Imidazole derivatives, method for their preparing, pharmaceutical compositions based on thereof and method for treatment by their using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

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

25 cl, 1 tbl, 14 ex

 

The level of technology

The present invention relates to new pharmacologically active derivatives of imidazole and their pharmaceutically acceptable salts and esters and to methods for their preparation and the pharmaceutical compositions.

It is known that some imidazole derivatives have affinity to alpha-1 and/or alpha-2-adrenoceptors. So, in the publication WO-A-9712874 described imidazole-substituted (1,2,3,4-tetrahydro-1-naphthalenyl)- and (2,3-dihydro-1H-inden-1-yl)derivatives, which are said to have affinity to alpha-2-adrenoceptors, and most of them are selective agonists alpha-2-adrenoceptors. In the patent EP-A-0717037 described derivatives of 4-(1,2,3,4-tetrahydro-1-naphthalenyl)- 4-(2,3-dihydro-1H-inden-1-yl)-1H-imidazole, which have alpha-2-adrenoceptor agonistic and alpha-1-adrenoceptor antagonistic activity. On the other hand, imidazole derivatives described in patent EP-A-0183492, are known to be a selective antagonist of alpha-2-adrenoceptors. Compounds acting on these alpha adrenoceptor, can provide a wide range of effects on the peripheral and/or Central nervous system (CNS) of mammals.

The invention

Found that imidazole derivatives of the present invention exhibit an affinity for alpha-2-adresie the toruses so, they can be useful in the treatment of various disorders or diseases involving the alpha-2-adrenoceptor. Such disorders or diseases include disorders of the Central nervous system (CNS), such as neurological disorders, psychiatric disorders or disturbances of cognitive ability, as well as various disorders of the peripheral system, such as diabetes, orthostatic hypotension, lipolytic disorders (such as obesity) or sexual dysfunction.

Detailed description of the invention

Imidazole derivatives of the present invention can be represented by the following formula (I):

where

X represents-CH2-(CH2)R-, -Oh, =NH, or-S-;

R1represents phenyl, naphthyl,

1,2,3,4-tetrahydronaphthyl,3-C7-cycloalkyl,5-C7-cycloalkenyl,5-C7-cycloalkenyl or mono - or bicyclic aromatic or partially or completely saturated heterocyclic group with 5 to 10 atoms in the cycle, which consists of carbon atoms and one to three heteroatoms selected from N, O and S;

where mentioned phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl,3-C7-cycloalkyl,5-C7-cycloalkenyl,5-C7-cycloalkenyl or mono - or b is a cyclic aromatic or partially or completely saturated heterocyclic group optionally substituted by one to three substituents, independently selected from halogen, -OH, -NH2, halogen-C1-C6-alkyl, C1-C6-alkyl, C2-C6-alkenyl,2-C6-quinil, C1-C6-alkoxygroup, HE(C1-C6-alkyl), NH2(C1-C6-alkyl) and mono - or di (C1-C6-alkyl) amino;

R2represents N or C1-C6-alkyl;

R3represents N or C1-C6-alkyl; and

R4represents N or C1-C6-alkyl;

R5represents H, or R5and R7together form a bond;

each R6independently represents a halogen, -OH, -NH2, halogen-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkoxygroup HE or(C1-C6)-alkyl;

R7represents H, HE or1-C4-alkyl, or R7and R5together form a bond;

each R8independently represents IT, C1-C6-alkyl, halogen-C1-C6-alkyl or C1-C6-alkoxygroup;

m is 0, 1, 2 or 3;

n is 0 or 1;

p is 0 or 1;

r is 0 or 1;

t is 0, 1 or 2;

or their pharmaceutically acceptable esters or salts.

When X represents-CH2-(CH2)pand R is 0, or when X is a =NH,

or

the volumetric Deputy -(CR2R3)r-R1preferably located in the 2 or 3 position of a 5-membered cyclic residue (resulting in the above formulas N-atom attached to the carbon atom of the cycle or the nitrogen atom of the cycle will be replaced by the specified proxy).

When X represents-CH2-(CH2)pand p is 1,

the volumetric Deputy -(CR2R3)r-R1preferably located in the 3 or 4 position of a 6-membered cyclic residue.

These subgroups are (1)to(17) compounds of the formula I, alone or in any combination with each other, are preferred:

1) n is 0;

2) n is 1;

3) n is 1 and R4and R3represent N;

4) r is 0;

5) r is 1, a R2and R3independently represent N or C1-C4-alkyl; preferably H;

6) t is 0;

7) R7represents N;

8) X represents-CH2-(CH2)pand p is 0 or 1;

9) X represents-CH2-(CH2)pand p is 0;

10) X represents-CH2-(CH2)pand p is 1;

11) X represents-O-;

12) R1represents Fe is Il, naphthyl, 1,2,3,4-tetrahydronaphthyl,5-C7-cycloalkyl,5-C7-cycloalkenyl,5-C7-cycloalkenyl, pyridyl, pyrimidinyl, thienyl, furyl, cyclohexyl, piperidyl, piperazinil or morpholinyl; preferably R1represents phenyl, naphthyl, pyridyl, thienyl, furyl or cyclohexyl; for example, R1represents phenyl; or R1represents cyclohexyl;

13) R1has the values defined above in the subgroup (12), substituted by one to three substituents, independently selected from halogen, -OH, -NH2, halogen-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkenyl, C1-C6-quinil and C1-C6-alkoxygroup; preferably one to three, e.g. one or two substituents selected independently from halogen, -HE, C1-C6-alkoxygroup and C1-C6-alkyl; more preferably from F, HE C1-C6-alkoxygroup;

14) m is 0; or m is 1 or 2;

15) m is 1 or 2, and each of the substituents R6independently represents halogen, HE, C1-C6-alkoxygroup or C1-C6-alkyl; preferably F, HE C1-C6-alkoxygroup;

16) n is 0 and X represents-CH2-(CH2)p-; and/or

17) n is 1 and X represents the FDS is th-CH 2-(CH2)p-, -Oh, =NH or

-S-, for example, -CH2-(CH2)p- or-O-.

Preferred subgroups of compounds of formula I are

or

where R1-R8, m, n, r and t have the above specified values.

In the subgroup of compounds of formula I, IA or IB, r is 0 or r is 1, and the substituents R2and R3represent N. In another subgroup of compounds of formula I, IA or IB, n is 0 or n is 1, and the substituents R4, R5and R7represent N.

Preferably t is 0. Optional substituent R6is, for example, in the 5th and/or 6th position of the system EndInvoke cycle.

In another preferred subgroup of compounds I, IA or IB substituent R1represents phenyl, naphthyl, pyridyl, thienyl, furyl or cyclohexyl, for example phenyl, pyridyl or cyclohexyl, for example phenyl or cyclohexyl, for example phenyl, each of which is optionally substituted with one to three substituents, for example one or two substituents selected independently from halogen, -OH, -NH2, halogen-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkenyl, C1-C6-quinil, C1-C6-alkoxygroup, HE-(C1-C6)-alkyl, NH2-(C1-C6)-alkyl and MES is - or di(C 1-C6-alkyl) amino group; for example, from halogen, -HE, C1-C6-alkoxygroup and C1-C6-alkyl; preferably from F, HE C1-C6-alkoxygroup.

In another preferred subgroup of compounds I, IA or IB m is 0 or m is 1 or 2, and each of the substituents R6independently represents halogen, HE or C1-C6-alkoxygroup.

Another subgroup of compounds of formula I are the compounds of formula IC or ID

where R1-R8, m, n, r and t have the above specified values.

Another subgroup of compounds of formula I are the compounds of formula IE

where R1-R8, m, n and r are as defined above values, a t is 0 or 1.

The terms used in the description have the following meanings. Halogen or halo represents fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, more preferably fluorine. The term "C1-C6is an alkyl group"used in the description, by itself or as part of another group includes both straight and branched radicals containing up to 6 carbon atoms, and preferably from 1 to 4 carbon atoms. The term "C1-C6-alkoxygroup" refers to-O(C1-C6)-alkyl, where (C1With 6)-alkyl is as defined above values. The term "C2-C6alkenyl" includes both linear and branched radicals containing up to 6 carbon atoms, preferably from 2 to 4 carbon atoms containing a double(s) relationship (s). The term "C1-C6-quinil" includes both linear and branched radicals containing up to 6 carbon atoms, preferably from 2 to 4 carbon atoms containing a triple(s) relationship (s). The term halogen-C1-C6-alkyl refers to C1-C6-the alkyl radical as defined above which is substituted by one or more halogen radicals defined above, such as trifluoromethyl, deformatio etc. the Term3-C7-cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term "C5-C7-cycloalkyl" means cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopentyl or cyclohexyl. The terms "C5-C7-cycloalkenyl" or "C5-C7-cycloalkenyl" refer to5-C7-cycloalkyl, which is defined above, containing in its cyclic structure double(s) relationship(s) or, respectively, a triple bond. The term "mono - or bicyclic aromatic or partially or completely saturated heterocyclic group of 5 to 10 atoms in the cycle,preferably from 5-6 atoms in the cycle, which consists of carbon atoms and one to three, preferably one or two heteroatoms selected from N, O and/or S refers to pyridyl, pyrimidinyl, tieniu, furillo, piperidinyl, piperazinil or morpholinyl, preferably to pyridyl, tieniu or furillo.

The compounds of formula I and compounds of subgroups IA, IB, IC, ID and IE, as well as their pharmaceutically acceptable esters and salts called hereinafter the compounds of the present invention, unless otherwise stated.

Compounds of the present invention in its structure can be chiral(s) atom(s) of carbon. The invention includes the volume of all possible stereoisomers of the compounds I, including geometric isomers, such as Z and E isomers (CIS - and TRANS-isomers, and optical isomers, for example diastereoisomers and enantiomers. In addition, the invention includes the scope of both the individual isomers and any mixtures thereof, such as racemic mixtures. The individual isomers can be obtained using the corresponding isomeric forms of the source material, or they can be selected after the final connection using a conventional separation methods. For separation of optical isomers such as enantiomers, mixtures thereof can be used conventional separation methods such as fractional crystallization.

Compounds of the present invention may make obyvaci acid additive salts with organic, and inorganic acids, are well known in the field of pharmaceuticals. Typical acid additive salts are, for example, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formate, tartratami, maleate, citrates, benzoate, salicylates, ascorbates. In addition, the compounds of the present invention, in which the substituents R6, R8and/or an optional substituent in the cyclic residue, such as R1represent IT, the HE-functionality can form esters with pharmaceutically acceptable acids that are common in the field of pharmaceuticals and which retain their pharmacological properties of free-form shapes. Examples of such esters are the esters of aliphatic or aromatic alcohols, for example lower alkalemia esters, for example methyl, ethyl and propyl esters.

Compounds of the present invention can be obtained using, for example, the following methods.

(a) Obtaining compounds of formula I where n is 1, can be illustrated, for example, using the following scheme of reactions:

where the substituents X, R1-R4, R6, R8m, r and t are as defined above values, a R' represents H or a conventional protective group for =NH in the imidazole ring is, for example benzyl, trityl (-CPh3or SO2NMe2.

