Substituted imidazole derivatives, method of administration of the active compounds and the method of treatment based on these compounds

 

(57) Abstract:

The invention relates to imidazole derivative of the formula (I), 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 based on these compounds. 13 N. and 76 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 in which cardiovascular or sedative side effects are greatly reduced by the introduction of mammals, including humans, compounds which are selective agonists adrenergic receptors only subtype 2 or subtype 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 blackovich States and scientific publications. In the art it is well known and generally accepted that the adrenergic activity useful for treatment of mammals, including humans, in order to cure or relieve symptoms and conditions of a number of diseases and conditions. In other words, in this area it is recognized that the pharmaceutical composition, having in its composition adrenergic compound or compounds as the active ingredients, useful for the treatment of glaucoma, chronic pain, nasal congestion, high blood pressure, congestive heart failure and to anestesiologia.

In this area, 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

According to the present invention it was found that adrenergic compounds that act selectively and preferably more specific as agonists of receptor subtype 2B or 2B/2C (referred to below as 2B or 2B/2C) in preference to the receptor subtype 2A, have the s, such as changes in blood pressure or sedative effect. For the purposes of the present invention a connection is defined as a 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 potent as an agonist with respect to either 2B and 2C, or to both receptor subtypes than in relation to the receptor subtype 2A, or if the difference in the effectiveness of this compound in relation 2B and 2B/2C receptor relative to 2A-receptor exceed 0.3, and its effectiveness against 2A-receptor is 0.4.

Accordingly, the present invention relates to methods for treating animals belonging to mammals, including humans, the pharmaceutical composition comprising as active ingredient one or more than one connection, which represents a specific or selective 2B or 2B/2C-adrenergic agonist, for the treatment of many diseases and conditions, against which the use of alpha-adrenergic compounds, including, without limitation, glaucoma, reduction of elevated intraocular pressure, chronic pain, diarrhea, and nasal congestion. In addition, the compounds according to this invention is suitable for, the Oli, including neuropathic pain, neurodegenerative diseases, including ocular neuropathy, spinal cord ischemia and stroke, deficits in memory and cognitive abilities, attention deficit, psychoses, including manic disorders, anxiety, depression, hypertension, congestive heart failure, ischemic heart and nasal congestion.

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

In particular, the present invention encompasses methods of treating diseases and conditions in which to ensure 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. According to the present invention, the compound is selective 2B or 2B/2C-agonist, if the difference in the effectiveness of this compound as an agonist 2B or 2B/is adtype 2A is 0.4 and/or it at least 10 times more effective. The compounds used according to the present invention, preferably are specific agonists of receptor subtype 2B or 2B/2C. Specifically, in this regard, specific agonist define in the sense that specific-adrenergic agonist does not act as an agonist of the receptor subtype 2A to any measurable or biologically significant extent.

Found many agents that are functionally selective with respect to 2B or 2B/2C-these subtypes of adrenergic receptors. This preferential activity can be determined through a series of functional tests, such as the production of cyclic AMP [Shimizu et al., J. Neurochem. 16, pp. 1609-1619 (1969)], TSR (technology selection and amplification of receptor) [Messier et al., Pharmacol. Toxicol. 76, pp. 308-311 (1995)] and citizenary microphysiometer [Neve et al., J. Biol. Chem. 267, pp. 25748-25753 (1992)], using cells that naturally Express individual subtypes or entered one of these subtypes. Used cells or recombinant receptors must be human or species for which it was shown that they have similar pharmacology. In the following study used TSAR analysis to glue the RNG) and human 2C receptor (gene C4). It has been shown that the rat pharmacology 2B-receptor corresponds to human 2V-receptor [Bylund et al., Pharmacol. Rev. 46, pp. 127-129 (1994)].

In the treatment, in particular glaucoma, you can use the local introduction. In eyes with glaucoma and skin after treatment for other indications can be applied to any ordinary product for local use, such as solution, suspension, gel, ointment or balm and the like. Preparation of such topical preparations are well described in the prior art of pharmaceutical preparations, for example in Remington''s Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania.

If the drug you want to enter systematically, it can be made in the form of powder, pills, tablets and the like or in the form of a syrup or elixir for oral administration. For intravenous, intraperitoneal, vnutriobektovogo or epidural injection compound is prepared in the form of a solution or suspension, which can be introduced by injection. In some cases it may be useful to include these compounds in the composition of the suppository or drug extended release, including in the form of a dermal patch for placement on the skin or under the skin or intramuscular inj is prohibited, they are treatable adrenergic compounds, carried out by the introduction of a therapeutically effective dose of one or more than one compounds of the present invention. Therapeutic concentration is concentration, which realizes reduction of a specific condition, or slows its spread. In some cases, the drug can potentially be used in order to prevent to prevent the occurrence of any specific state. Assigned therapeutic concentration will vary from state to state and in some cases can vary depending on the severity of the condition to be treated, and give the patient treatment. Accordingly, the assigned therapeutic concentrations it is best to determine on the spot and at the time of routine experimentation. However, it is assumed that in the treatment of, for example, glaucoma preparation containing between 0.001 and 5 wt.%, preferably from about 0.01 to 3 wt.%, usually will constitute a therapeutically effective concentration. When the system maintenance in most cases, therapeutic result will give a number between 0.001 and 50 mg / 1 KGO from 0.01 to 1.0 mg per 1 kg of body weight per day.

Because the connections representing 2B and 2B/S-specific selective agonists, do not have significant side effects caused by the action 2A receptors, the treatment of diseases or conditions such compounds of the present invention is an advantage, especially when treating humans with cardiovascular problems.

General patterns of examples of compounds representing specific 2B and 2C agonists or selective 2B and 2B/C-agonists, which are used in pharmaceutical compositions and methods of treatment of the present invention represented by the following General formulas.

In one aspect of this invention, the compound having the activity of a selective agonist in relation to adrenergic receptor subtype(s) 2V or 2V/s, compared with 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, which is cobbled integer from 1 to 3, -CH=CH - or-Y1CH2- where Y1represents O, N or S; x is an integer from 1 to 2, and x is 1 when R2, R3or R4associated with unsaturated carbon atom, and x is 2 when R2, R3or R4linked to a saturated carbon atom; R2represents H, lower alkyl, halogen, hydroxy or lower alkoxy, or being attached to a saturated carbon atom, R2can represent oxo; R3and R4each represents H, lower alkyl, hydroxy, lower alkoxy or phenyl, or together 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)x)-, where z is an integer from 3 to 5, z' is an integer from 2 to 4, and x and y are such as defined above, and, further, each end of each of these divalent groups may be attached to or R3or R4with the formation of a condensed ring structure

and educated so what about the ring carbon is not more than 4 valences, nitrogen is not more than three, and S have no more than two.

In another aspect of the invention the above-mentioned compound represented by the formula

where X can be represented as C(H)R1, a 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 R4may be tert-bootrom, or R3and R4can represent H, or R3can represent N, and R4may be the stands or ethyl.

An alternative compound of formula I, R1can stands, and

can be farnily radical.

An alternative in these 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 phenyl, and R4and R4can represent H, or R3and R4together may represent (CH)4or R3can represent N, and R4may be the stands, or R3can represent bromo, and R4can represent H, or R3can be hydrogen, and R4can represent chloro, or R3can stands, and R4can be hydrogen.

As an alternative, compounds of formula II

can be a tsiklogeksilnogo radical.

In such tsiklogeksilnogo derivatives of the formula II, R2can be hydrogen, and R3and R4may together represent (CH)4or R2can represent oxo, and R3and R4may together represent (CH)4or R2can be hydrogen or oxo, and R3and R4may together represent (CH)2S, or R2can be hydrogen, and R3and R4may together represent (CH2)4forming octahydronaphthalene, or R2can represent oxo, and R3and R4may together represent (CH2)4, R2can represent oxo, and R3and Rand R4may together represent S(CH2)2or R2, R3and R4can represent H, or R2can represent oxo, and R3and R4may together represent (CH2) (OCH3)CH, or R3and R4may together represent a-Y1-C(R2)x-C(R2)x-Y1- where Y1represents N, forming tetrahydroquinoxalin, where R2can be hydrogen or oxo.

As an alternative, compounds of formula II

can be tetrahydroquinoline radical, where3and R4together represent-Y1-C(R2)x-C(R2)x-C(R2)x- where Y1represents N. In such tetrahydroquinoline derivatives (R2)xcan be hydrogen or oxo or may be tetrahydroisoquinoline radical, where R3and R4together represent-C(R2)x-Y1-C(R2)x-C(R2)x- where Y1represents N, a (R2)xcan be hydrogen or oxo.

As an alternative, compounds of formula II

can be a cyclopent is, and R3and R4may together represent (CH)4or R2can represent oxo, and R3and R4may together represent (CH)4or R2can be hydrogen, and R3and R4may together 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 CH2and R2can represent N. Or R3and R4together may represent (CH)4, Y can represent a CH2C(CR12)2where R1is hydrogen, or Y can represent a-CH2(IU)-, and R2can be hydrogen or oxo.

Finally, in compounds of formula II

can be a phenyl radical.

In such phenyl derivatives of formula I, X may represent a CH2, R can represent N or CH3, R2, R3and R4can represent H, or R3and R4together represent O(CR2)2O with the formation of 1,4-benzodioxane derivative, or X necte 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 compounds of formula IV, Y1can represent O, R2can represent oxo, and X represents CH or CH2or one of R2represents hydroxy and the other can represent H, or R2can represent N.

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

In another aspect of the invention the compounds having selective activity against adrenergic receptor subtype(s) 2V or 2V/s, compared with adrenergic receptor subtype 2A, represented by the formula

P>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 alkyl, phenyl or phenyl substituted lower alkyl, a Z represents O or NH. Compounds where W is norbornyl, disclosed and claimed in the joint consideration of the application 09/003902, filed January 7, 1998, which in its entirety is included here by reference.

In one aspect of the invention, Z can represent O, W can be a

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

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

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

Alternatetitle.

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

Example

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

Procedure

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 (K. T.), and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude product (0.5 mm RT.art., 115-S) gave of 38.7 g (76%) transparent and colorless oil. Upon cooling, the product solidified with the formation of white crystals (2). 1-(Dimethylsulphamoyl)imidazole (2) (18,8 g, 0.11 mol) was added to 430 ml of tetrahydrofuran (THF). This 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). After the addition the reaction mixture was stirred during the course is THF. After the addition was completed, the reaction mixture was slowly heated to K. so, 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) gave a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals (3).

1-Dimethylsulphamoyl-2-tert-butyldimethylchlorosilane (3) (5.0 g, 17.3 mmol) was added to 100 ml of THF. This solution was cooled to-20C. In the reaction flask was added dropwise a solution of secondary utility (sec-BuLi) in hexane (1.3 M; 14,6 ml; 19 mmol). After the reaction mixture was stirred for 1 hour at-20C. To the reaction mixture were added 8 ml of dimethylformamide (DMF), and then mixed it with K. so for 3.5 hours. The reaction mixture was diluted with water and the organic layer was separated. The organic phase was washed with brine, and then dried over sodium sulfate. This mixture was filtered and the filtrate was concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane) gave with email-2-tert-butyldimethylsilyl-5-imidazolecarboxaldehyde (4).

Example A-0

Method for producing 3-(1H-imidazol-4-ylmethyl)-1-methyl-1H-indole fumarata AND

A solution of imidazole (1) (1.08 g, 6,9 mmol) in DMF (dimethylformamide) (5 ml) at 20 ° C was added to a suspension of NaH (370 mg, 9.25 mmol) in DMF (5 ml). After 30 min the mixture was cooled to 0C. Added a solution of MeI (5,2 ml, 2 M in tert-butylmethylether ether) and the solution was left to react at room temperature for 18 hours. Added water (10 ml) and tO (15 ml). The organic layer was separated, dried over gSO4was filtered and boiled away the dryness. The residue was purified by chromatography on SiO2using tO to obtain 0.65 g (55%) methylated indole (2).

