Derivatives (indole-3-yl) heterocyclic compounds as agonists of cannabinoid receptors cb1

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

 

The present invention relates to a derivative (indol-3-yl)heterocyclic compounds containing pharmaceutical compositions and to the use of these derivatives (indol-3-yl)heterocyclic compounds in therapy, especially in the treatment of pain.

Treatment of pain is often limited by side effects of currently available drugs. For pain from moderate to severe, widely used opioids. These tools are inexpensive and effective, but have a serious and potentially life-threatening side effects, especially respiratory depression and muscle rigidity. In addition, the dose of opioids that can be entered is limited to nausea, vomiting, constipation, itching, and urinary retention, which often leads to patients is preferable to choose sub-optimal pain, than to endure these afflictive side effects. Moreover, these side effects often lead to the fact that patients need prolonged hospitalization. Opioids are causing severe addiction means and the listed drug in many areas. Therefore, there is a need for new pain means, which has an improved side effect profile compared with currently used products with equal bol is the satisfier of the doses.

Accumulated evidence that cannabinoid agonists have potential as an analgesic and anti-inflammatory drugs. Cannabinoid receptors include two types of receptors: cannabinoid CB1 receptors, which are mainly located in the Central nervous system, but are also expressed in peripheral neurons and to a lesser extent in other peripheral tissues; and the cannabinoid receptor CB2, which are mainly located in the cells of the immune system (Howlett, A.C. et al.: International Union of Pharmacology. XXVII. Classification of cannabinoid chemistry Receptors. Pharmacol. Rev. 54, 161-202, 2002). While the CB2 receptor is involved in the modulation of immune and inflammatory response cannabinoids, cannabinoid receptor agonists have mainly those that interact with CB1 receptors, have been proposed as suitable for treatment of pain (see Iversen, L. and Chapman, V., Current Opinion in Pharmacology, 2, 50-55, 2002 and are there links).

In U.S. patent 4939138 (Sterling Drug Inc.) pain as a means described WIN 55,212-2, mutilata salt of (R)-(+)-[2,3-dihydro-5-methyl[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazine]-(1-naphthalenyl)methanone. This connection represents the prototype of aminoalkylindoles (Eissenstat, M.A. et al., J. Med. Chem. 38, 3094-3105, 1995), which are strong agonists of CB1 receptors, can cause antinociception with equal General is the effectiveness in animal models of acute pain, long-term pain inflammation and neuropathic pain.

Key structural attributes of aminoalkylindoles with cannabimimetic properties (Adam, J. and Cowley, P. Expert Opin. Ther. Patents, 12, 1475-1489, 2002), are aminoalkyl the substituent in position 1 of the indole group and, in addition, bulk of the substituent in position 3 of the indole ring, an example of which is arolina group aminoalkylindole described in U.S. patent 4939138 (Sterling Drug Inc.) or in a later application WO02060447 (University of Connecticut), or substituted aminogroup in the compounds described in WO0158869 (Bristol-Myers Squibb). Recently WO0236590 (Amrad Operations PTY Ltd.) as modulators of cannabinoid receptors and are useful as analgesics were described 1-(aminoalkyl)indole derivatives having substituted oxadiazol-5-ilen ring in position 3.

There remains a need in the cannabinoid agonists with improved properties such as increased solubility in water, for use as therapeutic agents.

In this regard, the present invention relates to a derivative (indol-3-yl)heterocyclic compounds having a General formula I

where A represents a 5-membered aromatic heterocyclic ring, where X1X2and X3independently selected from N, O, S, and CR;

R submitted is H or a (C 1-4)alkyl; or

R, when present in the X2or X3with R3to form a 5-8-membered ring;

R1is a 5-8-membered saturated carbocyclic ring, optionally containing a heteroatom selected from O and S;

R2represents H, CH3or CH2-CH3; or

R2connected with R7with the formation of 6-membered ring, optionally containing a heteroatom selected from O and S, and where the heteroatom is connected to the position 7 of the indole ring;

R3and R4independently represent H, (C1-6)alkyl or (C3-7)cycloalkyl, where these alkyl groups optionally substituted by OH, (C1-4)alkyloxy, (C1-4)alkylthio, (C1-4)alkylsulfonyl, CN or halogen; or

R3together with R4and the N to which they are bound, form a 4-8-membered ring, optionally containing an additional heteroatom selected from O and S, and optionally substituted by OH, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy-(C1-4)alkyl or halogen; or

R3together with R5form a 4-8-membered ring, optionally containing an additional heteroatom selected from O and S, and optionally substituted by OH, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy-(C1-4)alkyl or halogen; or

R3 together with R, when it is present in the X2or X3, form a 5-8-membered ring;

R5represents H, (C1-4)alkyl; or

R5together with R3form a 4-8-membered ring, optionally containing an additional heteroatom selected from O and S, and optionally substituted by OH, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy-(C1-4)alkyl or halogen;

R5' represents H, (C1-4)alkyl;

R6represents 1-3 substituting groups, independently selected from H, (C1-4)alkyl, (C1-4)alkyloxy, CN or halogen;

R7represents H, (C1-4)alkyl (C1-4)alkyloxy, CN or halogen; or

R7connected with R2with the formation of 6-membered ring, optionally containing an additional heteroatom selected from O and S, and where the heteroatom is connected to the position 7 of the indole ring; or their pharmaceutically acceptable salts, as agonists of cannabinoid receptors CB1, which can be used to treat pain, such as perioperative pain, chronic pain, neuropathic pain, pain and cancer pain and pain and muscle spasticity in multiple sclerosis.

As used in the definition of formula I, heterocycle represents A 5-membered aromatic heterocyclic ring which contains 1-3 heteroatoms, chosen is different from N, O and S. This means that at least one of X1X2and X3used to define A heterocycle, there can be a CR. Representative heterocycles are A heterocycles derivatives of thiophene, furan, triazole, thiazole, thiadiazole, oxazole, oxadiazole and their isomers, including isothiazol, isothiazol, isoxazol and isoxazol. Preferred heterocycles represent A 1,2,4-oxadiazol (X1represents N, X2represents O, X3is a (N), 1,2,4-thiadiazole (X1represents N, X2represents S, X3is a (N) and thiazole (X1represents S, X2represents CR, X3is a (N).

In the definition of formula I R, when present in the X2or X3, can form with R35-8-membered ring, thus forming together with ring A bicyclic ring system containing 5-8-membered N-containing ring fused with 5-membered aromatic heterocyclic ring A. Examples of such condensed ring systems are condensed ring system, derivatives of 5,6-dihydro-4H-pyrrolo[3,4-d]isoxazol, 4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine, 4,5,6,7-tetrahydrothieno[5,4-c]pyridine, 5,6,7,8-tetrahydro-4Hisoxa the olo[5,4- c]azepine, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole and 5,6-dihydro-4H-pyrrolo[3,4-d]isothiazole.

As used in the definition of formula I, the term (C1-4)alkyl means a branched or unbranched alkyl group with 1-4 carbon atoms, such as butyl, isobutyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

In the term (C1-4)alkyloxy, (C1-4)alkyl has the meaning specified above.

The term halogen means F, Cl, Br or I.

As used in the definition of R1formula I, the term 5-8-membered saturated carbocyclic ring represents cyclopentamine, tsiklogeksilnogo, cycloheptyl or cyclooctyl ring. Such rings may contain a heteroatom selected from O and S, which forms a saturated heterocyclic ring, such as tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranyl. Preferred carbocyclic rings are cyclohexyl and tetrahydropyranyl.

In the definition of formula I R2can be connected with R7with the formation of 6-membered ring, optionally containing a heteroatom selected from O and S, which is associated with position 7 of the indole ring. In such (indol-3-yl)substituted 5-membered-heterocyclic compounds of this invention indole-3-ilen group is part of tricyclic condensed number is zeway system, i.e. system 2,3-dihydropyrrolo[3,2,1-ij]quinoline (R7and R2represent-CH2-CH2- , 2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (R7and R2represent-O-CH2-or system-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzothiazin (R7and R2represent-S-CH2-).

In the definition of formula I R3together with R4and the N to which they are bound, form a 4-8-membered ring, optionally containing an additional heteroatom selected from O and S. Examples of such rings are pyrrolidin-1-yl, piperidine-1-yl, azepin-1-yl, morpholine-4-yl and thiomorpholine-4-yl. Preferred are pyrrolidin-1-yl, piperidine-1-yl and morpholine-4-yl.

In the definition of formula I R3together with R5may form a 4-8-membered ring, optionally containing an additional heteroatom selected from O and S. it is Clear that N is associated with R3and the carbon atom is linked to R5represent part 4-8-membered rings. Examples of such rings are pyrrolidin-2-yl, piperidine-2-yl, azepin-2-yl, morpholine-3-yl and thiomorpholine-3-yl.

In accordance with formula I there is a preference for derivatives (indol-3-yl)heterocyclic compounds, where R2represents H or R2connected with R7with the formation of 6-membered rings, optionally soda is containing a heteroatom, selected from O and S, and where the heteroatom is connected to the position 7 of the indole ring.

In addition, preferred are derivatives (indol-3-yl)heterocyclic compounds of the present invention, where R, R5, R5' and R6represent H.

Also preferred are derivatives (indol-3-yl)heterocyclic compounds in accordance with formula I, where R1represents a cyclohexyl or tetrahydropyranyl.

Especially preferred are derivatives (indol-3-yl)heterocyclic compounds in accordance with formula I, where the heterocycle A is a 1,2,4-oxadiazol (X1represents N, X2represents O, X3is a (N), 1,2,4-thiadiazole (X1represents N, X2represents S, X3represents N or thiazole (X1represents S, X2represents CR, X3is a (N).

Especially preferred derivatives (indol-3-yl)heterocyclic compounds of the present invention are:

7-chloro-3-(5-{[N-ethyl-N-(2-methoxyethyl)amino]methyl}-[1,2,4]thiadiazole-3-yl)-1-(tetrahydropyran-4-yl)methyl-1-H-indole;

7-chloro-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]thiadiazole-3-yl}-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-chloro-3-(5-{[N-ethyl-N-(2-hydroxyethyl)amino]m is Tyl}-[1,2,4]thiadiazole-3-yl)-1-(tetrahydropyran-4-yl)methyl-1 H-indole;

7-chloro-3-(4-{[N-(2-hydroxyethyl)-N-isopropylamino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-chloro-3-(4-{[N-ethyl-N-(2-hydroxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-chloro-3-(4-{[N-(2-methoxyethyl)-N-methylamino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-chloro-3-{5-[(2,2-dimethylpiperidin-1-yl)methyl]-[1,2,4]oxadiazol-3-yl}-1-(tetrahydropyran-4-yl)methyl-1H-indole,

or their pharmaceutically acceptable salts.

As a rule, derivatives (indol-3-yl)heterocyclic compounds of the present invention can be obtained by methods known in organic chemistry. For example, derivatives (indol-3-yl)heterocyclic compounds of the formula I can be obtained from compounds of formula II where Y is a leaving group such as halogen or alkylsulfonate group, nucleophilic substitution of the leaving group with the amine of the formula with other3R4. The compounds of formula II where Y represent alkylsulfonate group, can be obtained from compounds of formula II where Y is a hydroxy-group, by reaction with alkylsulfonamides in the presence of a base such as triethylamine. Derivatives (indol-3-yl)heterocyclic compounds of the formula I, where R5' represents hydrogen, can be on ucati of compounds of formula III by reductive amination, using the amine of the formula with other3R4in the presence of a reducing agent, such as triacetoxyborohydride sodium. In this field it is well known that the compounds of formula II where Y is a hydroxy-group, and R5' represents hydrogen, can vzaimoprevrascheny with compounds of formula III by oxidation and restore using suitable oxidizing agents or reducing agents, as described Burke D.S., Danheiser, R.L. in Handbook of Reagents for organic Synthesis: Oxidising and Reducing agents (Wiley: New York, 1999). Similarly, the compounds of formula II where Y is a hydroxy-group, and R5and R5' represent hydrogen, and the compounds of formula III, where R5represents hydrogen, can be obtained from compounds of formula IV, where R8represents hydrogen or (C1-4)alkyl, recovery using suitable reducing agents. The compounds of formula II where Y is a hydroxy-group, and R5' is a (C1-4)alkyl, can be obtained from compounds of formula III nucleophilic attach using (C1-4)altimetrical reagent such as an alkyl Grignard reagent or alkylate.

The compounds of formula I, formula II, formula III or formula IV can be obtained from compounds of formula V-XII, inclusive, using well and is known in the field of construction of heterocyclic rings of ways. Such methods are described in the main link Katritzky, A.R.: Comprehensive heterocyclic chemistry (First Edition, Pergamon Press, 1984, see especially Volume 4, Part 3, Five-membered rings with one oxygen, sulfur or nitrogen atom, and Volume 6, Part 4B, Five-membered rings with two or more oxygen, sulfur or nitrogen atoms).

The compounds of formula V-XII, inclusive, where R1, R2, R6and R7are as defined above meanings and R8represents H or (C1-4)alkyl, can be obtained are described in the literature or known to the person skilled in the art the modifications described in the literature methods.

For example, the compounds of formula VI can be obtained from compounds of formula V or their activated derivatives by reaction with ammonia in an acceptable solvent.

The compounds of formula VII can be obtained from compounds of formula VI using tianyoude reagents, such as pentasulfide phosphorus or reagent Lawesson.

Alternatively, the compounds of formula VII can be obtained from compounds of formula VIII by reaction with thioacetamide in a solvent such as dimethylformamide.

The compounds of formula VIII can be obtained from compounds of formula VI by dehydration, for example, using triperoxonane anhydride in the presence of a base such as triethylamine.

The compounds of formula X can be obtained from compounds of formula IX by reaction with the hydroxyl is increasing in an acceptable solvent.

The compounds of formula XI where Y represents NH2can be obtained from compounds of formula V or their activated derivatives by reaction with cyanide anion with the formation of oxoazetidin, followed by reduction of nitrile to the primary amine using a reducing agent such as hydrogen gas, in the presence of a catalyst such as palladium on charcoal.

The compounds of formula XII can be obtained from compounds of formula VIII by reaction with hydroxylamine in an acceptable solvent.

The compounds of formula V and compounds of formula XI can be obtained by acylation of compounds of formula XIII. For example, the compounds of formula V, where R8represents hydrogen, can be obtained by acylation of compounds of formula XIII using triperoxonane anhydride in a solvent such as dimethylformamide, followed by hydrolysis using aqueous sodium hydroxide at elevated temperatures. The compounds of formula XI where Y is chlorine, can be obtained by acylation of compounds of formula XIII using chloroacetaldehyde in the presence of a base, such as pyridine.

The compounds of formula IX can be obtained from compounds of formula XIII formirovanie, for example, using the reaction of Vilsmeier (for review see Jutz, Adv. Org. Chem. 9, pt. 1, 225-342, 1976).

Alternatively, the joint is of the formula V can be obtained from compounds of formula XIV using methods described Wijngaarden et al. (J. Med. Chem. 36, 3693-3699, 1993) or Hwu et al. (J. Org. Chem. 59, 1577-1582, 1994), or using modifications of these methods.

The compounds of formula XIII can be obtained are described in the literature or known to the person skilled in the art the modifications described in the literature methods. For example, the compounds of formula XIII can be obtained by alkylation of compounds of formula XV by treatment with base such as sodium hydride, followed by reaction with an alkylating agent R1R2CHY where Y is a leaving group such as halogen or alkylsulfonate group. The compounds of formula XV can be obtained from commercial sources, can be obtained are described in the literature or known to the person skilled in the art the modifications described in the literature methods.

Alternatively, the compounds of formula XIII can be obtained from compounds of formula XIV using synthesis of indoles Fisher or its modifications (Chem. Rev. 69, 227-250, 1969).

The compounds of formula XIV can be obtained are described in the literature or known to the person skilled in the art the modifications described in the literature methods. For example, the compounds of formula XIV, where R2connected with R7with the formation of 6-membered carbocyclic ring, can be obtained from compounds of formula VI recovery using a reducing agent, such as sodium borohydride, in the presence of a catalyst such as Nickel chloride (II). The compounds of formula XVI can be obtained, for example, by a condensation reaction such as the reaction of 2-chlorhydrin with a Grignard reagent in the presence of a catalyst of Nickel (II).

The compounds of formula XIV, where R2connected with R7with the formation of 6-membered rings containing oxygen or sulfur, can be obtained by reaction with a compound of formula XVII, where Z represents OH or SH, with a compound of formula XVIII, where Y is a leaving group, with the formation of ether or tiefer and subsequent reduction of the nitro group to an amine and reductive cyclization. Restoration and cyclization can be accomplished, for example, using gaseous hydrogen in the presence of a catalyst such as palladium on charcoal.

The compounds of formula XVII and the compounds of formula XVIII can be obtained from commercial sources, can be obtained are described in the literature or known to the person skilled in the art the modifications described in the literature methods. For example, the compounds of formula XVIII, where Y represents bromine, can be obtained from compounds of formula XIX using brainwashes agents, such as bromine, in a solvent such as methanol.

Alternatively, the joint is of the formula I, formula II, formula III or formula IV can be obtained from compounds of formula XX using transition metal, a catalytic reaction mix as described in the main link Hegedus, L.S. Transition Metals in the Synthesis of Complex Organic Molecules (Second Edition, University Science: Sausalito 1999).

For example, the compounds of formula III can be obtained by reaction of compounds of formula XX, where Y1represents a halogen, to the compounds of formula XXI, where Y2represents Bronevoy acid or ester Bronevoy acid, using a Suzuki reaction (Chem. Rev. 95, 2457-2483, 1995) or its modifications.

The compounds of formula XX and the compounds of formula XXI can be obtained from commercial sources, can be obtained are described in the literature or known to the person skilled in the art the modifications described in the literature methods. For example, the compounds of formula XX, where Y1represents bromine, can be obtained by bromirovanii compounds of formula XIII using bromine in a solvent such as dimethylformamide.

The person skilled in the art it is clear that the nitrogen of indole under the above transformations may be temporarily protected with protective groups, such as arylsulfonyl group, with subsequent removal of the protection and alkylation in the later stages of the synthesis. In addition, it is clear that such protective the group can be used to change the stability of the intermediates and reactivity of the indole ring against electrophiles. Suitable protective groups are described Kocienski, P.J.: Protecting Groups, Thieme, Stuttgart; New York, 1994.

Also a specialist in this area it is clear that various derivatives (indol-3-yl)heterocyclic compounds of the formula I can be obtained by suitable reactions for the conversion of functional groups corresponding to particular substituents R3-R7. For example, the compounds of formula I, where R3or R4represent a linear, branched or cyclic C1-C6alkyl group, optionally substituted by hydroxyl, (C1-4)alkyloxy, (C1-4)alkylthio,

(C1-4)alkylsulfonyl or cyano, can be obtained by reaction of compounds of formula I, where R3or R4represents hydrogen, C1-C6alkylhalogenide or functionalized with C1-C6alkylhalogenide in the presence of a base such as potassium carbonate.