Stage (a) is a normal reaction mix poppy-Murri, i.e. reductive carbonyl combination of imidazolecarboxaldehyde or imidazolylalkyl III ketone II in the presence of a catalyst, for example titanium(0) (for example, obtained in situ), in an inert solvent, such as THF, at room or elevated temperatures. The resulting compounds of formula I where the substituents R5and R7together form a bond (I')may be withdrawn protection, if necessary, and the connection can be isolated by known methods, or transformed by hydrogenation of the double bond into another compound of formula I where the substituents R5and R7represent H (Ia, stage b). At the stage of hydrogenation (b) simultaneously removed possible present protective group in the imidazole ring. The resulting compound of formula I is isolated and processes known in the field of ways;

(b) Obtaining compounds of formula (I), where n is 0 and R7represents H, can be illustrated, for example, by the reaction scheme:

where X, R1-R3, R6and R8, m, r and t are as defined above values, a R' represents a conventional protective group for =NH in the imidazole ring, such as benzyl, Tr is Teal (-CPh 3or SO2NMe2.

In the scheme of reactions In the compound of formula II is initially interacts with the compound of the formula IV in the presence of Grignard reagent, such as EtMgBr, in a suitable solvent, for example in CH2Cl2in dry conditions the reaction at room or elevated temperature, and the reaction mixture is then treated with an aqueous solution of NH4Cl obtaining the compounds of formula V. the Hydroxyl group and aminosidine group R' in the compounds of formula V can be removed by a method known in this field, for example, using TMSCl-NaI-CH3CN in a suitable solvent, for example in CH2Cl2at room or elevated temperatures. At the stage of removal can be obtained intermediate inden-imidazole compound, which then restore method known in this field. The compound of formula I(b), thus obtained, isolated in the usual way.

(C) Obtaining compounds of formula (I), where n is 0, can also be illustrated, for example, by the reaction scheme:

where R1-R3, R6, R7, m and r have the above specified values, X represents-CH2(CH2)p-, p is 0 or 1, a R' represents a conventional protective group for =NH in the imidazole ring, such as benzyl or trityl (-CPh3 ).

In the method of scheme With compound III' reacts with Grignard reagent VI at room or elevated temperature in a suitable solvent. The obtained compound VII is subjected to cyclization method known in this field, with the final product Ic.

Other compounds of formula I, are not represented in the above schemes, can be obtained by methods or analogously to the methods described above or known from the prior art, on the basis of appropriate starting materials. As methods of the prior art can be referenced, for example, on the ways in publication WO-A-9712874, the contents of which are incorporated in this description by reference.

Starting compound II are commercially available or they can be obtained using a number of known methods of synthesis using suitable starting materials and conventional methods known qualified in this area specialists. For example, the compounds of formula II, where X represents-CH2-(CH2)p-, p is 0 or can be obtained by methods analogous to the methods described in Sommer M.B. et al., J.Org. Chem., vol.55, 1990, R; W.M. Welch et al., J. Med. Chem., vol.27, 1984, p.1508, and/or B⊘ges⊘ K.R., J. Med. Chem., vol.26, 1983, R, the contents of which are incorporated in this description by reference. As an additional example, the doctrine of the compounds II can be made by the following methods or similar methods, described in the above-mentioned publication WO-A-9712874, L.L. Miller, R.F. Boyer, J. Am. Chem. Soc., vol.93(3), 1971, p.650-656, or Smonou I., M. Orfanopoulos, Synthetic Communications, vol.20(9), 1990, p.1387-1397.

As the starting material, compound III, III' and IV are commercially available, for example, in unprotected form, or they can be obtained by methods known qualified in this area specialists (see Kirk, K.L., J. Heterocycl. Chem., vol.22, 1985, 57). If necessary, the group =NH imidazole can be protected using conventional methods and the protective groups (R'), such as benzyl or trityl. It should be understood that due to tautomerism protective group R' may be joined to either of the two nitrogen atoms of imidazole ring.

If necessary, the substituents R6, R8and/or an optional substituent in the cyclic part of the R1can be protected by a method known in this field. Such protective group, and an optional protective group R' may be removed at the final stage using the suitable normal(s) method(s) unprotect known(s) in this field.

It should be noted that the above synthesis methods are intended to illustrate how compounds of the invention, and receipt of them does not in any way limited, there are other synthesis methods, which are within the General idea of the kV is limitirovannoe in this field specialist also possible.

Compounds of the present invention can be converted, if desired, pharmaceutically acceptable salt or ester using methods well known in the field.

As mentioned above, the compounds of the present invention are noteworthy pharmacological properties, namely they have affinity to alpha-2-adrenoceptors. Specified activity of the compounds of the invention demonstrate the following pharmacological tests.

Antagonistic activity against alpha-2-adrenoceptors (2R) in seed flows (vas deferens) rats in vitro.

Rats killed by strangulation with CO2. The seminal ducts (Vas deferentia) cut and the two halves of the prostate is placed in the camera for tissues containing solution Krebbs of the following composition (mm): NaCl 118, KCl 4.7 In, CaCl22,5 KN2PO41,2, MgSO40,6, NaHCO325, glucose 11.1 in aerated 5% Carbogen, temperature 37°C, pH 7.4. Type 260 g/l propranolol and 2 g/ml desipramine to prevent the possible effects of alpha-adrenergic receptors and prevent reuptake of released norepinephrine, respectively. The drugs bind to the hooks on the bottom of the incubation chambers and above the isometric force sensor offset. E is stricescu stimulation begin after a period of equilibrium (5 minutes at a residual tension of 0.5 g) by introducing field stimulation with the following parameters: double ripple, voltage 70 V, a frequency of 0.2 Hz, a delay of 5 msec, the duration of 2 msec. After stabilization induced by electric reaction of reducing enter the test compound cumulative method half-log-logarithmic increase at five minute intervals. The inhibition caused by electric contractions is measured as the response to agonists 2R. Antagonist injected into the incubation medium at least five minutes before the agonist. The average value of the ±cf. square error of percentage inhibition calculated in the absence and in the presence of antagonist and is present in the form of curves dose-response. In order to show the effectiveness of the antagonist, calculate the value of RA2. The test results are presented in table 1.

/tr>
Table 1
ConnectionVas deferens
Alfa antagonistic activity
Connection 1RA2=7,0
Connection 2RA2=6,0
Connection 3RA2=5,6
Connection 4RA2=6,9
Connection 5RA2=6,3
Connection 6RA2=6,6
Connection 7RA2=7,6
Compound 8RA2=6,7
Connection 9RA2=6,2
Connection 10RA2=6,2
Connection 11RA2=6,2
Connection 12RA2=6,3
Connection 13RA2=5,6
The connection 14RA2=5,5
The connection 15RA2=6,2
The connection 16RA2=6,5

In General, compounds of the present invention, showing the alpha 2-antagonist activity can be used in the case of therapeutic indications for which useful alpha-2-antagonists. They can also be used to cancel the actions of alpha-2-agonists.

Thus, the compounds of the invention can be used, inter alia, in the treatment of various neurological disorders, psychiatric disorders or impairment of cognitive ability. In addition, they can be used in the treatment of various peripheral disorders such as diabetes, orthostatic hypotension, lipolytic diseases (such as obesity) or sexual dysfunction.

Compounds of the invention can be introduced enterline, locally or parenterally.

Compounds of the invention can be prepared the Department is or together with another active ingredient and/or together with a pharmaceutically acceptable diluent, the carrier and/or excipient in the form of various standard pharmaceutical dosage forms, for example in the form of tablets, capsules, solutions, emulsions, powders, etc. depending on the method of administration using conventional techniques. Pharmaceutically acceptable diluent, carrier and/or the filler may be selected from generally used in the field of pharmaceuticals, based on the selected method of administration.

The amount of the active ingredient is in the range from 0.01 to 75 wt.% depending on the dosage form.

Specific level doses of the compounds of the present invention depends on various factors such as input connection type, age and sex of the subject being treated, exposed to the treatment condition and the manner and method of administration. For example, the dose for parenteral administration is usually in the range from 0.5 μg/kg to 10 mg/kg, and the dose for oral administration is in the range from 5 μg/kg to 100 mg/kg for an adult mammal.

The present invention also provides a compound of the invention or its ester or salt for use in the method of treatment of a human or animal.

The present invention also provides a compound of the invention or its ester or salt for use in the treatment of various CNS disorders, such as neurological in which osenia, psychiatric disorders and disturbances of cognitive abilities, or in the treatment of various peripheral diseases, such as diabetes, orthostatic hypotension, lipolytic diseases (such as obesity) or sexual dysfunction.

The present invention also provides the use of compounds of the invention or a complex ester or salt for the production of medicaments for the treatment of various CNS disorders, such as neurological disorders, psychiatric disorders and disturbances of cognitive abilities, or in the treatment of various peripheral diseases, such as diabetes, orthostatic hypotension, lipolytic diseases (such as obesity) or sexual dysfunction.

The invention also relates to a method for treatment of various CNS disorders, such as neurological disorders, psychiatric disorders and disturbances of cognitive abilities, or the treatment of various peripheral diseases, such as diabetes, orthostatic hypotension, lipolytic diseases (such as obesity) or sexual dysfunction, by introducing the subject in need of such treatment, an effective amount of a compound of the invention or pharmaceutically acceptable complex ester or salt.

The present invention is explained in more detail using the following examples. The examples are intended for illustration only and do not limit the scope of the invention, which is defined in the claims.

EXAMPLE 1

4-(6-Methoxy-3-phenylindane-1-ylmethyl)-1H-imidazol

To a suspension of zinc powder (8.8 g) in dry tetrahydrofuran (200 ml) under cooling with ice and with stirring in a nitrogen atmosphere is added dropwise chloride titanium(IV) (7,4 ml). The resulting mixture was refluxed with stirring for 2 hours. Add a solution of 6-methoxy-3-phenyl-1-indanone (4.0 g) and 3-benzyl-3H-imidazole-4-carbaldehyde (4.5 g) in dry tetrahydrofuran (40 ml), and boiling under reflux continued for 5 hours. The cooled reaction mixture is alkalinized with dilute sodium hydroxide solution. The suspension is filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in acidified water and extracted with dichloromethane. The combined organic phase washed with water and evaporated to dryness.

The crude intermediate compound (1-benzyl-5-(6-methoxy-3-phenylindane-1-ylidenemethyl-1H-imidazole) was dissolved in ethanol (200 ml), water (20 ml) and hydrochloric acid (1.0 ml). The mixture hydronaut at 50-50°using as catalyst 10%palladium on coal to stop the consumption of hydrogen. The mixture is filtered and the filtrate evaporated to dryness. The residue is dissolved in water, salacious using sodium hydroxide solution and extracted with ethyl acetate. The combined organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure to get crude product is racemic CIS - and TRANS-diastereoisomers. The product was then purified flash chromatography (elute using a gradient mixture of dichloromethane-methanol). Basically the product is dissolved in ethyl acetate and converted into its hydrochloride with gaseous hydrogen chloride dissolved in ethyl acetate.

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6, (ppm): 1.62-1.70 (m, 1H), 2.50-2.57 (m, 1H),2.82 (DD, J=14.7 Hz, J=9.5 Hz, 1H),3.45 (DD, J=14.7 Hz, J=4.6 Hz, 1H),3.48-3.56 (m, 1H), 3.75 (s, 3H), 4.16-4.21 (m, 1H),6.67-7.34 (m, 8H), 7.46 (s, 1H),9.03 (S, 1H).