(1-Methyl-1H-indol-3-yl)-acetonitrile (2) in CH2CL2(10 ml) was restored DiBAL (diisobutylaluminium) (7 ml, 1 M in cyclohexane) at C for 1 hour. The mixture was added to a solution of Rochelle salt and stirred for 0.5 hours. The organic layer was separated, dried over MgSO4was filtered and boiled away the dryness. The crude aldehyde (3) used in the next stage without additional purification.

The aldehyde (3) was subjected to a "Protocol Bucha" ("Buchi protocol", see Horne, D. A.; Yakushijin, K.; Buchi, G. Heterocycles, 1994, 39, 139). A solution of aldehyde 3 (1 mmol) in EtOH (5 ml) was treated with toiletries is their 20 minutes The solvent was removed in vacuo and the residue was dissolved in ~ 7 M NH3in Meon and moved to seal the tube. This mixture was heated at 100C for 15 hours. The mixture was concentrated and purified by chromatography on SiO2using 5% Meon (us. mass/NH3) CH2Cl2. The compound of imidazole was additionally purified in the form of a salt fumarata 4 by recrystallization from Meon using 20% Et2O/Hx 3-(1H-imidazol-4-ylmethyl)-1-methyl-1H-indole fumarata A.

1H NMR (300 MHz, DMSO-d6w/TMS) : 7.81 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.40-7.39 (m, 2H), 7.20-7.00 (m, 2H), 6.47 (s, 2H), 3.76 (s, 3H), 3.14 (s, 2H).

Example a-1

Application (1H-indol-3-yl)acetonitrile (commercially available from Aldrich) in method A (stages 2-5) to obtain 3-(1H-imidazol-4-ylmethyl)-1H-indole fumarata.

1H NMR (500 MHz, DMSO-d6w/TMS) : 7.85 (s, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.13 (s, 1H), 7.05 (t, J=7.3 Hz, 1H). 6.86 (s, 1H), 6.61 (s, 2H), 3.99 (s, 2H).

Example a-2

Application (1-methyl-1H-pyrrol-2 yl)acetic acid methyl ester (from Aldrich) in method A (stages 2-5) to obtain 4-(1-methyl-1H-pyrrol-2-ylmethyl)-1H-imidazole fumarata.

1H NMR (300 MHz, MeOD-d4) : 8.44 (s, 1H), 7.07 (s, 1H), 6.72 (s, 2H), 6.61 (s, 1H), 5.97-5.86 (m, 2H), 4.02 (s, 2H), 3.53 (s, 3H).

Procedure

telematically-5-imidazolecarboxaldehyde (2) (2.7 g; 8.5 mmol). This reaction mixture was heated for 24 hours at 90°C. After cooling to K. so the reaction mixture was made alkaline using an excess of concentrated ammonium hydroxide. This mixture was twice extracted with tetrahydrofuran. 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), consisting of 3-(3H-imidazol-4(5)-ylmethylene)-7-methoxypropan-4-it. The crude product is suspended in 100 ml of ethanol was added catalyst is palladium on carbon (10%, 0.27 g). This mixture was dissolved in apparatus for Parr hydrogenation under hydrogen pressure of 40 pounds per square inch (880 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 gave 1,05 g (46%) solid color bronze, consisting of 2-[3H-imidazol-4(5)-ylmethyl]-7-methoxy-3,4-dihydro-2H-naphthalene-1-she (4) (B-1A). The compound (4) (0.5 g; 1,95 mmol) was added to 20 ml of methanol. To this solution was added borohydride sodium (74 mg; 1,95 mmol). After mixing the acetate. 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 0.5 g of a white solid substance (5), consisting of 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 mmol) and triperoxonane acid (4.8 ml; of 62.3 mmol) and stirred the reaction mixture at K. so for 22 hours. The reaction mixture was podslushivaet 2 N. NaOH and the organic layer was separated and washed with brine. The solution was dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. Column chromatography using 7% methanol in chloroform gave 0.39 g (83%) yellow-brown oil (6). This product was dissolved in methanol and was added an excess of hydrogen chloride (HCl) in the air. This solution was concentrated under reduced pressure to obtain 0.3 g of solid bronze color. Column chromatography using 7% methanol in chloroform gave, after recrystallization from a mixture of acetone and methanol 0.25 g (46%) cleaners containing hydrochloride salt of 4(5)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H - 6.66 (d, 1H, J=8.4 Hz), 6.57 (s, 1H), of 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).

To obtain the following derivatives of imidazole, following the procedure of example B-1, the interaction was subjected to different compounds with condensed rings.

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-imidazol-4(5)-ylmethyl)thiochroman-4-one

Example B-6

Cleaners containing hydrochloride salt of the previous connection get on stage 5 the method of example B-1 above.

thiochroman

4(5)-thiochroman-3-ylmethyl-1H-imides the P>(7b) 2-(3H-imidazol-4(5)-ylmethyl)indan-1-he

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

Cleaners containing hydrochloride salt of this compound was obtained by way 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

Cleaners containing hydrochloride salt of this compound was obtained by the method of example B-6

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

Cleaners containing hydrochloride salt of this compound was obtained by the method of example B-6

(9b) 5-(octahedrons[b]-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

1-Benzocoumarin

Example B-11 (a-b)

(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-tetrahydrobenzaldehyde-5-he

Example-1

The technique of (4(5)-thiophene-3-ylmethyl-1H-they who in 42 ml of anhydrous THF and cooled to-S. To a solution of compound (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-butyldimethylsilyl (TBS-CL) (1.6 g; 10.6 mmol) in 8 ml THF. This reaction mixture is heated to K. T. and stirred over night. The next day the reaction mixture is cooled to-20C and add n-BuLi (7.3 ml; 11.6 mmol). 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 K. T. and stirred over night. The next day the reaction mixture was 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 remove the solvent under reduced pressure. Flash chromatography (2:5 ethyl acetate/hexane) to give 3.0 g (7.5 mmol) of dimethylamine 2-(tert-butyldimethylsilyl)-5-(hydroxythiophene-2-ylmethyl)imidazole-1-sulfonic acid (3). Connection (3) (1.5 g; 3,74 mmol) is transferred into a 37 ml of THF. To a solution of compound (3) is added dropwise a 1 M solution of Tetra-n-butylammonium (TBA-F) in THF (of 4.1 ml, 4.1 mmol). This reaction mixture is stirred over night at K. so the next day the reaction mixture g is positive phase is dried over sodium sulfate and remove the solvent under reduced pressure. Allocate 0,94 g (3.3 mmol) of dimethylamine 5-(hydroxythiophene-2-ylmethyl)imidazole-1-sulfonic acid (4). The compound (4) (0.5 g; 1,74 mmol) is transferred to a 23 ml of dichloromethane, and to this solution was added 2.2 ml (a 13.9 mmol) of triethylsilane and 4.3 ml (55,7 mmol) triperoxonane acid. This reaction mixture is stirred at K. I. during the night, 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 remove the solvent under reduced pressure. Flash chromatography using mixtures of ethyl acetate and hexane (1:1) gives 0,42 g (1.55 mmol) of dimethylamine 5-(thiophene-2-ylmethyl)imidazole-1-sulfonic acid (5). The compound (5) is transferred into 10 ml of 1.5 N. HCl and heated under reflux for 3 hours and then stirred at K. I. during the night. The reaction mixture was diluted with ethyl acetate, neutralized with solid sodium bicarbonate, and then alkalinized 2 N. NaOH.

The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate and remove the solvent under reduced pressure. Flash chromatography using a mixture of chloroform and methanol (10:1) to give 0.17 g (1.0 mmol) 4(5)-thiophene-3-ylmethyl-1H-them">

Example b-2

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

Example b-3

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

Example b-4

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

Example B-5

In the method of example 1 using 2-furancarboxaldehyde obtaining 4(5)-furan-2-ylmethyl-1H-imidazole.

Example B-6

In the method of example 1 using 3-furancarboxaldehyde obtaining 4(5)-furan-3-ylmethyl-1H-imidazole.

Example B-7

In the method of example 1 using 5-methyl-2-furancarboxaldehyde obtaining 4(5)-(5-methylfuran-2-ylmethyl)-1H-imidazole.

Example B-8

In the method of example B-1 using benzaldehyde with obtaining 4(5)-benzyl-1H-imidazole.

Example B-9

In the method of example 1 using 2-tjanapengaronline obtaining 4(5)-benzo[b]thiophene-2-ylmethyl-1H-imidazole.

Example B-11

In the method of example 1 using 5-ethyl-2-furancarboxaldehyde obtaining 4(5)-(5-ethylfuran-2-ylmethyl)-1H-imidazole.

Example b-12

In the method of example 1 using 4-bromo-2-thiophenecarboxaldehyde obtaining 4(5)-(4-bromothiophene-2-ylmethyl)-1H-imidazole.

Example b-13

In the method of example 1 using 4-phenyl-2-thiophenecarboxaldehyde obtaining 4(5)-(4-phenylthiophene-2-ylmethyl)-1H-imidazole.

Example B-14

In the method of example 1 using 4-methyl-2-thiophenecarboxaldehyde obtaining cleaners containing hydrochloride salt of 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:

Procedure

Connection with endo, Exo relative stereochemical configuration, obtained by synthesizing nitrosothiol, as shown above. Processing methanolic solution of benzaldehyde (10 g; 94,3 mmol) nitromethane (51 ml; 943 mmol) in the presence of sodium hydroxide (3 N. in methanol to pH 8) gave nitrospira with the release of 60%. Dehydration of the alcohol is carried out by treatment with methanesulfonanilide (3.5 g; and 31.1 mmol) and then triethylamine (6.3 g; 62,2 mmol) in dichloramine bicyclo[2.2.1]heptane skeleton was performed in one stage. The reaction of the Diels-alder reaction was performed by heating nitrostyrene (4.5 g; 30.2 mol) with cyclopentadiene (3.98 g; 60,4 mmol) in 1,2-dichloroethane (10 ml). The reaction of the Diels-alder reaction proceeds at a ratio of endo : Exo on nitro 3:1. As this ratio and relative stereochemical configuration was confirmed by x-ray diffraction data analysis. Recovery as the nitro group and the olefin was carried out in an atmosphere of hydrogen in the presence of 10 % wt. palladium on coal. Separation of the isomers at this stage was carried out by flash chromatography using 5% methanol saturated with ammonia in dichloromethane. Amine (0.7 g; 3,74 mmol) was treated first 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) in 51% yield.

1H-NMR (300 MHz, CDCl3d: 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), 7.17-7.29 (m, 5H).

Example D-2

Oxazolidin-2-ilidene-(3-o-televizija[2.2.1]hept-2-yl)amine get using o-methyl-nitrosothiol in method D-1.