Derivatives (indol-3-yl)heterocyclic compounds of the formula I and their salts may contain at least one chiral center and therefore exist as stereoisomers, including enantiomers and diastereoisomers. The present invention in its scope includes the aforementioned stereoisomers and each of R and S enantiomers of the compounds of formula I and their salts, essentially pure, i.e. associated with less than 5%, preferably is the Eney than 2%, specifically, less than 1% of the other enantiomer, and a mixture of such enantiomers in any ratio, including a racemic mixture, which contains essentially equal amounts of the two enantiomers.

Methods of asymmetric synthesis or chiral separation, which receive the stereoisomers are well known in this field, for example the synthesis of chiral induction or proceeding from commercially available chiral substrates, or the separation of stereoisomers, for example, chromatography on chiral environment, or crystallization with chiral counterion.

Pharmaceutically acceptable salts can be obtained by treatment of the free base of the compounds of formula I with inorganic acid, such as hydrochloric acid, Hydrobromic acid, phosphoric acid and sulfuric acid, or organic acid such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid and methanesulfonamide acid.

Compounds of the present invention can be in resolutional form, and in the solvated form with a pharmaceutically acceptable solvent, such as water, ethanol, etc. mainly for the purposes of this izaberete the Oia solvated forms are considered equivalent nonsolvated.

In addition, the present invention relates to pharmaceutical compositions containing the derivative (indol-3-yl)heterocyclic compounds of General formula I or its pharmaceutically acceptable salt, in a mixture with pharmaceutically acceptable additives and optionally other therapeutic agents. The term "acceptable” means compatible with other ingredients of the composition and harmless to its consumers. For example, the compositions include compositions acceptable for oral, sublingual, subcutaneous, intravenous, epidural, intrathecal, intramuscular, transdermal, pulmonary, local or rectal administration and the like, all in a unit dosage forms for injection. The preferred route of administration is intravenous.

For oral administration the active ingredient may be in the form of separate units such as tablets, capsules, powders, granular forms, solutions, suspensions and the like For parenteral administration of the pharmaceutical composition of the present invention may be in the container for a single dose or multiple doses, for example of injection fluid in predetermined amounts, for example in sealed vials and vials and may be stored in dried by freezing condition (dried), which is not bhodemon only the addition of sterile liquid carrier, for example water, before use.

Mixed with pharmaceutically acceptable additives, for example, as described in the standard reference, Gennaro, A.R. et al., Remington: The Science and Practice of Pharmacy (20th Edition, Lippincott Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing), an active agent can be compressed into a solid unit dose, such as pills, tablets, or be processed by receiving capsules, suppositories or patches. By means of pharmaceutically acceptable liquids the active agent can be applied as a liquid composition, for example, as an injectable in the form of a solution, suspension, emulsion or spray, for example nazalnogo spray.

For solid dosage units provided by the use of conventional additives such as fillers, dyes, polymeric binders, etc. basically you can use any pharmaceutically acceptable additives, which do not prevent the action of the active compounds. Acceptable carriers, with which the active substance of the present invention can be introduced in the form of solid compositions, which include derivatives, lactose, starch, cellulose and the like, or mixtures thereof, used in the right quantities. For parenteral administration can be applied aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing the pharmaceutical is acceptable dispersing means and/or humectants, such as propylene glycol or butyleneglycol.

In addition, this invention relates to the above pharmaceutical composition in combination with suitable for the specified composition of packaging materials, where these packaging materials include instructions for use of the composition for the above application.

Discovered that derivatives (indol-3-yl)heterocyclic compounds of the present invention are agonists of the CB1 receptor, as determined in the analysis of the reporter of the human CB1 receptors using CHO cells. Methods for determining binding of receptors and biological activity of modulators of cannabinoid receptorsin vitrowell known in this field. In General, the downregulation of the receptor is brought into contact with the connection, which must be tested, and measuring the binding, or stimulation or inhibition of a functional response.

To measure the functional response of selected DNA encoding a gene of the CB1 receptor, preferably the receptor of the person, Express in suitable host cells. Such cells may represent cells of the ovary of the Chinese hamster, but is also suitable to other cells. Preferably, the cells come from mammals.

The methods of constructing expressing recombinant CB1 cell onigoroshi known in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). Expression of the receptor achieve by the expression encoding the desired protein DNA. All methods of ligation of additional sequences and construct expressing suitable systems to date are well known in this field. Part or all of the DNA encoding the desired protein can be constructed synthetically using standard solid-phase methods, preferably with the introduction of restriction sites to facilitate ligation. For coding DNA sequences can provide appropriate control elements for transcription and translation of the introduced coding sequences. As is well known, currently available expression systems that are compatible with a wide variety of hosts, including prokaryotic hosts, such as bacteria, and eukaryotic hosts such as yeast, plant cells, insect cells, mammalian cells, bird cages, etc.

Then expressing the receptor cells are put in contact with the test compound for the study of binding, or stimulation or inhibition of a functional response.

Alternatively, to measure binding compounds can be applied isolated cell membranes containing expressionevaluator CB1 (or CB2).

To measure the binding can be applied radioactively or fluorescently labeled compounds. The most widely used radioactive cannabinoid probe is a [3H]CP55940, which has approximately equal affinity for binding sites CB1 and CB2.

Another study involves the screening of compounds for agonist cannabinoid CB1 by determining the response of second messengers, such as measurement of receptor-mediated changes in the ways of camp or MAP-kinase. Thus, this method involves the expression of CB1 receptor on the cell surface of the host cell and the effect on the cell under test connection. Then measure the response of second messengers. The level of second messengers will be reduced or increased depending on the actions of the test compounds upon binding with the receptor.

In addition to direct measurement, for example, camp levels in the affected cell, you can use cells that, in addition to transfection encoding the receptor DNA, transliterowany second DNA that encodes a reporter gene, the expression of which correlates with the activation of the receptor. Basically the reporter gene expression can be controlled by any responsible element that responds to the changed levels of the second messenger. Acceptable reporter genes before the hat is, for example, LacZ, alkaline phosphatase, Firefly luciferase and green fluorescent protein. Principles such transactivation assays well known in this field, for example, Stratowa, Ch, Himmler, A. and Czernilofsky, A. P., Curr. Opin.Biotechnol. 6, 574 (1995). To select the active compounds agonist for the CB1 receptor is EC50should be <10-5M, preferably <10-7M

The compounds can be used as analgesics for treatment of pain, such as perioperative pain, chronic pain, neuropathic pain, pain and cancer pain and pain and spasticity associated with multiple sclerosis.

Also cannabinoid agonists according to this invention may be potentially useful in the treatment of other disorders, including multiple sclerosis, spasticity, inflammation, glaucoma, nausea and vomiting, loss of appetite, sleep disorders, respiratory disorders, allergies, epilepsy, migraine, cardiovascular disorders, neurodegenerative disorders, anxiety, traumatic brain injury and stroke.

Connections can also be used in combination with other drugs, such as analgesic drugs such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors.

Connections on this image is the shadow you can enter people in sufficient quantity and for a sufficient period of time to relieve symptoms. To illustrate dosing levels for men can be in the range of 0.001 to 50 mg per 1 kg of body weight, preferably in a dose of 0.01 to 20 mg per kg of body weight.

The invention is illustrated in the following examples.

General procedures

Unless otherwise stated, microwave reactions were conducted using Emrys™ Optimizer (Personal Chemistry). Column flash chromatography was performed on silica gel. Prepreparation high-performance liquid chromatography (prepreparation HPLC) was carried out using the following methods:

Method (i): Agilent CombiHT (SB-C18, 5 µm) 12 mm ID×100 mm; 5 to 95% acetonitrile-water at a 9 min gradient; 25 ml/min; 0.1% of trifurcating acid buffer; detection by UV at 254 nm.

Method (ii): Waters Xterra (RP18, 5 μm) 30 mm×100 mm; 10-100% acetonitrile-water at 25 minute gradient; 30 ml/min; 0.1% of trifurcating acid buffer; detection by UV at 254 nm.

Constant interaction1H NMR are given in Hertz.

Example 1

1-(Cyclohexyl)methyl-3-{5-[(dimethylamino)methyl]-[1,2,4]oxadiazol-3-yl-7-methoxy-1H-indole, cleaners containing hydrochloride salt

A solution of 7-methoxyindole (45,0 g, 306 mmol) in dimethylformamide (360 ml) was cooled to 5°C in nitrogen atmosphere for 20 minutes and added triperoxonane anhydride (60,5 ml, 433 mmol), keeping the temperature below 10°C. the Mixture was stirred is at 5-10°C for 2 hours, then poured into water (1600 ml). The resulting suspension was stirred for 15 minutes and the precipitate 7-methoxy-3-[(trifluoromethyl)carbonyl]-1H-indole was filtered, washing with water to neutrality.

The wet solid is suspended in a 4M aqueous sodium hydroxide (1700 ml) and heated to boiling point under reflux with stirring for 2 hours. The mixture was cooled and washed with diethyl ether (2×400 ml). Then the aqueous phase was acidified to pH 1 using 5M hydrochloric acid and the resulting net precipitate was filtered, washed with water to neutrality and dried to obtain 7-methoxy-1H-indole-3-carboxylic acid in the form of a solid pink matter (42.7 g).

To a solution of 7-methoxy-1H-indole-3-carboxylic acid (42.7 g, 224 mmol) in dimethylformamide (1250 ml) at 10°C in nitrogen atmosphere portions over 20 minutes, keeping the temperature below 15°C, was added sodium hydride (60% dispersion in mineral oil, 23,0 g, 575 mmol). The cooling bath was removed and the suspension was stirred for 90 minutes. Added cyclohexylethylamine or 64.7 ml, 464 mmol). The mixture was heated at 60°C under stirring for 3 hours. The mixture was cooled to 10°C and poured into water (3600 ml). The emulsion was washed with diethyl ether (3×500 ml). The aqueous phase was acidified to pH 1 using 5M hydrochloric acid and the precipitate was filtered whom, washed with water to neutrality and dried to obtain 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (55 g) as a white solid.

To a mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (7.0 g, 24.4 mmol) and dichloromethane (150 ml) under cooling with ice water was added dropwise oxalicacid (12.4 g, of 97.4 mmol) and the resulting mixture was stirred at room temperature for 18 hours. Dichloromethane and excess oxalicacid was removed by evaporation and the resulting residue was mixed with dichloromethane (150 ml). Gaseous ammonia was barbotirovany in the mixture for 30 minutes under cooling in an ice bath-water. The reaction mixture was concentrated in vacuo, then the resulting solid was sequentially washed with 0,5M hydrochloric acid, 5% aqueous sodium carbonate and water and dried under reduced pressure to obtain amide 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (5.1 g) as a brown solid substance.

To a mixture of amide 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (4.1 g, and 14.3 mmol), triethylamine (11.6 g, 115 mmol) and 1,4-dioxane (250 ml) under cooling in ice-cold water was added dropwise triperoxonane anhydride (12.0 g, to 57.1 mmol). The resulting mixture was stirred at room temperature for 12 hours. Was added water (30 ml) and the floor is obtained, and the mixture was concentrated in vacuum. To the precipitate obtained was added water (300 ml) and the mixture was extracted with dichloromethane (4×300 ml). The organic layers were combined, washed with 5% aqueous sodium bicarbonate and saturated salt solution, dried over magnesium sulfate and concentrated in vacuum. The obtained residue was purified column chromatography, elwira 10% (vol./about.) the ethyl acetate in n-heptane to obtain 1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-carbonitrile in the form of a crystalline solid (2.48 in).

To a mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-carbonitrile (2,48 g, 9,24 mmol), triethylamine (1,41 g, a 13.9 mmol) and ethanol (50 ml) was added hydroxylamine hydrochloride (966 mg, a 13.9 mmol), then the resulting mixture was stirred while boiling under reflux for 20 hours. After cooling to room temperature the reaction mixture was concentrated in vacuum. The obtained residue was mixed with water (150 ml), brought to pH 10 by addition of aqueous sodium hydroxide and was extracted with dichloromethane (4×100 ml). The organic layers were combined, washed with saturated salt solution, dried over magnesium sulfate and concentrated in vacuum. The obtained residue was purified column chromatography, elwira 10% (vol./about.) acetone in dichloromethane, to obtain 1-(cyclohexyl)methyl-Nhydroxy-7-methoxy-1H-indol-3-carboxamidine (940 mg).

To a suspension of 1-(cycle is hexyl)methyl -Nhydroxy-7-methoxy-1H-indol-3-carboxamidine (250 mg, 0,829 mmol) in tetrahydrofuran (6 ml) under nitrogen atmosphere was added molecular sieves (4 Å, powdered, 200 mg) and the mixture was stirred at room temperature for 30 minutes was Added sodium hydride (60% suspension in oil, 36 mg, to 0.900 mmol), and then the resulting mixture was stirred at 60°C for 20 minutes the Reaction mixture was cooled to room temperature and to the mixture was addedN,N-dimethylglycinamide ester (194 mg, of 1.66 mmol). The resulting mixture was stirred at the boiling point under reflux for 2 hours and then concentrated in vacuum. The obtained residue was mixed with dichloromethane (200 ml), washed with 5% aqueous sodium carbonate, dried over magnesium sulfate and concentrated in vacuum. The resulting oil was purified column flash chromatography, elwira of 0.6% (vol./about.) methanol in dichloromethane, to obtain the oil. The resulting oil was dissolved in isopropanol (3 ml), to the solution was added hydrogen chloride (1M solution in diethyl ether; 3 ml). The resulting mixture was concentrated in vacuum to obtain specified in the header of the substance (1:1 cleaners containing hydrochloride salt) (66 mg).

1H NMR (400 MHz, CD3OD) δ 0,96-of 1.30 (5H, m), 1,52-of 1.94 (6H, m), of 3.13 (6H, s), of 3.97 (3H, s), 4,30 (2H, d, J=6,8), a 4.83 (2H, s), for 6.81 (1H, d, J=8,0), 7,13 (1H, DD, J=8.0 a, 8,0), 7,71 (1H, d, J=8,0), a 7.85 (1H, s). EsIMS: m/z 369,2 [M+H]+.

Example 2

Next, the method of example 1 was used to obtain the following compounds, using alternative synthetic or commercially available esters of amino acids instead ofN,N-dimethylglycinamide ether.

Methods of synthesis of intermediate esters of amino acids

Method And

To a mixture of pyrrolidine (171 mg, of 2.40 mmol) and sodium carbonate (254 mg, of 2.40 mmol) in tetrahydrofuran (7 ml) was added benzylbromide (500 mg, of 2.18 mmol). The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The residue was mixed with water (200 ml) and was extracted with dichloromethane (3×100 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuum. Purification with flash chromatography with elution 0-10% (vol./about.) methanol in dichloromethane resulted in the receipt of benzyl ether pyrrolidin-1-yl-acetic acid (230 mg, 1.05 mmol).

Method B

To a mixture of (S)-2-methoxypiperidine (268 μl, 2,17 mmol), potassium carbonate (319 mg, 2,31 mmol) and sodium iodide (315 mg, 2.10 mmol) in acetonitrile (3 ml) was added methylbromide (199 μl, 2.10 mmol). The mixture was subjected to microwave irradiation for 5 min at 160°C, then was distributed between dichloromethane and water. The aqueous layer was extracted with dichloromethane and combined organic layers were washed with a saturated solution with the Lee, was dried over sodium sulfate and concentrated in vacuum. Purification with flash chromatography with elution 0-10% (vol./about.) methanol in dichloromethane resulted in the receipt of methyl ester (S)-(2-methoxypiperidine-1-yl)acetic acid (133 mg, 0.71 mmol).

The method C

To a solution of sulfuric acid (3.5 ml, 65.3 mmol) in methanol (45 ml) was added D-Proline (10.0 g, of 86.9 mmol). The mixture was boiled under reflux with stirring for 18 hours. Then the solution was cooled to 0°C and neutralized by addition of aqueous potassium carbonate (2,5M; 10 ml). Was added formaldehyde (37% solution in water, 11 ml, 136 mmol) and the mixture was stirred at 0°C for 15 minutes. Was added sodium borohydride (1.6 g, of 42.3 mmol) at 0°C and the mixture was stirred at room temperature for 3 hours. The precipitate was filtered and the filtrate was distributed between dichloromethane and water. The separated aqueous layer was brought to pH 10 with solid sodium carbonate and was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuum to obtain crude methyl ester (R)-1-methylpyrrolidine-2-carboxylic acid (13,13 g).

A portion of the crude product (5.0 g) was purified column flash chromatography, elwira 0-2% (vol./about.) methanol in dichloromethane to obtain methyl ester (R)-1-methylpyrrole the Jn-2-carboxylic acid (1.30 grams).

2A:1-(Cyclohexyl)methyl-7-methoxy-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]oxadiazol-3-yl}-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained following the method of example 1 using benzyl ether pyrrolidin-1-luxusni acid obtained by the method of A.

1H NMR (400 MHz, CD3OD) δ of 0.98 to 1.31 (5H, m), 1,54-of 1.94 (6H, m), 2,10-of 2.24 (4H, m), 3.46 in-3,74 (4H, m), of 3.97 (3H, s), 4,30 (2H, d, J=7,2), a 4.86 (2H, s), for 6.81 (1H, d, J=8,0), 7,14 (1H, DD, J=8.0 a, 8,0), of 7.70 (1H, d, J=8,0), 7,84 (1H, s). EsIMS: m/z 395,2 [M+H]+.

2B:1-(Cyclohexyl)methyl-3-{5-[(Nethyl-N-isopropylamino)methyl]-[1,2,4]oxadiazol-3-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using methyl ether (Nethyl-N-isopropylamino)acetic acid, which was obtained by method a using methylpropanoate andNethylisopropylamine. EsIMS: m/z 411,1 [M+H]+.

2C:1-(Cyclohexyl)methyl-7-methoxy-3-(5-{[bis-(2-methoxyethyl)amino]methyl}-[1,2,4]oxadiazol-3-yl}-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using methyl ester [bis-(2-methoxyethyl)amino]acetic acid, which was obtained by method a using methylpropanoate and bis-(2-methoxyethyl)amine. EsIMS: m/z rate of 457.5 [M+H]+.

2D:1-(Cyclohexyl)methyl-3-{5-[1-(dimethylamino)ethyl]-[1,2,4]oxadi the evil-3-yl}-7-methyl-1 H-indole, cleaners containing hydrochloride salt.

Specified in the title compound was obtained using methyl ester 2-dimethylaminopropionic acid, which was obtained by method a using methyl 2-bromopropionate and dimethylamine. EsIMS: m/z of 383.0 [M+H]+.

2E:(S)-1-(Cyclohexyl)methyl-7-methoxy-3-{5-[(2-methoxypiperidine-1-yl)methyl]-[1,2,4]oxadiazol-3-yl-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using methyl ether (S)-(2-methoxypiperidine-1-yl)acetic acid, which was obtained by method B. EsIMS: m/z RUR 439,3 [M+H]+.