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6, (ppm): 2.08-2.17 (m, 1H),2.23-2.31 (m, 1H),2.84 (DD, J=14.7 Hz, J=9.5 Hz, 1H),3.12 (DD, J=14.7 Hz, J=4.6 Hz, 1H),3.60-3.69 (m, 1H),3.72 (s, 3H), 4.32-4.39 (m, 1H), 6.75-7.35 (m, 8H), 7.43 (s,1H), 8.99 (s, 1H).

When using this method we obtained the following compounds:

4-(3-Phenylindane-1-ylmethyl)-1H-imidazol

(Compound 1)

Range1H NMR (TRANS isomer in the form of HCl salt, DMSO-d6δ ppm): 1.64-1.72 (m, 1H), 2.51-2.58 (m, 1H),2.82 (DD, J=15.0 Hz, J=9.6 Hz, 1H), 3.45 (DD, J=15.0 Hz, J=4.3 Hz, 1H),3.49-3.57 (m, 1H), 4.24-4.29 (m, 1H),6.79 (d, J=7.5 Hz, 1H), 7.16-7.35 (m, 8H), 7.47 (d, J=1.3 Hz, 1H), 8.99 (d, J=1.3 Hz, 1H).

4-(5,6-Dimethoxy-3-phenylindane-1-ylmethyl)-1H-imidazol

(Compound 2)

Range1H NMR (CIS-isomer as HCl-salt, MeOH-d4that δ ppm): 1.611.71 (m, 1H), 2.62-2.72 (m, 1H), 2.91 (DD, J=15.1 Hz, J=9.1 Hz, 1H),3.43 (DD, J=15.1 Hz, J=4.6 Hz, 1H),3.49-3.55 (m, 1H),3.66 (s, 3H), 3.85 (s, 3H),4.21-4.25 (m, 1H),6.43 (s, 1H), 6.92 (s, 1H), 7.10-7.33 (m, 6N), 8.79 (d, J=1.1 Hz, 1H).

4-[6-Methoxy-3-(4-methoxyphenyl)indan-1-ylmethyl)-1H-imidazol

(Compound 5)

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.57-1.65 (m, 1H), 2.46-2.54 (m, 1H), 2.80 (DD, J=14.8 Hz, J=9.4 Hz, 1H), 3.44 (DD, J=14.8 Hz, J=4.6 Hz, 1H), 3.46-3.54 (m, 1H),3.73 (s, 3H),3.75 (s, 3H), 4.10-4.14 (m, 1H), 6.67 (d, J=8.3 Hz, 1H),6.74 (DD, J=8.3 Hz, J=2.2 Hz, 1H),6.85-6.90 (m, 3H),7.06-7.10 (m, 2H),7.47 (s, 1H),9.02 (s, 1H).

4-[3-(4-Methoxyphenyl)indan-1-ylmethyl)-1H-imidazol

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.59-1.70 (m, 1H),2.46-2.55 (m, 1H),2.83 (DD, J=14.7 Hz, J=9.5 Hz, 1H), 3.45 (DD, J=14.7 Hz, J=4.7 Hz, 1H),3.49-3.57 (m, 1H), 3.74 (s, 3H), 4.16-4.22 (m, 1H), 6.78 (d, J=7.3 Hz, 1H),6.86-6.91 (m, 2H), 7.07-7.12 (m, 2H), 7.13-7.34 (m, 3H), 7.46 (d, J=1.4 Hz, 1H), 9.05 (d, J=1.4 Hz, 1H).

4-[3-(4-Forfinal)indan-1-ylmethyl)-1H-imidazol

(Compound 7)

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.62-1.71 (m, 1H), 2.50-2.57 (m, 1H), 2.83 (DD, J=14.8 Hz, J=9.7 Hz, 1H),3.46 (DD, J=14.8 Hz, J=4.5 Hz, 1H),3.53-3.60 (m, 1H), 4.26-4.31 (m, 1H), 6.78 (d, J=7.4 Hz, 1H), 7.13-7.35 (m, 7H), 7.47 (d, J=1.3 Hz, 1H), 9.05 (d, J=1.3 Hz, 1H).

4-[3-(3-Forfinal)indan-1-ylmethyl)-1H-imidazol

(Compound 9)

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.67-1.76 (m, 1H),2.51-2.58 (m, 1H),2.85 (DD, J=14.9 Hz, J=9.7 Hz, 1H),3.46 (DD, J=14.9 Hz, J=4.5 Hz, 1H),3.53-3.59 (m, 1H), 4.29-4.34 (m, 1H),6.81 (d, J=7.4 Hz, 1H)6.99-7.41 (m, 7H), 7.47 (d, J=1.2 Hz, 1H), 9.05 (d, J=1.2 Hz, 1H).

4-[3-(2-Forfinal)indan-1-ylmethyl)-1H-imidazol

(Compound 10)

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.71-1.79 (m, 1H), 2.65-2.72 (m, 1H), 2.95 (DD, J=15.1 Hz, J=9.2 Hz, 1H), 3.43 (DD, J=15.1 Hz, J=4.8 Hz, 1H), 3.58-3.65 (m, 1H), 4.58-4.62 (m, 1H),6.89 (d, J=7.3 Hz, 1H), 7.06-7.34 (m, 8H),8.79 (d, J=1.3 Hz, 1H).

4-[3-(3,4-Differenl)indan-1-ylmethyl)-1H-imidazol

(Compound 11)

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.66-1.75 (m, 1H), 2.50-2.57 (m, 1H),2.84 (DD, J=14.9 Hz, J=9.7 Hz, 1H), 3.46 (DD, J=14.9 Hz, J=4.4 Hz, 1H),3.52-3.58 (m, 1H), 4.29-4.33 (m, 1H),6.81 (d, J=7.4 Hz, 1H), 7.05-7.43 (m, 6N),7.48 (d, J=1.3 Hz, 1H), 9.05 (d, J=1.3 Hz, 1H).

4-[6-Fluoro-3-(4-forfinal)indan-1-ylmethyl)-1H-imidazol

(Compound 15)

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.65-1.76 (m, 1H),2.52-2.61 (m, 1H), 2.84 (DD, J=14.8 Hz, J=9.5 Hz, 1H),3.44 (DD, J=14.8 Hz, J=4. 6 Hz, 1H),3.50-3.56 (m, 1H),4.23-4.30 (m, 1H),6.76-7.25 (m, 7H),7.47 (d, J=1.2 Hz, 1H), 9.00 (d, J=1.2 Hz, 1H).

4-[3-(4-Forfinal)-6-methoxyindol-1-ylmethyl)-1H-imidazol

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.62-1.70 (m, 1H), 2.62-2.69 (m, 1H), 2.91 (DD, J=14.9 Hz, J=9.1 Hz, 1H), 3.46 (DD, J=14.9 Hz, J=4.8 Hz, 1H),3.52-3.57 (m, 1H),3.79 (s, MN), 4.20-4.25 (m, 1H), 6.72-7.20 (m, 7H), 7.34 (d, J=1.3 Hz, 1H), 8.83 (d, J=1.3 Hz, 1H).

4-[3-(4-Forfinal)-6-triptoreline-1-ylmethyl)-1H-imidazol

Range1H NMR (CIS-isomer as HCl-salt, MeOH-d4that δ ppm): 1.74-1.83 (m, 1H),2.70-2.77 (m, 1H),2.95 (DD, J=14.9 G is, J=9.5 Hz, 1H), 3.57 (DD, J=14.9 Hz, J=4.7 Hz, 1H), 3.60-3.65 (m, 1H), 4,36-and 4.40 (m, 1H), 7.02-7.09 (m, 3H), 7.18-7.23 (m, 2H), 7.39 (d, J=1.1 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 8.85 (s, 1H).

4-(6-Fluoro-3-phenylindane-1-ylmethyl)-1H-imidazol

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.69-1.78 (m, 1H), 2.53-2.60 (m, 1H),2.85 (DD, J=14.9 Hz, J=9.7 Hz, 1H), 3.47 (DD, J=14.9, J=4.3 Hz, 1H), 3.56-3.63 (m, 1H), 4.21-4.26 (m, 1H), 6.76-7.35 (m, 8H), 7.48 (s, 1H), 9.06 (s, 1H).

Range1H NMR (TRANS isomer in the form of HCl salt, DMSO-d6that δ ppm): 2.14-2.21 (m, 1H), 2.28-2.35 (m, 1H), 2.86 (DD, J=14.8 Hz, J=9.2 Hz, 1H), 3.14 (DD, J=14.9 Hz, J=5.2 Hz, 1H), 3.68-3.75 (m, 1H), 4.42-4.46 (m, 1H), 6.92-7.32 (m, 8H), 7.45 (s, 1H), 9.06 (s, 1H).

EXAMPLE 2

4-(3-Phenyl-1,3-dihydroisobenzofuran-1-ylmethyl)-1H-imidazol

(Compound 12)

This connection receive in accordance with the method of example 1 except that use the 3-phenolphtalein instead of 3-phenyl-1-indanone.

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 3.22 (DD, J=15.4 Hz, J=7.4 Hz, 1H),3.46 (DD, J=15.4 Hz, J=4.1 Hz, 1H),5.56-5.60 (m, 1H),6.10 (s, 1H),6.94 (d, J=7.4 Hz, 1H), 7.20-7.39 (m, N), 9.00 (d, J=1.3 Hz, 1H).

EXAMPLE 3

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

This connection receive in accordance with the method of example 1 except using 4-phenyl-1-tetralone instead of 3-phenyl-1-indanone.

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.51-1.57 (m, 1H), 1.70-1.78 (m, 1H), 1.91-1.96 (m, 2H), 3.03 (DD, J=14.8 Hz,J=10.2 Hz, 1H), 3.12 (DD, J=14.8 Hz, J=4.4 Hz, 1H), 3.24-3-31 (m, 1H), 4.04-4.08 (m, 1H), 6.70 (d, J=7.1 Hz, 1H), 7.00-7.45 (m, N), 9.06 (d, J=1.3 Hz, 1H).

EXAMPLE 4

3-(1H-Imidazol-4-ylmethyl)-1-phenylindane-5-ol

(Compound 4)

A mixture of 4-(6-methoxy-3-phenylindane-1-ylmethyl)-1H-imidazole (500 mg) and 48%Hydrobromic acid (20 ml) is refluxed under stirring for 1 hour. The cooled reaction mixture was poured into water and alkalinized with ammonium hydroxide solution. The precipitate is filtered off and washed with water. The product was then purified flash chromatography (elution with a gradient mixture of dichloromethane-methanol).

Range1H NMR (CIS-isomer, MeOH-d4that δ ppm): 1.62-1.71 (m, 1H), 2.54-2.61 (m, 1H), 2.74 (DD, J=14.6 Hz, J=8.8 Hz, 1H), 3.22 (DD, J=14.6 Hz, J=5.2 Hz, 1H), 3.40-3.49 (m, 1H), 4.09-4.14 (m, 1H), 6.55-6.77 (m, 4H), 7.12-7.28 (m, 5H), 7.57 (d, J=1.1 Hz, 1H).

Range1H NMR (TRANS isomer, MeOH-d4that δ ppm): 2.09-2.16 (m, 1H), 2.29-2.35 (m, 1H), 2.74 (DD, J=14.6 Hz, J=8.8 Hz, 1H),2.94 (DD, J=14.6 Hz, J=5.4 Hz, 1H), 3.50-3.58 (m, 1H), 4.23-4.28 (m, 1H), 6.53-6.73 (m, 4H),7.07-7.25 (m, 5H), 7.58 (s, 1H).