Example D-3

Bicyclo[2.2.1]hept-2-isoxazol the ia imidazolidin-2-ilidene-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)amine:

Procedure

To 2-amino-4-metoprolo (1) (4,00 g; 25,95 mmol), triethylamine (15,20 ml; 109,0 mmol) and 4-dimethylaminopyridine (0,063 g; 0.52 mmol) as a suspension in anhydrous CH2CL2(250 ml) at 0C under argon via syringe was added chlorocatechol of 2.27 ml; 28,55 mmol). After heating under reflux for 72 hours of pure product was filtered and washed with water. Uterine fluid then washed with phosphoric acid (0.5 M), saturated sodium bicarbonate, water and brine, and then dried over gS4. This solution was applied onto silica and purified flash chromatography on silica using a mixture of hexane/ethyl acetate (4:6) to give 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) with a yield of 82%. To a suspension of compound (2) (1,49 g, 7,65 mol) in anhydrous THF (40 ml) under argon in a two-neck round bottom flask equipped with a reflux condenser, was added borane-dimethylsulfide complex (15.3 ml; 30,62 mmol). This mixture was heated at a temperature of education phlegmy up until by thin-layer chromatography not will be determined by the absence of starting material (2 hours). The reaction is round education phlegmy for another 10 minutes. The crude reaction mixture was concentrated in vacuo, and purified flash chromatography on silica, using a mixture of hexane/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 a yield of 99%. To the compound (3) (0,032 g; 0,178 mmol) and formalin (37% in N2About; 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). This solution was stirred for 30 minutes, then was added glacial acetic acid (to 0.032 ml; 0,534 mol). The resulting mixture was stirred for another 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/ethyl acetate (7:3), to obtain pure 4-methyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (4) (0,031 g) with a yield of 93%. To the compound (4) (2.16 g; 11,12 mmol) and 10% palladium on carbon (0,216 g; 10 mass.) under argon was added methanol (Meon) (30 ml), and then THF (30 ml). After the resulting mixture was passed hydrogen up until by thin-layer chromatography not be opredelennymi methanol. 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-yellow oil with a yield of 100%, without additional purification. To the compound (5) (1.86 g; 11,34 mmol) and imidazolin-2-sulfonic acid (1.84 g; 12,24 mmol) in anhydrous acetonitrile (50 ml) under argon at 0°C was added triethylamine (3,26 ml; 23,36 mmol). This solution was slowly heated to ambient temperature and was stirred for 16 hours. At this point, was added an additional amount of imidazolin-2-sulfonic acid (0,86 g; 5,55 mol) and stirred the mixture for another 5 hours. This solution was concentrated in vacuo and the residue was transferred into a H2O. the Organic substances were extracted in CH2Cl2and twice washed with NaOH 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 the pure imidazolidin-2-ilidene-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)amine (6) (D-1) (0,905 g) with a yield of 34%.

1H-NMR (Dl3): 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=8.2H4, Zin-3-one (E) and imidazolidin-2-ilidene-(5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)amine (G):

Procedure

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 0C under argon via syringe dropwise added chlorocatechol (10.0 ml; 0,126 mol). After complete addition, 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 gSO4. 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 a yield of 63%. To the compound (2) (14,64 g; 89,72 mmol) dissolved in concentrated H2SO4(65 ml) at-10C was added 70% concentrated NGO3(8,08 g; 89,72 mmol) and concentrated H2SO4(25 ml) with rapid mechanical stirring at a rate at which the internal temperature was maintained below-5C. Once the addition was completed, the mixture was poured on crushed ice (500 ml) and the resulting solid was filtered and suspended in cold water (300 ml), adding led silicon and purified flash chromatography, using a mixture of 60% hexane and ethyl acetate, to obtain the nitrated product as a mixture of two regioisomers, namely the desired 6-substituted aromatics, consisting of 6-nitro-5-methyl-4H-benzo[1,4]oxazin-3-one (3) (55%) and 8-substituted by-product consisting of 8-nitro-5-methyl-4H-benzo[1,4]oxazin-3-one (4) (22%). At this stage, these isomers are separated with difficulty, and in the form of a mixture sent to the next stage. To a mixture of compounds (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) under argon was added 10% palladium on carbon (1.20 g). The resulting solution was subjected to the action of H2at atmospheric pressure. 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]oxazin-3-one (5) (0.96 g) with a yield of 46% and 8-amino-5-methyl-4H-benzo[1,4]oxazin-3-one (6) (0.17 g) with a yield of 8%. The compound (5) (1.20 g; 6,74 mmol), imidazoline-2-sulfonic acid (2,02 g; 13,48 mmol) and triethylamine (2,45 g; 16,85 mmol) was heated at a temperature of education phlegmy in anhydrous acetonitrile (50 ml) under argon for 48 hours. At this time added to updat shivali the mixture for another 24 hours. This solution was concentrated in vacuo, the residue was transferred into a solution l3/isopropyl alcohol (3:1) and then washed with sodium hydroxide (1 BC) and brine, dried over MgSO4and concentrated in vacuum. The resulting foam was purified flash chromatography on silica, using a mixture of 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 mg) in the form of a foam with a yield of 27% at the same time with 55% of newly received source material. 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).

The compound (6), imidazolin-2-sulfonic acid (0,223 g; for 1.49 mmol) and triethylamine (0,415 ml; 2,98 mmol) was heated at C in anhydrous acetonitrile (10 ml) in a sealed tube for 2 hours. After this time added an additional amount of imidazolin-2-sulfonic acid (0,12 mg; 0.75 mmol) and continued the reaction for another 16 hours. This solution was concentrated in vacuo and the residue was transferred into a solution l3/isopropyl alcohol (3:1), then PR is recristallization of l3to obtain pure 6-(imidazolidin-2-ylideneamino)-5-methyl-4H-benzo[1,4]oxazin-3-one (8) (E) (0,048 g) as a white powder with a yield of 15% along with 35% of newly received source material. To a suspension of compound (8) (0.08 g; 0,321 mmol) in anhydrous THF (50 ml) in a three-neck round bottom flask equipped with a reflux condenser, under argon was added borane-dimethylsulfide complex of 0.48 ml; 0,936 ml). This mixture was heated at a temperature of education phlegmy until the original material is no longer detected by thin-layer chromatography (3 hours). The reaction mixture was cooled to room temperature and carefully extinguished by adding methanol dropwise. The crude mixture was concentrated in vacuo, and purified flash chromatography on silica, using a mixture of 20% methanol saturated with ammonia/chloroform, to obtain imidazolin-2-ilidene-(5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)amine (9) (G) (0.03 g) as a HCl-salt with a yield of 37%.

1H-NMR (Dl3): 2.07 (s, 3H); 3.46 (t, J=4.3 Hz, 2H); 3.55 (s, 4H), 4.24 (t, J=4.3 Hz, 2H); 5.60-5.95 (vbrs, 2H); 6.44 (d, J=8.0 Hz, 1H); (d, J=8.0 Hz, 1H).

Example 3

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

Procedure

1-(N,N-Dimethylsulphamoyl)imidazole (1.5 g; pole stirring at C for 1 hour was added to TBS-CL (1.3 g; 8,56 mol) in 10 ml of THF. Bath was removed and the reaction mixture was allowed to warm to K. so 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 min was added phenoldisulfonic (1,9 g; 8.6 mmol) in 8 ml THF. The reaction mixture was stirred at K. so within 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. This solution was dried over sodium sulfate and solvent was removed under reduced pressure. Flash chromatography (2.5% of tO/hexane) gave 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 the solution was cooled to 0C. To the solution was added dropwise TBA-F (7,0 ml; 7.0 mmol). This reaction mixture was stirred over night at K. so the next day the reaction mixture was extinguished with water and was extracted with ethyl acetate. The organic layer was washed with water and then brine. This solution was dried over sodium sulfate and solvent was removed under reduced pressure. Flash chromatography (50% tO/hexane) gave 474 mg dimethylamide 5-phenylsulfanyl. Cl and the solution was heated at a temperature of education phlegmy within 2 hours. The reaction mixture was made alkaline 2 N. sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with water and then brine. This solution was dried over sodium sulfate and solvent was removed under reduced pressure. Flash chromatography (tO) gave (3) in the form of a white crystalline substance. The total yield (3) was 360 mg (2.0 mmol).

1H-NMR (300 MHz, CD3D): 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 salt 4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4,5-dihydro-1H-imidazole, salt methanesulfonic acid:

Procedure

To 1,2,3,4-tetrahydronaphthalen-2-carboxylic acid (1) (4,93 g; 27,42 mmol) in anhydrous THF (250 ml) at 20 ° C under argon syringe was added 3,26 ml (32,90 mmol) of borane-dimethyl sulfide (BH3-Me2S). After stirring for 16 hours was added Meon (4 ml) and the mixture was heated to 55C, until he ceased to stand out gas. The mixture was concentrated to oil, carried in Et2O and then washed with 2 M phosphoric acid, saturated sodium bicarbonate, water and brine, and then dried over gSO4and again receive the pure alcohol (1,2,3,4-tetrahydronaphthalen-2-yl)methanol (2) (4.09 g) with a yield of 93%. 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) and benzene (75 ml), and then the compound (2) in benzene (50 ml). After 3 hours was filtered, the solids and the filtrate was evaporated in vacuo to a volume of 50 ml, to which was added hexane (200 ml). The obtained solid substance was filtered, the filtrate was washed successively 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 a yield of 90%. To the compound (3) (10,02 g; eur36, 85 mmol) and CuI (1,41 g; 7,37 mmol) in anhydrous THF (50 ml) at-C under argon slowly, with the speed at which appeared the color, added vinylmania (1M in THF; 73,70 ml; 73,70 mmol). This solution was allowed to warm up and stirred it for 6 hours. The resulting mixture was again cooled to-40C and extinguished by careful addition of 2 M phosphoric acid (35 ml). This solution was diluted with water (100 ml) and was extracted with hexane. The organic fraction was washed successively with water and brine, dried over MgSO4and concentrated in vacuum. On the of trihydroxyflavone (4) (5,618 g) with a yield of 88%. The compound (4) (5,615 g; 32,645 mmol) and m-chlorbenzoyl acid (m-KBC) (14,08 g; 81,613 mmol) was stirred in anhydrous methylene chloride (50 ml) for 16 hours. Was filtered solids, was added potassium fluoride (KF) (5,11 g; 88,142 mmol) and stirred the mixture for another 1 hour. Was filtered, the solids and the reaction mixture was concentrated in vacuum. The resulting oil was purified flash chromatography on silica using 5% ethyl acetate in hexane, to obtain 2-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)oxirane (5) (5,41 g) with a yield of 88%. To the compound (5) (1,62 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 85C and was stirred for 48 hours. The solution was concentrated in vacuo, the residue was transferred into a CH3CL and washed successively with water and brine, dried over gSO4and concentrated in vacuum. The resulting oil was purified flash chromatography on silica, using a mixture of 30% ethyl acetate in hexane, to obtain pure 1-azido-3-(1,2,3,4-tetrahydronaphthalen-2-yl)propan-2-ol (6) (1,762) with the release of 88%. A mixture of compound (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) were the Xan (25 ml) and ether (25 ml) and was stirred for 16 hours. Was filtered, the solids and the filtrate was concentrated in vacuum. The resulting oil was purified flash chromatography on silica with a mixture of 20% ethyl acetate in 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 impurities, which is used further without additional purification. A mixture of compound (7) (3,93 g; 10,917 mmol) and hydrazine (0,680 ml; 21,833 mmol) was heated in ethanol (60 ml) at a temperature of education phlegmy for 16 hours. Was filtered, the solids and the filtrate was concentrated in vacuum. The residue was purified flash chromatography on silica with a mixture of 5% Meon in CH2Cl2obtaining 1-azidomethyl-2-(1,2,3,4-tetrahydronaphthalen-2-yl)ethylamine (8) (2.057 g) with a yield of 88%. A mixture of compound (8) (2,056 g; 8,940 mmol) and 10% palladium on carbon (is 0.260 g) was stirred in Meon (30 ml) under hydrogen at atmospheric pressure for 16 hours. Was filtered, the solids and the filtrate was concentrated in vacuum. The residue was purified flash chromatography on silica with a mixture of 10% methanol saturated with ammonia in CH2Cl2with 3-(1,2,3,4-tetrahydronaphthalen-2-yl)propane-1,2-dione (9) (1,557 mg) with a yield of 85%. The mixture of compounds within 3 hours. Concentrated the reaction mixture under vacuum and filtered solids. Subsequent recrystallization of these solids from a mixture of the Meon and ether gave pure salt methanesulfonic acid 4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4,5-dihydro-1H-imidazole (I) (0,435 g) with a yield of 48%.