2F:(R)-1-(Cyclohexyl)methyl-7-methoxy-3-{5-[(2-methoxypiperidine-1-yl)methyl]-[1,2,4]oxadiazol-3-yl}-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using methyl ether (R)-(2-methoxypiperidine-1-yl)acetic acid, which was obtained by method B using (R)-2-methoxypiperidine.

EsIMS: m/z 439,1 [M+H]+; [α]D22+21,6° (c=0.8 mg/ml in chloroform).

2G:(R)-1-(Cyclohexyl)methyl-7-methoxy-3-[5-(1-methylpyrrolidine-2-yl)-[1,2,4]oxadiazol-3-yl]-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using methyl ether (R)-1-methylpyrrolidine-2-carboxylic acid, p which were given by method C.

EsIMS: m/z 395,0 [M+H]+[α]D22+50,1° (c=1.70 mg/ml in chloroform).

2H:(S)-1-(Cyclohexyl)methyl-7-methoxy-3-[5-(1-methylpyrrolidine-2-yl)-[1,2,4]oxadiazol-3-yl]-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using methyl ether (S)-1-methylpyrrolidine-2-carboxylic acid, which was obtained by method C, using L-Proline instead of D-Proline. EsIMS: m/z 395,0 [M+H]+[α]D22-51,7 (c=1.35 mg/ml in chloroform).

2I:1-(Cyclohexyl)methyl-7-methoxy-3-[5-(1-methylpiperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained following the method of example 1, using ethyl-1-methylpiperidine instead of the methyl esterN,N-dimethylglycine.

EsIMS: m/z 409,3 [M+H]+.

Example 3

1-(Cyclohexyl)methyl-3-[(5-aminomethyl)-[1,2,4]oxadiazol-3-yl]-7-methoxy-1H-indole, cleaners containing hydrochloride salt

To a suspension of 1-(cyclohexyl)methyl-Nhydroxy-7-methoxy-1H-indol-3-carboxamidine (500 mg, of 1.66 mmol) in tetrahydrofuran (10 ml) was added molecular sieves (4 Å, powdered, 300 mg) and the resulting mixture was stirred at room temperature for 30 minutes was Added sodium hydride (60% suspension in oil, 100 mg, 2.55 mmol) and the resulting mixture was stirred at 65°C for 20 min Reactions is nnow the mixture was cooled to room temperature and to the mixture was added N-hydroxysuccinimidyl etherN-Boc-glycine (871 mg, of 3.32 mmol). The resulting mixture was heated to boiling point under reflux with stirring for 2 hours, then cooled to room temperature. Was added aqueous sodium hydroxide (4M, 5 ml) and the resulting mixture was stirred for 14 hours. The reaction mixture was concentrated in vacuo, then the residue was mixed with water (200 ml). The resulting mixture was extracted with dichloromethane (4×200 ml). The organic layers were combined, washed with saturated salt solution, dried over magnesium sulfate and concentrated in vacuum. The resulting oil was purified column chromatography, elwira of 0.4% (vol./about.) methanol in dichloromethane, to obtain tert-butyl ether ({3-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]-[1,2,4]oxadiazol-5-yl}methyl)carbamino acid (125 mg).

A mixture of tert-butyl methyl ether ({3-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]-[1,2,4]oxadiazol-5-yl}methyl)carbamino acid (110 mg, 0.25 mmol) and triperoxonane acid (4 ml) was stirred at room temperature for 1.5 hours. The reaction mixture was carefully poured into 5% aqueous sodium carbonate (200 ml) and the resulting mixture was extracted with dichloromethane (4×200 ml). The organic layers were combined, then washed with saturated salt solution, dried over magnesium sulfate and koncentrirovalisb vacuum. The resulting oil was purified column chromatography, elwira of 1.5% (vol./about.) methanol in dichloromethane, to obtain the free base specified in the title compound as a yellow oil. The resulting oil was dissolved in diethyl ether and then to the solution was added hydrogen chloride (1M solution in diethyl ether; 3 ml). The resulting mixture was concentrated in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt, 1:1 (71 mg).

1H NMR (400 MHz, CD3OD) δ 0,98-of 1.29 (5H, m), 1,52-of 1.78 (5H, m), 1,79-of 1.94 (1H, m), 3,98 (3H, s), or 4.31 (2H, d, J=7,2), 4,55 (2H, s), for 6.81 (1H, d, J=7,6), 7,14 (1H, DD, J=7,6, 8,0), 7,72 (1H, d, J=8,0), 7,83 (1H, s). EsIMS: m/z 341,1 [M+H]+.

Example 4

1-(Cyclohexyl)methyl-3-{5-[(dimethylamino)methyl]-[1,2,4]oxadiazol-3-yl}-7-fluoro-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained following the method of example 1, using 7-farindola instead of 7-methoxyindole. EsIMS: m/z 357,3 [M+H]+, 247,4.

Example 5

7-Chloro-1-(cyclohexyl)methyl-3-{5-[(dimethylamino)methyl]-[1,2,4]oxadiazol-3-yl}-1H-indole, cleaners containing hydrochloride salt.

Specified in the title compound was obtained following the method of example 1, using 7-chloroindole instead of 7-methoxyindole EsIMS: m/z 375,1, 373,1 [M+H]+.

Example 6

1-(Cyclohexyl)methyl-3-(5-{[N-isopropyl-N(2-methoxyethyl)amino]methyl}-[1,2,4]-triazole-3-yl)-7-m the toxi-1 H-indole, cleaners containing hydrochloride salt

Gaseous hydrogen chloride was barbotirovany within 30 minutes to a chilled (0°C) solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-carbonitrile (obtained as described in example 1; 3,15 g, 11.0 mmol) in methanol (200 ml). Before concentrating the resulting mixture was allowed to stand for 72 hours by two-thirds in vacuum. Crystallization of the product was performed by adding diethyl ether, the solid product was collected by filtration to obtain methyl ester 1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-carboximidic acid in the form of cleaners containing hydrochloride salt (3,82 g).

Methyl ester 1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-carboximidic acid cleaners containing hydrochloride salt (0.10 g, 0,297 mmol), hydrazine hydrate (0,289 ml, 5,94 mmol), aluminum chloride to 39.6 mg, 0,297 mmol) and toluene (18 ml) were mixed and the mixture was subjected to microwave irradiation for 60 min at 120°C. the resulting mixture was concentrated in vacuo, re-dissolved in toluene and concentrated in vacuo twice. The precipitate suspended in a mixture of toluene/acetonitrile (12/1) (19,5 ml) was added chlorocatechol (amount of 0.118 ml, 1,49 mmol), then the mixture was subjected to microwave irradiation for 12 min at 120°C. the resulting mixture was concentrated in vacuo and re-dissolved in acetonitrile (3 ml). The mixture was defended within 72 is aces, addedN-(2-methoxyethyl)Isopropylamine (0,068 ml, 0,446 mmol), potassium carbonate (45,2 mg, 0,327 mmol) and sodium iodide (44 mg, 0,297 mm, and then subjected to microwave irradiation for 5 min at 160°C and then concentrated in vacuum. The obtained residue was purified column chromatography, elwira of 2.5%-5% (vol./about.) methanol in dichloromethane, to obtain specified in the connection header in the form of cleaners containing hydrochloride salt, 1:1 (46 mg).

1H NMR (400 MHz, CD3OD): 0,95-1,12 (2H, m), 1,13-1,24 (3H, m)of 1.50 (6H, (OSiR.)), 1,55-of 1.73 (5H, m), 1,79-of 1.93 (1H, m), 3,34-3,50 (5H, m), 3,70-3,99 (6H, m), 4,24 (2H, d, J=6,4), of 4.67 (2H, c(user.)), 6,70 (1H, d, J=7,7), 7,16 (1H, t, J=7,7), 7,95 (1H, d, J=7,7), 8,02 (1H, (OSiR.)); EsIMS: m/z 440,3 [M+H]+.

Example 7

1-(Cyclohexyl)methyl-3-{5-[(diethylamino)methyl]-[1,2,4]thiadiazole-3-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt

To a suspension of amide 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (obtained from 7-methoxyindole as described in example 1; 4.0 g, 14 mmol) in tetrahydrofuran (120 ml) was added chlorocarbonylsulfenyl (2.4 ml, 28.4 mmol) and the reaction mixture is boiled under reflux for 15 minutes and allowed to cool. The solution and the excess reagent was then removed in vacuo to obtain 5-(1-cyclohexylmethyl-7-methoxy-1H-indole)-[1,3,4]oxadiazol-2-it (5,2 g, 14.4 mmol) as a solid pink substance.

To a suspension of 5-(1-cyclohexylmethyl-7-methoxy-1 -indole)-[1,3,4]oxadiazol-2-she (1.0 g, 2.77 mmol) in m-xylene (15 ml) was added achilleifolia (2,74 ml, 27.7 mmol) and the reaction mixture was subjected to microwave irradiation at 160°C for 10 min using Emrys™ Optimizer EXP. The reaction was repeated three times under the same quantities, combining and cleaning flash chromatography, elwira 0-50% (vol./about.) dichloromethane in heptane, to obtain the ethyl ester of 3-(1-cyclohexylmethyl-7-methoxy-1Hindol-3-yl)-[1,2,4]thiadiazole-5-carboxylic acid (of 4.38 g, 11 mmol) as a white solid.

To a cooled solution (ice bath/methanol) ethyl ester of 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-carboxylic acid (4.0 g, 10 mmol) in tetrahydrofuran (80 ml) and methanol (80 ml) consecutive portions was added sodium borohydride. The reaction mixture was stirred for additional 20 minutes and extinguished 1M hydrochloric acid (20 ml). Methanol and tetrahydrofuran was removed in vacuo and added dichloromethane (200 ml) and 2M hydrochloric acid (50 ml). Organic matter was separated and washed with saturated salt solution (50 ml), dried over magnesium sulfate and the solvent was removed in vacuum. The obtained residue was purified column flash chromatography, elwira 50% (vol./about.) diethyl ether in heptane, to obtain [3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-and the]methanol (3,15 g, 8,8 mmol) as a solid light pink substance.

To a cooled solution (ice bath/methanol) [3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-yl]methanol (2.3 g, 6.4 mmol) in dichloromethane (150 ml) was sequentially added methanesulfonamide (0,595 ml of 7.68 mmol) and triethylamine (1,16 ml, 8,32 mmol). The reaction mixture was stirred for 10 min and then poured into a separating funnel. Organic matter washed with 5% aqueous sodium carbonate solution (2×100 ml), saturated salt solution (100 ml), dried over magnesium sulfate and the solvent was removed in vacuo to obtain 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-Eletropaulo ether methanesulfonate acid (2.9 g, 6.7 mmol), which was used without further purification.

To a solution of 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-Eletropaulo ether methanesulfonate acid (93 mg, 0.2 mmol) in tetrahydrofuran (1 ml) was added diethylamine (0,22 ml, 2,13 mmol) and the reaction mixture was subjected to microwave irradiation at 150°C for 15 minutes. The reaction mixture was poured into a separating funnel and was diluted with dichloromethane (40 ml). The combined organic phase washed with 5% aqueous sodium carbonate solution (2×20 ml), saturated salt solution (2×20 ml), dried over magnesium sulfate and the solvent was removed in vacuum. According to the scientists the residue was purified column flash chromatography with obtaining specified in the title compound (54 mg, 0.13 mmol) in the form of free base. The free base was dissolved in dichloromethane and was added hydrogen chloride (2M solution in diethyl ether; 1.0 ml, 2.0 mmol). The mixture was concentrated in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt of 1:1.

1H NMR (400 MHz, CD3OD): 0,95-1,12 (2H, m), 1,16-of 1.27 (3H, m)of 1.45 (6H, t, J=7), 1,55-to 1.63 (2H, m), 1,63 of 1.8 (3H, m), 1,8-of 1.95 (1H, m), 3,28-of 3.32 (4H, m), of 3.97 (3H, s), 4,3 (2H, d, J=7), 4,96 (2H, s), 6,79 (1H, d, J=8), 7,13 (1H, t, J=8), 7,95 (1H, s), of 8.04 (1H, d, J=8); EsIMS: m/z 413,1 [M+H]+.

Example 8

Next, the method of example 7 was used to obtain the following compounds:

8A:1-(Cyclohexyl)methyl-7-methoxy-3-(5-{[bis-(2-methoxyethyl)amino]methyl}-[1,2,4]thiadiazole-3-yl)-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using bis-(2-methoxyethyl)amine instead of diethylamine. EsIMS: m/z 473,1 [M+H]+.

8B:1-(Cyclohexyl)methyl-7-methoxy-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]thiadiazole-3-yl-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using pyrrolidine instead of diethylamine. EsIMS: m/z 411,1 [M+H]+, 342,0.

8C:1-(Cyclohexyl)methyl-7-methoxy-3-{5-[(2-methylpiperidin-1-yl)methyl]-[1,2,4]thiadiazole-3-yl}-1H-indole, salt triperoxonane acid

Specified in the title compound was obtained using 2-methylpiperidin is instead of diethylamine. The free base was purified prepreparation HPLC [method (i)] to obtain specified in the connection header in the form of a salt triperoxonane acid, 1:1. EsIMS: m/z RUR 439,3 [M+H]+.

8D:1-(Cyclohexyl)methyl-3-(5-{[N-(2-hydroxyethyl)-Nmethylamino]methyl}-[1,2,4]thiadiazole-3-yl)-7-methoxy-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using (2-hydroxyethyl)methylamine instead of diethylamine. The free base was purified prepreparation HPLC [method (i)] to obtain specified in the connection header in the form of a salt triperoxonane acid, 1:1. EsIMS: m/z of 415.3 [M+H]+, 328,3.

8E:1-(Cyclohexyl)methyl-7-methoxy-3-(5-{[N-(2-methoxyethyl)-Nmethylamino]methyl[1,2,4]thiadiazole-3-yl)-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained usingN(2-methoxyethyl)-Nof methylamine instead of diethylamine. EsIMS: m/z 429,4 [M+H]+.

Example 9

1-(Cyclohexyl)methyl-3-{5-[1-(diethylamino)ethyl]-[1,2,4]thiadiazole-3-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt

To a cooled solution (bath of dry ice/acetone) ethyl ester of 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-carboxylic acid (500 mg, 1.3 mmol) in diethyl ether (50 ml) was added a solution of methylacrylamide (0,52 ml, 3M in diethyl ether, 1.56 mmol) and actionnow the mixture was stirred for 15 minutes, then added another part of the solution methylacrylamide (0.25 ml, 3M in diethyl ether, 0.75 mmol) and the reaction mixture was stirred for 5 minutes. Then the reaction was suppressed saturated aqueous ammonium chloride (5 ml) and the reaction mixture was allowed to warm to room temperature. The reaction mixture was poured into a separating funnel and the organic phase washed with water (20 ml). Then the aqueous layer was washed with diethyl ether (20 ml). The combined organic layers were dried over magnesium sulfate, filtered and solvent was removed in vacuum. The obtained residue was purified column flash chromatography to obtain 1-[3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-yl]ethanone (170 mg, 0.46 mmol)as a yellow solid substance.

To a solution of 1-[3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-yl]ethanone (90 mg, 0.24 mmol) in acetonitrile (3 ml) was added diethylamine (0,248 ml, 2.4 mmol) and acetic acid (0,137 ml, 2.4 mmol) and the reaction mixture was stirred for 30 minutes. To the reaction mixture were added applied to the polymer cyanoborohydride (204 mg, 2.35 download molg-1, 0.48 mmol) and the reaction mixture was subjected to microwave irradiation at 150°C for 10 minutes. The reaction mixture was filtered through a column of 5 g Strata™ SCX giga. The column was washed with methanol and then was suirable 2M ammonia in methanol. Dissolve the ammonia in methanol evaporated and the obtained residue was purified column flash chromatography with obtaining specified in the title compound (62 mg, 0,145 mmol) in the form of free base. The free base was dissolved in dichloromethane (1 ml) was added 2M HCl in diethyl ether (1 ml, 2 mmol), excess reagent and solvent was removed in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt of 1:1.

1H NMR (400 MHz, CD3OD): 1,0-1,2 (2H, m), 1,16-of 1.26 (3H, m), 1,38-1,5 (6H, m), 1,55-of 1.78 (5H, m), 1,82-of 1.94 (4H, m), 3,32-3,68 (4H, m), of 3.97 (3H, s), 4,3 (2H, d, J=7,5), are 5.36-of 5.48 (1H, m), 6,8 (1H, d, J=8), 7,14 (1H, t, J=7,5), 7,94 (1H, s), 8,02 (1H, d, J=8); EsIMS: m/z 427,4 [M+H]+, 328,4.

Example 10

1-(Cyclohexyl)methyl-3-{5-[(diethylamino)methyl]-[1,2,4]thiadiazole-3-yl}-7-fluoro-1H-indole, salt triperoxonane acid

Specified in the title compound was obtained following the method of example 7, using amide 1-(cyclohexyl)methyl-7-fluoro-1H-indole-3-carboxylic acid (obtained from 7-farindola) and diethylamine. The free base was purified prepreparation HPLC [method (i)] to obtain specified in the connection header in the form of a salt triperoxonane acid, 1:1. EsIMS: m/z 401,3 [M+H]+.

Example 11

7-Chloro-1-(cyclohexyl)methyl-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]thiadiazole-3-yl}-1H-indole, salt triperoxonane acid

Specified in the title compound was obtained following the method of example 7, using amide 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carboxylic acid (obtained from 7-chloroindole)and using pyrrolidine instead of diethylamine. The free base was purified prepreparation HPLC [method (i)] to obtain specified in the connection header in the form of a salt triperoxonane acid, 1:1. EsIMS: m/z 417,3 and 415.3 [M+H]+.

Example 12

1-(Cyclohexyl)methyl-7-ethyl-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]thiadiazole-3-yl}-1H-indole, salt triperoxonane acid

Specified in the title compound was obtained using the method of example 7, using amide 1-(cyclohexyl)methyl-7-ethyl-1H-indole-3-carboxylic acid (obtained from 7-ethylindole) and using pyrrolidine instead of diethylamine. The free base was purified prepreparation HPLC [method (i)] to obtain specified in the title compound in the form of salts triperoxonane acid, 1:1. EsIMS: m/z 409,3 [M+H]+.

Example 13

(R)-3-cyclohexyl-6-{5-[(diethylamino)methyl]-[1,2,4]thiadiazole-3-yl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin, cleaners containing hydrochloride salt

To a mixture of (R)-NBoc-2-cyclohexylethylamine (obtained as described for (S) enantiomer, Luly et al., J. Org. Chem. 52, 1487-1492, 1987; 29,4 g of 94.5 mmol) and triphenylphosphine (37,2 g, 141,8 mmol) in toluene (150 ml) at 0°C was added diisopropylethylamine (19,5 ml of 99.2 mmol). After stirring for 1 hour to the mixture was added 2-bromophenol (12.1 ml, 104,0 mmol) at 0°C. the Reaction mixture was stirred for 2 hours at 0°C for 20 hours the ri room temperature. The resulting mixture was distributed between dichloromethane and water. The aqueous layer was extracted with dichloromethane, the combined organic layers were washed 2n. the sodium hydroxide solution and saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified column flash chromatography, elwira 0-10% (vol./about.) the ethyl acetate in heptane, to obtain the (R)-2-(2-tert-butoxycarbonylamino-2-cyclohexylmethoxy)bromine benzol (12,80 g, 32.1 mmol).