Using the same method the following compounds:

4-[3-(1H-Imidazol-4-ylmethyl)indan-1-yl]phenol

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.58-1.66 (m, 1H),2.45-2.50 (m, 1H),2.80 (DD, J=14.7 Hz, J=9.5 Hz, 1H), 3.44 (DD, J=14.7 Hz, J=4.6 Hz, 1H), 3.46-3.52 (m, 1H), 4.11-4.16 (m, 1H), 6.70-6.74 (m, 2H),6.78 (d, J=7.4 Hz, 1H), 6.95-6.99 (m, 2H), 7.14-7.23 (m, 2H),7.31 (d, J=7.4 Hz, 1H), 7.47 (d, J=1.3 Hz, 1H), 903 (d, J=1.3 Hz, 1H), 9.30 (s, 1H).

1-(1H-Imidazol-4-ylmethyl)-3-phenylindane-5,6-diol

(Compound 3)

Range1H NMR (CIS-isomer as HCl-salt, Meon-d4that δ ppm): 1.56-1.66 (m, 1H),2.57-2.66 (m, 1H),2.87 (DD, J=15.0 Hz, J=8.9 Hz, 1H), 3.31 (DD, J=15.0 Hz, J=4.9 Hz, 1H), 3.39-3.46 (m, 1H), 4.12-4.17 (m, 1H), 6.28 (s, 1H),6.69 (s, 1H), 7.13-7.30 (m, 6N), 8.79 (s, 1H).

1-(4-Hydroxyphenyl)-3-(1H-imidazol-4-ylmethyl)indan-5-ol

(Compound 6)

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.52-1.60 (m, 1H), 2.41-2.48 (m, 1H), 2.75 (DD, J=14.7 Hz, J=9.4 Hz, 1H), 3.32 (DD, J=14.7 Hz, J=5.1 Hz, 1H), 3.36-3.43 (m, 1H), 3.99-4.03 (m, 1H), 6.57-6.98 (m, 7H), 7.45 (d, 1.3 Hz, 1H), 9.01 (d, 1.3 Hz, 1H), 9.22 (s, 1H), 9.24 (s, 1H).

1-(4-Forfinal)-3-(1H-imidazol-4-ylmethyl)indan-5-ol

(Compound 8)

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 1.56-1.64 (m, 1H), 2.47-2.54 (m, 1H),2.77 (DD, J=14.9 Hz, J=9.6 Hz, 1H), 3.34 (DD, J=14.9 Hz, J=5.0 Hz, 1H), 3.40-3.46 (m, 1H), 4.14-4.18 (m, 1H), 6.55-6.69 (m, 3H), 7.10-7.23 (m, 4H),7.47 (d, 1.3 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.33 (s, 1H).

EXAMPLE 5

4-(2-Benzylidene-1-ylmethyl)-1H-imidazol

a) 2-Benzylidene-1-he

To a solution of 1-indanone (5.0 g) and benzaldehyde (4.1 g) in methanol (40 ml) is added 2.2 ml of 48%aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature for 0.5 hour. The precipitate is filtered off and washed with water. The output is 7.9,

Range1H NMR (DMSO-d6that δ ppm): 4.14 (s, 2H), 7.47-7.81 (m, 10H).

b) 2-Benzylidene-1-the n

2-Benzylidene-1-he (6.0 g) hydronaut in 100 ml of ethanol using a catalyst 0.1 g of 10%palladium on coal at room temperature. The catalyst is filtered off and the filtrate evaporated to dryness.

Range1H NMR (DMSO-d6that δ ppm): 2.67-2.72 (m, 1H), 2.78-2.83 (m, 1H), 3.01-3.08 (m, 1H), 3.10-3.21 (m, 2H), 7.17-7.68 (m, N)

C) 4-(2-Benzylidene-1-ylmethyl)-1H-imidazol

This connection receive in accordance with the method of example 1 except using 2-benzylidene-1-it instead of 3-phenyl-1-indanone.

Range1H NMR (CIS-isomer in the form of HCl salt, DMSO-d6that δ ppm): 2.47-2.53 (m, 1H), 2.63-2.67 (m, 2H), 2.74-2.82 (m, 1H), 2.86-2.93 (m, 2H), 3.02-3.07 (m, 1H), 3.59-3.65 (m, 1H), 6.75 (d, J=7.4 Hz, 1H), 7.02-7.32 (m, 8H), 7.39 (d, J=1.2 Hz, 1H),9.07 (d, J=1.2 Hz, 1H).

EXAMPLE 6

4-[(2,3-Dihydro-6-methoxy-2-phenyl-1H-inden-1-yl)methyl]-1H-imidazole (compound 13) and

3-(1H-imidazol-4-ylmethyl)-2-phenylindane-5-ol (compound 14)

a) 3-(4-Methoxyphenyl)-2-phenylacrylate acid

A mixture of 4-methoxybenzaldehyde (30.0 g, 0.22 mol), phenylacetic acid (31.5 g, 0.23 mol) and triethylamine (31 ml) in acetic anhydride (75 ml) is heated at 90°5 hours. After cooling gently for 15 minutes, added dropwise 18 ml of water. Then added dropwise a solution of potassium carbonate (243 g) in water (1800 ml) and the resulting solution was heated at 60°With 1 hour. After cooling, the solution is extracted with dichloromethane. After under which Alenia aqueous phase (pH 6-7), the product precipitates. After stirring at 0°the product is filtered and dried.

Range1H NMR (CDCl3that δ ppm): 3.75 (3H, s), 6.68 (2H, d,3J=8.8 Hz), 6.99 (2H, d,3J=9.0 Hz), 7.23-7.26 (2H, m),7.35-7.42 (3H, m), 7.84 (1H, s).

b) 3-(4-Methoxyphenyl)-2-phenylpropane acid

Palladium on charcoal (10 wt.%, 2,77 g) are added to a solution of 3-(4-methoxyphenyl)-2-phenylacetic acid (27.7 g, 0.11 mol) in acetic acid (1000 ml). The mixture hydronaut at room temperature. The mixture is then filtered through celite, and the solvent evaporated. The product is recrystallized from a small amount of ethyl acetate. Melting point 220-221°C.

Range1H NMR (CDCl3that δ ppm): 2.84 (1H, DD,2Jheme=13.8 Hz,3J=9.5 Hz), 3.23 (1H, DD,2Jheme=13.9 Hz,3J=5.9 Hz), 3.48 (1H, DD,3J=9.4 Hz,3J=6.1 Hz), 3.67 (3H, s), 6.65 (2H, d,3J=8.7 Hz), 6.87 (2H, d,3J=8.6 Hz), 7.04-7.14 (5H, m).

c) 3-(4-Methoxyphenyl)-2-phenylpropionamide

3-(4-Methoxyphenyl)-2-phenylpropane acid (12.5 g, 0,049 mol) is converted into the acid chloride of the acid by treatment with thionyl chloride (8.2 ml) in dry dichloromethane (75 ml) at 40°C. the Excess thionyl chloride and dichloromethane evaporated. The crude product used in the next stage without purification.

Range1H NMR (CDCl3that δ ppm): 3.02 (1H, DD,2Jheme=14.1 Hz,3J=7.2 Hz), 3.43 (1H, DD,2J=14.1 Hz,3J=7.9 Hz), 3.76 (3H, s),4.22 (1H, t,3J=7.5 Hz), 6.77 (2H, d,3J=8.7 Hz), 6.99 (2H, d,3J=8.7 Hz), 7.23-7.26 (2H, m), 7.30-7.38 (3H, m).

d) 6-Methoxy-2-phenylindol-1-he

Aluminium chloride (345 mg) and one quarter of the crude 3-(4-methoxyphenyl)-2-phenylpropionylamino from the previous stage is added to the dry dichloromethane (45 ml) at 0°C. After 1 hour, add aluminum chloride (345 mg) and the second quarter of the acid chloride. Stirring is continued and twice repeated adding. After the last addition stirring is continued for half an hour at 0°and then 2 hours at room temperature. The reaction mixture was poured into ice acidified water. The organic phase is separated and the aqueous phase is twice extracted with dichloromethane. The combined organic phases are washed with water, and 2.5%sodium hydroxide solution in water and again with water. Solution in dichloromethane, dried and evaporated.

Range1H NMR (CDCl3that δ ppm): 3.19 (1H, DD,2Jheme=17.1 Hz,3J=3.8 Hz), 3.62 (1H, DD,2Jheme=17.1 Hz,3J=8.1 Hz), 3.85 (3H, s), 3.92 (1H, DD,3J=8.1 Hz,3J=3.8 Hz), 7.17-7.19 (2H, m), 7.23-7.27 (3H, m), 7.30-7.34 (2H, m), 7.40-7.43 (1H, m).

(e) 1-Benzyl-5-(6-methoxy-2-phenylindol-1-ylidenemethyl)-1H-imidazol

Chloride titanium(IV) (13,2 ml of 22.8 g, 0.12 mol) is added dropwise with stirring to a suspension of activated zinc powder (15.9 g, 0.24 mol) in dry tetrahydrofuran (240 ml) (-5)-(-10)� C in nitrogen atmosphere. At the end of the addition the mixture is refluxed 2 hours with stirring. To boiling under reflux the mixture is added dropwise a solution of 6-methoxy-2-phenylindol-1-it (rate of 7.54 g, to 0.032 mol) and 3-benzyl-3H-imidazole-4-carbaldehyde (7,37 g, 0.040 mol) in dry tetrahydrofuran (110 ml). After the addition the mixture is refluxed 5 hours. The mixture is then cooled to 50°and add 50 ml of methanol and 25 ml of water. The cooled reaction mixture is alkalinized (pH 8-9) 50%sodium hydroxide solution in water. The suspension is filtered through celite and the filtrate evaporated to dryness under reduced pressure. To the residue is added ethyl acetate and the mixture is heated. The cooled mixture is filtered, and the filtrate washed with water. The organic phase is dried and evaporated to dryness. The crude product used in the next stage.

(f) 4-[(2,3-Dihydro-6-methoxy-2-phenyl-1H-inden-1-yl)methyl]-1H-imidazole (compound 13)

A solution of crude 1-benzyl-5-(6-methoxy-2-phenylindol-1-ylidenemethyl)-1H-imidazole (1,00 g) in acetic acid (100 ml) was shaken with 10%palladium on coal (100 mg) for 7 h at 80°at a pressure of 3 ATM hydrogen in the hydrogenation apparatus Parra. The mixture is filtered through celite, and the filtrate evaporated to dryness. The residue is dissolved in water, alkalinized (pH 9) and extracted with ethyl acetate. The combined organic phases ol myauth water, dried with sodium sulfate and evaporated under reduced pressure to get crude product, which is a mixture of CIS - and TRANS-diastereomers of 4-[(2,3-dihydro-6-methoxy-2-phenyl-1H-inden-1-yl)methyl]-1H-imidazole. The product was then purified flash chromatography (elution with a gradient mixture of dichloromethane-methanol). Basically the product is converted into its hydrochloride by dissolving the base in ethyl acetate and adding hydrogen chloride in ethyl acetate. The product is a mixture of diastereomers (CIS:TRANS, 94:6, TPL 158-159°).