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), 3.38-3.59 (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:

Procedure

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 compound (1) are added dropwise n-BuLi (8,9 ml; of 14.2 mmol). The resulting solution was stirred at-20 ° C for 45 minutes. Then the reaction mixture is added dropwise cyclohexylmaleimide (2) (3,13 mg, 14 mmol). Then heat the reaction mixture to K. T. and stirred over night. The next day, quench the reaction mixture with saturated ammonium chloride and diluted with water. This mixture is extracted with ethyl acetate (3100 ml). Combine the organic layers and washed with water and then brine. Dried organize/hexane) gives of 2.26 g (5.6 mmol) of 5-cyclohexylmethyl-2-tert-butyldimethylsilyl-1-dimethylsuberimidate (3). Connection (3) (of 2.26 g; 5.6 mmol) is transferred in 56 ml of THF and cooled to 0C. To a solution of compound (3) is added dropwise a 1 M solution of TBA-F in THF (5.6 ml; 5.6 mmol). This reaction mixture is heated to K. T. 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. Dried the organic phase over sodium sulfate and remove the solvent under reduced pressure. Flash chromatography (1:1, ethyl acetate/hexane) to give 1.2 g (4,42 mmol) 5-cyclohexylmethyl-1-dimethylsuberimidate (4). The compound (4) (1.2 g; was 4.42 mmol) is transferred into 25 ml of 1.5 n HCl and heat at a temperature of education phlegmy within 2 hours. Bring the pH of this mixture to 13 with sodium hydroxide (2 BC), and then extracted with her chloroform (4100 ml). The organic layers are combined and washed with water and then brine. Dried the organic phase over sodium sulfate and remove the solvent under reduced pressure. Flash chromatography (9:1, chloroform/methanol) to give 700 mg (4,27 mmol) 4(5)-cyclohexylmethyl-1H-imidazole (5) (K-1).

1H-NMR (CDCl3): 0.92-1.0 (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 using dmutil-1,2,3,4-tetrahydronaphthalen was obtained from (S)-1,2,3,4-tetrahydro-2-Naftowy acid. (S)-1,2,3,4-Tetrahydro-2-Naftowy acid was obtained by separation of 1,2,3,4-tetrahydro-2-Naftowy acid (J. Med. Chem. 1983, 26, 328-334).

Example K-3

In the method of example-1 was used (R)-2-iodomethyl-1,2,3,4-tetrahydronaphthalen obtaining (R)-4(5)-(1,2,3,5)-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole. (R)-2-Iodomethyl-1,2,3,4-tetrahydronaphthalen was obtained from (R)-1,2,3,4-tetrahydro-2-Naftowy acid. (R)-1,2,3,4-Tetrahydro-2-Naftowy acid was obtained by separation of 1,2,3,4-tetrahydro-2-Naftowy 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:

Procedure

4,5,6,7-Tetrahydrobenzo[b]thiophene (1) (2.1 g, 15 mmol) is transferred into 75 ml of anhydrous THF and cooled to-S. To a solution of compound (1) are added dropwise n-BuLi (6.0 ml; 15 mmol). The resulting solution was stirred at-C within 60 minutes. To this 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 room temperature and stirred for 2 hours and then quenched with water and diluted with ethyl acetate. The organic layer is washed with water, and then rosolare (1:3, the ethyl acetate/hexane) to give 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). Connection (3) (5,2 g; 11.3 mmol) is transferred in 57 ml of THF. To a solution of compound (3) is added dropwise a 1 M solution of Tetra-n-butylammonium (TBA-F) in THF (11.3 ml; 11.3 mmol). The reaction mixture is stirred for 1 hour and 15 minutes, and then quenched with water then extracted with ethyl acetate. Washed the organic layer with water and then brine. Dried the organic phase over sodium sulfate and remove the solvent under reduced pressure. Recrystallization from a mixture of hexane/ethyl acetate gives dimethylamide 5-[hydroxy-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)methyl]imidazole-1-sulfonic acid (4) (2.1 g; 6.2 mmol). Besides, additionally give 2 g of crude product. The compound (4) (2.0 g; 5.9 mmol) is transferred in 78 ml of dichloromethane, are added to a solution of 7.5 ml (46,9 mmol) of triethylsilane and 14.4 ml (0,19 mol) triperoxonane acid. This reaction mixture is stirred overnight and then quenched with water and neutralized with sodium hydroxide (2 BC). The organic layer was washed with water and then brine. Dried the organic phase over sodium sulfate and remove the solvent in below the amide 5-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-ylmethyl)imidazole-1-sulfonic acid (5). The compound (5) (0,42 g; 1.55 mmol) is transferred into 15 ml of 1.5 n HCl and heated at a temperature of education phlegmy for 2 hours and then stirred at K. I. during the night. This reaction mixture was diluted with ethyl acetate and neutralized with sodium hydroxide (2 BC). The organic layer was washed with water and then brine. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. 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); 2.65-2.69 (m, 2H); 2.51-2.55 (m, 2H); 1.74-1.83 (m, 4H).

Example L-2

In the method of example L-1 was used 2-(tert-butyl)furan with obtaining 4(5)-(5-tert-butylfuran-2-ylmethyl)-1H-imidazole.

Example L-3

In the method of example L-1 was used 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:

Procedure

2-(tert-Butyldimethylsilyl)-1-(dimethylsulphamoyl)imballi n-BuLi (7.2 ml; of 11.4 mmol). The resulting solution was stirred at-S within 30 minutes. To this reaction mixture are added 2-furfural (2) (0,94 ml; of 11.4 mmol). The reaction mixture is heated to room temperature and stirred over night. The next day the reaction mixture was quenched with saturated ammonium chloride and diluted with ethyl acetate. Washed the organic layer with water and then brine. Dried the organic phase over sodium sulfate and remove the solvent under reduced pressure. Flash chromatography (4:1 ethyl acetate/hexane) to give 4.4 g (11,4 mmol) dimethylamine 2-(tert-butyldimethylsilyl)-5-(furan-2-elgeroctober)imidazole-1-sulfonic acid (3). Connection (3) (4.4 g, to 11.4 mmol) is transferred in 110 ml of THF and cooled to 0C. To a solution of compound (3) is added dropwise a 1 M solution of Tetra-n-butylammonium (TBA-F) in THF (11,4 ml of 11.4 mmol). The reaction mixture was stirred at K. I. during the night. The next day the reaction mixture was quenched with water then extracted with ethyl acetate. Washed the organic layer with water and then brine. Dried the organic phase over sodium sulfate and remove the solvent under reduced pressure. Allot of 3.9 g of the crude dimethylamide 5-(furan-2-elgeroctober)imidazole-1-sulfonic acid (4). Connection th the mixture is stirred over night, and then filtered through celite. Collect the eluent and remove the solvent under reduced pressure. Flash chromatography using mixtures of ethyl acetate and hikasa (1:1) gives 0,69 g (2.6 mmol) of dimethylamine 5-(furan-2-ylcarbonyl)imidazole-1-sulfonic acid (5). The compound (5) (0,69 g; 2.6 mmol) is transferred in 26 ml of THF. This solution is cooled to -78°C. 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 K. T. and stirred for further 1 hour. The reaction mixture was quenched with water then extracted with ethyl acetate. Washed the organic layer with water and then brine. Dried the organic phase over sodium sulfate and remove the solvent under reduced pressure. Crystallization from a mixture of ether/hexane gives 0.39 g (1.4 mmol) of dimethylamine 5-(1-furan-2-yl-1-hydroxyethyl)imidazole-1-sulfonic acid (6). Allocate additional 0,19 g of compound (6). The compound (6) (0,58 g; 2.0 mmol) is transferred into 27 ml of dichloromethane, and to this solution was added to 2.6 ml (16.3 mmol) of triethylsilane and 5.5 ml (71,4 mmol) triperoxonane acid. This reaction mixture is stirred at K. I. during the night and neutralized with solid sodium bicarbonate. Washed the organic layer with water and then brine. Dry fotografia using a mixture of ethyl acetate and hexane (2:1) gives 0,53 g (2.0 mmol) of dimethylamine 5-(1-furan-2-retil)imidazole-1-sulfonic acid (7). Compound (7) is transferred into 10 ml of 1.5 n HCl and heat at a temperature of education phlegmy for 30 minutes and then stirred at K. I. during the night. The reaction mixture was diluted with ethyl acetate, and then made alkaline with sodium hydroxide (1 BC). Washed the organic layer with water and then brine. Dried the organic phase over sodium sulfate and remove the solvent under reduced pressure. Flash chromatography (10:1 chloroform/methanol) to give 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 (t, 1H), 6.06-6.07 (t, 1H), 4.22 (q, J=7.2 Hz, 1H), 1.63 (d, J=7.2 Hz, 3H).

Example N

Method for producing 4(5)-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-methyl-1H-imidazole:

Procedure

4-Methyl-1-(dimethylsulphamoyl)imidazole (1) (2.0 g; 10.6 mmol) was transferred in 42 ml of anhydrous THF and cooled to-S. To a solution of compound (1) was added dropwise n-BuLi (6.6 ml; 10.6 mmol). The resulting solution was stirred at-S within 30 minutes. To the reaction mixture was added tert-butyldimethylsilyl (TBS-CL) (1.6 g; 10.6 mmol). The reaction mixture was heated to K. T. and stirred over night. The next day the reaction mixture was cooled to-20C and DOB is dioxane-6-carboxaldehyde (2) (1.92 g; 11.7 mmol) in 10 ml of THF. Then the reaction mixture was heated to K. T. and stirred for 3 hours. The reaction mixture was extinguished with water and diluted with ethyl acetate. Washed the organic layer with water and then brine. Dried the organic phase over sodium sulfate and solvent was removed under reduced pressure. Flash chromatography (1:2, ethyl acetate/hexane) gave 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). Connection (3) (1.0 g; 2.14 mmol) was transferred in 21 ml of THF. To a solution of compound (3) was added dropwise a 1 M solution of Tetra-n-butylammonium (TBA-F) in THF (2.35 ml of 2.35 mmol). The reaction mixture was stirred at K. I. within 30 minutes. The reaction mixture was extinguished with water, and then extracted with ethyl acetate. Washed the organic layer with water and then brine. Dried the organic phase over sodium sulfate and solvent was removed under reduced pressure. Flash chromatography using ethyl acetate as eluent gave 0.75 g (2,12 mmol) dimethylamide 5-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydroxymethyl]-4-Mei-1-sulfonic acid (4). The compound (4) (0.75 g; 2,12 mmol) was transferred into 28 ml of dichloromethane and added to this is ivali during the night when K. T., and then extinguished with water and neutralized with solid sodium bicarbonate. The organic layer was washed with water and then brine. Dried the organic phase over sodium sulfate and solvent was removed under reduced pressure. Flash chromatography using mixtures of ethyl acetate and hikasa (3:1) gave 0,63 g (of 1.87 mmol) dimethylamide 5-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-Mei-1-sulfonic acid (5). The compound (5) (0,63 g; of 1.87 mmol) was transferred into 10 ml of 1.5 n Hcl solution and was heated at a temperature of education phlegmy. This reaction mixture was diluted with ethyl acetate and neutralized with solid sodium bicarbonate. Washed the organic layer with water and then brine. Dried the organic phase over sodium sulfate and solvent was removed under reduced pressure. Crystallization from a mixture of ether/hexane gave 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 (O-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):

2SO4when the forming temperature phlegmy. The reaction mixture was cooled to K. T., and made alkaline with saturated K2CO3. This solution was extracted with a mixture of THF/ethyl acetate. Combined organic layers was washed with brine. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification with flash chromatography (15:1, CH3CL/Meon) gave 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).

