including manic disorders, anxiety, depression, hypertension, congestive series the x side effects when the specified connection has adrenergic activity and is a selective agonist of adrenergic receptor subtype(s) 2B or 2B/2C, in preference to the adrenoreceptor subtype 2A.

77. Method introduction the mammalian host, including a human, a pharmaceutical composition containing an effective dose of active compound having adrenergic activity, which is selected from the group consisting of compounds having the formula

where the dotted lines represent possible double bonds;

R represents H or lower alkyl;

X represents S or C(H)R1where R1represents H or lower alkyl, or R1absent when X represents S or when the relationship between X and the ring represented by the formula

is a double bond;

Y represents O, N, S, (CR1x)ywhere y is an integer from 1 to 3, CH=CH - or-Y1CH2- where Y1represents O, N or S; x is an integer 1 or 2, and x=1 when R2, R3or R4associated with unsaturated carbon atom, and x=2 when R2, R3or R42can represent oxo, when it is attached to a saturated carbon atom;

each of R3and R4represents H, lower alkyl, hydroxy, lower alkoxygroup or phenyl, or together they represent-C(R2)x)z-; -Y1(C(R2)x)z'-; -Y1C(R2x)yY1-; -(C(R2)x)-Y1-(C(R2)x)-; -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x) and Y1-(C(R2)x)-Y1-(C(R2)x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4, and x and y are as defined above, and, in addition, either end of each of these divalent groups may be attached either to R3or R4with the formation of a condensed ring structure

and thus formed ring may be fully unsaturated, partially unsaturated or fully saturated, provided that the carbon ring has a valence of not more than 4, the nitrogen has a valence of not more than 3, and S have a valence not more than 2; or from compounds having the formula

where W represents bicyclic is UP> selected from the group consisting of H and lower alkyl, provided that at least one of R5and R6or R6and R7represents OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo and R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted lower alkyl, a Z represents O or NH,

for treatment of muscle spasticity, including overactive bladder, diarrhea, diuresis, withdrawal symptoms, pain, including neuropathic pain, neurodegenerative diseases, including optic neuropathy, spinal ischemia and stroke, deficits in memory and cognitive abilities, attention deficit, psychoses, including manic disorders, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and obstruction of nasal channel without sedative and cardiovascular side effects, but such a connection has the biological property, such the compound is a selective agonist of receptors on arena in the analysis using cells which in natural conditions Express individual subtypes 2 or had one of these subtypes, and the receptor is a human or a species which, as shown, has similar pharmacology, and in this analysis, we measured that the effectiveness of the active compounds relative to the standard connections in the receptor subtype 2B or 2C at least 0.3 greater than the effectiveness of the active compounds relative to the standard connections in the receptor subtype 2A, and its effectiveness receptor subtype 2A does not exceed 0,4, and/or the active compound is at least approximately ten times more potent receptor subtype 2B or 2C than in receptor subtype 2A.

78. Method introduction the mammalian host, including a human, a pharmaceutical composition containing an effective dose of active compound having adrenergic activity, which is selected from the group consisting of compounds having the formula

where the dotted lines represent possible double bonds;

R represents H or lower alkyl;

X represents S or C is an S or when the relationship between X and the ring, represented by the formula

is a double bond;

Y represents O, N, S, (CR1x)ywhere y is an integer from 1 to 3, CH=CH - or-Y1CH2- where Y1represents O, N or S; x is an integer 1 or 2, and x=1 when R2, R3or R4associated with unsaturated carbon atom, and x=2 when R2, R3or R4linked to a saturated carbon atom;

R2represents H, lower alkyl, halogen, hydroxy or lower alkoxygroup, or R2can represent oxo, when it is attached to a saturated carbon atom;

each of R3and R4represents H, lower alkyl, hydroxy, lower alkoxygroup or phenyl, or together they represent-C(R2)x)z-; -Y1(C(R2)x)z'-; -Y1C(R2x)yY1-; -(C(R2)x)-Y1-(C(R2)x)-; -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x) and Y1-(C(R2)x)-Y1-(C(R2)x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4, and x and y are as defined above, and, in addition, obrazovanie condensed ring structure

and thus formed ring may be fully unsaturated, partially unsaturated or fully saturated, provided that the carbon ring has a valence of not more than 4, the nitrogen has a valence of not more than 3, and S have a valence not more than 2; or from compounds having the formula

where W is a bicyclic radical selected from the group consisting of

where R5, R6, R7and R8selected from the group consisting of H and lower alkyl, provided that at least one of R5and R6or R6and R7represents OC(R9)C(R9)N(R9) forming a condensed ring with