CIS-diastereoisomer in the form of its hydrochloride: Range1H NMR (CD3OD, δ ppm); 2.52 (1H, distorted DDD,2Jheme=15.2 Hz3J=7.4 Hz,4J=0.8 Hz), 2.67 (1H, distorted DDD,2Jheme=15.4 Hz3J=8.0 Hz,4J=0.6 Hz), 3.16 (1H, distorted DD,2Jheme=15.4 Hz3J=7.6 Hz), 3.27-3.33 (1H, m), 3.71 (3H, s), 3.76 (1H, m), 3.90 (1H, m), 6.39 (1H, d, Jmeta=2.4 Hz), 6.79 (1H, DD, Jortho=8.2 Hz, Jmeta=2.5 Hz), 6.96 (1H, d,4J=1.2 Hz), 7.18-7.29 (6N, m), 8.68 (1H, d,4J=1.4 Hz).

(g) 3-(1H-Imidazol-4-ylmethyl)-2-phenylindane-5-ol

(Compound 14)

A mixture of 4-[(2,3-dihydro-6-methoxy-2-phenyl-1H-inden-1-yl)methyl]-1H-imidazole (370 mg base) and 48%Hydrobromic acid (15 ml) is heated at 130-140°C for 2 hours under stirring. The cooled reaction mixture was poured into water and alkalinized (pH 8). The floor is built precipitate is filtered off and washed with water. The product was then purified using fast chromatography (elution with a gradient mixture of dichloromethane-methanol).

CIS-diastereoisomer: range1H NMR (CD3OD, δ ppm): 2.37 (1H, distorted DDD,2Jheme=14,7 Hz3J=6.2 Hz,4J=0.8 Hz), 2.44 (1H, distorted DDD,2Jheme=14,7 Hz3J=8.9 Hz), 3.10 (1H, distorted DD,2Jheme=15.0 Hz,3J=7.3 Hz), 3.16 (1H, distorted DD,2Jheme=15.1 Hz3J=7.4 Hz), 3.68-3.80 (2H, m), 6.23 (1H, d, Jmeta=2.3 Hz), 6.52 (1H, s), 6.60 (1H, DD, Jortho=8.1 Hz, Jmeta=2.4 Hz), 7.06 (1H, d, Jortho=8.1 Hz), 7.14-7.19 (3H, m), 7.21-7.25 (2H, m), 7.63 (1H, d,4J=1.0 Hz).

TRANS-diastereoisomer: range1H NMR (CD3OD, δ ppm): 2.84-2.91 (2H, m), 3.04 (1H, distorted DD,2Jheme=14.9 Hz3J=6.4 Hz), 3.16-3.23 (1H, m), 3.26-3.29 (1H, m),3.58 (1H, m),6.55 (1H, d, Jmeta=2.2 Hz), 6.63 (1H, DD, Jortho=8.6 Hz, Jmeta=2.3 Hz), 6.79 (1H, s), 7,01 (1H, d, Jortho=8.1 Hz), 7.07-7.13 (3H, m),7.15-7.21 (2H, m), 7.79 (1H, s).

EXAMPLE 7

4-[(2,3-Dihydro-2-phenyl-1H-inden-1-yl)methyl]-1H-imidazol

(Compound 16)

a) 2,3-Diphenylpropanoic acid

Add 10%palladium on coal (0.8 g) to a solution α-phenylcarbinol acid (10.0 g, 0,0445 mol) in ethanol (200 ml). The mixture hydronaut at room temperature. The mixture is filtered through celite and the solvent evaporated.

Range1H NMR (DMSO-d6that δ ppm): 2.94 (1H, DD,2Jheme=13.8 Hz,3/sup> J=6.9 Hz), 3.29 (1H, DD,2Jheme=13.8 Hz,3J=8.5 Hz), 3.86 (1H, DD,3J=8.7 Hz,3J=6.9 Hz), 7.12-7.25 (6N, m),7.28-7.34 (4H, m).

b) 2-Phenylindol-1-he

Polyphosphoric acid (50 g) is heated on an oil bath at 140-145°and add 2,3-diphenylpropanoic acid (2.5 g). The heating is continued for 45 minutes Add water. The mixture is cooled and extracted with ethyl acetate. The organic extracts are washed with 1 M NaOH solution and water. After drying, the solvent is evaporated under reduced pressure. The resulting product is optionally purified, rubbing it in heptane.

Range1H NMR (DMSO-d6that δ ppm): 3.21 (1H, DD,2Jheme=17.4 Hz,3J=4.2 Hz), 3.69 (1H, DD,2Jheme=17.6 Hz,3J=8.3 Hz), 4.01 (1H, DD,3J=8.3 Hz,3J=4.2 Hz), 7.16-7.19 (2H, m),7.22-7.27 (1H, m), 7.30-7.35 (2H, m), 7.47-7.51 (1H, m), 7.65-7.77 (3H, m).

C) 1-Benzyl-5-(2-phenylindol-1-ylidenemethyl)-1H-imidazol

1-Benzyl-5-(2-phenylindol-1-ylidenemethyl)-1H-imidazol receive, as described above, 1-benzyl-5-(6-methoxy-2-phenylindol-1-ylidenemethyl)-1H-imidazol except that as the source of material used 2-phenylindol-1-it. In this case, after evaporation of the filtrate the residue is dissolved in dilute hydrochloric acid. The product is extracted with dichloromethane. The combined organic phases are washed with water, dried over sodium sulfate and evaporated under reduced on the no. The crude product as hydrochloride use in the next stage without purification.

d) 4-[(2,3-Dihydro-2-phenyl-1H-inden-1-yl)methyl]-1H-imidazol

Crude 1-benzyl-5-(2-phenylindol-1-ylidenemethyl)-1H-imidazole in acetic acid is shaken with palladium on coal, as described above, 1-benzyl-5-(6-methoxy-2-phenylindol-1-ylidenemethyl)-1H-imidazol except that in this case, the processing is carried out 2 days at 60-70°at normal pressure. Hydrochloride purified product is a mixture of CIS - and TRANS-diastereomers (CIS:TRANS, 96:4).

CIS-diastereoisomer as hydrochloride: range1H NMR (DMSO-d6that δ ppm): 2.36 (1H, distorted DD,2Jheme=15.0 Hz,3J=5.2 Hz), 2.55 (1H, distorted DD,2Jheme=15.1 Hz3J=8.8 Hz), 3.19 (1H, distorted DD,2Jheme=15.6 Hz,3J=7.2 Hz), 3.28-3.36 (2H, m), 3.87 (2H, m), 6.73 (1H, d, Jortho=7.4 Hz), 7.06-7.11 (2H, m), 7.18-7.36 (7H, m), 8.95 (1H, d,4J=1.3 Hz).

EXAMPLE 8

4-[(3-Cyclohexyl-2,3-dihydro-1H-inden-1-yl)methyl]-1H-imidazol

a) 3-Cyclohexylidene-1-he

The specified connection receive in accordance with the method described in ..Trost, L.H.Latimer (J. Org. Chem., 42, 1977, 3212). The parent compounds are 1-indanone and cyclohexylamin.

Range1H NMR (CDCl3that δ ppm): 0.83-1.35 (6N, m),1.65-1.90 (5H, m), 2.51 (1H, DD,2Jheme=19.1 Hz3J=3.0 Hz), 2.67 (1H, DD,2Jheme=19.1 Hz, J=7.8 Hz), 3.38 (1H, m), 7.36 (1H, m), 7.49 (1H, m), 7.59 (1H, m), 7.73 (1H, m).

b) 1-Benzyl-5-(3-cyclohexylidene-1-ylidenemethyl)-1H-imidazol

1-Benzyl-5-(3-cyclohexylidene-1-ylidenemethyl)-1H-imidazol receive, as described above, 1-benzyl-5-(2-phenylindol-1-ylidenemethyl)-1H-imidazole, except that as starting material used 3-cyclohexylidene-1-it. The crude product as hydrochloride use in the next stage without purification.

C) 4-[(3-Cyclohexyl-2,3-dihydro-1H-inden-1-yl)methyl]-1H-imidazol

4-[(3-Cyclohexyl-2,3-dihydro-1H-inden-1-yl)methyl]-1H-imidazol receive, as described above, 4-[(2,3-dihydro-6-methoxy-2-phenyl-1H-inden-1-yl)methyl]-1H-imidazole, except that in the source material, using 1-benzyl-5-(3-cyclohexylidene-1-ylidenemethyl)-1H-imidazole.

The crude product, which is a mixture of CIS - and TRANS-diastereomers of 4-[(3-cyclohexyl-2,3-dihydro-1H-inden-1-yl)methyl]-1H-imidazole, purified flash chromatography (eluent: a mixture of dichloromethane-methanol, 9,75:0,25 (about./vol.)). The free base is converted into the hydrochloride, which is a mixture of diastereomers (CIS:TRANS, 98:2).

CIS-diastereoisomer as hydrochloride: range1H NMR (CD3OD, δ ppm): 0.92 (1H, m),1.10-1.43 (5H, m),1.46 (1H, dt,3J=12.4 Hz,3J=9.5 Hz), 1.67-1.84 (4H, m), 1.92 (1H, m), 2.18 (1H, dt,3J=12.4 Hz,3J=7.7 Hz), 2.86 (1H, DD,2Jheme=14.6 the C, 3J=8.7 Hz), 3.10 (1H, m), 3.34-3.45 (2H, m),7.16-7.21 (4H, m), 7.31 (1H, d,4J=1.2 Hz), 8.82 (1H, d,4J=1.4 Hz).

EXAMPLE 9

4-[(3-Benzyl-2,3-dihydro-1H-inden-1-yl)methyl]-1H-imidazol

a) 3-Benzylidene-1-he

The specified connection receive in accordance with the method described ..Trost, L.H.Latimer (J. Org. Chem., 42, 1977, 3212). The parent compounds are 1-indanone and benzylbromide.

Range1H NMR (CDCl3that δ ppm): 2.44 (1H, DD,2Jheme=19.2 Hz3J=3.1 Hz), 2.76 (1H, DD,2Jheme=19.2 Hz3J=7.5 Hz), 2.82 (1H, DD,2Jheme=13.8 Hz,3J=9.1 Hz), 3.17 (1H, DD,2Jheme=13.8 Hz,3J=6.0 Hz), 3.72 (1H, m), 7.16-7.19 (2H, m), 7.22-7.41 (5H, m), 7.57 (1H, TD, Jortho=7.5 Hz, Jmeta=1.2 Hz), 7.74 (1H, d, Jortho=7.6 Hz).

b) 1-Benzyl-5-(3-benzylidene-1-ylidenemethyl)-1H-imidazol receive, as described above, 1-benzyl-5-(2-phenylindol-1-ylidenemethyl)-1H-imidazole, except that as starting material used 3-benzylidene-1-it. The crude product as hydrochloride use in the next stage without purification.

C) 4-[(3-Benzyl-2,3-dihydro-1H-inden-1-yl)methyl]-1H-imidazol

4-[(3-Benzyl-2,3-dihydro-1H-inden-1-yl)methyl]-1H-imidazole receive, as described above, 4-[(2,3-dihydro-6-methoxy-2-phenyl-1H-inden-1-yl)methyl]-1H-imidazole, except that in the source material, using 1-benzyl-5-(3-benzylidene-1-ylidenemethyl)-1H-imidazole. The crude product is CT, which is a mixture of CIS - and TRANS-diastereomers of 4-[(3-benzyl-2,3-dihydro-1H-inden-1-yl)methyl]-1H-imidazole, purified flash chromatography (eluent: a mixture of dichloromethane-methanol, 9,75:0,25 (about./vol.)). The free base is converted into the hydrochloride, which is a mixture of diastereomers (CIS:TRANS, 86:14).