With the use of NaOH cleaners containing hydrochloride salt of O-1 was obtained free base was added to diethylene glycol (100 ml). To this solution was added hydrazinehydrate (3.2 ml; 100 mmol) and the reaction mixture is left overnight to paramashiva the reaction mixture was cooled to K. so and diluted with water. This solution was extracted with a mixture of THF/ethyl acetate. Combined organic layers was washed with brine. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification with flash chromatography (8:1, CH3CL/Meon) gave 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).

Connection O-2 (1.0 g; 4.6 mmol) was added to 10 ml of concentrated HCl. This solution was stirred at K. I. for 30 min, and then neutralized with potassium carbonate. The solution was extracted with a mixture of THF/ethyl acetate. Combined organic layers was washed with brine. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification with flash chromatography (15:1, CH3CL/Meon) gave 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

Method for producing 4(5)-octahydrophenanthrene-2-ylmethyl)-1H-imidazole hydrochloride:

Procedure

A. Following the synthesis of white and Whitsell (White and Whitesell, Synthesis, pp. 602-3, 1975), in a flame dried flask, cooled to 0 C and under argon atmosphere, was added ether (10 ml). Then slowly added n-utillity the ri 0C for 30 minutes. To this resulting solution of diisopropylamide lithium was added oxide cyclooctene (5.0 g; 1.0 EQ.). The mixture was stirred at K. so in one day, and then was heated to a temperature of education phlegmy in argon atmosphere for 2 days. The reaction mixture was suppressed by the addition of NH4Cl. The solution was extracted with a mixture of THF/tO. Combined organic extracts were washed them with brine, dried over magnesium sulfate and concentrated to obtain a yellow-brown oil, which was a 1-hydroxyacetophenone. This compound was used in the next stage without additional purification.

B. thus Obtained alcohol (5.0 g; 1 EQ.) was dissolved in dichloromethane (200 ml), was added to this solution chlorproma pyridinium (13 g; 1.5 EQ.) and stirred the mixture at K. T. in one day. Then filtered the solution through a short column with SiO2using as eluent diethyl ether. The resulting solution was concentrated in vacuum to obtain a pale yellow-green oil which was used in the next stage without additional purification.

Century Octahydrophenanthrene-1-he (5.0 g; 1.0 EQ.) from the previous stage was added to 4(5)-imidazolecarboxaldehyde (3.8 g; 1.0 EQ.) and oxide ammonium and extracted the reaction mixture with a mixture of tetrahydrofuran/ethyl acetate. Combined organic extracts were washed their brine and dried over magnesium sulfate. The obtained organic layer was neutralized with a mixture of HCl/NH4Cl. Re-extracted water layer, as described above, and has concentrated the combined organic fractions in vacuo to obtain an orange solid.

Was This orange solid was dissolved in ethanol, to which was added palladium on carbon (0.5 g). The reaction flask in one day was placed under hydrogen at a pressure of 40 pounds per square inch). The reaction solution was filtered through celite with additional ethanol as eluent. The solution was concentrated in vacuum to obtain a yellow-brown oil. Purification of column chromatography using a mixture of chloroform/methanol (17:1) gave the product, a ketone, a few dirty.

D. Ketone functional group was removed by adding the product from the previous 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, and then was added potassium hydroxide (1.0 g; 5.0 EQ.) and the solution was heated at a temperature of education phlegmy in one day. The reaction solution was cooled to K. T. and prabhatam magnesium and concentrated to obtain a yellow oil. Salt, monohydrochloride, was obtained by dissolving this oil in anhydrous ethanol saturated with Hcl, and heated.

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):

Procedure

A. 3,4-Lutidine (21,44 g; 1 EQ.) was dissolved in 200 ml of water at 20°C was added potassium permanganate portions on 6,32 g twice a day for 5 days (total of 63.2 g; 2 EQ.). After 5 days, the solution was kept in the freezer, then thawed and filtered through celite. The obtained colorless solution was concentrated at 90 ° C in a rotary evaporator to yield a white solid. This solid is recrystallized from 5 N. Hcl obtaining of 9.56 g of white crystals. NMR showed the presence of a mixture of two regioisomers, and the main product was the desired isomer.

B. the crystals within 6 hours was heated in anhydrous ethanol saturated Hcl, under argon and at a temperature of education phlegmy. The ethanol is then removed from the solution on a rotary evaporator, the residue was transferred into 100 ml of water and brought the pH to 7-8 with solid sodium bicarbonate. Three times were extracted aqueous phase with diethyl ether, echolucent colorless oil (are 5.36 g; the output of 10.8 per cent).

Century To n-BuLi (11,21 ml; 1.3 EQ.) in 100 ml of anhydrous THF under argon at-S was added via syringe Diisopropylamine (2,84 g; 1.3 EQ.) obtaining in situ diisopropylamide lithium. To this solution in the syringe was added the product of the above stage B (of 3.56 g; 1 EQ.) in 20 ml of tetrahydrofuran and stirred the mixture at-C for 20 minutes. At this point, was added dropwise via cannula MMA (4,85 ml; 2.5 EQ.) in 20 ml of tetrahydrofuran. The solution was stirred for another 2 hours, and then extinguished by the addition of 40 ml of 10% potassium acetate. The solution was allowed to warm to 20 ° C, and then focused it on a rotary evaporator. The aqueous residue was extracted three times with chloroform. Combined fractions were washed with brine and dried over magnesium sulfate, filtered and concentrated to a black solid, which was kept under a deep vacuum. Chromatography on silica gel with a mixture of hexane/ethyl acetate (7/36/4) gave to 2.41 g (58,2%) of the desired product which was used in the next stage without additional purification.

Was the Substance from the stage (0,48 g; 1 EQ.) was dissolved in 1 ml of 6 M HCl and heated at 105C for 16 hours, then concentrated solution on a rotary evaporator at 80 ° C until solid. The residue was transferred into a 2 ml in the om, combined fractions were washed with brine, dried over magnesium sulfate and concentrated to a colorless oil (0,456 g; 93,4%).

D. Isohedron (1,91 g; 1 EQ.), obtained in stage D above, was heated with 4(5)-imidazolecarboxaldehyde (1,25 g; 1 EQ.) when 110S in 15 ml of 40% sulfuric acid for 30 hours. This reaction mixture is kept for several days at 0C under argon. Then the solution was diluted with water (20 ml) and podslushivaet to a pH of 8.9-ammonium hydroxide. The solids were collected by filtration and dried using high vacuum. The product was a yellow solid (2,81 g; 96,1%), consisting of both positional isomers on the Exo-double bond.

That is, the Product of stage D above was dissolved in 150 ml of methanol and to this solution was added Pd/C (0,412 g; 0.15 wt. EQ.). This methanolic solution is then saturated with hydrogen by repeated pumping and re-download of hydrogen. The solution was stirred under hydrogen at a pressure of 1 ATM for 20 hours until TLC did not reveal that the source of unsaturated substances remained. This solution was filtered through celite and concentrated to oil. Chromatography on silica using dichloromethane and methanol (9:1) gave pure product (1.835 squa g; 65,04%) in the form of BS in order the dissolution of solids. Slowly cooled the solution and were not quite white crystals (0,826 g; 74%), which represented a compound R-1. Compound P-2 was obtained by reduction with hydrazine in the same manner as described in stage D of example Paragraph above.

Example

Method for producing (Z)-6-(3H-imidazol-4(5)-ylmethylene)-7,8-dihydro-6N-quinoline-5-it (P-1), (E)-6-(3H-imidazol-4(5)-ylmethylene)-7,8-dihydro-6N-quinoline-5-it (p-2), 6-(3H-imidazol-4(5)-ylmethyl)-7,8-dihydro-6N-quinoline-5-it (p-3), dihydrochloride 6-(3H-imidazol-4(5)-ylmethyl)-5,6,7,8-tetrahydroquinoline (C-4) and 6-(3H-imidazol-4(5)-ylmethyl)octahedrally-5-it (p-5)

Procedure

A. Reactive isidorean first stage was formed in situ by adding dropwise through the addition funnel of monochloride iodine (67,6 g; 1.15 EQ.) in 50 ml of acetonitrile to a stirred suspension of sodium azide (58,84 g; 2.5 EQ.) in 350 ml of anhydrous acetonitrile at-10 ° C under argon. The addition was completed after 30 minutes, the mixture was stirred for another 30 minutes and the syringe was added cyclohexene (34,81 g; 1.0 EQ.), and then was stirred at 20 ° C for another 20 hours. Then poured the mixture in a quart of water and was extracted with three portions of 200 ml of diethyl ether. Combined fractions were washed with 5% solution of thiosulfate at 20C. The residue was transferred into 1 l of dimethyl sulfoxide at 0 C, was added to the second portion NN3and stirred the mixture, stirring to ambient temperature. Then diluted the mixture with ice water (2.5 l) and ten times was extracted with dichloromethane (10250 ml). Concentrated the combined organic fractions on a rotary evaporator to a volume of about 1 liter and was extracted with this concentrate with three portions of 250 ml of water, then brine, and then dried over magnesium sulfate and concentrated to a dark oil (39.5 g) and kept at 40C.

This oil was purified by chromatography on silica, using a mixture of hexane and ethyl acetate (gradient from 9:1 to 8:2). Allocated two isomers, and the first with sidegroups in position relative to the ketone functional group was obtained with the yield 13,22 g, 26.6 per cent. -Isomer was obtained with the yield 15,825, 32,0%.

B. Triphenylphosphine were dissolved in 20 ml dichloromethane and placed in an argon atmosphere at 20 ° C. To this stirred solution was added via cannula-isomer obtained as described above, and kept for 2 hours at 20C. As the reaction of the solution stood out nitrogen, and after 2 hours TLC showed that starting material remained. This solution was concentrated iretan with methanol in a ratio of 95/5. Aminophosphonates intermediate product was obtained with the yield 2,139 g of 65.1%.

Century Aminophosphonate was dissolved in 100 ml of anhydrous o-xylene, and then with stirring, was added 10% Pd/C. Then, to this mixture, a syringe was added freshly acrolein and within 4 hours was heated to a temperature of education phlegmy, then added the rest of acrolein and continued heating at a temperature of education phlegmy for 44 hours under finger reflux condenser under argon. At this point TLC showed that there remains a certain amount of the intermediate product, therefore, was added 0.5 g of Pd/C and again for 8 hours was heated mixture to a temperature of education phlegmy. The mixture was cooled to K. T. and concentrated on a rotary evaporator to remove excess acrolein as there was about 100 ml of o-xylene solution. This solution was cooled by adding ice and was extracted three times 1 N. hydrochloric acid. The combined aqueous fractions were extracted three times Et2O. Then the aqueous phase was cooled to 0C and brought the pH up to about 10 using concentrated NaOH. Then the aqueous phase was extracted five times with 100 ml of chloroform. The combined chloroform fractions were washed with water and then brine and dried over which the SLA with the release of 84.4 per cent.

, 4(5)-Imidazolecarboxaldehyde are condensed with this Hinayana, as described in stage D of example R, and received as C-1 and C-2.

D. Exo-double bond then vosstanavlivali palladium on carbon as described in stage E of example Paragraph above, obtaining two products which were separated by chromatography to obtain p-3 and A.

E. Ketogroup removed the same recovery procedure hydrazine, as described above in stage D of example P, obtaining p-4.

J. the Product of the C-5 with a fully restored quinoline ring received standard reconnection And lithium/ammonia (Li, 10 EQ., in NH3at C for 10 minutes, hydrated NH4OH, gradual heating of the evaporation of NH3).

Example T-1

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

Procedure

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 under argon for 15 hours, after which TLC showed the presence of mainly the desired product with the remnants of a number of the original substances. The initial substance was removed by vacuum at a temperature of from 170 to 220C. The first fraction was slightly contaminated source materials (4.71 g). The second fraction was clean (18,9 g). After application of high vacuum to the first faction, it crystallized. The total yield of fractions amounted to USD 20.11 g (51%).