A mixture of (R)-2-(2-tert-butoxycarbonylamino-2-cyclohexylmethoxy)bromine benzol (500 mg, of 1.26 mmol), tetrakis(triphenylphosphine)palladium (0) (146 mg, 0,126 mmol) and tert-butoxide sodium (181 mg, 1.88 mmol) in toluene (4.0 ml) was subjected to microwave irradiation for 10 min at 120°C. the resulting mixture was distributed between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified column flash chromatography, elwira 0-17% (vol./about.) the ethyl acetate in heptane, to obtain the (R)-4-tert-butoxycarbonyl-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (270 mg, 0.85 mmol). This reaction was repeated 13 times in the same quantities with the receipt of the above intermediate compound (a total of 3.98 g, 12.5 mmol).

A mixture of (R)-4-tert-butoxycarbonyl-3-cyclog the KSIL-3,4-dihydro-2 H-1,4-benzoxazine (3.98 g, 12.5 mmol), 5N. hydrochloric acid (10 ml) and ethanol (10 ml) was stirred at 70°C for 50 minutes, the Ethanol was removed in vacuo and the residue was distributed between dichloromethane and 2n. the sodium hydroxide solution. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with saturated salt solution, dried over sodium sulfate and concentrated to obtain (R)-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (2,72 g, 12.5 mmol).

(R)-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazin (2,72 g, 12.5 mmol) was dissolved inN,N-dimethylformamide (20 ml) and the solution was added sodium nitrite (949 mg, of 13.8 mmol) in water (3.0 ml) at 0°C. Then was added 5N. hydrochloric acid (6.0 ml) at 0°C. the Reaction mixture was stirred at 0°C for 1 hour, then was distributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated salt solution, dried over sodium sulfate and concentrated. The precipitate was dissolved in diethyl ether (50 ml) was added sociallyengaged in tetrahydrofuran (1.0m; 9,51 ml of 9.51 mmol) at 0°C. the Reaction mixture was stirred at 0°C for 1 hour, then put ice water. To the mixture was added ethyl acetate, and the mixture was filtered through celite and the filter cake was washed with ethyl acetate. Shown that the antibodies were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified column flash chromatography, elwira 0-17% (vol./about.) the ethyl acetate in heptane, to obtain the (R)-4-amino-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (1.47 g, 6,33 mmol).

Etherpiraat (882 mg, to 7.59 mmol) was added to a solution of (R)-4-amino-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (1.47 g, 6,33 mmol) in ethanol (40 ml). The reaction mixture was stirred at room temperature for 15 minutes To the reaction mixture was added sulfuric acid (10% vol./about. in ethanol; 8,0 ml). The reaction mixture is boiled under reflux for 2 hours. The mixture was cooled to room temperature and distributed between ethyl acetate and sodium carbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified column flash chromatography, elwira 0-10% (vol./about.) the ethyl acetate in heptane, to obtain ethyl-(R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin-5-carboxylate (1,49 g, 4.76 mmol).

To a solution of ethyl-(R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin-5-carboxylate (1,49 g, 4.76 mmol) in ethanol (50 ml) was added 4n. sodium hydroxide (5,94 ml of 23.8 mmol). The mixture is stirred at 70°C for 40 minutes The ethanol was removed in vacuo, the residue was neutralized 2n. hydrochloric acid and was distributed between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with saturated salt solution, dried over sodium sulfate and concentrated. The residue was dissolved in quinoline (20 ml), then was added copper powder (453 mg, 7,13 mmol). The mixture was stirred at 210°C for 1 hour. To the mixture was added ethyl acetate and water at room temperature, the mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was acidified 5h. hydrochloric acid and separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed 1H. hydrochloric acid and saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified column flash chromatography, elwira 0-10% (vol./about.) the ethyl acetate in heptane, to obtain the (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (984 mg, 4,08 mmol).

To a solution of (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (600 mg, 2.49 mmol) inN,N-dimethylformamide (5.0 ml) at 0°C was added triperoxonane anhydride (0,311 ml, 2,73 mmol). The mixture was stirred at room temperature for 5 hours, then was distributed between dichloromethane and water. Water layer which was extracted with dichloromethane and the combined organic layers were washed with saturated salt solution, dried over Na2SO4and concentrated. The residue was purified flash chromatography, elwira 0-25% (vol./about.) the ethyl acetate in heptane, to obtain the (R)-3-cyclohexyl-6-trifloromethyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (628 mg, of 1.86 mmol).

To a solution of (R)-3-cyclohexyl-6-trifloromethyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (628 mg, of 1.86 mmol) in 1,4-dioxane (20 ml) was added 4n. NaOH (5.0 ml). The mixture was boiled under reflux for 42 hours, then acidified to pH 1 with 5N. hydrochloric acid, and was distributed between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with saturated salt solution, dried over Na2SO4and concentrated to obtain (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin-6-carboxylic acid (572 mg).

Specified in the title compound, following the method of example 7, using amide (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin-6-carboxylic acid (obtained from (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin-6-carboxylic acid) instead of the amide 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid. EsIMS: m/z 411,0 [M+H]+; [α]D22-30,7° (c=1.50 mg/ml in chloroform).

Example 14

The following connection is Uchali, following the method of example 7, using amide 7-fluoro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid amide instead of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid.

Amide 7-fluoro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid was obtained by following the method of example 1, using 7-farindola instead of 7-methoxyindole and tetrahydropyran-4-Eletropaulo ester toluene-4-sulfonic acid instead of cyclohexylethylamine.

The method of synthesis intermediate tetrahydropyran-4-Eletropaulo ester toluene-4-sulfonic acid

To a mixture of tetrahydro-2HPiran-4-ylmethanol (20,0 g, 172 mmol) and pyridine (25,2 ml, 313 mmol) in dichloromethane (200 ml) portions was added p-toluensulfonate (29,8 g, 157 mmol). The mixture was stirred at room temperature for 17 hours, then extinguished aqueous solution of hydrochloric acid (2M; 100 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2×100 ml). The organic layers were combined and concentrated in vacuum. Recrystallization from a mixture of dichloromethane:heptane (5:1) resulted in obtaining tetrahydropyran-4-Eletropaulo ester toluene-4-sulfonic acid. Then the mother solution was purified by chromatography on a column of silica gel, elwira 50% dichloromethane in n-heptane, with additional amounts tetrahydropyran-4-yl is amylovora ester toluene-4-sulfonic acid (the total yield of 41.6 g, 154 mmol).

14A:3-{5-[(Diethylamino)methyl]-[1,2,4]thiadiazole-3-yl}-7-fluoro-1-(tetrahydropyran-4-yl)methyl-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using diethylamine. EsIMS: m/z 403,1 [M+H]+.

14B:7-Fluoro-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]thiadiazole-3-yl}-1-(tetrahydropyran-4-yl)methyl-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using pyrrolidine instead of diethylamine. EsIMS: m/z 401,0 [M+H]+.

14C:3-{5-[(Dimethylamino)methyl}-[1,2,4]thiadiazole-3-yl}-7-fluoro-1-(tetrahydropyran-4-yl)methyl-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using dimethylamine instead of diethylamine. EsIMS: m/z 375,0 [M+H]+.

Example 15

The following compounds were obtained following the method of example 7, using amide 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid amide instead of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid.

Amide 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid was obtained by following the method of example 1, using 7-chloroindole instead of 7-methoxyindole and tetrahydropyran-4-Eletropaulo ester toluene-4-sulfonic acid instead of cyclohexylethylamine.

15A:7-Chloro-3-(5-{[N-ethyl-N(2-ethoxyethyl)amino]methyl}-[1,2,4]thiadiazole-3-yl)-1-(tetrahydropyran-4-yl)methyl-1 H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained usingN-ethyl-N-(2-methoxyethyl)amine instead of diethylamine. EsIMS: m/z 451,0, 449,0 [M+H]+.

15B:7-Chloro-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]thiadiazole-3-yl}-1-(tetrahydropyran-4-yl)methyl-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using pyrrolidine instead of diethylamine. EsIMS: m/z 419,3, 417,3 [M+H]+.

15C:7-Chloro-3-(5-{[N-ethyl-N(2-hydroxyethyl)amino]methyl}-[1,2,4]thiadiazole-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indol

Specified in the title compound was obtained usingN-ethyl-N(2-hydroxyethyl)amine instead of diethylamine. EsIMS: m/z 437,1, 435,1 [M+H]+.

Example 16

1-(Cyclohexyl)methyl-7-methoxy-3-(4-{[N-(2-methoxyethyl)-N-methylamino]methyl}-[1,3]thiazol-2-yl)-1H-indole, cleaners containing hydrochloride salt

A mixture of amide 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (obtained from 7-methoxyindole as described in example 1; 5.10 g, 17.8 mmol), reagent Lawesson (7,92 g and 19.6 mmol) and toluene (150 ml) was stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuo and the resulting residue was purified column chromatography, elwira dichloromethane, to obtain the amide 1-(cyclohexyl)methyl-7-methoxy-1 -indol-3-thiocarbonic acid (3.58 g).

A mixture of amide 1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-thiocarbonic acid (200 mg, 0.66 mmol), 1,3-dichloroacetone (126 mg, 0,99 mmol) and ethanol (2.0 ml) was stirred at 60°C for 1 hour. The reaction mixture was concentrated in vacuo and the resulting residue was mixed with 5% aqueous sodium carbonate (100 ml). The resulting mixture was extracted with dichloromethane (4×100 ml). The organic layers were combined, washed with saturated salt solution, dried over magnesium sulfate and concentrated in vacuum. The obtained residue was purified column chromatography, elwira 25% (vol./about.) the ethyl acetate in n-heptane, to obtain 3-[4-(chloromethyl)thiazol-2-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (200 mg).

A mixture of 3-[4-(chloromethyl)thiazol-2-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (100 mg, 0.27 mmol), (2-methoxyethyl)methylamine (119 mg, of 1.33 mmol), 1,4-dioxane (2 ml) and acetonitrile (1 ml) was subjected to microwave irradiation for 10 min at 160°C. the Reaction mixture was concentrated in vacuo and the resulting residue was mixed with aqueous sodium hydroxide (1M; 50 ml) and was extracted with dichloromethane (4×50 ml). The combined organic layers were washed with saturated salt solution, dried over magnesium sulfate and concentrated in vacuum. The obtained residue was purified column chromatography, elwira with ethyl acetate, obtaining free the th grounds specified in the connection header in the form of oil. Education cleaners containing hydrochloride salt was obtained by addition of hydrogen chloride (1M solution in diethyl ether; 3 ml) to a solution of free base in diethyl ether (15 ml). The mixture was concentrated in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt, 1:1 (95,1 mg).

1H NMR (400 MHz, CD3OD) δ 1,00-1,30 (5H, m), 1,55-of 1.94 (6H, m)of 3.00 (3H, s), 3,32-3,66 (5H, m), 3,80 (2H, t, J=5.0)and of 3.97 (3H, s), the 4.29 (2H, d, J=7,2), to 4.52 (2H, s), for 6.81 (1H, d, J=8,0), 7,16 (1H, DD, J=8.0 a, 8,0), a 7.62 (1H with), 7,80 (1H, d, J=8,0), a 7.85 (1H, s). EsIMS: m/z 428,1 [M+H]+, 339,0.

Example 17

Next, the method of example 16 was used to obtain the following compounds using alternative amines instead of (2-methoxyethyl)methylamine.

17A:1-(Cyclohexyl)methyl-7-methoxy-3-{4-[(morpholine-4-yl)methyl]-[1,3]thiazol-2-yl}-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using the research instead of (2-methoxyethyl)methylamine. EsIMS: m/z 426,3 [M+H]+, 339,1.

17B:1-(Cyclohexyl)methyl-3-{4-[(4-hydroxypiperidine-1-yl)methyl]-[1,3]thiazol-2-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using 4-hydroxypiperidine instead of (2-methoxyethyl)methylamine. EsIMS: m/z 440,1 [M+H]+, 399,0.

17C:1-(Cyclohexyl)methyl-3-(4-{[N-isopropyl-N(2-methoxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-7-methoxy- H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained usingN-isopropyl-N-(2-methoxyethyl)amine instead of (2-methoxyethyl)methylamine. EsIMS: m/z 456,4 [M+H]+, 339,1.

17D:(S)-1-(Cyclohexyl)methyl-3-{4-[(2-hydroxyethylpyrrolidine-1-yl)methyl]-[1,3]thiazol-2-yl-7-methoxy-1H-indol

Specified in the title compound was obtained using (S)-(+)-prolinol instead of (2-methoxyethyl)of methylamine and was isolated as free base. EsIMS: m/z 440,1 [M+H]+, 339,1; [a]D22-10,0° (c=0.65 mg/ml in chloroform).

17E:1-(Cyclohexyl)methyl-7-methoxy-3-{4-[(thiomorpholine-4-yl)methyl]-[1,3]thiazol-2-yl}-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using thiomorpholine instead of (2-methoxyethyl)methylamine. EsIMS: m/z 442,0 [M+H]+, 339,0.

Example 18

1-(Cyclohexyl)methyl-7-methoxy-3-{4-[1-(pyrrolidin-1-yl)ethyl]-[1,3]thiazol-2-yl}-1H-indole, cleaners containing hydrochloride salt

A solution of 1-chloro-2,3-butandione (0,717 g, 5,95 mmol) in ethanol (3 ml) was added dropwise to a solution of amide 1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-thiocarbonic acid (obtained as in example 16; 1.20 g, of 3.97 mmol) in ethanol (12 ml) at room temperature and then the mixture was stirred at room temperature for 3 days. The reaction mixture is the end of what was tribali in vacuum, the obtained residue was mixed with dichloromethane (50 ml) and then washed with water and saturated salt solution, dried over magnesium sulfate and concentrated in vacuum. The obtained residue was purified column chromatography, elwira 33% (vol./about.) the ethyl acetate in n-heptane, to obtain 1-{2-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]thiazole-4-yl}ethanone in the form of a brown solid substance (1,11 g).

A mixture of 1-{2-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]thiazole-4-yl}ethanone (100 mg, 0.27 mmol), pyrrolidine (193 mg, a 2.71 mmol), acetic acid (163 mg, a 2.71 mmol) and acetonitrile (3 ml) was stirred at room temperature for 2 hours. Added macroporous methylolacrylamide of triethylamine (MP-cyanoborohydride, download: 2,35 mmol/g, 231 mg, 0,543 mmol) and the resulting mixture was subjected to microwave irradiation at 130°C for 10 min, the Resin was removed by filtration, washing with dichloromethane, and the filtrate was concentrated in vacuum. The precipitate was mixed with aqueous sodium hydroxide (1M; 100 ml) and was extracted with dichloromethane (4×100 ml). The organic layers were combined, then washed with saturated salt solution, dried over magnesium sulfate and concentrated in vacuum. The obtained residue was purified column chromatography, elwira 5% methanol in ethyl acetate. The resulting oil was dissolved in diethyl ether (10 m is), then to the solution was added HCl (1M solution in diethyl ether; 3 ml). The resulting mixture was concentrated in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt, 1:1 (30.1 mg).

1H NMR (400 MHz, CD3OD) δ 0,98-1,32 (5H, m), 1,54-2,22 (13H, m), 3,22-3,44 (3H, m), 3,66-a-3.84 (1H, m), of 3.97 (3H, s), the 4.29 (2H, d, J=7,2), 4,60-4,72 (1H, m), for 6.81 (1H, d, J=7,6), to 7.15 (1H, DD, J=7,6, 8,0), 7,51 (1H, s), 7,79-of 7.90 (2H, m). EsIMS: m/z 424,1 [M+H]+, 353,1.

Example 19

1-(Cyclohexyl)methyl-7-fluoro-3-(4-{[N-isopropyl-N(2-methoxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-1H-indole, salt triperoxonane acid

Specified in the title compound was obtained following the method of example 16, using amide 1-(cyclohexyl)methyl-7-fluoro-1H-indole-3-carboxylic acid (obtained from 7-farindola) andN-isopropyl-N(2-methoxyethyl)amine. The free base was purified prepreparation HPLC [method (i)] to obtain specified in the connection header in the form of a salt triperoxonane acid, 1:1. EsIMS: m/z 444,3 [M+H]+, 327,3.

Example 19A

1-(Cyclohexyl)methyl-6-fluoro-3-[4-(diethylamino)methyl]-[1,3]thiazol-2-yl)-1H-indole, salt triperoxonane acid

Specified in the title compound was obtained following the method of example 16, using amide 1-(cyclohexyl)methyl-6-fluoro-1H-indole-3-carboxylic acid (obtained from 6-Florinda) and diethylamine. Free osnovaniya prepreparation HPLC [method (i)] to obtain specified in the connection header in the form of a salt triperoxonane acid, 1:1. EsIMS: m/z 400,1 [M+H]+, 327,1.

Example 20

7-Chloro-1-(cyclohexyl)methyl-3-(4-{[N-isopropyl-N(2-methoxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained following the method of example 16, using amide 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carboxylic acid (obtained from 7-chloroindole) andN-isopropyl-N(2-methoxyethyl)amine. EsIMS: m/z 462,3, 460,3 [M+H]+, 343,1.

Example 21

1-(Cyclohexyl)methyl-7-ethyl-3-(4-{[N-isopropyl-N(2-methoxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-1H-indole, salt triperoxonane acid

Specified in the title compound was obtained following the method of example 16, using amide 1-(cyclohexyl)methyl-7-ethyl-1H-indole-3-carboxylic acid (obtained from 7-ethylindole) andN-isopropyl-N-(2-methoxyethyl)amine. The free base was purified prepreparation HPLC [method (i)] to obtain specified in the connection header in the form of a salt triperoxonane acid, 1:1. EsIMS: m/z 454,5 [M+H]+, 337,3.

Example 22

The following compounds were obtained following the method of example 16, using amide (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin-6-carboxylic acid (obtained from (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin-6-carboxylic acid is, described in example 13) instead of the amide 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid.

22A:(R)-3-cyclohexyl-6-{4-[(diethylamino)methyl]-[1,3]thiazol-2-yl}-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin, cleaners containing hydrochloride salt

Specified in the title compound was obtained using diethylamine instead of (2-methoxyethyl)methylamine. EsIMS: m/z 410,3 [M+H]+, 337,3; [α]D22-37,5° (c=1,30 mg/ml in chloroform).