CIS-diastereoisomer in the form of establishment: range1H NMR (CDCl3that δ ppm): 1.40 (1H, dt,2Jheme=12.7 Hz,3J=9.1 Hz), 2.29 (1H, dt,2Jheme=12.7 Hz,3J=7.5 Hz), 2.58 (1H, DD,2Jheme=13.7 Hz,3J=9.5 Hz), 2.75 (1H, DD,2Jheme=14.8 Hz,3J=8.5 Hz), 3.19 (1H, DD,2Jheme=15.4 Hz3J=5.2 Hz), 3.25 (1H, DD,2Jheme=13.7 Hz,3J=5.3 Hz), 3.36-3.47 (2H, m), 6.77 (1H, d,4J=0.7 Hz), 7.14-7.31 (M, m),7.53 (1H, d,4J=0.8 Hz).

EXAMPLE 10

4-(4-Phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-imidazol

a) 1-(3-Benzyl-3H-imidazol-4-yl)-4,4-diphenylbutane-1-ol

Magnesium turnings (0.5 g) cover with dry tetrahydrofuran (4 ml). Add dropwise 1-bromo-3,3-diphenylpropane (5.6 g) in 20 ml of dry tetrahydrofuran. The mixture is stirred while boiling under reflux for one hour. After cooling to room temperature, the Grignard reagent is added dropwise 3-benzyl-3H-imidazole-4-carbaldehyde (3.8 g) in 20 ml of dry tetrahydrofuran, and the mixture is refluxed for two hours. Cooled the reaction is ionic mixture is then poured into a dilute hydrochloric acid solution. Treatment of the mixture gives the crude product, which was converted into its hydrochloride in ethyl acetate using dry hydrochloric acid.

Range1H NMR (HCl salt, DMSO-d6that δ ppm): 1.51-1.59 (m, 2H), 1.86-1.92 (m, 1H), 1.99-2.06 (m, 1H),3.78 (t, J=7.9 Hz, 1H), 4.51 (m, 1H), 5.36 (s, 2H), 5.51 (s, 1H), 7.14-7.39 (m, N), 8.46 (s, 1H)

b) 1-(1H-Imidazol-4-yl)-4,4-diphenylbutane-1-ol

In 150 ml of ethanol was dissolved 3.0 g of 1-(3-benzyl-3H-imidazol-4-yl)-4,4-diphenylbutane-1-ol. The solution hydronaut at 45°using as catalyst 10%palladium on coal for 5 hours. The reaction mixture was filtered, and the filtrate is evaporated to dryness under reduced pressure.

Range1H NMR (HCl salt, DMSO-d6that δ ppm): 1.58-1.64 (m, 2H), 1.91-2.01 (m, 1H), 2.08-2.17 (m, 1H), 3.91 (t, J=7.9 Hz, 1H), 4.65 (t, J=6.4 Hz, 1H), 5.49 (s, 1H), 7.12-7.28 (m, 11N), 8.51 (s, 1H).

C) 4-(4-Phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-imidazol

A mixture of the hydrochloride of 1-(1H-imidazol-4-yl)-4,4-diphenylbutane-1-ol (2.0 g) and methanesulfonic acid (40 ml) is heated at 100°C for 40 minutes the Cooled reaction mixture was poured into water, and then alkalinized with sodium hydroxide solution. The product is extracted in ethyl acetate which is washed with water, dried with sodium sulfate and evaporated under reduced pressure to get crude product in the form of a racemic mixture of CIS - and TRANS-diastereoisomers. The product was then purified flash chromatography (elution with a gradient mixture dichlo the methane-methanol). Basically the product is dissolved in ethyl acetate and converted into its hydrochloride with gaseous hydrogen chloride.

Range1H NMR (TRANS isomer as HCl-salt, Meon-d4that δ ppm): 1.93-2.04 (m, 2H), 2.21-2.28 (m, 2H), 4.25-4.29 (m, 1H), 4.52-4.56 (m, 1H), 6.90-7.31 (m, 10H), 8.80 (d, J=1.4 Hz, 1H).

Range1H NMR (CIS-isomer as HCl-salt, Meon-d4that δ ppm): 1.74-1.85 (m, 2H), 2.08-2.18 (m, 2H), 4.16-4.20 (m, 1H), 4.42-4.45 (m, 1H), 6.88-7.30 (m, 10H), 8.84 (d, J=1.4 Hz, 1H).

EXAMPLE 11

4-[3-(4-Forfinal)-2,3-dihydro-1H-inden-1-yl]-1H-imidazol

a) TRANS-3-(4-Forfinal)-1-phenylpropene

A solution of 3.8 g (0,095 mol) of sodium hydroxide in 38 ml of water is gradually added dropwise into a solution of acetophenone (9.0 g, 0,075 mol) and 4-forventelige (9.4 g, 0,076 mol) in ethanol (20 ml). The mixture is stirred for 2 hours at room temperature. Add water (80 ml), and Ames neutralize 6 M HCl solution. The precipitate is filtered off TRANS-3-(4-forfinal)-1-phenylpropene, washed with water and dried.

Range1H NMR (DMSO-d6that δ ppm): 7.31 (2H, t,3J=8.9 Hz), 7.59 (2H, t,3J=7.5 Hz), 7.68 (1H, t,3J=7.3 Hz), 7.76 (1H, d,3JTRANS=15.7 Hz), 7.92 (1H, d,3JTRANS=15.5 Hz), 7.99 (2H, m), 8.16 (2H, m).

b) 3-(4-Forfinal)indan-1-he

Polyphosphoric acid (102 g) is heated on an oil bath to 140°and add 3-(4-forfinal)-1-phenylpropene (5.9 g). Heating continued for 30 min at 140°C. the Mixture is cooled is about 80° With and carefully add water. The mixture is extracted with ethyl acetate. The organic extracts washed with water. After drying over sodium sulfate the solvent is evaporated under reduced pressure. The obtained 3-(4-forfinal)indan-1-he is recrystallized from a mixture of heptane-ethyl acetate, 8:2.

Range1H NMR (CDCl3that δ ppm): 2.64 (1H, DD,2Jheme=19.2 Hz3J=3.9 Hz), 3.23 (1H, DD,2Jheme=19.2 Hz3J=8.1 Hz), 4.57 (1H, DD,3J=8.0 Hz,3J=3.9 Hz), 7.00 (2H, distorted t,3J=8.7 Hz), 7.06-7.11 (2H, m), 7.25 (1H, m), 7.43 (1H, t, Jortho=7.4 Hz), 7.58 (1H, TD, Jortho=7.5 Hz, Jmeta=1.2 Hz), 7.82 (1H, d, Jortho=7.7 Hz).

C) 3-(4-Forfinal)-1-(1-trityl-1H-imidazol-4-yl)indan-1-ol

To a solution of 4-iodine-1 trityl-1H-imidazole (7,22 g, 0,0165 mol, obtained in accordance with the methodology K.L.Kirk, J.Heterocycl. Chem., 22, 1985, 57) in 70 ml of dry methylene chloride added at room temperature, 3.0 M solution ethylacetamide (5,9 ml, 0,0177 mol) in diethyl ether. After 1 hour, add a solution of 3-(4-forfinal)indan-1-she (2.00 g, 0,00884 mol) in 6 ml of dry methylene chloride and stirred for 45 hours. Add a saturated solution of ammonium chloride to stop the reaction. Methylenchloride phase is separated, and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts washed with brine, dried and concentrated. Crude 3-(4-forfinal)-1-(1-trityl-1H-they shall Gasol-1-yl)indan-1-ol purified flash chromatography using as an eluent of methylene chloride.

d) 4-[3-(4-Forfinal)-3H-inden-1-yl]-1H-imidazol

3-(4-Forfinal)-1-(1-trityl-1H-imidazol-4-yl)indan-1-ol (2,22 g) in 22 ml of 2M HCl solution heated at 70°C for 2 hours. Add the water. The mixture is extracted with methylene chloride. Then the methylene chloride phase is extracted with 2 M HCl solution. All the combined water layers is alkalinized and extracted with methylene chloride. The organic phase is washed with water and dried. The solvent is removed under reduced pressure. Crude 4-[3-(4-forfinal)-3H-inden-1-yl]-1H-imidazole, which is a mixture of isomers (in the ratio 73:27), and purified flash chromatography (elute with a gradient mixture of dichloromethane-methanol).

e) 4-[3-(4-Forfinal)-2,3-dihydro-1H-inden-1-yl]-1H-imidazol

The mixture of isomers of 4-[3-(4-forfinal)-ZN-inden-1-yl]-1H-imidazole hydronaut in ethanol using as catalyst 10%palladium on coal. The mixture is filtered through celite, the solvent is evaporated. Crude 4-[3-(4-forfinal)-2,3-dihydro-1H-inden-1-yl]-1H-imidazole, which is a mixture of CIS - and TRANS-diastereomers (ratio 95,5:4,5), and purified flash chromatography (elution with a gradient mixture of dichloromethane-methanol).

CIS-diastereoisomer in the form of establishment: range1H NMR (CDCl3that δ ppm): 2.14 (1H, dt,2Jheme=11.1 Hz,3J=11.0 Hz), 2.89 (1H, dt,2Jheme=12.3 Hz,3J=7.1 Hz), 4.30 (1H, DD,3J=10.8 Hz,3J=72 Hz), 4.44 (1H, DD,3J=10.8 Hz,3J=7.2 Hz), 6.87-6.90 (2H, m), 6.96 (2H, t,3J=8.7 Hz), 7.12-7.19 (5H, m), 7.43 (1H, s).

EXAMPLE 12

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

3-Benzyl-1-(1-trityl-1H-imidazol-4-yl)indan-1-ol

The specified connection is obtained from 4-iodine-1 trityl-1H-imidazole and 3-benzylidene-1-it method described for 3-(4-forfinal)-1-(1-trityl-1H-imidazol-1-yl)indan-1-ol, as described above. 3-Benzyl-1-(1-trityl-1H-imidazol-4-yl)indan-1-ol purified flash chromatography (eluent: heptane-ethyl acetate, 1:1).

4-(3-Benzyl-3H-inden-1-yl)-1H-imidazol

Triethylsilane (1 ml, 0,728 g, 6.26 mmol) and triperoxonane acid (1.9 ml, of 2.81 g of 24.7 mmol) are added to a solution of 3-benzyl-1-(1-trityl-1H-imidazol-4-yl)indan-1-ol (0,387 g, 0.73 mmol) in dichloromethane (13 ml). The reaction mixture was stirred at room temperature for 20 hours. Then the reaction is stopped by the water, and the reaction mixture is alkalinized with 2 m sodium hydroxide solution. The dichloromethane layer is washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure. Flash chromatography using as eluent a mixture (gradient dichloromethane-methanol to obtain 4-(3-benzyl-3H-inden-1-yl)-1H-imidazole.

Range1H NMR (CDCl3that δ ppm): 2.69 (1H, DD,2Jheme=13.5 Hz,3J=9.4 Hz), 3.13 (1H, DD,2Jheme=13.5 Hz,3J=6.7 Hz), 3.80 (1H, m), 6.64 (1H, d,3J=2.2 Hz), 7.16-7.33 (M, m), 7.37 (1H, s), 7.60 (1H, d,3J=0.6 Hz), 7.69 (1H, d, Jortho=7.6 Hz).