B. the Product of the above stage And was dissolved in 100 ml of methanol and slightly warmed, then cooled to a temperature of from -35 to-40C and through the solution to missed ozone. After a few minutes of the original substance was begun yet to crystallize from the solution, the solution was heated and added to it another 200 ml of methanol, and then resumed reaction. After about 30 minutes the solution became pale blue. Then it was injected nitrogen passing through the solution for 30 minutes, and then injected into this solution metilsulfate (3.5 ml), then stirred solution for 30 minutes at -30 ° C, and then gave him to be heated with stirring to ambient temperature. After about 48 hours at 20 ° C the mixture was distilled with steam to remove the solvent to obtain a residue in the form of 8.4 g of a yellow-brown oil. This residue was transferred into diethyl ether and was extracted with three portions of 25 ml of 1 N. HCl. The combined aqueous fractions washed three times with diethyl ether. Water restoy phase chloroform. The combined chloroform extracts were twice washed with brine, dried over MgSO4and concentrated to a yellow oil (3,01 g). After keeping under high vacuum for 1 hour remained 2,97, This amount 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 under argon followed by the addition of piperidine, and then acetic acid. This mixture was stirred for 16 hours at 20C. After 20 hours, as was shown by TLC, traces of honokalani not remained. The solids were collected by filtration and washed with a small amount of tetrahydrofuran, and then chloroform. The solids were dried under high vacuum to obtain 6,85 g T-1. The yield of 90.3%.

Example T-2 and T-3

Like to obtain 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.) followed by distillation under vacuum and used in the next stage without additional purification. Yield (crude) 8,28,

The crude product (of 7.96 g) of Viseu,18 g of a pale oil. The yield of 97.8%, assuming that the original substance is pure.

Received 7,8-dihydro-6N-isoquinoline-5-he (1,692 g, 1 EQ.) are condensed with 4(5)-imidazolecarboxaldehyde, as described above in stages, with the receipt of 2.23 g of unsaturated compounds similar to the compound T-1) on the above diagram, with the release of 92.8%. This product was treated with palladium on carbon as described in stage E of example R, in order to restore the Exo-double bond to obtain 6-(3H-imidazol-4(5)-ylmethyl)-7,8-dihydro-6N-isoquinoline-5-it (T-2) with the release of 52%.

The above ketone was reduced by hydrazine and turned into salt, fumarate, as detailed in example P, the phase that is Output during recovery of 62%. Output fumarata after recrystallization 30.4% of 6-(3H-imidazol-4(5)-ylmethyl)-5,6,7,8-tetrahydroisoquinoline (T-3).

Example

The way of measuring selectivity-agonist includes analysis based on technology selection and amplification of the receptor (TSR), as 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, adapted for use with alpha2-receptors. The analysis allows to measure mediated by receptors loss of contact Engibarov antich cells. The increase in the number of cells evaluated using the corresponding transfected gene marker, such as-galactosidase activity, which can be easily measured in the tablet to 96-wells. This reaction causes the receptors that activate G protein, Gq. Alpha2receptors, which are usually associated with Giactivate TSAR-reaction when co-expressed with a hybrid protein Gqwith a domain name recognition Gireceptor, called G2qi5[Conklin et al. (1993) "Substitution of three amino acids switches receptor specificity of Gqa to that of CiA." Nature 363:274-6].

Seeded cells NIH-T at a density of 2106cells in 15-cm plates and incubated in modified according Dulbecco environment the Needle with the addition of 10% calf serum. After one day, cells co-transferout by precipitation of calcium phosphate plasmids for expression in mammalian coding p-SV--galactosidase (5-10 mg), receptor (1-2 mg) and protein G (1-2 mg). In the mix for transfection can be enabled 40 mg DNA salmon sperm. The next day, and 1-2 days add fresh medium, the cells are harvested and freeze an aliquot of 50 tests. Plates of 96 wells of cells thawed and add 100 ál to Alik is prodoljayutsya 72-96 hours at S. After rinsing, phosphate buffered saline determine the enzymatic activity of-galactosidase by adding 200 ml chromogenic substrate (consisting of 3.5 mm o-nitrophenyl--D-galactopyranoside and 0.5% nonidet the P-40 in phosphate buffered saline), 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 receptor-mediated cell proliferation. Define EC50and the maximum effect of each drug on each alpha2the receptor. Efficiency or internal 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 alpha2Cuse brimonidine, also called UK14,304-18. Oxymetazoline is a standard agonist used for alpha2B-receptor.

The following table 1 presents the values of the internal activity against subtype 2-adrenergic receptors, as they opredeleniya activity selective agonists with respect to the subtype(s) 2B or 2B/C. With respect to the subtype 2A compounds of these examples are not active or show low efficiency (0,4). They have a higher efficiency compared to subtype 2B and 2C, than to subtype 2A. Therefore, unlike ophthalmic 2-adrenergic compounds such as clonidine, brimonidine, the compounds of examples B to T can selectively activate 2-adrenergic receptors

Example f

Reduction of intraocular pressure (IOP) and sedative side effects

IOP was measured at being in full consciousness of female cynomolgus monkeys weighing 3-4 kg with sustained elevated IOP, which was induced in the right eye by photocoagulation of the trabecular network by means of an argon laser. Animals were suitable for experiments within approximately 2 months after surgery. During the experiments, monkeys were sitting in chairs special design (Primate Products, San Francisco) and when you need them fed orange juice and fruit. To measure IOP used pneumotonometer Digilab model 30 R (Alcon, Texas).

Before measurement of IOP each monkey topically applied 25 ál anesthetic (proparacaine) to minimize caused by tonometry discomfort in the eye. Before instillation did two dimensions esteramide compounds were injected in one eye one drop volume of 50 μl, the other eye received the same volume of saline.

The monkeys were tested many 2V or 2V/S-selective compounds of the examples cited. Suddenly, as table 2 shows, that all of these structurally different compounds decrease IOP in the treated eye.

At the same time to measure and evaluate sedative effect according to the following scoring system: 0 = busy condition, typical sounds, movements, etc.; 1 = calm, less movements; 2 = poorly sedation are some sounds, there is a reaction to the stimulation; 3 = sedation, sounds out of print, there are some reactions to the stimulation; 4 = sleep.

Compounds of the present invention also had no sedative action. This contrasts with the effect of clonidine and brimonidine that have a sedative effect.

Table 2. The effects of agonists 2-adrenergic receptors on IOP and sedative state in the minds of cynomolgus monkeys after administration in the eye, in one of which there is increased pressure caused by photocoagulation by an argon laser. Sedation was assessed subjectively during the experiments IOP using the following system of the laboratory sedation, are some sounds, there is a reaction to the stimulation; 3 = sedation, sounds out of print, there are some reactions to the stimulation; 4 = sleep. The number of animals in the group = (6-9).

Example X

Measurement of cardiovascular side effects

Cardiovascular measurements were done in different groups of monkeys using an automatic sphygmomanometer BP 100 S (Nippon Colin., Japan). Intravenous (centuries) introduction of some compounds of the present invention in doses that are 10-30 times higher than the dose of clonidine and brimonidine, not reduced heart rate or not lowered blood pressure. Interestingly, compound 4(5)-3-methylthiophene-2-ylmethyl)-1H-imidazole, which has an intrinsic activity of 0.43 compared to 2A-subtype, had a weak effect on heart rate. Clonidine and brimonidine had even stronger effects on heart rate. See table 3 below.

Table 3. The effects of agonists 2-adrenergic receptors on cardiovascular parameters in conscious cynomolgus monkeys after centuries of doing. The measurements were made periodically during the term of up to 6 hours. The number of animals per group = (6-10).

Of A2-adrenergic agonists, known from the prior art, which can activate all three subtypes of A2-receptors, has a sedative effect, hypotension and bradycardia, which prevents or severely restricts their use to treat diseases and disorders, which are known to be facilitated by these agonists. Such diseases and disorders include muscle spasticity, including hyperactive urination, diarrhea, diuresis, withdrawal symptoms, pain, including neuropathic pain, neurodegenerative diseases, including ocular neuropathy, ischemia of the spinal cord and stroke, deficits in memory and cognitive abilities, attention deficit disorder, psychoses, including manic disorders, anxiety, depression, hypertension, congestive heart failure, ischemia of the heart and nasal congestion [Hieble et al. "Therapeutic application of agents interacting with alpha-adrenoreceptors, in Alpha-adrenoreceptors: molecular biology, biochemistry and pharmacology". Prog. Basic Clin. Pharmacol. (Basel, Karger) 8, pp. 180-220 is Anna with cancer and neurogenic pain. But, as has been established [Maze M. B. and Tranquilli W. "Alpha-2 adrenoreceptor agonists: defining the role in clinical anesthesia". Anesthesiology 74, 581-605 (1991)], "full clinical perspective" of this and other of A2-agonists requires the development of compounds that do not have a sedative action, hypotension and bradycardia.

The above diseases and disorders can be treated by activating receptor subtype 2B or 2B/C. Therefore, A2-compounds described above, which, as shown, does not have a sedative and cardiovascular effects, suitable and have the advantage of treating these conditions.

Another new example of the usefulness of the compounds according to the invention is an improvement relating to neuronal degeneration in glaucomatous neuropathy. Recent studies have shown that clonidine and other of A2-agonists are neuroprotective in relation to the cells of the retina in several models of neuronal degeneration in rats. These models are called the light of the degeneration of photoreceptors in white rats, as described in Wen et al., "Alpha2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage." J. Neurosci. 16, 5986-5992, and calibrated damage to the optic nerve, which leads to W is ha-2-adrenergic 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 (from 0.1 to >1 mg/kg intraperitoneal and intramuscular) also has a sedative effect and cardiovascular effects. Sensitive indicator of activation of A2-receptors in the retina is the induction of expression of basic fibroblast growth factor (ORF) (see Wen et al. above), and measurement of the induction off after local injection of A2-agonists in the eyes of rats shows that about 1% of the dose required to induce increasing levels off 2-3 times, which corresponds mediated by A2-agonists are neuroprotective action (see Wen et al. above and Lai et al., "Neuroprotective effect of ocular hypotensive agent brimonidine", in Proceedings of XIth Congress of the European Society of Ophthalmology (Bologna, Monduzzi Editore), 439-444). It is known that these existing local dose of A2-agonists, such as clonidine, lead to systemic side effects such as sedation and hypotension, which would prevent their use as eye neuroprotective agents. In addition, the use of some non-selective 2-adrenergic agents in the treatment of neuronal damage disclosed and claimed in the es here by reference.

Compounds of the present invention does not have a sedative and cardiovascular effects in monkeys after local injection in doses of at least 3%. Thus, it is possible to achieve neuroprotective concentrations of these compounds in humans without causing side effects. In fact, as mentioned below, it was shown that the compound of example B-9(b) is neuroprotective in a model calibrated to damage to the optic nerve in rats, which is described in the above work Yoles et al. Cm. table 4 below.

This level of neurotoxity effect is comparable to that observed in previous studies with the standard agonist at A2-adrenergic receptors, brimonidine, and neuroprotective agent MC.

Example H

Relief of pain, including neuropathic pain, which is another example of a disorder in which useful and have the advantages of the compounds according to this invention, since the pain eases without unwanted side effects. Clonidine, an agonist that activates all three subtypes of A2-receptors, was used for the treatment of chronic pain clinically, but its applicability for this indication is limited because he okazyvaniya and brimonidina in a model of neuropathic pain in rodents which, as you know, gives the opportunity to predict clinical activity [S. Kim And J. Chung, "An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat." Pain 50, pp. 355-363 (1992)]. After ligation of the two spinal nerves in animals have evolved a sensitivity to not normally painful stimuli, such as touch. The ability of compounds which are of A2-agonists to reverse this sensitivity is called allodynia was tested 30 minutes after a dose in the meninges or in the abdominal cavity. Also measured the sedative activity of each connection using the camera to determine the activity.