22B:(R)-3-cyclohexyl-6-{4-[(N-ethyl-Nisopropylamino)methyl]-[1,3]thiazol-2-yl}-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin, salt triperoxonane acid

Specified in the title compound was obtained usingN-ethyl-NIsopropylamine instead of (2-methoxyethyl)methylamine. The free base was purified prepreparation HPLC [method (i)] to obtain specified in the connection header in the form of a salt triperoxonane acid, 1:1. EsIMS: m/z 424,3 [M+H]+, 337,3; [α]D22-27,4° (c=1.25 mg/ml in chloroform).

22C:(R)-3-cyclohexyl-6-{4-[(pyrrolidin-1-yl)methyl]-[1,3]thiazol-2-yl}-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin, salt triperoxonane acid

Specified in the title compound was obtained using pyrrolidine instead of (2-methoxyethyl)methylamine. The free base was purified prepreparation HPLC [method (i)] to obtain specified the title compound as a salt triperoxonane acid, 1:1.

EsIMS: m/z 408,3 [M+H]+, 337,3; [a]D22-32,6° (c=2,15 mg/ml in chloroform).

22D:(R)-3-cyclohexyl-6-(4-{[N-isopropyl-N(2-methoxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin, salt triperoxonane acid

Specified in the title compound was obtained usingN-isopropyl-N(2-methoxyethyl)amine instead of (2-methoxyethyl)methylamine. The free base was purified prepreparation HPLC [method (i)] to obtain specified in the connection header in the form of a salt triperoxonane acid, 1:1. EsIMS: m/z of 454.3 [M+H]+, 337,3; [α]D22-58,4° (c=2.09 mg/ml in methanol).

22E:(R)-3-cyclohexyl-6-(4-{[bis-(2-methoxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin, salt triperoxonane acid

Specified in the title compound was obtained using bis-(2-methoxyethyl)amine instead of (2-methoxyethyl)methylamine. The free base was purified prepreparation HPLC [method (i)] to obtain specified in the connection header in the form of a salt triperoxonane acid, 1:1. EsIMS: m/z 470,3 [M+H]+, 337,3; [α]D22-28,5° (c=1.20 mg/ml in chloroform).

Example 23

The following compounds were obtained following the method of example 16, using amide 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic sour the s instead of the amide 1-(cyclohexyl)methyl-7-methoxy-1 H-indole-3-carboxylic acid.

Amide 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid was obtained by following the method of example 1, using 7-chloroindole instead of 7-methoxyindole and tetrahydropyran-4-Eletropaulo ester toluene-4-sulfonic acid (obtained as described in example 14) instead of cyclohexylethylamine.

23A:7-Chloro-3-{4-[(diethylamino)methyl]-[1,3]thiazol-2-yl}-1-(tetrahydropyran-4-yl)methyl-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained using diethylamine. EIMS: m/z 420,0, 418,4 [M+H]+, 347,0, 345,0.

23B:7-Chloro-3-{4-{{N-(2-hydroxyethyl)-Nisopropylamino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indol

Specified in the title compound was obtained usingN-(2-hydroxyethyl)-NIsopropylamine. EIMS: m/z 448,4 [M+H]+, 347,1, 345,1.

23C:7-Chloro-3-(4-{[N-ethyl-N(2-hydroxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyranyl-4-yl)methyl-1H-indol

Specified in the title compound was obtained usingN-ethyl-N(2-hydroxyethyl)amine. EIMS: m/z 436,3, 434,4 [M+H]+, 347,0, 345,0.

23D: 7-Chloro-3-(4-{[N-(2-methoxyethyl)-Nmethylamino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound floor is Ali using N-(2-methoxyethyl)-Nof methylamine. EIMS: m/z 436,1, of 434.1 [M+H]+, 347,0, 345,0.

Example 24

1-(Cyclohexyl)methyl-3-{4-[(dimethylamino)methyl]-5-ethyl-[1,3]thiazol-2-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt

Ethoxide sodium (0.68 g, 9,94 mmol) was added in portions to a mixture of ethyldichlorosilane (1,22 ml, 9,94 mmol) and diethyl ether (10 ml) under cooling in iced water and the resulting mixture was stirred at 0°C for 30 minutes. Then was added propionic aldehyde (0,79 ml of 10.93 mmol) and the reaction mixture gave to slowly warm to room temperature, stirring continuously for 72 hours. Then the reaction mixture was poured into water (10 ml) and was extracted with diethyl ether (2×15 ml). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuum to obtain crude ethyl ester of 3-chloro-2-oxopentanoic acid (1.8 g)which was used in the next stage without additional purification.

A mixture of amide 1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-thiocarbonic acid (0,227 g, 0,754 mmol) and the crude ethyl ester of 3-chloro-2-oxopentanoic acid (1,34 g, 7,52 mmol) in dimethylformamide (4 ml) was subjected to microwave irradiation for 25 min at 140°C. the Reaction mixture was concentrated in vacuo and the resulting residue was purified column chromatography on silica gel, elwira 25% Aceto the om in heptane, obtaining the crude ethyl ester of 2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-5-utiltity-4-carboxylic acid (0,490 g). The obtained substance was used in the next stage without additional purification.

To a mixture of ethyl ester of 2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-5-utiltity-4-carboxylic acid (490 mg, 1.15 mmol) and tetrahydrofuran (5 ml) was added portions of lithium borohydride (200 mg, 9.09 mmol) under cooling in iced water and the resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was extinguished aqueous solution of hydrochloric acid (2M; 2 ml) and the aqueous layer was extracted with dichloromethane (2×100 ml). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to obtain the crude product. Column chromatography on silica gel was obtained the crude [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-5-utiltity-4-yl]methanol (210 mg), elwira 66% ethyl acetate in heptane. The obtained substance was used in the next stage without additional purification.

To a mixture of [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-5-utiltity-4-yl]methanol (210 mg, 0,547 mmol), diisopropylethylamine (150 μl, of 0.91 mmol) and dichloromethane (5 ml) was added while cooling in an ice water methanesulfonamide (90 μl, of 1.16 mmol) and the mixture was let to rise slowly to on the th temperature. Stirring was continued for 22 hours. The reaction mixture was extinguished 5% aqueous sodium carbonate (2 ml) and the aqueous layer was extracted with dichloromethane (2×10 ml). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to obtain the crude product. Column flash chromatography with elution with 10% acetone in n-heptane resulted in the receipt of 3-(4-chloromethyl-5-utiltity-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (109 mg).

To a mixture of 3-(4-chloromethyl-5-utiltity-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (38 mg, 0,095 mmol), potassium carbonate (16 mg, 0,113 mmol) and sodium iodide (14 mg, 0,095 mmol) in acetonitrile (2 ml) was added dimethylamine (2,2M solution in tetrahydrofuran; and 0.50 ml). The mixture was subjected to microwave irradiation for 5 min at 160°C, then was distributed between dichloromethane (20 ml) and 5% aqueous sodium carbonate (5 ml). The aqueous layer was extracted with dichloromethane (10 ml) and the combined organic layers were dried over magnesium sulfate and concentrated in vacuum. The resulting oil was dissolved in diethyl ether was then added to a solution of hydrogen chloride (1M solution in diethyl ether; 3 ml). The resulting mixture was concentrated in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt, 1:1 (40 mg, 0,089 mmol).

1H NMR (400 MHz, CD3OD) δ 1.04 million-to 1.15 (2H, m), 1,16-of 1.30 (3H, m), USD 1.43 (3, t, J=7,0), 1,55-of 1.78 (5H, m), 1,82-of 1.92 (1H, m), 3,05 (8H, m)to 3.99 (3H, s)to 4.33 (2H, d, J=7), to 4.62 (2H, s)6,91 (1H, d, J=8,0), 7,29 (1H, t, J=8,0), a 7.62 (1H, d, J=8), 8,30 (1H, s). EsIMS: m/z 412,3 [M+H]+, 367,0.

Example 25

1-(Cyclohexyl)methyl-3-{5-[(diethylamino)methyl]-4-methyl[1,3]thiazol-2-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt

To a solution of amide 1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-thiocarbonic acid (604 mg, 2.00 mmol) in EtOH (5.0 ml) was added ethyl-2-chloro-3-oxobutanoate (of 0.332 ml, of 2.40 mmol). The mixture was boiled under reflux for 1 hour. After cooling to 0°C the precipitate was collected by filtration to obtain 1-cyclohexylmethyl-3-(5-etoxycarbonyl-4-methylthiazole-2-yl)-7-methoxy-1H-indole (505 mg, 1,22 mmol).

To a solution of 1-cyclohexylmethyl-3-(5-etoxycarbonyl-4-methylthiazole-2-yl)-7-methoxy-1H-indole (680 mg, of 1.65 mmol) in THF (20 ml) was added sociallyengaged (125 mg, 3,30 mmol) at 0°C. the Mixture was stirred at 0°C for 1 hour, then snuffed out the ice water and was extracted with dichloromethane. The combined organic layers were washed with saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified flash chromatography, elwira 25-50% (vol./about.) the ethyl acetate in heptane, then with 10% (vol./about.) methanol in dichloromethane, to obtain 1-cyclohexylmethyl-3-(5-hydroxymethyl-4-methylthiazole-2-yl)-7-methoxy-1H-indole (532 mg, 1.44 mmol).

To a solution of 1-cyclohexylmethyl the l-3-(5-hydroxymethyl-4-methylthiazole-2-yl)-7-methoxy-1 H-indole (74 mg, 0.20 mmol) and triethylamine (26 mg, 0.26 mmol) in dichloromethane (1.0 ml) was added methanesulfonamide (28 mg, 0.24 mmol). The mixture was stirred at room temperature for 40 min and was distributed between dichloromethane and 5% aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane, then the combined organic layers were washed with saturated salt solution, dried over sodium sulfate and concentrated to obtain crude 1-cyclohexylmethyl-3-(5-methanesulfonylaminoethyl-4-methylthiazole-2-yl)-7-methoxy-1H-indole (65 mg, 0.15 mmol). A mixture of crude 1-cyclohexylmethyl-3-(5-methanesulfonylaminoethyl-4-methylthiazole-2-yl)-7-methoxy-1H-indole (64 mg, 0.14 mmol), potassium carbonate (29 mg, 0.21 mmol), sodium iodide (31 mg, 0.21 mmol) and diethylamine (21 mg, 0.28 mmol) in THF (1.5 ml) and acetonitrile (1.5 ml) was subjected to microwave irradiation for 5 min at 160°C. the resulting mixture was distributed between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified flash chromatography, elwira 50-100% (vol./about.) the ethyl acetate in heptane, to obtain 1-cyclohexylmethyl-3-(5-diethylaminomethyl-4-methylthiazole-2-yl)-7-methoxy-1H-indole (27 mg, 0,064 mmol). Education cleaners containing hydrochloride salt achievements of the Ali added hydrogen chloride (1M solution in diethyl ether; 1 ml) to a solution of free base in diethyl ether (1 ml) and ethanol (2 ml). The solvent was removed in vacuum and the residue was dried to obtain specified in the connection header in the form of cleaners containing hydrochloride salt, 1:1 (26 mg, 0,056 mmol).

1H NMR (400 MHz, DMSO-d6) δ 0.95 to-1,25 (5H, m)of 1.29 (6H, t, J=7,2), 1,40-of 1.52 (2H, m), 1,55-1,70 (3H, m), 1,72-of 1.84 (1H, m), 3,10-of 3.25 (4H, m), 3,93 (3H, s), 4,27 (2H, d, J=7,0), 4,56 (2H, d, J=5.0)and PC 6.82 (1H, d, J=7,6), 7,14 (1H, t, J=7,6), 7,72 (1H, d, J=7,6), of 8.00 (1H, s), for 9.90 (1H, user. s); EsIMS: m/z 426,3 [M+H]+, 353,1.

Example 26

1-(Cyclohexyl)methyl-3-{2-[(diethylamino)methyl]-[1,3]thiazol-4-yl-7-methoxy-1H-indole, cleaners containing hydrochloride salt

To a solution of 7-methoxyindole (5,00 g 34,0 mmol) in dimethylformamide (50 ml) under nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil; 1.50 g, or 37.4 mmol). Before adding bromeilles (5,20 ml, or 37.4 mmol) and the mixture was stirred at room temperature for 10 minutes. The resulting mixture was stirred at room temperature for 42 hours and then was distributed between ethyl acetate (150 ml) and water (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml) and the combined organic layers were washed with saturated salt solution (150 ml), dried over sodium sulfate and concentrated in vacuum. The crude intermediate compound was purified column flash chromatography, elwira 0-10% (vol./about.) the ethyl acetate in n-heptane, with receipt is m 1-(cyclohexyl)methyl-7-methoxy-1 H-indole (of 7.48 g, 30.7 mmol).

To a stirred solution of pyridine (2.20 ml of 27.2 mmol) and 1-(cyclohexyl)methyl-7-methoxy-1H-indole (6.60 g, to 27.2 mmol) in toluene (50 ml) at 55°C for 1.5 hours was added dropwise chlorocatechol (8,66 ml, 109 mmol). The resulting mixture was heated to 55°C within a further 0.5 hour, then allowed to cool to room temperature. Was added water (60 ml) and methanol (10 ml). The organic layer was separated and concentrated under reduced pressure to obtain a dark brown precipitate. The residue was purified column chromatography, elwira 5% (vol./about.) the ethyl acetate in n-heptane. The obtained solid is repeatedly recrystallized from ether to obtain 2-chloro-1-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]ethanone in the form of a white solid. (1.40 g).

2-chloro-1-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]alanon (0.73 g, 2,30 mmol) and 2-(tert-BUTYLCARBAMATE)thioacetamide (1,21 g, 6,89 mmol) suspended in ethanol (10 ml) and the resulting mixture was subjected to microwave irradiation at 150°C for 10 min using Emrys™ Optimizer EXP. The reaction mixture was concentrated in vacuo and the resulting residue was purified column flash chromatography, elwira 5% (vol./about.) the ethyl acetate in n-heptane, to obtain 1-(cyclohexyl)methyl-7-methoxy-3-{2-[(tert-BUTYLCARBAMATE)methyl]thiazol-4-yl}-1H-indole as a yellow is the asle (1.01 g).

1-(Cyclohexyl)methyl-7-methoxy-3-{2-[(tertBUTYLPEROXY)methyl]thiazol-4-yl}-1H-indole (0,92 g, 2.10 mmol) was dissolved in methanol (20 ml) was added 4n. sodium hydroxide (5 ml). The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and taken to a residue in dichloromethane. Added water and the separated organic layers. The aqueous layer was extracted with dichloromethane and the combined organic layers were concentrated in vacuo to obtain 1-(cyclohexyl)methyl-3-[2-(hydroxymethyl)thiazol-4-yl]-7-methoxy-1H-indole as a pale orange foam (0.55 g).

Methanesulfonanilide (174 μl, 2.25 mmol) was added to a solution of 1-(cyclohexyl)methyl-3-[2-(hydroxymethyl)thiazol-4-yl]-7-methoxy-1H-indole (0.40 g, 1.12 mmol) and pyridine (182 μl, 2.25 mmol) in dichloromethane (8 ml). The resulting mixture was stirred at room temperature overnight. Then add methanesulfonanilide (87 μl, 1.12 mmol) and continuously stirred for 0.5 hours. The mixture was concentrated in vacuo and the resulting orange residue was purified column flash chromatography, elwira dichloromethane, to obtain 3-[2-(chloromethyl)thiazol-4-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole as a yellow oil (0,415 g).

3-[2-(chloromethyl)thiazol-4-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (0.08 g, 0,214 mmol) and diethylamine (221 μl, 2.14 mmol who) was dissolved in acetonitrile (2 ml). The resulting mixture was subjected to microwave irradiation at 100°C for 5 minutes the Mixture was concentrated in vacuo and the resulting residue was purified column chromatography, elwira 33% (vol./about.) the ethyl acetate in n-heptane. The resulting product was transferred into diethyl ether was added hydrogen chloride (1M solution in diethyl ether; 1 ml). The solution was concentrated in vacuo and the resulting solid triturated with ether, then dried to obtain specified in the connection header in the form of cleaners containing hydrochloride salt, 1:1 (0,034 g).

1H NMR (400 MHz, CD3OD) δ 0,99-1,25 (5H, m), USD 1.43 (6H, t, J=7,5), 1.56 to 1,90 (6H, m), 3,35-of 3.42 (4H, m), of 3.96 (3H, s), 4,27 (2H, d, J=7,5), 4,75-4,80 (2H, s, masked by the peak of the H2O)to 6.75 (1H, d, J=8,0), was 7.08 (1H, DD, J=8,0, 8,0), 7,64-7,68 (3H, m). EsIMS:

m/z 412,1 [M+H]+, 339,0.

Example 27

1-(Cyclohexyl)methyl-7-methoxy-3-{2-[(pyrrolidin-1-yl)methyl]-[1,3]thiazol-4-yl}-1H-indole, cleaners containing hydrochloride salt

Specified in the title compound was obtained by the method of example 26 using pyrrolidine instead of diethylamine. EsIMS: m/z 410,3 [M+H]+, 339,1.

Example 28

1-(Cyclohexyl)methyl-3-{2-[(dimethylamino)methyl]-[1,3]thiazol-5-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt

To a suspension of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (5 g, of 17.4 mmol) in dichloromethane (100 ml) was added oxalicacid (3.04 from ml, 34.8 mmol) and the resulting solution was displaced is ivali during the night. Then the excess solvent and reagent were removed by evaporation. To the obtained precipitate was added copper cyanide (I) (6.2 g, to 69.6 mmol), toluene (200 ml) and acetonitrile (10 ml) and the reaction mixture is boiled under reflux for 7 hours. Then added another portion of copper cyanide (I) (1.6 g, to 17.9 mmol) and the reaction mixture is boiled under reflux during the night. The reaction mixture was cooled and filtered through a layer dicalite, washed with acetonitrile and the combined filtrate evaporated to obtain solid red substance. The solid was purified column flash chromatography, elwira 50% (vol./about.) dichloromethane in heptane, to obtain (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)oxoacetate (4.7 g, 14.7 mmol).

To a solution of (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)oxoacetate (975 mg, 3,29 mmol) in acetic acid (40 ml) under nitrogen atmosphere was added 10% palladium on activated carbon (90 mg). The reaction mixture was placed in an atmosphere of hydrogen and stirred for 14 hours. Then the reaction mixture was filtered through a layer dicalite. Dicalite washed with acetic acid and the combined filtrate evaporated to obtain a red oil. The red oil was transferred to a dichloromethane (50 ml) and to it was added methylchlorosilanes (0,393 ml, to 4.28 mmol), followed by adding dropwiseN-atilde is Propylamine (1.7 ml, 9,87 mmol). The reaction mixture was stirred for 1 hour and was poured into a separating funnel. The organic layers are successively washed with 2M aqueous hydrochloric acid (50 ml), 5% aqueous sodium carbonate (50 ml) and saturated salt solution (50 ml). Organic matter was dried over sodium sulfate, filtered and the solvent was removed in vacuum to obtain a brown oil. The oil was purified column flash chromatography using dichloromethane and then 66% (vol./about.) diethyl ether in heptane to obtain methyl esterN-[(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxoethyl]assalamou acid (573 mg, 1.48 mmol) as a solid yellow/brown substance.