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

4-(3-Benzyl-3H-inden-1-yl)-1H-imidazol hydronaut in ethanol using as catalyst 10%palladium on coal. The mixture is filtered through celite, and the solvent evaporated. Crude 4-(3-benzyl-2,3-dihydro-1H-inden-1-yl)-1H-imidazole, which is a mixture of CIS - and TRANS-diastereomers (ratio of 94:6), purified flash chromatography (elution with a gradient mixture of dichloromethane-methanol).

CIS-diastereoisomer in the form of establishment: range1H NMR (CDCl3that δ ppm): 1.82 (1H, dt,2Jheme=12.5 Hz,3J=9.7 Hz), 2.53 (1H, dt,2Jheme=12.5 Hz,3J=7.4 Hz), 2.69 (1H, DD,2Jheme=13.6 Hz,3J=9.4 Hz), 3.31 (1H, DD,2Jheme=13.6 Hz,3J=5.3 Hz), 3.49 (1H, m),4.31 (1H, m), 6.80 (1H, s), 7.08 (1H, distorted d, Jortho=7.4 Hz), 7.15-7.30 (8H, m), 7.46 (1H, m).

EXAMPLE 13

4-(2,3-Dihydro-3-phenylindane-1-yl)-1H-imidazol

Dimethylamide 2-(tert.-butyldimethylsilyl)-5-(2,3-dihydro-1-hydroxy-3-phenyl-1H-inden-1-yl)-1H-imidazole-1-sulfonic acid

The solution dimethylamide imidazol-1-sulfonic acid (1,96 g, 0,0112 mol, obtained by the method D.J.Chadwick, R.I.Ngochindo, J. Chem. Soc. Perkin Trans. I (1984) 481), in dry tetrahydrofuran (90 ml) under nitrogen atmosphere cooled to -78°C and treated dropwise with a 15%n-butyllithium in hexane (8.2 ml, 0,01393 the ol). After 30 minutes add tert.-butyldimethylsilyloxy (2.1 g, 0,01393 mol) in dry tetrahydrofuran (5 ml), and the mixture is allowed to warm to room temperature. After 1.5 h the mixture was again cooled to -78°and treated With a 15%n-butyllithium in hexane (8.5 ml, 0,01360 mol). After 30 minutes add 3-phenyl-1-indanone (3,40 g, 0,01633 mol) in dry tetrahydrofuran, and the mixture is allowed to warm to room temperature over night. The mixture was quenched with a saturated solution of sodium carbonate, and the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane, washed twice with water, dried, filtered and concentrated under reduced pressure. Cleaning is performed flash chromatography (elution with a gradient mixture of heptane-ethyl acetate).

Range1H NMR (CDCl3that δ ppm): 0.40 (3H, s), 0.41 (3H, s), 0.98 (S, s), 2.47 (1H, DD,2Jheme=12.9 Hz,3J=10.0 Hz), 2.88 (6N, s), 3.24 (1H, DD,2Jheme=12.9 Hz,3J=7.2 Hz), 4.05 (1H, DD,3J=9.9 Hz,3J=7.3 Hz), 6.14 (1H, s), 6.92 (1H, d, Jortho=7.0 Hz), 7.20-7.36 (7H, m), 7.52 (1H, d, Jortho=7.0 Hz).

Dimethylamide 5-(2,3-dihydro-1-hydroxy-3-phenyl-1H-inden-1-yl)-1H-imidazole-1-sulfonic acid

To a solution of dimethylamine 2-(tert.-butyldimethylsilyl)-5-(2,3-dihydro-1-hydroxy-3-phenyl-1H-inden-1-yl)-1H-imidazole-1-sulfonic acid (637 mg, 1.28 mmol) in tetrahydrofuran (13 ml) was added dropwise 1.1 M solution of tetrabutyl is iflorida in tetrahydrofuran (1.4 ml, 1.54 mmol). The reaction mixture was stirred over night at room temperature. The reaction is stopped by the water, and then the reaction mixture was extracted with ethyl acetate. The organic layer is washed with water and brine. The organic phase is dried, and the solvent is removed under reduced pressure. The product is recrystallized from ethyl acetate.

Range1H NMR (CDCl3that δ ppm): 2.47 (1H, DD,2Jheme=13.0 Hz,3J=10.0 Hz), 3.04 (6N, s), 3.31 (1H. DD,2Jheme=12.9 Hz,3J=7.2 Hz), 4.09 (1H, DD,3J=9.9 Hz,3J=7.2 Hz), 6.07 (1H, s), 6.96 (1H, d, Jortho=7.6 Hz), 7.19-7.27 (4H, m), 7.30-7.40 (3H, m), 7.54 (1H, d, Jortho=6.8 Hz), 7.94 (1H, s).

Dimethylamide 5-(3-phenyl-3H-inden-1-yl)-1H-imidazole-1-sulfonic acid

Triethylsilane (760 μl, 554 mg, 4.77 mmol) and triperoxonane acid (1,43 ml, 2,12 g of 18.6 mmol) are added to a solution of dimethylamine 5-(2,3-dihydro-1-hydroxy-3-phenyl-1H-inden-1-yl)-1H-imidazole-1-sulfonic acid (230 mg, 0.06 mmol) in dichloromethane (8 ml). The reaction mixture was stirred at room temperature overnight. Then the reaction is stopped by the water, and the reaction mixture is alkalinized with 2 m sodium hydroxide solution. The dichloromethane layer is washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure. Flash chromatography using as eluent a mixture of dichloromethane-methanol (gradient) is to obtain a mixture of isomers (ratio 65:35) dimethylamide 5-(3-phenyl-3H-inden-1-yl)-1H-imidazole-1-sulfonic acid.

4-(3-Phenyl-3H-inden-1-yl)-1H-imidazol

Dimethylamide 5-(3-phenyl-3H-inden-1-yl)-1H-imidazole-1-sulfonic acid (158 mg, 0.43 mmol) in 5 ml of 1.5 M HCl solution is refluxed for 1.5 hour. The reaction mixture is alkalinized, and then extracted with ethyl acetate. The organic phase is washed with water and dried. The solvent is removed under reduced pressure. Crude 4-(3-phenyl-3H-inden-1-yl)-1H-imidazole, which is a mixture of isomers (ratio 75:25), and purified flash chromatography (elution with a mixture of dichloromethane-methanol, 9,75:0,25).

4-(2,3-Dihydro-3-phenylindane-1-yl)-1H-imidazol

The mixture of isomers of 4-(3-phenyl-3H-inden-1-yl)-1H-imidazole hydronaut in acetic acid at 50°using as catalyst 10%palladium on coal. The mixture is filtered through celite, and the solvent evaporated. Add water, and the solution is alkalinized. The aqueous solution is extracted with ethyl acetate. The organic phase is washed with water, dried and the solvent evaporated. The hydrochloride of the product is obtained in ethyl acetate. The product 4-(2,3-dihydro-3-phenylindane-1-yl)-1H-imidazole is a mixture of CIS - and TRANS-diastereomers (ratio 95:5).

CIS-diastereoisomer in the form of its hydrochloride: range1H NMR (CD3OD, δ ppm): 2.19 (1H, dt,2Jheme=12.2 Hz,3J=11.0 Hz), 2.99 (1H, dt,2Jheme=12.2 Hz,3J=7.1 Hz), 4.43 (1H, DD,3J=0.9 Hz, 2Jheme=7.0 Hz), 4.66 (1H, DD,3J=11.0 Hz,3J=7.0 Hz), 6.92-6.94 (1H, m), 7.07-7.09 (1H, m), 7.23-7.37 (7H, m), 7.52 (1H, d,4J=1.2 Hz), 8.89 (1H, d,4J=1.4 Hz).

EXAMPLE 14

4-[(1,2,3,4-Tetrahydro-3-phenylnaphthalene-1-yl)methyl]-1H-imidazol

1-Benzyl-5-(3-phenyl-3,4-dihydro-2H-naphthalene-1-ylidenemethyl)-1H-imidazol

1-Benzyl-5-(3-phenyl-3,4-dihydro-2H-naphthalene-1-ylidenemethyl)-1H-imidazol receive, as described above, 1-benzyl-5-(2-phenylindol-1-ylidenemethyl)-1H-imidazole, except that in the source material, using 3-phenyl-3,4-dihydro-2H-naphthalene-1-he (obtained in accordance with the methodology J.Vebrel, R.Carrie, Bull. Soc. Chem. Fr., 1982, 116). The crude product in the form of its hydrochloride use in the next stage without purification.

4-[(1,2,3,4-Tetrahydro-3-phenylnaphthalene-1-yl)methyl]-1H-imidazol

4-[(1,2,3,4-Tetrahydro-3-phenylnaphthalene-1-yl)methyl]-1H-imidazol receive, as described above, 4-[(2,3-dihydro-6-methoxy-2-phenyl-1H-inden-1-yl)methyl]-1H-imidazole, except that in the source material, using 1-benzyl-5-(3-phenyl-3,4-dihydro-2H-naphthalene-1-ylidenemethyl)-1H-imidazole.

The hydrochloride of the product is a mixture of two diastereomers (82:18, TPL 198°).

1. Derived imidazole of the formula (I)

where X represents-CH2-(CH2)p-, -O-;

R1represents phenyl, nafti is, 1,2,3,4-tetrahydronaphthyl,3-C7-cycloalkyl, where mentioned phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl,3-C7-cycloalkyl optionally substituted with one to three substituents, independently selected from halogen, -HE, halogen-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkoxygroup and HE-(C1-C6)-alkyl;

R2represents N or C1-C6-alkyl;

R3represents N or C1-C6-alkyl;

R4represents N or C1-C6-alkyl;

R5represents N or R5and R7together form a bond;

each R6independently represents halogen, -HE, halogen-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkoxygroup or HE-(C1-C6)-alkyl;

R7represents N or R7and R5together form a bond;

each R8independently represents IT, WITH1-C6-alkyl, halogen-C1-C6-alkyl or C1-C6-alkoxygroup;

m is 0, 1, 2 or 3;

n is 0 or 1;

p is 0 or 1;

r is 0 or 1;

t is 0,

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where X represents-CH2-(CH )pand p is 0.

3. The compound according to claim 1, where X represents-CH2-(CH2)pand p is 1.

4. The compound according to claim 1, where X represents-O-.

5. The compound according to claim 1, which is a compound of the formula

where R1-R8, m, n, r and t have the meanings given in claim 1.

6. The compound according to claim 1, which is a compound of the formula

where R1-R8, m, n, r and t have the meanings given in claim 1.

7. The compound according to any one of claims 1 to 6, where r is 0.

8. The compound according to any one of claims 1 to 6, where r is 1, a R2and R3represent N.

9. The compound according to any one of claims 1 to 8, where n is equal to 0.

10. The compound according to any one of claims 1 to 8, where n is equal to 1.

11. The compound according to any one of claims 1 to 8, where n is 1, a R4and R5represent N.

12. The compound according to any one of claims 1 to 11, where R7represents N.

13. The compound according to any one of claims 1 to 12, where R1represents phenyl, naphthyl or cyclohexyl, each of which is optionally substituted with one to three substituents, independently selected from halogen, -HE, halogen-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkoxygroup and HE-(C1-C6)-alkyl.