Compounds according to this invention, presented as example compound O-1, is able to alleviate allodynia without sedative action even at very high doses. This contrasts with clonidine and brimonidine that have a sedative effect at doses only slightly higher their anthologising doses. Cm. tables 5 and 6 below.

The results of these examples demonstrate that the usual side effects 2-adrenoceptor drugs mediated by receptor subtype 2A and that their action against increased intraocular tocapture connection unrelated structural classes, who have low functional activity against receptor subtype 2A, reduce IOP and provide other therapeutic effects without limiting dose side effects.

The example of the pharmaceutical compositions according to the invention

Solution, %:

Active connection

(5-phenylsulfanyl-1H-imidazol

in the form of a white crystalline substance) 2

Saline

(0.9% NaCl in water) 98

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

Although specific embodiments of this invention have been described, it should be clear that the invention is not limited, as there can be many obvious modifications, and that the invention will include any such modification, which will fall under the scope of the attached claim.

1. The compounds having the activity of a selective agonist in relation to adrenergic receptor subtype(s) 2B or 2B/2C on CPA who mules:

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 that represents the

is a double bond;

Y represents O, N, S, (CR1x)ywhere I = 1, 2, or 3, -CH=CH - or-Y1CH2- where Y1represents O, N or S; x = 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 alkoxy, or being attached to a saturated carbon atom, R2can represent oxo;

R3and R4each represents H, lower alkyl, hydroxy, lower alkoxy or phenyl, or together represent -(C(R2)x)z-, -Y1(C(R2x)z’-, -Y1(C(R2)x)yY1- and -(C(R2)x)-Y1-(C(R23or R4with the formation of a condensed ring structure

and educated thus the ring may be fully unsaturated, partially unsaturated or fully saturated, provided that a ring carbon is not more than 4 valences, nitrogen is not more than three, and S have no more than two,

including its pharmaceutical acceptable salts, excluding the compounds in which

a) X represents-CH2-; R2and R4are N; Y is S; R3represents a bromine or methyl and R represents hydrogen;

(b) R3and R4together represent -(CH)4-; Y represents -(CH2)2-; X represents-CH2-; Deputy R2on the circular structure represents H or oxo and R represents hydrogen;

(C) X represents-CH2- or =CH-; Y represents -(CH2)-; R3and R4together represent -(CH)4-; Deputy R2on the circular structure represents oxo and R is CR4together represent -(CH)4-; Deputy R2on the circular structure represents H or oxo and R represents hydrogen; and

(d) R3and R4together represent -(CH)2(OCH3)CH-; Y represents -(CH2)2-; X represents-CH2-; Deputy R2on the circular structure represents H or oxo and R represents hydrogen.

2. Connection on p. 1, where the aforementioned compound represented by the formula

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

3. Connection on p. 2, where X represents a C(H)R1.

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. 5, where R3represents N, and R4represents tert-butyl.

8. Connection on p. 5, where R3and R4represent N.

9. Connection on p. 5, where R3represents N, and R4p is

represents a thienyl radical.

11. Connection on p. 10, where R3and R4together are (CH2)4.

12. Connection on p. 10, where R3represents phenyl, and R4represents N.

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

14. Connection on p. 10, where R3and R4represent N.

15. Connection on p. 10, where R3and R4together are (CH)4.

16. Connection on p. 10, where R3represents H, a R4represents methyl.

17. Connection on p. 10, where R3represents bromo, and R4represents N.

18. Connection on p. 4, where

represents tsiklogeksilnogo radical.

19. Connection on p. 18, where R2represents N, and R3and R4together are (CH)4.

20. Connection on p. 18, where R2represents N, and R3and R4together are (CH)2S.

21. Connection on p. 18, where R2represents N, and R3and R4together are (CH4.

23. Connection on p. 18, where Y represents-CH2CH(CH3)-, R2represents hydrogen or oxo, and R3and R4together are (CH)4.

24. Connection on p. 18, where R2represents oxo and R3and R4together are S(CH)2.

25. Connection on p. 18, where R2represents oxo and R3and R4together are (CH)4.

26. Connection on p. 18, where R2represents oxo and R3and R4together are (CH)2(OCH3)CH.

27. Connection on p. 4, where

represents cyclopentadienyl radical.

28. Connection on p. 27, where R2represents N, and R3and R4together are (CH)4.

29. Connection on p. 27, where R2represents hydrogen, a R3and R4together are (CH2)3.

30. Connection on p. 4, where

represents a benzyl radical.

31. Connection on p. 30, where R2, R3and R4represent N.

32. Connection on p. 1, where the specified connection is UP> such, as defined in paragraph 1.

33. Connection on p. 32, where X represents C(H)R1, a R, R1, R2, R3and R4represent N.

34. Connection on p. 33, where Y represents O.

35. Connection on p. 34, where Y represents S.

36. Connection on p. 1, where the specified connection has the formula

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

37. Connection on p. 36, where R3and R4together are (CH)4.

38. Connection on p. 37, where Y1represents O.

39. Connection on p. 38, where R2represents oxo.

40. Connection on p. 39, where X represents CH.

41. Connection on p. 39, where X represents CH2.

42. Connection on p. 38, where one of R2represents hydroxy and the other represents N.

43. Connection on p. 38, where R2represents N.

44. Connection on p. 37, where Y1represents S.

45. Connection on p. 44, where X represents CH2.

46. Connection on p. 45, where R2represents oxo.

47. Connection P>represents oxo.

49. Connection on p. 3, where Y is (CH2)3.

50. Connection on p. 49, where X represents CH, and R2represents oxo.

51. Connection on p. 49, where X represents CH2and R2represents N.

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

represents phenyl.

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

is furanyl.

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

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

55. The compound represented by the formula

56. Connection on p. 1, represented by formula

where Y is (CR1x)2;

R3+R4represents (C(R2)x)4;

X attached in one of two positions of the ring, indicated with a wavy line, and the remaining position is occupied by hydrogen, provided that two double bonds may not be the same calzezane compound represented by the formula

in which R2)xrepresents hydrogen or oxo.

58. Connection on p. 56, where the structure is a

59. Connection on p. 57, where the structure is a

60. Connection on p. 2, where R represents hydrogen;

R3+R4 represents -(C(R2)x)-N-(C(R2)x)-(C(R2)x)-, a X is a CHR1as represented by the formula

and the group CHR1attached in one of two positions of the ring, indicated with a wavy line, and the remaining position is occupied by hydrogen, and provided that two double bonds can't be in the same ring atom;

R1and R2such, as defined in paragraph 1.

61. Connection on p. 60, where the specified connection has the formula

and (R2)xrepresents hydrogen or oxo.

62. Connection on p. 60, where the specified connection has the formula

and (R2)xrepresents hydrogen or oxo.

63. Connection on p. 1, where R3+R4selected from the group consisting of-Y1-(C(R2)x)-(C(R2)x-Y1and, as represented by the formula

in which X and X' is selected from the group consisting of N, O and S, and at least one of X and X' represents N;

R1and R2such, as defined in paragraph 1.

64. Connection on p. 63, where the aforementioned compound represented by the formula

in which R1)xrepresents hydrogen or oxo.

65. Connection on p. 63, where the aforementioned compound represented by the formula

in which R2)xrepresents hydrogen or oxo.

66. The compounds having the activity of a selective agonist in relation to adrenergic receptor subtype(s) 2B or 2B/2C or 2B and 2C in comparison with the adrenergic receptor subtype 2A, represented by the formula

and its pharmaceutically acceptable salts.

67. The use of compounds of the formula I

where (a) X represents-CH2-; R2and R4are N; Y is S; R3represents a bromine or methyl and R represents hydrogen;

(b) R3and R4together represent -(CH)4-; Y represents -(CH2)2-; X predstavlja a hydrogen;

(C) X represents-CH2- or =CH-; Y represents -(CH2)-; R3and R4together represent -(CH)4- Deputy R2on the circular structure represents oxo and R represents hydrogen; or

(g) X represents-CH2-; Y represents -(CH2)-; R3and R4together represent -(CH)4- Deputy R2on the circular structure represents H or oxo and R represents hydrogen; and

(d) R3and R4together represent -(CH)2(OCH3)CH-; Y represents -(CH2)2-; X represents-CH2- Deputy R2on the circular structure represents H or oxo and R represents hydrogen,

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

68. The method of introduction of the owner of the mammal, including humans, 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 before the other H or lower alkyl or R1absent when X represents S or when the relationship between X and the ring that represents the

is a double bond;

Y represents O, N, S, (CR1x)ywhere I = 1, 2, or 3, -CH=CH - or-Y1CH2- where Y1represents O, N or S; x = 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 alkoxy, or being attached to a saturated carbon atom, R2can represent oxo;

R3and R4each represents H, lower alkyl, hydroxy, lower alkoxy or phenyl, or together represent -(C(R2)x)z-, -Y1(C(R2)x)z'-, -Y1(C(R2)x)yY1- and -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x)-, where z = 3, 4 or 5, z' = 2, 3, or 4, and x and y are such as defined above,

and, further, each end of each of these divalent groups may be attached to or R3or R4education to the unsaturated color, partially unsaturated or fully saturated, provided that a ring carbon is not more than 4 valences, nitrogen is not more than three, and S have no more than two; 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 R7are OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo;

R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted by lower alkyl;

Z represents O or NH,

for treating or preventing glaucoma without sedative and cardiovascular side effects, and the specified connection has adrenergic activity and is selective agonist adrenergic receptor subtype 2 or subtype(s) 2B/2C in preference adrenergic is, the which is relatively standard full agonist of at least about 0.3 times higher with respect to the adrenergic receptor subtype 2B or 2C than in relation to adrenergic receptor subtype 2A, and its effectiveness in relation to adrenergic receptor subtype 2A is 0.4.

70. The method according to p. 68, wherein the active compound is at least ten times stronger effect on adrenergic receptor subtype 2B or 2C, than adrenergic receptor subtype 2A.

71. The method according to p. 70, wherein from about 0.001 to 5 wt.% active compound is administered to the host topically to a mammal in a daily or twice daily dose.

72. The method according to p. 71, wherein from about 0.01 to 3 wt.% active compound is administered to the host topically to a mammal in a daily or twice daily dose.

73. The method according to p. 68, wherein the specified connection does not have activity against adrenergic receptor subtype 2A.

74. The method according to p. 68, wherein the specified connection does not have activity against adrenergic receptor subtypes 2A and 2C.

75. The method of introduction of the owner of the mammal, including humans, pharmaceutical to the response 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 that represents the

is a double bond;

Y represents O, N, S, (CR1x)ywhere I = 1, 2, or 3, -CH=CH - or-Y1CH-, where Y1represents O, N or S; x = 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 alkoxy, or being attached to a saturated carbon atom, R2can represent oxo;

R3and R4each represents H, lower alkyl, hydroxy, lower alkoxy or phenyl, or together represent -(C(R2)x)z-, -Y1(C(R2)x)z’-, -Y1(C(R2)x)yY1- and -(C(R2)xCLASS="ptx2">

and, further, each end of each of these divalent groups may be attached to or R3or R4with the formation of a condensed ring structure

and educated thus the ring may be fully unsaturated, partially unsaturated or fully saturated, provided that a ring carbon is not more than 4 valences, nitrogen is not more than three, and S have no more than two,

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 R7are OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo;

R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted by lower alkyl;

Z represents O or NH,

the rich the specified connection has adrenergic activity and is selective agonist adrenergic receptor subtype(s) 2B or 2B/2C in preference adrenergic receptor subtype 2A.