To a solution of methyl esterN-[(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxoethyl]assalamou acid (429 mg, 1.11 mmol) in chloroform (20 ml) was added pentasulfide phosphorus (538 mg, to 1.21 mmol) and the reaction mixture was heated for 3.5 hours. The reaction mixture was cooled, poured into a separating funnel, washed with water and then a saturated solution of salt. Then the organic layers were dried over magnesium sulfate, filtered and the solvent was removed in vacuum. The obtained solid was purified column flash chromatography, elwira dichloromethane, to obtain the methyl ester 5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazole-2-carboxylic acid (418 mg, 1,09 mmol) as a brown solid substance.

To a solution of methyl ester 5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazole-2-carboxylic acid (418 mg, of 1.09 mmol) in methanol (10 ml) and tetrahydrofuran (10 ml) was added sodium borohydride (83 mg, to 2.18 mmol) in portions over 2 minutes. Then the reaction mixture was stirred for 1 hour and then extinguished aqueous solution of hydrochloric acid (1M, 10 ml). The mixture was poured into a separating funnel, diluted with dichloromethane (50 ml) and washed with water (20 ml). The combined organic layers were dried, filtered and the solvent was removed in vacuum to obtain a yellow oil. The oil was purified column flash chromatography using 50-100% (vol./about.) diethyl ether in heptane to obtain [5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazol-2-yl]methanol (308 mg, 0.86 mmol) as not quite white foam.

To a solution of 5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazol-2-yl]methanol (308 mg, 0.86 mmol) in dichloromethane (20 ml) was added methanesulfonamide (80 μl, of 1.03 mmol) and then triethylamine (0,156 ml, 1.12 mmol). The reaction mixture was stirred for 30 minutes, then poured into a separating funnel, washed with 5% aqueous sodium carbonate, then saturated salt solution and dried over magnesium sulfate. The solvent was removed in vacuo to obtain methyl ester 5-(1-cyclo is exility-7-methoxy-1 H-indol-3-yl)thiazol-2-immeasureably acid (411 mg, of 0.94 mmol). To a solution of methyl ester 5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazol-2-immeasureably acid (93 mg, 0,215 mmol) in tetrahydrofuran (2 ml) was added dimethylamine (2M in tetrahydrofuran (THF; 1 ml, 2 mmol) and the reaction mixture was subjected to microwave irradiation at 150°C for 15 minutes. The reaction mixture was diluted with dichloromethane (40 ml) and washed with a mixture of saturated salt solution and saturated sodium bicarbonate in a ratio of 1:1 (vol./vol.), was dried over magnesium sulfate, filtered and the solvent was removed in vacuum. The resulting oil was purified flash column-chromatography with obtaining specified in the title compound (70 mg, 0.18 mmol) in the form of free base. The free base was dissolved in dichloromethane (5 ml)was added hydrogen chloride (2M solution in diethyl ether; 1 ml, 2 mmol) and the solvent was removed in vacuum to obtain specified in the title compound in the form of cleaners containing hydrochloride salt of 1:1.

1H NMR (400 MHz, CD3OD): 0,96-1,12 (2H, m), 1,13-of 1.26 (3H, m), 1,5-of 1.62 (2H, m), 1,62-of 1.78 (3H, m), 1,78-of 1.92 (1H, m), 3,01 (6H, s), of 3.96 (3H, s), 4.26 deaths (2H, d, J=5.5), the 4,71 (2H, s), is 6.78 (1H, d, J=8,0), 7,11 (1H, t, J=8,0), 7,41 (1H, d, J=8,0), 7,52 (1H, s), 8,08 (1H, s); EsIMS: m/z 384,0 [M+H]+, 339,0, 243,1.

Example 29

1-(Cyclohexyl)methyl-3-{4-[(diethylamino)methyl]-[1,3]oxazol-2-yl-7-methoxy-1H-indole, cleaners containing hydrochloride Sol is

To a solution of amide 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (500 mg, about 1.75 mmol) in toluene (4 ml) was added 1,3-dichloroacetone (333 mg, 2,62 mmol) and the reaction mixture was subjected to microwave irradiation at 150°C for 30 minutes. Received the black solution was diluted with dichloromethane (50 ml) and washed with 5% aqueous sodium carbonate solution (5×20 ml), dried over magnesium sulfate, filtered and the solvent was removed in vacuum. The obtained brown oil was purified column flash chromatography using 5% (vol./about.) acetone in petroleum ether 40-60 ml with 3-(4-chlormethiazole-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (510 mg, of 1.42 mmol) as a white solid.

To a solution of 3-(4-chlormethiazole-2-yl)-1-cyclohexylmethyl-7-methoxy-1-indole (100 mg, 0.28 mmol) in tetrahydrofuran (1 ml) was added diethylamine (0,29 ml, 2.8 mmol) and the reaction mixture was subjected to microwave irradiation at 150°C for 15 minutes. The reaction mixture was introduced into a separating funnel, diluted with dichloromethane (40 ml) and washed with 5% aqueous sodium carbonate solution (2×25 ml), saturated salt solution (20 ml), dried over magnesium sulfate and the solvent evaporated in vacuum to obtain an orange oil. The oil was purified column flash chromatography using 10% (vol./about.) methanol in dichloromethane to obtain the decree of the frame in the title compound (92 mg, 0.23 mmol) in the form of free base. The free base was dissolved in dichloromethane and was added hydrogen chloride (1M solution in diethyl ether; 2 ml, 2 mmol). The mixture was concentrated in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt of 1:1.

1H NMR (400 MHz, CD3OD): 0,97 of 1.28 (5H, m)of 1.44 (6H, t, J=7,0), 1,5-1,8 (5H, m), 1,8-of 1.95 (1H, m), 3,3-3,5 (4H, m), of 3.97 (3H, s), the 4.29 (2H, d, J=7,0), to 4.38 (2H, s), 6,8 (1H, d, J=8,0), 7,2 (1H, t, J=8,0), and 7.8 (1H, (C), of 7.82 (1H, s), and 8.2 (1H, s); EsIMS: m/z 396,0 [M+H]+, 323,4, 295,4, 268,3.

Example 30

1-(Cyclohexyl)methyl-7-methoxy-3-{5-[(pyrrolidin-1-yl)methyl]-[1,3]oxazol-2-yl}-1H-indole, salt triperoxonane acid

A mixture of amide 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (563 mg, 1.97 mmol), methyl ester 2-chloro-3-oxopropanoic acid (Gangjee et al., J. Med. Chem. 44, 1993-2003, 2001; 1.48 g, 9,85 mmol) and dimethylacetamide (10 ml) was subjected to microwave irradiation at 90°C for 2×5 minutes using the Emrys™ Optimizer EXP. The reaction mixture was diluted with dichloromethane (150 ml), then washed with 5% aqueous magnesium sulfate (2×100 ml) and saturated salt solution (150 ml). The organic extracts were dried over magnesium sulfate and concentrated in vacuum. The obtained residue was purified column flash chromatography, elwira 25% (vol./about.) the ethyl acetate in heptane, to obtain the inseparable mixture of methyl ester of 2-(1-cyclohexylmethyl-7-m the toxi-1 H-indol-3-yl)-oxazol-5-carboxylic acid and 1-cyclohexylmethyl-7-methoxy-3-oxazol-2-yl-1H-indol ratio (HPLC 87:13; 0,613 g).

To a mixture of methyl ester of 2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)oxazol-5-carboxylic acid and 1-cyclohexylmethyl-7-methoxy-3-oxazol-2-yl-1H-indole (557 mg)dissolved in tetrahydrofuran (10 ml)while cooling in the system ice-methanol was added dropwise a solution of sociallyengaged (1M solution in diethyl ether; 2,88 ml, is 2.88 mmol). The resulting mixture was stirred for 30 minutes at 0°C, then diluted with diethyl ether (40 ml). Then added an excess of decahydrate sodium sulfate and the resulting mixture was stirred at room temperature for 18 hours. The mixture was filtered through a layer dicalite and washed with diethyl ether (100 ml); then the filtrate was concentrated in vacuum. The obtained residue was purified column chromatography, elwira 50% ethyl acetate in n-heptane, to obtain [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxazol-5-yl]methanol in the form of a yellow solid substance (242 mg, 0.71 mmol).

To a solution of [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxazol-5-yl]methanol (242 mg, 0.71 mmol)dissolved in dichloromethane (15 ml)while cooling in the system ice-methanol was added dropwise methanesulfonanilide (98 mg, 0.85 mmol)and then dropwise added triethylamine (93 is g, to 0.92 mmol), and then stopped cooling and the mixture was stirred for 16 hours. Then the mixture was diluted with dichloromethane (30 ml), washed with saturated solution of sodium carbonate (30 ml) in a hydrophobic tube with Frit. The organic extracts were dried over magnesium sulfate and then concentrated in vacuum. A mixture of the obtained residue (110 mg, 0.26 mmol), pyrrolidine (185 mg, 2,60 mmol) and tetrahydrofuran (2.5 ml) was subjected to microwave irradiation at 150°C for 15 minutes. The resulting mixture was concentrated in vacuo and was purified column flash chromatography (2% (vol./about.) the ammonia in the system methanol/dichloromethane in the ratio of 1:49 as eluent) to give a brown tar. Then the resin was purified prepreparation HPLC [method (i)] to obtain 1-cyclohexylmethyl-7-methoxy-3-(5-pyrrolidin-1-ylmethylamino-2-yl)-1H-indole in the form of a salt triperoxonane acid (14 mg).

1H NMR (400 MHz, CD3OD) δ 0,99-of 1.27 (5H, m), 1,54-of 1.78 (5H, m)to 1.86 (1H, m), 2,00-2,24 (4H, m), 3.25 to 3,44 (2H, m), 3,53-3,74 (2H, m), of 3.97 (3H, s), the 4.29 (2H, d, J=7,0), with 4.64 (2H, s), for 6.81 (1H, s, J=7,0), to 7.15 (1H, t, J=8,0), 7,41 (1H, s), 7,79 (1H, d, J=7,5), of 7.82 (1H, s). EsIMS: m/z 394,1 [M+H]+, 323,1.

Example 31

1-(Cyclohexyl)methyl-3-{5-[(diethylamino)methyl]-4-methyl[1,3]oxazol-2-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt

A mixture of amide 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (500 mg, about 1.75 mmol), ethyl-2-chloroacetoacetate 2,88 g, 17.6 mmol) and dimethylformamide (10 ml) was subjected to microwave irradiation at 185°C for 15 minutes using the Emrys™ Optimizer EXP. The reaction mixture was diluted with dichloromethane (100 ml), then washed with 5% aqueous magnesium sulfate (2×50 ml), water (50 ml) and saturated salt solution (50 ml). The organic extracts were dried over magnesium sulfate and concentrated in vacuum. The obtained residue was purified column chromatography, elwira 33% (vol./about.) dichloromethane in n-heptane, to obtain an undivided mixture of ethyl ester of 2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-4-methoxazole-5-carboxylic acid and 1-cyclohexylmethyl-7-methoxy-3-(4-methoxazole-2-yl)-1H-indole (ratio of 78:22 according to HPLC; 0,586 g). This reaction was repeated with the same amounts.

To a mixture of ethyl ester of 2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-4-methoxazole-5-carboxylic acid and 1-cyclohexylmethyl-7-methoxy-3-(4-methoxazole-2-yl)-1H-indole (1171 mg)dissolved in tetrahydrofuran (20 ml)while cooling in the system ice-methanol was added dropwise sociallyengaged (1M solution in diethyl ether; 5.8 ml, 5.8 mmol). The resulting mixture was stirred for 20 minutes at 0°C, then diluted with diethyl ether (40 ml). Added excess decahydrate sodium sulfate and the resulting mixture was stirred at room temperature for 18 hours. See the camping was filtered through a layer dicalite, washing with diethyl ether (100 ml) and the filtrate was concentrated in vacuum. The residue was purified column flash chromatography, elwira 50% (vol./about.) the ethyl acetate in n-heptane, to obtain [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-4-methoxazole-5-yl]methanol as white solid (774 mg). To a solution of [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-4-methoxazole-5-yl]methanol (724 mg, 2.04 mmol) in dichloromethane (40 ml) at -78°C under nitrogen atmosphere was added dropwise methanesulfonanilide (281 mg, 2.45 mmol). Dropwise added triethylamine (269 mg, of 2.66 mmol) and the mixture was allowed to warm to room temperature with stirring for 2 hours. Then the mixture was diluted with dichloromethane (100 ml), washed with saturated solution of sodium carbonate (2×100 ml) and saturated salt solution (100 ml). The organic extracts were dried over magnesium sulfate and then concentrated in vacuum. A mixture of the obtained residue (100 mg, 0.23 mmol), diethylamine (169 mg, 2,30 mmol) and tetrahydrofuran (2 ml) was subjected to microwave irradiation at 150°C for 15 minutes. The resulting mixture was concentrated in vacuo, and purified flash column-chromatography, elwira 2% ammonia in the system methanol/dichloromethane in the ratio of 1:49, obtaining a brown resin. The resin was dissolved in dichloromethane (0.5 ml), then was added hydrogen chloride (1M solution in diethyl ether; 0.5 ml) ismes concentrated in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt, 1:1 (32 mg).

1H NMR (400 MHz, CD3OD) δ 0,85-to 1.38 (6H, m)of 1.46 (6H, t, J=7,5), 1,55-of 1.78 (4H, m), a 1.88 (1H, m), 2,39 (3H, s)to 3.34 (4H, q, J=7,6), 3,98 (3H, s), 4,34 (2H, d, J=6,9)and 4.65 (2H, s), to 6.88 (1H, d, J=8,2), of 7.23 (1H, t, J=8,0), 7,74 (1H, d, J=8.0 a), of 8.00 (1H, s). EsIMS: m/z 410,3 [M+H]+that sauce 337,1.

Example 32

1-(Cyclohexyl)methyl-3-{2-[(diethylamino)methyl]-[1,3]oxazol-5-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt

To a solution of (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxoacetate (obtained as described in example 28; 2,39 g of 8.06 mmol) in acetic acid (50 ml) under nitrogen atmosphere was added 10% palladium on activated carbon (240 mg). The reaction mixture was placed in an atmosphere of hydrogen and stirred overnight. Then the reaction mixture was filtered through a layer of loose dicalite. Dicalite washed with acetic acid and the combined filtrate evaporated to obtain a red oil. The red oil was transferred to a dichloromethane (50 ml), was added to it chlorocatechol (of 0.77 ml, 9,67 mmol) followed by drop wise addition of triethylamine (3.4 ml, and 24.2 mmol). The reaction mixture was stirred for 30 minutes and placed in a separating funnel. Organic matter is successively washed with 5% aqueous sodium carbonate (2×30 ml) and saturated salt solution (30 ml). Organic matter was dried over magnesium sulfate, filtered, solvent was removed in vacuum to obtain a red/brown oil. The oil was purified to Nochnoi flash chromatography using 20-100% (vol./about.) dichloromethane in heptane and then 25-50% (vol./about.) diethyl ether in heptane to obtain 2-chloro -N[2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxoethyl]ndimethylacetamide (2,32 g, 6.1 mmol).

To a solution of 2-chloro-N[2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxoethyl]ndimethylacetamide (200 mg, of 0.53 mmol) in tetrahydrofuran (2 ml) was added diethylamine (0,55 ml, 5.3 mmol) and the reaction mixture was subjected to microwave irradiation at 150°C for 15 minutes. The reaction mixture was poured into a separating funnel and was added dichloromethane (30 ml). Organic matter is successively washed with 5% aqueous sodium carbonate and saturated salt solution. Organic matter was dried over magnesium sulfate, filtered and the solvent was removed in vacuum to obtain brown solid substance. Solid brown substance was dissolved in tetrahydrofuran (2 ml) was added hydroxide (methoxycarbonylamino)triethylamine, inner salt (505 mg, 2,12 mmol). The resulting reaction mixture was subjected to microwave irradiation at 150°C for 15 minutes and extinguished with methanol (20 ml). The solvent was removed in vacuum and the residue was purified flash chromatography using 50% (vol./about.) ethyl acetate in heptane, followed prepreparation HPLC [method (ii)] to obtain white solid. The solid was dissolved in dichloromethane (≈5 ml) was added hydrogen chloride (1M solution in diethyl ether; 1 ml). The mixture was concentrated in in the cosmology vacuum obtaining specified in the connection header in the form of cleaners containing hydrochloride salt, 1:1 (77 mg, 0.2 mmol).

1H NMR (400 MHz, CD3OD) δ 0,97 by 1.12 (2H, m), 1,15-1,25 (3H, m)of 1.44 (6H, t, J=6,9), 1,52-of 1.62 (2H, m), 1,62-to 1.77 (3H, m), 1.77 in-1,9 (1H, m)to 3.36 (4H, q, J=6,7), of 3.95 (3H, s), 4.26 deaths (2H, d,J=7), with 4.64 (2H, s), 6,77 (1H, d, J=8), 7,11 (1H, t, J=8), 7,38 (1H, s), 7,41 (1H, d, J=8), 7,56 (1H, s); EsIMS: m/z 396,1 [M+H]+, 323,4, 268,4.

Example 33

1-(Cyclohexyl)methyl-3-(5-ethyl-5,6-dihydro-4H-pyrrolo[3,4-d]isothiazol-3-yl)-7-methoxy-1H-indole, cleaners containing hydrochloride salt

To a suspension of 5-(1-cyclohexylmethyl-7-methoxy-1H-indole)-[1,3,4]oxadiazol-2-it (obtained as described in example 7; 100 mg, 0.25 mmol) in m-xylene (0.5 ml) was added diethylazodicarboxylate (0.2 ml, 1.25 mmol) and the reaction mixture was subjected to microwave irradiation at 200°C for 5 minutes. Then the reaction mixture was directly purified column flash chromatography using 0-100% (vol./about.) dichloromethane in heptane to obtain diethyl ether 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-isothiazol-4,5-dicarboxylic acid (141 mg, 0.3 mmol). This reaction was repeated with the number of 1,255 mmol, all were combined and purified flash column-chromatography using 50-60% (vol./about.) dichloromethane in heptane with obtaining the above intermediate compound (882 mg, of 1.87 mmol).