where R9represents H, lower alkyl or oxo and R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted lower alkyl, a Z represents O or NH,

for treatment of muscle spasticity, including overactive bladder, diarrhea, diuresis, withdrawal symptoms, pain, including neuropathic pain, neurodegenerative bolezn and, attention deficit, psychoses, including manic disorders, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and obstruction of nasal channel without sedative and cardiovascular side effects, but such a connection has the biological property, such that the compound is a selective agonist of the receptor subtype(s) 2B or 2B/2C, in preference to the receptor subtype 2A, and the selectivity is defined in the analysis RSAT (technology selection and amplification of the receptor), in which activation of the receptor subtypes 2A and 2C of the test compound compared to brimonidine, and receptor subtype 2B compare with Oxymetazoline, and where the respective receptors subtypes 2A, 2B and 2C are expressed in cells NIH-3T3, and in this analysis, we measured that the effectiveness of the active compounds relative to brimonidine receptor subtype 2C or the effectiveness of the active compounds relative to Oxymetazoline in relation to the 2B receptor subtypes at least 0.3 greater than the effectiveness of the active compounds relative to brimonidine receptor subtype 2A, and its effectiveness receptor subtype rosenii receptor subtype 2B or 2C, what receptor subtype 2A.

79. The method according to p. 60, where the active compound is at least one hundred times more effective against adrenoreceptor subtype 2B or 2C than adrenoreceptor subtype 2A.

80. Connection on p. 4, where

represents cyclopentadienyl or cyclohexadienyl radical.

81. Connection on p. 80, where

represents cyclohexadienyl radical.

82. Connection on p. 81, where

represents the

a R2represents hydrogen and methyl.

83. Connection on p. 82, where R3represents hydrogen or methyl, and R4represents hydrogen or methyl, or one of R3represents methyl and the other R3and R4together are (CH2)4.

84. Connection on p. 81, where

represents the

and R2represents hydrogen.

85. Connection on p. 84, where R3represents hydrogen or methyl, and R4represents hydrogen, methyl, ethyl or n-pentyl.

86. Connection on p. 80, where

is with the

 

Same patents:

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

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

showing property to activate the germination of wheat seeds

3-piperidine, methods for their preparation and pharmaceutical composition based on them" target="_blank">

The invention relates to tricyclic3-piperidinol General formula (1), where X is O or S, R1means hydrogen, halogen, C1-6alkyl or C1-4alkyloxy, Alk means C1-6alcander, a D such as defined in the claims

The invention relates to new derivatives of thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione of General formula (I) or their pharmaceutically-acceptable salts, having immunosuppressive activity

The invention relates to novel condensed to thienopyrimidine formula I and their physiologically acceptable salts, having the effect of inhibitors of phosphodiesterase V(PDE V), and which can be used for the treatment of diseases of the cardiovascular system and for the treatment and/or therapy of disorders of potency

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

The invention relates to new thienopyrimidine formula I, their pharmaceutically acceptable salts, having the effect of inhibitors of phosphodiesterase V, which can be used to combat diseases of the cardiovascular system and for the treatment and/or therapy of disorders, to pharmaceutical compositions in a form suitable for the treatment

The invention relates to omega-Amida N-arylsulfonamides formula I

and/or stereoisomeric forms of the compounds I and/or physiologically acceptable salts of the compounds I where R1means phenyl, phenyl, substituted once with halogen, the rest of the heterocycle of the following groups: morpholine, pyrrolidine; R2means N; R3means -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa, IIe

moreover, in formula IIa, IIe q indicates an integer of zero or 1, Z denotes the carbon atom or a covalent bond, and R8means a hydrogen atom or halogen, or R3means -(C1-C4)-alkyl-C(O)-Y, where Y means the remainder of the formula IIC or IId

moreover, in formulas IIc and IId, R8means H or halogen, R9means H, or R3means -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9has the above values, means the integer 2 and R is substituted by-O-, And means covalent bond, B means -(CH2)m- where m is zero, X is-CH=CH-

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

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

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

The invention relates to new derivatives of 2-aminopyridine F.-ly (1) where denotes unsubstituted or substituted phenyl, pyridyl, thienyl, thiazolyl, hinely, cinoxacin-2-yl or Antonelliana derivatives; D is unsubstituted or substituted phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, hinely, triazolyl, oxazolyl, isoxazolyl or Antonelliana derivatives, provided that C and D are not simultaneously have the following values: S - phenyl, and D is phenyl, S - phenyl, and D - pyridyl, With - pyridyl and D - phenyl, - pyridyl and D - pyridyl; R1- R4- hydrogen, NO2or NH2

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

< / BR>
where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid
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