76. The method according to p. 75, wherein the active compound has an efficiency which is relatively standard full agonist of at least about 0.3 times higher with respect to the adrenergic receptor subtype 2B or 2C than in relation to adrenergic receptor subtype 2A, and its effectiveness in relation to adrenergic receptor subtype 2A is 0.4.

77. The method according to p. 76, wherein from about 0.001 to 5 wt.% active compound is administered to the host topically to a mammal in a daily or twice daily dose.

78. The method according to p. 77, wherein from about 0.01 to 3 wt.% active compound is administered to the host topically to a mammal in a daily or twice daily dose.

79. The method according to p. 75, wherein the specified connection does not have activity against adrenergic receptor subtype 2A.

80. The method according to p. 75, wherein the specified connection does not have activity against adrenergic receptor subtypes 2A and 2C.

81. 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 grapestone double bond;

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 that represents the

is a double bond;

Y represents O, N, S, (CR1x)ywhere I = 1, 2, or 3, -CH=CH - or-Y1CH2- where Y1represents O, N or S; x = 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 alkoxy, or being attached to a saturated carbon atom, R2can represent oxo;

R3and R4each represents H, lower alkyl, hydroxy, lower alkoxy or phenyl, or together represent -(C(R2)x)z-, -Y1(C(R2)x)z’-, -Y1(C(R2)x)yY1- and -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x)-, where z = 3, 4 or 5, z' = 2, 3, or 4, and x and y are such as defined above,P>3
or R4with the formation of a condensed ring structure

and educated thus the ring may be fully unsaturated, partially unsaturated or fully saturated, provided that a ring carbon is not more than 4 valences, nitrogen is not more than three, and S have no more than two,

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 R7are oc(r9)c(r9)n(r) forming a condensed ring with

where R9represents H, lower alkyl or oxo;

R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted by lower alkyl;

Z represents O or NH,

and have a selective agonistic action on the adrenergic receptor subtype 2 or subtype of(action on adrenergic receptor subtype 2B or adrenergic receptor subtype 2B/2C without agonistic action on the adrenergic receptor subtype 2A, when administered therapeutically effective amount of a selective agonist(s) - receptor subtype 2B or 2B/2C, representing a 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 that represents the

is a double bond;

Y represents O, N, S, (CR1x)ywhere y = 1,2, or 3, -CH=CH - or-Y1CH2- where Y1represents O, N or S; x = 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 alkoxy, or being attached to a saturated carbon atom, R2can represent oxo;

R3and R4each represents-Y1(C(R2)x)z’-, -Y1(C(R2)x)yY1- and -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x)-, where z = 3, 4 or 5, z' = 2, 3, or 4, and x and y are such as defined above,

and, further, each end of each of these divalent groups may be attached to or R3or R4with the formation of a condensed ring structure

and educated thus the ring may be fully unsaturated, partially unsaturated or fully saturated, provided that a ring carbon is not more than 4 valences, nitrogen is not more than three, and S have no more than two,

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 R7are OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo;

R represents H or is Chille alkyl, phenyl or phenyl substituted by lower alkyl;

Z represents O or NH.

83. The use of 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 R7are OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H or oxo;

R represents H;

Z represents NH,

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

84. The method of introduction of the owner of the mammal, including humans, pharmaceutical compositions 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)R

is a double bond;

Y represents O, N, S, (CR1x)ywhere I = 1, 2, or 3, -CH=CH - or-Y1CH2- where Y1represents O, N or S; x = 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 alkoxy, or being attached to a saturated carbon atom, R2can represent oxo;

R3and R4each represents H, lower alkyl, hydroxy, lower alkoxy or phenyl, or together represent -(C(R2)x)z-, -Y1(C(R2)x)z’-, -Y1(C(R2)x)yY1- and -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x)-, where z = 3, 4 or 5, z' = 2, 3, or 4, and x and y are such as defined above,

and, further, each end of each of these divalent groups may be attached to or R3or R4with the formation of a condensed ring structure

and educated tackleway, that ring carbon is not more than 4 valences, nitrogen is not more than three, and O and S have no more than two; 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 R7are OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo;

R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted by lower alkyl;

Z represents O or NH,

for the treatment or prevention of glaucoma, and an active connection has the biological property, which is that this compound is a selective agonist of the receptor subtype(s) 2B or 2B/2C in preference to the receptor subtype 2A, and the specified selectivity measured in the analysis using cells that natural about the human or of the form against which shows that it has similar pharmacology, and in this analysis determined that the effectiveness of the active compounds relative to the standard connections in relation to the receptor subtype 2B or 2C at least 0.3 times higher than the efficiency of active connections relative to the standard connections in relation to the receptor subtype 2A, and its effectiveness in relation to the receptor subtype 2A is 0.4, and/or the active compound is at least about 10 times stronger effect on the receptor subtype 2B or 2C, than the receptor subtype 2A.

85. The method according to p. 84, wherein the host is a mammal is administered topically from about 0.001 to 5 wt.% active compounds in the day.

86. The method of introduction of the owner of the mammal, including humans, pharmaceutical compositions 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 R1no, when what is a double bond;

Y represents O, N, S, (CR1x)ywhere I = 1, 2, or 3, -CH=CH - or-Y1CH2- where Y1represents O, N or S; x = 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 alkoxy, or being attached to a saturated carbon atom, R2can represent oxo;

R3and R4each represents H, lower alkyl, hydroxy, lower alkoxy or phenyl, or together represent -(C(R2)x)z-, -Y1(C(R2)x)z’-, -Y1(C(R2)x)yY1- and -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x)-, where z = 3, 4 or 5, z' = 2, 3, or 4, and x and y are such as defined above,

and, further, each end of each of these divalent groups may be attached to or R3or R4with the formation of a condensed ring structure

and educated thus the ring may be fully unsaturated, partially unsaturated or floor is and S have no more than two;

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 R7are OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo;

R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted by lower alkyl;

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 ocular neuropathy, spinal cord ischemia and stroke, deficits in memory and cognitive abilities, attention deficit, psychoses, including manic disorders, anxiety, depression, hypertension, congestive heart not item the specified connection has adrenergic activity and is selective agonist adrenergic receptor subtype(s) 2B or 2B/2C in preference adrenergic receptor subtype 2A.

87. The method of introduction of the owner of the mammal, including humans, pharmaceutical compositions 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 that represents the

is a double bond;

Y represents O, N, S, (CR1x)ywhere I = 1, 2, or 3, -CH=CH - or-Y1CH2- where Y1represents O, N or S; x = 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 alkoxy, or being attached to a saturated carbon atom, R2can represent oxo;

R3and the t a -(C(R2)x)z-, -Y1(C(R2)x)z'-. -Y1(C(R2)x)yY1- and -(C(R2)x)-Y1-(C(R2)x)-(C(R)x)-, where z = 3, 4 or 5, z' = 2, 3, or 4, and x and y are such as defined above,

and, further, each end of each of these divalent groups may be attached to or R3or R4with the formation of a condensed ring structure

and educated thus the ring may be fully unsaturated, partially unsaturated or fully saturated, provided that a ring carbon is not more than 4 valences, nitrogen is not more than three, and S have no more than two;

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 R7are OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo;

R of t is to place a N, lower alkyl, phenyl or phenyl substituted by lower alkyl;

Z represents O or NH,

for treatment of muscle spasticity, including overactive bladder, diarrhea, diuresis, withdrawal symptoms, pain, including neuropathic pain, neurodegenerative diseases, including ocular neuropathy, spinal cord ischemia and stroke, deficits in memory and cognitive abilities, attention deficit, psychoses, including manic disorders, anxiety, depression, hypertension, congestive heart failure, ischemic heart and nasal congestion without sedative and cardiovascular side effects, and an active connection has biological property that is that this compound is a selective agonist of the receptor subtype(s) 2B or 2B/2C in preference to the receptor subtype 2A, and the specified selectivity measured in the analysis using cells that naturally Express individual 2-subtypes or entered one of these subtypes, and these receptors of the human or of the form on which it is shown that he has similar pharmacology, and in this analysis determines that effective least 0.3 times higher than the effectiveness of the active compounds relative to the standard connections in relation to the receptor subtype 2A, and its effectiveness in relation to the receptor subtype 2A is 0.4, and/or the active compound is at least about 10 times stronger effect on the receptor subtype 2B or 2C, than the receptor subtype 2A.

88. The method of introduction of the owner of the mammal, including humans, pharmaceutical compositions 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 that represents the

is a double bond;

Y represents O, N, S, (CR1x)ywhere I = 1, 2, or 3, -CH=CH - or-Y1CH2- where Y1represents O, N or S; x = 1 or 2, and x = 1 when R2, R3or R4is gerada;

R2represents H, lower alkyl, halogen, hydroxy or lower alkoxy, or being attached to a saturated carbon atom, R2can represent oxo;

R3and R4each represents H, lower alkyl, hydroxy, lower alkoxy or phenyl, or together represent- ((R2)x)z-, -Y1(C(R2x)z’-, -Y1(C(R2)x)yY1- and -(C(R2)x)-Y1-(C(R2)x)-(C(R2)x)-, where z = 3, 4 or 5, z' = 2, 3, or 4, and x and y are such as defined above,

and, further, each end of each of these divalent groups may be attached to or R3or R4with the formation of a condensed ring structure

and educated thus the ring may be fully unsaturated, partially unsaturated or fully saturated, provided that a ring carbon is not more than 4 valences, nitrogen is not more than three, and S have no more than two; or from compounds having the formula

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

where R5, R6, R7and R6or R6and R7are OC(R9)C(R9)N(R) forming a condensed ring with

where R9represents H, lower alkyl or oxo;

R represents H or lower alkyl,

and the group consisting of

where R10represents H, lower alkyl, phenyl or phenyl substituted by lower alkyl;

Z represents O or NH,

for treatment of muscle spasticity, including overactive bladder, diarrhea, diuresis, withdrawal symptoms, pain, including neuropathic pain, neurodegenerative diseases, including ocular neuropathy, spinal cord ischemia and stroke, deficits in memory and cognitive abilities, attention deficit, psychoses, including manic disorders, anxiety, depression, hypertension, congestive heart failure, ischemic heart and nasal congestion without sedative and cardiovascular side effects, and an active connection has biological property that is that this compound is a selective agonist of the receptor subtype(s) 2B or 2B/2C in preference to the receptor subtype 2A, and the criminal code of the torus activation receptor subtype 2A and 2C of the test compound compared to brimonidine, and receptor subtype 2B compare with Oxymetazoline, and in which the corresponding receptor subtypes 2A, 2B and 2C Express in cells NIH-3T3, and in this analysis determined that the effectiveness of the active compounds relative to brimonidine against the receptor subtype 2C or the effectiveness of the active compounds relative to Oxymetazoline against the receptor subtype 2B at least 0.3 times higher than the efficiency of active connections relative to brimonidine against the receptor subtype 2A, and its effectiveness in relation to the receptor subtype 2A is 0.4, and/or the active compound is at least about 10 times stronger effect on the receptor subtype 2B or 2C, than the receptor subtype 2A.

89. The method according to p. 70, wherein the active compound is at least 100 times stronger effect on the receptor subtype 2B or 2C, than the receptor subtype 2A.

 

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

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

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

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

showing property to activate the germination of wheat seeds

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 a method for producing compounds of formula I:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid, R1means phenyl or a straight or branched alkyl or alkenyl and R2means hydrogen or acetyl, which comprises: (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III:

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or a straight or branched alkyl or alkenyl, obtaining the compounds of formula IV:

(C) removing trichloroethylene protective groups of the compounds of formula IV with connection inflectional acetylation of the hydroxyl group in position 10 of the compounds of formula V to obtain the compounds of formula VI:

e) acid hydrolysis oxazolidinone ring compounds of the formula VI to obtain the compounds of formula I

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

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