To a cooled solution (ice bath/methanol) diethyl ether 3-(1-cyclohexylmethyl-7-methoxy-1Hindol-3-yl)-isothiazol-4,5-dicarboxylic acid (400 is g, 0.85 mmol) in tetrahydrofuran (20 ml) was added sociallyengaged (1M solution in THF; at 1.91 ml, at 1.91 mmol) and the reaction mixture was stirred for 20 minutes. To the reaction mixture was added an excess of decahydrate sodium sulfate and the reaction mixture was vigorously stirred for 1.5 hours. The resulting mixture was filtered through a layer of loose dicalite, rinsing with diethyl ether. The filtrate was concentrated in vacuum and the oil obtained was purified flash column-chromatography to obtain 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-4-hydroxymethylimidazole-5-yl]methanol (141 mg, 0.3 mmol). To a solution of 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-4-hydroxymethylimidazole-5-yl]methanol (194 mg, 0.5 mmol) in dichloromethane (10 ml) was added methanesulfonamide (of 0.182 ml of 1.16 mmol), then triethylamine (0,175 ml of 1.26 mmol) and the reaction mixture was stirred for 45 minutes. Added additional portion of methanesulfonanilide (0,07 ml, 0.44 mmol) and triethylamine (0.15 ml, 1 mmol) and the reaction mixture was stirred for the next 2 hours. The reaction mixture was placed in a separating funnel, washed with 5% aqueous sodium carbonate solution, then with saturated salt solution, dried over magnesium sulfate and the solvent evaporated in vacuum. The obtained residue was purified column flash chromatography using 33-100% (vol./about.) dichloromethane is in heptane and then diethyl ether to obtain methyl ester {4-chloromethyl-3-[1-(cyclohexyl)methyl-7-methoxy-1 H-indol-3-yl]isothiazol-5-yl}methanesulfonamide acid (113 mg, 0.23 mmol).

To a solution of methyl ester {4-chloromethyl-3-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]isothiazol-5-immeasureably acid (90 mg, 0,19 mmol) in tetrahydrofuran (1 ml) was added ethylamine (0,186 ml of 0.37 mmol) and triethylamine (0.05 ml, of 0.37 mmol) and the reaction mixture was subjected to microwave irradiation at 150°C for 15 minutes. The reaction mixture was placed in a separating funnel, diluted with dichloromethane (30 ml) and washed with 5% aqueous sodium carbonate solution (2×10 ml), saturated salt solution (10 ml), dried over magnesium sulfate and the solvent was removed in vacuum. The reaction was repeated with the number 0,166 mmol obtaining the above intermediate compounds. The crude products were combined and purified column flash chromatography using ethyl acetate to obtain specified in the title compound (36 mg, 0.09 mmol) in the form of free base. The free base was dissolved in dichloromethane and was added hydrogen chloride (2M solution in diethyl ether; 1 ml, 2 mmol). The mixture was concentrated in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt of 1:1.

1H NMR (400 MHz, CD3OD): 0,97-of 1.15 (2H, m), 1,15-of 1.27 (3H, m)of 1.47 (3H, t, J=7), 1,52-to 1.61 (2H, m), 1,62-to 1.77 (3H, m), 1,81-of 1.95 (1H, m), 3,63 (2H, q, J=7), of 3.95 (3H, s), 4,28 (2H, d, J=7), 4,62-of 4.75 (2H, m), 4,95-5,12 (2H, m, 6,77 (1H, d, J=8), to 7.09 (1H, t, J=8), the 7.43 (1H, s), 8,01 (1H, d, J=8); EsIMS: m/z 396,0 [M+H]+, 353,4, to 351.3, 320,3.

Example 34

1-(Cyclohexyl)methyl-7-methoxy-3-{5-[(pyrrolidin-1-yl)methylisoxazol-3-yl]-1H-indole, salt triperoxonane acid

The phosphorus oxychloride (12 ml, 0.13 mol) was slowly added over 30 minutes to dimethylformamide (30 ml) at -10°C. the Solution was allowed to warm to 0°C for 1 hour, then portions were added 1-(cyclohexyl)methyl-7-methoxy-1H-indole (obtained as in example 26; 3.2 g, 13 mmol) and the solution was stirred at room temperature for 16 hours. The solution was cooled in an ice bath and diluted with water, then carefully neutralized with sodium bicarbonate and was extracted with ethyl acetate (3×50 ml). The organic extracts were combined and the solvent was removed in vacuum. The residue (3.5 g) was dissolved in aqueous sodium hydroxide solution (5M; 100 ml) and the mixture is boiled under reflux at 100°C for 16 hours. The solution was cooled and was extracted with ethyl acetate (3×50 ml). The organic extracts were combined and the solvent was removed in vacuum to obtain 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbaldehyde (2.2 g, 8,12 mmol) as a white solid.

To a solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbaldehyde (780 mg, 2.9 mmol) in a mixture of ethanol (8 ml) and water (2 ml) were added hydrochloride hydroxyl is in (403 mg, 5.8 mmol) and sodium acetate (713 mg, 8,7 mmol) and the solution was stirred for 64 hours at room temperature. The mixture was concentrated in vacuo, the residue was diluted with water (50 ml) and was extracted with ethyl acetate (3×50 ml). The product was recrystallized from system diethyl ether/hexane to obtain the oxime 1-cyclohexylmethyl-7-methoxy-1H-indol-3-carbaldehyde (380 mg, 1.3 mmol) as a yellow powder.

To a solution of oxime 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carbaldehyde (170 mg, 0.59 mmol) in dichloromethane (5 ml), cooled to 0°C, was addedN-chlorosuccinimide (119 mg, 0.89 mmol) and the mixture was allowed to warm to room temperature with stirring for 1 hour. Added propylbromide (8 μl, of 0.65 mmol) and triethylamine (9 μl, of 0.65 mmol) and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuum and the residue was purified column flash chromatography, elwira 60-80% (vol./about.) dichloromethane in n-heptane, to obtain 3-(5-bromomethylisoxazole-3-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (150 mg, and 0.37 mmol) as a yellow solid substance.

To a solution of 3-(5-bromomethylisoxazole-3-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (120 mg, 0.31 mmol) in acetonitrile (3 ml) was added diethylamine (0,024 ml, 0.34 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was filtered and solvent is removed in vacuum. The residue was purified prepreparation HPLC [method (ii)] to obtain specified in the connection header in the form of a salt triperoxonane acid (20 mg).

1H NMR (400 MHz, CD3OD) δ 1,03-of 1.09 (2H, m)to 1.21 (3H, m), 1,57-of 1.74 (5H, m), 1,83-1,89 (1H, m), and 2.14 (4H, m), 3,38-of 3.60 (4H, m), of 3.96 (3H, s), 4,27-the 4.29 (2H, d, J=6,9), 4,69 (2H, s), is 6.78 (1H, d, J=7,5), 7,02 (1H, s), 7,08-for 7.12 (1H, m), to 7.67 (1H, s), to 7.67-of 7.69 (1H, d, J=8,1). EsIMS: m/z 394,1 [M+H]+, 323,4.

Example 35

1-(Cyclohexyl)methyl-7-methoxy-3-(5-{[bis-(2-hydroxyethyl)amino]methyl}isoxazol-3-yl)-1H-indole, salt triperoxonane acid

Specified in the title compound was obtained by the method of example 34 using diethanolamine instead of pyrrolidine. EsIMS: m/z 428,4 [M+H]+, 323,4.

Example 36

1-(Cyclohexyl)methyl-7-fluoro-3-{5-[(pyrrolidin-1-yl)methyl]thiophene-2-yl)-1H-indole, cleaners containing hydrochloride salt

It chilled with ice to a solution of 7-farindola (2.0 g, of 14.8 mmol) in dimethylformamide (50 ml) was added sodium hydride (60% dispersion in mineral oil, 0.88 g, of 22.2 mmol), the mixture was stirred for 15 min and then was added dropwise benzosulphochloride (and 2.26 ml, 17.8 mmol). Then the mixture was stirred at room temperature for 18 hours. Then the suspension was diluted with water (200 ml), was extracted with tert-butylmethylamine ether (3×100 ml) and the combined organic layers were washed with water (3×100 ml), dried with sodium sulfate and concentrated in vacuumized was purified column flash chromatography, elwira 20% (vol./about.) the ethyl acetate isohexane, obtaining 1-benzazolyl-7-farindola in the form of a colorless solid substance. (3,96 g, 14.4 mmol). To a solution of 1-benzazolyl-7-farindola (2.0 g, 7,27 mmol) in dimethylformamide (10 ml) was added dropwise a solution of bromine (0.75 ml, 14,55 mmol) in dimethylformamide (25 ml) for 3 minutes and Then the mixture was stirred at room temperature for 10 min and poured into a mixture of sodium metabisulfite (2 g), ammonium hydroxide solution (3 ml), water (100 ml) and crushed ice (100 g). The resulting suspension was stirred until the discoloration and was extracted with tert-butylmethylamine ether (2×100 ml). The combined organic layers were washed with water (2×100 ml), dried with sodium sulfate and the solvent was removed in vacuum to obtain 1-benzazolyl-3-bromo-7-farindola in the form of a solid orange-pink matter (2.35 g, only 6.64 mmol).

A solution of 1-benzazolyl-3-bromo-7-farindola (0.5 g, of 1.41 mmol), 5-formyl-2-tiefenbronn acid (0.24 g, 1.55 mmol), dichloride bis(triphenylphosphine)palladium (II) (0.06 g, 0.08 mmol) and triethylamine (of 0.39 ml, 2.82 mmol) in ethanol (4 ml) was subjected to microwave irradiation at 150°C for 420 C. the resulting suspension was concentrated under reduced pressure and the residue was passed through a layer of silicon dioxide, elwira dichloromethane, to obtain crude 5-(1-benzazolyl-7-Florinda-3-yl)-thiophene-2-is carboxaldehyde in the form of a brown solid substance (0,42 g), which was used in the next stage without additional purification.

To the crude 5-(1-benzazolyl-7-Florinda-3-yl)thiophene-2-carboxaldehyde sequentially added 4 E molecular sieves (1 g), pyrrolidine (of 0.44 ml, are 5.36 mmol), cyanoborohydride sodium (0,034 g, 0.54 mmol) and glacial acetic acid (1 drop). Then the resulting mixture was stirred at room temperature for 18 hours, filtered and the filter cake washed with methanol (2×30 ml) and dichloromethane (2×30 ml). The combined filtrate was concentrated in vacuo, dissolved in dichloromethane (20 ml), washed with aqueous sodium hydroxide (2M; 15 ml), dried with sodium sulfate and concentrated in vacuum. Then the residue was purified column flash chromatography, elwira 0-10% (vol./about.) methanol in dichloromethane, to obtain 1-benzene-sulfonyl-7-fluoro-3-(5-pyrrolidin-1-ilmatieteen-2-yl)indole as a yellow oil (0,22 g, 0.46 mmol).

1-benzazolyl-7-fluoro-3-(5-pyrrolidin-1-ilmatieteen-2-yl)indole (0.20 g, 0.46 mmol) and potassium carbonate (0.25 g, 1.82 mmol) was treated with a mixture of methanol and water (3:1 vol./vol.; 4 ml) and subjected to microwave irradiation at 100°C for 600 C. Then, the resulting suspension was concentrated under reduced pressure and was distributed between dichloromethane (10 ml) and water (10 ml). The organic phase was separated and the aqueous phase washed with dichloromethane (10 ml). United agencies is practical layers were dried with sodium sulfate and concentrated in vacuum. The residue was purified column flash chromatography, elwira 0-10% (vol./about.) methanol in dichloromethane, to obtain 7-fluoro-3-(5-pyrrolidin-1-ilmatieteen-2-yl)indole as a colorless solid matter (0.10 g, 0.35 mmol).

To a solution of 7-fluoro-3-(5-pyrrolidin-1-ilmatieteen-2-yl)indole (0.10 g, 0.35 mmol) in dimethylformamide (3 ml) was added sodium hydride (60% dispersion in mineral oil; 0.03 g, 0.71 mmol) and the mixture was stirred at room temperature for 15 minutes. Added bromeilles (0.05 ml, 0,39 mmol) and the mixture was stirred at 60°C for 18 hours. Then the suspension was diluted with water (30 ml), was extracted with tert-butylmethylamine ether (2×30 ml), the combined organic layers were washed with water (2×20 ml), dried with sodium sulfate and evaporated under reduced pressure. The residue was purified flash chromatography, elwira 5% (vol./about.) dichloromethane in methanol, to obtain specified in the title compound (free base) as a colorless solid(0.05 g, 0.13 mmol). The resulting substance was dissolved in diethyl ether (3 ml) and was treated with hydrochloric acid (1M solution in diethyl ether) to obtain by evaporation specified in the connection header (1:1 salt of hydrochloric acid) in the form of a colorless solid.

1H NMR (400 MHz, CD3OD) δ of 1.02 to 1.34 (5H, m), 1,57-of 1.93 (6H, m), 2,11-2,19 (4H, m), 3,38-357 (4H, m), 4,19 (2H, d, J=7,4)and 4.65 (2H, s), 6,91 and 7.36 (4H, m), 7,58 (1H, s), 7,71 (1H, d, J=8,1); EsIMS: m/z 396,9 [M+H]+, of 326.0.

Example 37

1-(Cyclohexyl)methyl-3-{5-[(diethylamino)methyl]-[1,3,4]oxadiazol-2-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt

To a suspension of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (1.0 g, of 3.48 mmol) in dichloromethane (20 ml) was added oxalicacid (0.6 ml, of 6.96 mmol) and the reaction mixture was stirred for 3.5 hours. The solvent is evaporated under reduced pressure and the resulting residue was re-dissolved in dichloromethane (20 ml). To the solution was added hydrazide Chloroacetic acid (1.3 g, 8,97 mmol) and triethylamine (2.9 ml, of 20.9 mmol) and the reaction mixture was stirred for 4 hours and then allowed to settle over night. The solvent is evaporated under reduced pressure and the obtained residue was purified column flash chromatography, elwira 50-100% (vol./about.) the ethyl acetate in heptane, to obtain theN-(2-chloroacetyl)hydrazide 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (397 mg, 1.05 mmol).

To a solution ofN'-(2-chloroacetyl)hydrazide 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (250 mg, to 0.662 mmol) in tetrahydrofuran (3 ml) was added inner salt hydroxide (methoxycarbonylamino)triethylamine (315 mg, of 1.32 mmol) and the resulting reaction mixture was subjected to microwave exposed the s at 150°C for 15 minutes. The reaction mixture was extinguished with methanol and the solvent evaporated. The obtained residue was purified flash chromatography using approximately 33-50% (vol./about.) ethyl acetate in heptane to obtain 3-(5-chloromethyl[1,3,4]oxadiazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (169 mg, 0.47 mmol) as a yellow solid substance. This reaction was repeated with the number of 0.53 mmol obtaining the above intermediate compound (a total of 276 mg, 0.77 mmol).

To a solution of 3-(5-chloromethyl[1,3,4]oxadiazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (92 mg, 0.26 mmol) in tetrahydrofuran (1 ml) was added diethylamine (0,134 ml, 1.28 mmol) and the reaction mixture was subjected to microwave irradiation at 150°C for 15 minutes. The resulting mixture was purified flash column-chromatography with obtaining specified in the title compound (87 mg, 0.22 mmol) in the form of free base. The free base was dissolved in dichloromethane and was added hydrogen chloride (2M solution in diethyl ether; 1 ml, 2 mmol). The excess reagent and solvent was removed by evaporation to obtain specified in the connection header (1:1 salt of hydrochloric acid) in the form of a white solid.

1H NMR (400 MHz, CD3OD): 0,97-1,12 (2H, m), 1,15-of 1.26 (3H, m)of 1.46 (6H, t, J=7), 1,53-to 1.63 (2H, m), 1,63-of 1.78 (3H, m), 1,8-of 1.95 (1H, m), 3,44 (4H, q, J=7), 3,98 (3H, s)to 4.33 (2H, d, J=7), 4,84 (2H, s), 6,85 (1H, d, J=7), 7,19 (1H, t, J=7,9), 7,73 (1H, d, J=8), 7,94 (1H, s). EsIM: m/z 397,1 [M+H] +, 324,4, 270,5.

Example 38

1-(Cyclohexyl)methyl-7-methoxy-3-{5-[(pyrrolidin-1-yl)methyl]-[1,3,4]thiadiazole-2-yl}-1H-indole, cleaners containing hydrochloride salt

To a solution ofN'-(2-chloroacetyl)hydrazide 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (obtained as described in example 37; 50 mg, 0,139 mmol) in tetrahydrofuran (0.5 ml) was added pentasulfide phosphorus (62 mg, 0,139 mmol) and the reaction mixture was subjected to microwave irradiation at 150°C for 5 minutes. The reaction was repeated two times when the amount of 0.7 mmol. The combined reaction mixture was placed in a separating funnel and was diluted with dichloromethane (60 ml). The organic phase is washed with 5% aqueous sodium carbonate (2×30 ml), saturated salt solution (30 ml), dried over sodium sulfate and the solvent was removed in vacuum. The obtained residue was purified column flash chromatography to obtain 3-(5-chloromethyl[1,3,4]thiadiazole-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (186 mg, 0.49 mmol).

To a solution of 3-(5-chloromethyl[1,3,4]thiadiazole-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (93 mg, 0.25 mmol) in tetrahydrofuran was added pyrrolidine (0,101 ml, 1,235 mmol) and the mixture was subjected to microwave irradiation at 150°C for 5 minutes. The resulting reaction mixture was purified flash column-chromatography with obtaining specified in the title compound (42 mg, 0.1 mmol) in view of the free base. The free base was dissolved in dichloromethane and was added hydrogen chloride (1M solution in diethyl ether; 1 ml, 1 mmol). The excess reagent and solvent was removed in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt of 1:1.

1H NMR (400 MHz, CDCl3): 0,94-1,1 (2H, m), 1,13-of 1.23 (3H, m), 1,5-1,75 (8H, m), 1,8-1,9 (5H, m), 2,66-by 2.73 (4H, m), of 3.95 (3H, s), of 4.12 (2H, s)to 4.23 (2H, d, J=7), was 6.73 (1H, d, J=7,8), 7,17 (1H, t, J=8), 7,66 (1H, s), to 7.77 (1H, d, J=8); EsIMS: m/z 411,1 [M+H]+, 340,0, 324,4, 286,1, 270,5.

Example 39

7-Chloro-3-{5-[(2,2-dimethylpiperidin-1-yl)methyl]-[1,2,4]oxadiazol-3-yl-1-(tetrahydropyran-4-yl)methyl-1H-indole, cleaners containing hydrochloride salt

The method of synthesis of 2,2-dimethylpyrimidine:

To a stirred and cooled solution (0°C) NiCl2·6H2Oh in methanol (200 ml) portions was added sodium borohydride (3,36 g, 89 mmol). The reaction mixture was stirred for 30 min and then was added methyl-4-methyl-4-nitropentane in the form of a solution in methanol (100 ml). The reaction temperature was maintained at 0°C before adding portions sodium borohydride (7,86 g, 208 mmol). The reaction mixture was allowed to stand for 72 hours before being filtered through a layer of celite. The precipitate was washed with methanol (150 ml) and the filtrate evaporated to dryness. The obtained solid was washed with dichloromethane (400 ml) and filtered through a layer of celite. After washing the precipitate dig what gmetadom (200 ml) the filtrate is evaporated to obtain the product 2,2-dimethylpyrimidine in the form of light green resin (6.8 g).