14. The compound according to any one of claims 1 to 13, where R1 represents a phenyl, naphthyl or cyclohexyl, each of which is optionally substituted with one to three substituents, independently selected from halogen, -HE1-C6-alkoxygroup and (C1-C6)-alkyl.

15. The compound according to any one of claims 1 to 13, where R1represents phenyl or cyclohexyl, each of which is optionally substituted with one to three substituents, independently selected from halogen, -HE1-C6-alkoxygroup and (C1-C6)-alkyl.

16. The compound according to any one of claims 1 to 13, where R1represents phenyl or cyclohexyl, each of which is optionally substituted with one to three substituents, independently selected from halogen, -HE, halogen-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkoxygroup and HE-(C1-C6)-alkyl.

17. The compound according to any one of claims 1 to 16, where m is equal to 0.

18. The compound according to any one of claims 1 to 17, where m is 1 or 2, and each of R6independently selected from halogen, -HE1-C6-alkoxygroup and (C1-C6)-alkyl.

19. The compound according to any one of paragraphs. 1-18, where t is 0.

20. The compound according to any one of claims 1 to 19 as an antagonist of alpha-2-adrenoceptors.

21. Pharmaceutical composition having affinity for alpha-2-adrenoceptors containing compound according to any one of claims 1 to 19 or its pharmaceutically acceptable ester, alisol and optionally a pharmaceutically acceptable carrier, the diluent and/or excipient.

22. The compound according to any one of claims 1 to 19 or its pharmaceutically acceptable ester or salt for use for the treatment of neurological disorders, psychiatric disorders or impairment of cognitive ability.

23. The compound according to any one of claims 1 to 19 or its pharmaceutically acceptable ester or salt for use for the treatment of diabetes, lipolytic disorders, orthostatic hypotension and sexual dysfunction.

24. Method of producing compounds of the formula I according to claim 1, characterized in that for producing compounds of formula I where n is 1, carry out the interaction of the compounds of formula II

where X, R1-R3, R6, R8, m, r and t have the meanings given in paragraph 1,

with the compound of the formula III

where R4is defined in paragraph 1 values, and R' represents H or a protective group,

obtaining the compounds of formula I'

where X, R1-R4, R6, R8, m, r, t and R' have the meanings given above,

which then remove the protective group and which emit in the usual way, or which make a hydrogenation into another compound of formula Ia

where X, R1-R4, R6, R8, m, r, t and R' have the meanings given above.

25. The method of treatment of neurological disorders, psychiatric disorders or impairment of cognitive abilities, diabetes, lipolytic disease, orthostatic hypotension and sexual dysfunction comprising administration to a subject in need of such treatment, an effective amount of a compound according to any one of claims 1 to 19 or its pharmaceutically acceptable complex ester or salt.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to benzimidazole derivatives or their salts useful in medicine of the general formula (1): wherein R1 and R2 can comprise similar or different values and represent independently of one another hydrogen atom, halogen atom, cyano-group, hydroxyl group, alkyl group comprising 1-4 carbon atoms, alkoxy-group comprising 1-4 carbon atoms, trifluoromethyl group; A represents unsubstituted, linear alkylene group comprising 1-7 carbon atoms; E represents group -COOR3 comprising 1-6 carbon atoms; G represents unsubstituted, linear alkylene group comprising 1-6 carbon atoms; M represents a simple bond or -S(O)m- wherein m represents a whole number in the range 0, 1 or 2; J represents substituted or unsubstituted heterocyclic group comprising 4-10 carbon atoms and one heteroatom in ring taken among the group consisting of nitrogen atom or sulfur atom excluding unsubstituted pyridine ring; a substitute in indicated aromatic heterocyclic group is taken among halogen atom, cyano-group, linear alkyl group comprising 1-6 carbon atoms, linear alkoxy-group comprising 1-6 carbon atoms, trifluoromethyl group and trifluoromethoxy-group wherein one or more indicated substituted can be replaced by random positions in ring; X represents methane group (-CH=). Also, invention relates to a pharmaceutical composition used in inhibition of human chymase activity based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for prophylaxis and/or treatment of inflammatory disease, cardiovascular disease, allergic disease, respiratory disease or osseous either cartilaginous metabolic disease.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 3 tbl, 20 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new 5-aryl-1-phenyl-4-heteroyl-3-hydroxy-3-pyrroline-2-ones of the formula:

wherein (1) X means sulfur atom (S); R means (CH3)2CH; (2) X means sulfur atom (S); R means (CH3)3C; (3) X means oxygen atom (O); R means (CH3)3C. Compounds of the formula (I) are prepared by interaction of the corresponding heteroylpyruvic acid methyl ester with mixture of aniline and aromatic aldehyde in acetic acid medium at short-time heating. Compounds elicit an anti-bacterial activity with value MIC = 3.9-7.8 mcg/ml as compared with 62-1000 mcg/ml for analogue.

EFFECT: valuable properties of compounds.

1 tbl, 3 ex

The invention relates to organic chemistry and can find application in medicine

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

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 derivatives of azetidine formula

in which R denotes an element of the formula

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

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

The invention relates to derivatives of cyclic amines and their use as pharmaceuticals, particularly to a compound represented by the General formula (I), its pharmaceutically acceptable acid additive salts or its pharmaceutically acceptable C1-C6alcaldicios salt, R1-phenyl, C3-8-cycloalkyl, aromatic heterocycle with 1-3 heteroatoms selected from O, S, N, or combinations thereof, and these groups may be condensed with benzene ring or an aromatic heterocyclic group with heteroatoms, selected from O, S or N, or combinations thereof, and may also have different substituents

The invention relates to new salts of pyridinium General formula (I) or their pharmaceutically acceptable salts, where R1is-R4- R5or-N(R7)N(R7R9, R4choose from the group of-N(R7R6O-, N(R7R6N(R7), -OR6O-,

-OR SIG6N(R7)-, where R6- alkyl, R5choose from the group of alkyl, aryl, including heteroaryl, -COR7, -SO2R7and-COR10where R7Is H, alkyl or aryl, including heteroaryl, R2Is F, Cl, Br, J, alkyl, aryl, including heteroaryl, formyl, acyl, C(O)NR7R10or C(O)or SIG7, m = 0, 1, or 2, R3selected from the group comprising R7OR7N(R7)(R10) and CH(R7)C(O)R8, R8is R7OR7and NR7R10, R9is hydrogen, alkyl, aryl, including heteroaryl, -C(O)R10, -SO2R10, -C(S)OTHER10, -C(NH)NH(R10), -C(O)OTHER10, R10- H, alkyl, or aryl, including heteroaryl, and in each case, it is not necessarily different from R7X represents an ion halogen provided that 1) when two alkyl groups are the same carbon or nitrogen, they are not necessarily linked together with the formation of a cyclic structure, and (2) nitrogen heteroaryl ring R1

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted indole compounds of Mannich bases of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C10)-alkyl, unsubstituted phenyl or naphthyl bound through (C1-C2)-alkylene group or that monosubstituted at least with hydroxy group (-OH), halogen atom, -CF3, -CN, (C1-C6)-alkyl, (C1-C6)-alkoxy group; R2 means atoms H, F, Cl, Br, groups -CF3, -CN, -OR10, -CO(OR11), -CH2CO(OR12), -COR19, (C1-C10)-alkyl, unsubstituted phenyl or naphthyl, or that monosubstituted at least with -OH, halogen atom, -CF3, -CN, (C1-C6)-alkyl and (C1-C6)-alkoxy group; R3 means -CH(R13)N(R14)(R15); R4, R5, R6 and R7 can have similar or different values and mean atoms H, F, Cl, Br and groups -CF3, -CN, -NO2, -OR10 and others; R10 means H, -COR17, (C1-C6)-alkyl and others; R13 means unsubstituted phenyl or phenyl monosubstituted with at least (C1-C4)-alkyl, halogen atom, -CF3, -CN and -OH; R14 and R15 can have similar or different values and mean unbranched or branched (C1-C6)-alkyl, or R14 and R15 represent in common (CH2)n wherein n means a whole number from 3 to 6, or (CH2)O(CH2)2; R17 means (C1-C6)-alkyl; R19 means -NHR20, (C1-C6)-alkyl and others; R20 means H, (C1-C6)-alkyl and others, and/or their racemates, enantiomers, diastereomers and/or corresponding bases, and/or corresponding salts of physiologically acceptable acids with exception of racemates of some compounds given in claim 1. Also, invention describes method for their preparing and using as a medicinal agent possessing analgesic effect.

EFFECT: valuable medicinal properties of compounds.

42 cl, 2 dwg, 3 tbl, 103 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new 5-aryl-1-phenyl-4-heteroyl-3-hydroxy-3-pyrroline-2-ones of the formula:

wherein (1) X means sulfur atom (S); R means (CH3)2CH; (2) X means sulfur atom (S); R means (CH3)3C; (3) X means oxygen atom (O); R means (CH3)3C. Compounds of the formula (I) are prepared by interaction of the corresponding heteroylpyruvic acid methyl ester with mixture of aniline and aromatic aldehyde in acetic acid medium at short-time heating. Compounds elicit an anti-bacterial activity with value MIC = 3.9-7.8 mcg/ml as compared with 62-1000 mcg/ml for analogue.

EFFECT: valuable properties of compounds.

1 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

New compounds // 2258703

FIELD: organic chemistry, medicine, pharmacy.

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

wherein R1 is taken among phenyl or pyridinyl and wherein each phenyl ring R1 or pyridinyl ring R1 can be substituted additionally and independently with chlorine, fluorine, bromine and iodine atom at any position of indicated ring, and also to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical composition based on these compounds eliciting δ-agonistic activity and to a method for pain treatment. Invention provides preparing new compounds of the formula (I) used in applying for pain treatment and for manufacturing drugs for this purpose.

EFFECT: valuable medicinal properties of new compounds.

8 cl, 3 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

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

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide that involves conversion of methylcyano acetate to the end compound for 8 or less stages. Also, invention relates to value intermediate compounds that are synthesized as result of realization of above indicated stages of the claimed method. 5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide is a value intermediate compound used in synthesis of the drug atorvastatin calcium that is used as hypolipidemic and/or hypocholesterolemic agent. Proposed method allows avoiding usage of expensive chiral parent substances and to reduce the synthesis process time.

EFFECT: improved preparing method.

12 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

The invention relates to new imidazole compounds of the formula I:

where R1represents hydrogen, hydroxy, protected hydroxy, or aryl, optionally substituted with a suitable(and) substituent(s) selected from the group consisting of halogen(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy, optionally substituted aryl, and lower alkyl, optionally substituted by hydroxy or protected carboxy; R2represents hydrogen or lower alkyl; R3is hydroxy or protected hydroxy; R4represents cyano, (hydroxy)minamino(lower)alkyl, carboxy, protected carboxy, N-containing heterocyclic group, optionally substituted amino, or carbarnoyl, optionally substituted with a suitable(s) of the substituent(s) selected from the group consisting of amino, hydroxy, lower alkyl, lower alkylsulfonyl, amidoamine(lower)alkyl, optionally substituted by hydroxy; and-And - is-Q -, or-O-Q-, where Q is a single bond or lower alkylene, or its salt, provided when R2is the lowest Ala the substituent(s), the above, and also provided that the compound of formula I is not 1-(hydroxyethyl)-4-(etoxycarbonyl)imidazole or anilide 1-(2-hydroxyethyl)imidazole-4-carboxylic acid

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

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