The method of synthesis of 2,2-dimethylpropyleneurea:

Sociallyengaged (1M solution in tetrahydrofuran; 120 ml, 120 mmol) was slowly added to a stirred solution of 2,2-dimethylpyrimidine (6 g, 53 mmol) in tetrahydrofuran (150 ml). At the end of the addition the reaction was heated to the boiling temperature under reflux and stirred while boiling under reflux in an argon atmosphere for 16 hours. The reaction mixture was allowed to cool to 0°C and then added water (2.2 ml), 10% sodium hydroxide solution (2.2 ml) and water (6.6 ml) with 45 minute intervals. The obtained pasty mixture was diluted with diethyl ether (150 ml) and filtered through a layer of celite. The precipitate was washed with diethyl ether (250 ml) and the filtrate was acidified with hydrochloric acid (1M solution in diethyl ether; 63 ml). The obtained yellow solid substance was filtered to obtain hydrochloride of 2,2-dimethylpyrimidine (4.8 g).

The method of synthesis of ethyl ether (2,2-dimethylpiperidin-1-yl)acetic acid:

Ethylchloride (0.15 ml, 1.37 mmol), potassium carbonate (416 mg, 1.5 mmol) and 2,2-dimethylpyrimidin (0,280 mg of 2.06 mmol) suspended in ethanol (3 ml) and subjected to microwave irradiation at 120°C for 45 minutes the resulting mixture was suspended in diethyl ether (30 ml), was extracted with 2M hydrochloric acid (30 ml) and otbi is Ali the organic layer. The aqueous layer was treated with a slight excess of 4 n sodium hydroxide solution and was extracted with diethyl ether (3×30 ml). The organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to obtain ethyl ester (2,2-dimethylpiperidin-1-yl)acetic acid (156 mg).

Specified in the title compound was obtained following the method of example 1, using 7-chloroindole instead of 7-methoxyindole; tetrahydropyran-4-Eletropaulo ester toluene-4-sulfonic acid (obtained as described in example 14) instead of cyclohexylethylamine and ethyl ether (2,2-dimethylpiperidin-1-yl)acetic acid instead of methyl esterN,N-dimethylglycine.

1H NMR (400 MHz, CD3OD) δ of 1.45 (10H, m), 2,22 (5H, m)to 3.35 (2H, m)and 3.59 (1H, users), 3,91 (2H, d, J=11,1), of 4.12 (1H, users), to 4.52 (2H, d, J=7,1), 4,71 (1H, users), of 4.95 (1H, users), of 7.23 (1H, t, J=7,6), 7,32 (1H, d, J=7,6), 8,08 (1H, C), 8,13 (1H, d, J=7,6). EsIMS: m/z of 429.5 [M+H]+.

Example 40

1-(Cyclohexyl)methyl-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]thiadiazole-3-yl}-1H-indol-7-carbonitrile, cleaners containing hydrochloride salt

A suspension of [3-(7-bromo-1-cyclohexylmethyl-1H-indol-3-yl)-[1,2,4]thiadiazole-5-yl]methanol (from 7-bromoindole as described in example 7; 2×250 mg, 0.16 mmol), cyanide zinc (II) (2×72 mg, 0.61 mmol) and tetrakis(triphenylphosphine)palladium (0) (2×21 mg, and 18.3 mol) in DMF (2×4 ml) was subjected to mikrovolnovaya irradiation at 200°C for 5 min using Emrys™ Optimizer EXP. The reaction mixtures were combined and poured into a separating funnel, was added dichloromethane (≈50 ml). The organic phase is then washed with water (2×20 ml), 1M aqueous solution of HCl (20 ml) and saturated salt solution (20 ml), dried over magnesium sulfate, filtered and the solvent was removed in vacuum. The resulting oil was purified column flash chromatography, elwira 50-100% (vol./about.) dichloromethane in heptane and then diethyl ether to obtain 1-cyclohexylmethyl-3-(5-hydroxymethyl[1,2,4]thiadiazole-3-yl)-1H-indol-7-carbonitrile (416 mg, 1.18 mmol) as a pale yellow oil, which crystallized upon standing.

To a solution of 1-cyclohexylmethyl-3-(5-hydroxymethyl[1,2,4]thiadiazole-3-yl)-1H-indol-7-carbonitrile (416 mg, 1.18 mmol) in dichloromethane (40 ml) was sequentially added methanesulfonamide (0,110 ml of 1.42 mmol) and triethylamine (0,214 ml, 1.53 mmol). The reaction mixture was stirred for 1 hour and was poured into a separating funnel. The organic phase is washed with 2M aqueous solution of sodium carbonate (20 ml), saturated salt solution (20 ml), dried over magnesium sulfate, filtered, the solvent was removed in vacuo to obtain 3-(7-cyano-1-cyclohexylmethyl-1Hindol-3-yl)-[1,2,4]thiadiazole-5-Eletropaulo ether methanesulfonate acid (503 mg, 1,17 mmol)which was used without further purification.

To a solution of 3-(7-cyan is-1-cyclohexylmethyl-1 H-indol-3-yl)-[1,2,4]thiadiazole-5-Eletropaulo ether methanesulfonate acid (120 mg, 0.28 mmol) in dichloromethane (3 ml) was added pyrrolidine (of 0.12 ml, 1.4 mmol) and the reaction mixture was subjected to microwave irradiation at 100°C for 5 minutes. The reaction mixture was directly purified column flash chromatography, elwira dichloromethane, then 25-50% (vol./about.) the ethyl acetate in heptane, to obtain specified in the title compound (71 mg, 0,175 mmol) in the form of free base. The free base (35 mg, 0,086 mmol) was dissolved in dichloromethane (2 ml) was added hydrogen chloride (1M solution in diethyl ether). The mixture was concentrated in vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt of 1:1.

1H NMR (400 MHz, CD3OD): 1,06-1,36 (7H, m), 1,62 and 1.80 (5H, m), 1.91 a-2,07 (1H, m), 2,09-of 2.34 (2H, user. m), 3,35-4,20 (4H, osirm), 4,42 (2H, d, J=7), 5,07 (2H, s), 7,37 (1H, t, J=8), of 7.69 (1H, DD, J=7, 1), 8,23 (1H, s); 8,84 (1H, DD, J=8,1). EsIMS: m/z to 406.4 [M+H]+.

Example 41

Definition ofin vitrostrength and efficiency of the human CB1 receptor expressed in CHO cells

The cells of the Chinese hamster ovary (CHO)expressing the human CB1 receptor and reporter gene luciferase, suspended in a mixture of phenol red/DMEM without serum/nutrient mixture F-12 containing penicillin/streptomycin (50 units/50 μg/ml) and Fungizone (1 μg/ml), and the seeding is whether in 96-well plates in a concentration of 3×10 4cells per well (final volume 100 µl). Before the test cells were incubated overnight (approximately 18 hours at 37°C, 5% CO2/95% air). The test compound (10 mm solution in dimethylsulfoxide) was dissolved nutrient mixture F12 with obtaining uterine fluids in the range from 0.11 mm to 0.11 nm. Royal solutions (10 ál) was directly added into the appropriate wells. To obtain agonists induced the expression of luciferase, the plates were incubated at 37°C for 5 hours. Poor lighting in each well was added LucLite substrate (Packard; reproduced according to the manufacturer's instructions; 100 μl). The tablets covered with the top cover and then incubated at room temperature for 5 minutes before counting on the device TopCount, Packard (counting single photon counting 0.01 minute, 5-minute delay).

To get the value EC50least-squares on schedule according to the account in the second (CPS) from the concentration of the compound (M) was selected curve of best fit. Table 1 shows the values of pEC50obtained for some representative compounds of the present invention.

Table 1
Example Chemical namechemical structurepEC50
2G(R)-1-(cyclohexyl)methyl-7-methoxy-3-[5-(1-methylpyrrolidine-2-yl)-[1,2,4]oxadiazol-3-yl]-1H-indole, cleaners containing hydrochloride salt7,5
13(R)-3-cyclohexyl-6-{5-[(diethylamino)methyl]-[1,2,4]thiadiazole-3-yl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazin, cleaners containing hydrochloride salt8,1
14B7-fluoro-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]thiadiazole-3-yl}-1-(tetrahydropyran-4-yl)methyl-1H-indole, cleaners containing hydrochloride salt7,3
15A7-chloro-3-(5-{[N-ethyl-N(2-methoxyethyl)amino]methyl}-[1,2,4]thiadiazole-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole, cleaners containing hydrochloride salt8,0
15B7-chloro-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]t is diazol-3-yl}-1-(tetrahydropyran-4-yl)methyl-1 H-indole, cleaners containing hydrochloride salt7,7
15C7-chloro-3-(5-{[N-ethyl-N(2-hydroxyethyl)amino]methyl}-[1,2,4]thiadiazole-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indol8,0
207-chloro-1-(cyclohexyl)methyl-3-(4-{[N-isopropyl-N(2-methoxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-1H-indole, cleaners containing hydrochloride salt8,3
23B7-chloro-3-{4-{{N-(2-hydroxyethyl)-Nisopropylamino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indol8,0
23C7-chloro-3-(4-{[N-ethyl-N(2-hydroxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyranyl-4-yl)methyl-1H-indol7,9
23D7-chloro-3-(4-{[N-(2-methoxyethyl)-Nmethylamino]methyl}-[1,3]thia the ol-2-yl)-1-(tetrahydropyran-4-yl)methyl-1 H-indole, cleaners containing hydrochloride salt8,2
321-(cyclohexyl)methyl-3-{2-[(diethylamino)methyl]-[1,3]oxazol-5-yl}-7-methoxy-1H-indole, cleaners containing hydrochloride salt7,3
331-(cyclohexyl)methyl-3-(5-ethyl-5,6-dihydro-4H-pyrrolo[3,4-d]isothiazol-3-yl)-7-methoxy-1H-indole, cleaners containing hydrochloride salt7,1
381-(cyclohexyl)methyl-7-methoxy-3-{5-[(pyrrolidin-1-yl)methyl]-[1,3,4]thiadiazole-2-yl}-1H-indole, cleaners containing hydrochloride salt7,1
397-chloro-3-{5-[(2,2-dimethylpiperidin-1-yl)methyl]-[1,2,4]oxadiazol-3-yl-1-(tetrahydropyran-4-yl)methyl-1H-indole, cleaners containing hydrochloride salt7,5

Example 42

The latent period otdergivanija tail in mice

Mice were trained to sit quietly in the device to test the project for otdergivanija tail (Ugo Basile, Italy) during the time of measurement of the latent period otdergivanija tail. The tail was subjected to thermal irradiation by the focused beam at a point approximately 2.5 cm from the end of the tail. The latent period otdergivanija tail was defined as the time interval between application of thermal stimulus and otdergivanija tail. To prevent damage to fabrics used 12-second intervals. Four groups of eight mice each were treated with media or one of three doses of the test compound, administered intravenously (carrier: 10% Tween-80 in saline solution; volume of 10 ml/kg). The latent period otdergivanija of the tail was measured before administration of test compounds, as well as at regular intervals (usually after 20, 40 and 60 minutes after administration of the compound. ED50calculated at Tmax.

Connection examples 2G, 13, 14B, 15A, 15B, 15C, 20, 23B, 23C, 23D and 39 significantly increased the latent period otdergivanija tail with ED50<5 µmol/kg

1. Derived (indol-3-yl)heterocyclic compounds of General formula I

where a represents a 5-membered aromatic heterocyclic ring, where X1, X2and X3independently selected from N, O, S, and CR;
R represents H or (C1-4)alkyl; or
R, when present in the X2or X 3with R3to form a 5-8-membered ring;
R1is a 5-8-membered saturated carbocyclic ring, optionally containing a heteroatom About;
R2represents N; or
R2connected with R7with the formation of 6-membered ring, optionally containing a heteroatom, and where the heteroatom is connected to the position 7 of the indole ring;
R3and R4independently represent H or (C1-6)alkyl, optionally substituted HE or (C1-4)alkyloxy; or
R3together with R4and the N to which they are bound, form a 4-8-membered ring, optionally containing an additional heteroatom selected from O and S, and optionally substituted by IT, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or
R3together with R5form a 4-8-membered ring, optionally substituted, (C1-4)alkyl, (C1-4)alkyloxy; or
R3together with R, when present in the X2or X3, form a 5-8-membered ring;
R5represents N; or
R5together with R3form a 4-8-membered ring, optionally substituted, (C1-4)alkyl or (C1-4)alkyloxy;
R5' represents H;
R6represents one Deputy, selected from H, (C1-4)alkyl, (C 1-4)alkyloxy or halogen;
R7represents H, (C1-4)alkyl, (C1-4)alkyloxy or halogen; or
R7connected with R2with the formation of 6-membered ring, optionally containing an additional heteroatom, and where the heteroatom is connected to the position 7 of the indole ring; or its pharmaceutically acceptable salt.

2. Derived (indol-3-yl)heterocyclic compounds according to claim 1, where R2represents H or is connected with R7with the formation of 6-membered ring, optionally containing a heteroatom O, associated with position 7 of the indole ring.

3. Derived (indol-3-yl)heterocyclic compounds according to claim 1 or 2, where R, R5, R5' and R6represent N.

4. Derived (indol-3-yl)heterocyclic compounds according to claim 1, where R1represents a cyclohexyl or tetrahydropyranyl.

5. Derived (indol-3-yl)heterocyclic compounds according to claim 4, where the heterocycle And represents a 1,2,4-oxadiazol (X1represents N, X2represents O, X3is a (N), 1,2,4-thiadiazole (X1represents N, X2represents S, X3represents N or thiazole (X1represents S, X2represents CR, X3is a (N).

6. Derived (indol-3-yl)heterocyclic what about the connection according to claim 1, chosen from:
7-chloro-3-(5-{[N-ethyl-N-(2-methoxyethyl)amino]methyl}-[1,2,4]thiadiazole-3-yl)-1-(tetrahydropyran-4-yl)methyl-1-H-indole;
7-chloro-3-{5-[(pyrrolidin-1-yl)methyl]-[1,2,4]thiadiazole-3-yl}-1-(tetrahydropyran-4-yl)methyl-1H-indole;
7-chloro-3-(5-{[N-ethyl-N-(2-hydroxyethyl)amino]methyl}-[1,2,4]thiadiazole-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;
7-chloro-3-(4-{[N-(2-hydroxyethyl)-N-isopropylamino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;
7-chloro-3-(4-{[N-ethyl-N-(2-hydroxyethyl)amino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;
7-chloro-3-(4-{[N-(2-methoxyethyl)-N-methylamino]methyl}-[1,3]thiazol-2-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;
7-chloro-3-{5-[(2,2-dimethylpiperidin-1-yl)methyl]-[1,2,4]oxadiazol-3-yl}-1-(tetrahydropyran-4-yl)methyl-1H-indole;
or their pharmaceutically acceptable salts.

7. Derived (indol-3-yl)heterocyclic compounds according to claim 1, active agonist for the cannabinoid receptor SW.

8. The pharmaceutical composition active agonist for the cannabinoid receptor SW containing derivative (indol-3-yl)heterocyclic compounds according to any one of claims 1 to 6 in a mixture with pharmaceutically acceptable additives.

9. The use of derivative (indol-3-yl)heterocyclic compounds of the formula I defined in claim 1, in the manufacture of a medicine for the treatment of pain.

10. Method l the treatment of pain, such as chronic pain, neuropathic pain and pain in cancer, including introduction to the needy in this patient a therapeutically effective amount of a derivative (indol-3-yl)heterocyclic compounds according to any one of claims 1 to 6.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel biologically active compounds - substituted benzoxazin isoindoles of formula 1: 8,9-dimethoxy-5,5-diphenyl-6a, 11-dihydro-5H-benzo[4,5][1,3]oxazin[2,3-a]isoindol-11-on of formula 1.1; 8,9-dimethoxy-5,5-diethyl-6a, 11-dihydro-5H-benzo[4,5][1,3]oxazin[2,3-a]isoindol-11-on of formula 1.2, protecting sunflower shoots against adverse impact of herbicide of 2,4-dichlorophenoxyacetic acid and method of obtaining them. Method of obtaining 8,9-dimethoxy-5,5-diphenyl-6a, 11-dihydro-5H-benzo[4,5][1,3]oxazin[2,3-a]isoindol-11-on of formula 1.1; 8,9-dimethoxy-5,5-diethyl 6a, 11-dihydro-5H-benzo[4,5][1,3]oxazin[2,3-a]isoindol-11-on of formula 1.2 includes interaction of o-aminophenyldiethyl-(diphenyl)carbinoles wth substituted 2-formyl-4,5-dimethoxybenzoic acids with ratio 1:1. Difference of claimed method from method-analogue lies in single-stage process.

EFFECT: creation of efficient method of substituted benzoxazin isoindoles.

2 cl, 3 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA) or (IB) given in the invention description wherein R1 means hydrogen atom, (C1-C7)-alkyl, -(CH2)n-OH, -(CH2)n-N(R6)2; R2 means (C1-C7)-alkyl, -(CH2)n-N(R6)2, -NR6C(O)C(O)O-(C1-C7)-alkyl, -NR6-(CH2)n-OH, -NR6C(O)-(C1-C7)-alkyl, -NH-benzyl; R3 means hydrogen atom or amine; or R2 and R3 in common with carbon atoms to which they are bound mean the group -N(R6)-CH2-O-CH2-; R4 means hydrogen atom or (C1-C7)-alkyl; R5 means hydrogen atom; R6 means independently of one another hydrogen atom or (C1-C7)-alkyl; R' means hydrogen atom or (C1-C7)-alkyl; n = 0, 1, 2 or 3. Also, invention relates to a medicinal agent possessing the selective blocking activity with respect of subspecies of NMDA-receptors and containing one or more compounds of the formula (IA) or (IB) or their pharmaceutically acceptable acid-additive salt or inert carrier. Invention provides preparing novel compounds possessing the high affinity to NMDA-receptors that can be used as components of a medicinal agent for treatment of diseases mediated by these receptors.

EFFECT: valuable medicinal properties of compounds and drug.

13 cl, 35 ex

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-heteroaryl derivatives of benzothiazole and benzoxazole of formula by boiling amine with general formula with acid chloride of general formula , where R=2-furyl or 2-thienyl, X = S or O, in 1-methyl-2-pyrrolidone.

EFFECT: method increases output of product to 78 to 90% and environmental friendliness of the process.

1 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 tbl

FIELD: chemistry; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I or their pharmaceutically acceptable salts R4 is hydrogen; X is selected from group, consisting of single bond, NH- and groups: , values of R1-R3 radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: medicine.

SUBSTANCE: invention refers to the compound of the formula (I) , where R1 is a group of the formula and, in which R2, R3, R4, R5, R6, R7 and R8, each one independently represents a hydrogen atom or C1-6alkyl or its salt, to the method of its producing, to the method of antagonist effect on angiotensin II in the mammal, to the application of compounds of formula (I) as well as to methods of diseases prevention or treatment.

EFFECT: there are produced and provided new compounds that can be applied for prevention or treatment of disturbed circulation.

16 cl, 2 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to salt N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide, particularly bismaleate N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide with antitumor activity.

EFFECT: cancer treatment availability.

11 cl, 35 dwg, 9 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

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