5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline derivatives as potassium channel modulators

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula I: wherein a dash line represents an optional double bond; R1 means phenyl, naphthyl, pyridyl optionally substituted by one or two substitutes optionally substituted from halogen, C1-C6 alkyl, mono-halo C1-C6 alkyl, di-halo C1-C6 alkyl, CF3; R2 means H, methyl, halogen; R3 and R4 optionally mean, CF3, halo, C1-C3 alkyl wherein C1-C3 alkyl groups are optionally substituted by one or more halogen atoms; X=O; q=0; R5 means C1-C6 alkyl or its pharmaceutically acceptable salt.

EFFECT: compounds possess potassium channel modulating activity that enables using them in pharmaceutical compositions.

28 cl, 1 tbl, 2 dwg

 

The technical field to which the invention relates.

The invention relates to new compounds that modulate potassium channels. These compounds are suitable for treatment and prevention of the diseases and disorders that are influenced by the activity of potassium ion channels. One such disorders are convulsive disorders.

The level of technology

Epilepsy is a well-known neurological disease found in about 3% of the population. Approximately 30% of patients with epilepsy do not respond to the treatments currently available. It was found that retigabine (ethyl ester of N-[2-amino-4-(4-foraminiferida)phenyl]carbamino acid] (Patent of the United States No. 5,384,330) underlies effective treatment of a wide range of models of epileptic disorders and apparently has an unusual mechanism of action. Bialer, M. et al., Epilepsy Research 1999, 34, 1-41; Wuttke, T.V., et al., Mol. Pharmacol. 2005, 67, 1009-1017. It was also found that retigabine is suitable for the treatment of pain, including neuropathic pain. Blackburn-Munro and Jensen, Eur. J. Pharmacol. 2003, 460, 109-116; Wickenden, A.D. et al., Expert Opin. Ther. Patents, 2004, 14(4).

"Benign family neonatal convulsions, inherited form of epilepsy associated with a mutation in the channels KCNQ2/3. Biervert, .et al., Science 1998, 27, 403-06; Singh, N.A., et al., Nat. Genet. 1998, 18, 25-29; Charlier, C. et al., Nat. Genet.1998, 18, 53-55; Rogawski, Trends in Neurosciences 2000, 23, 393-398. Subsequent research has established that one of the important places retigabine is the channel KCNQ2/3. Wickenden, A.D. et al., Mol. Pharmacol. 2000, 58, 591-600; Main, M.J. et al., Mol. Pharmacol. 2000, 58, 253-62. It was shown that retigabine increases the conductivity of the channels at the membrane resting potential by using a possible mechanism, which applies binding to the activation gate channel KCNQ 2/3. Wuttke, T.V., et al., Mol. Pharmacol. 2005, op.cit. With the deepening of research in this area has been shown that retigabine increases neuronal M-currents and increases the probability of opening channels of KCNQ 2/3. Delmas, P. and Brown, D.A. Nat. Revs Neurosci., vol. 6, 2005, 850-62; Tatulian, L. and Brown, D.A., J. Physiol., (2003) 549, 57-63.

The most resistant to treatment type cramps are so-called "complex partial seizures". It was found that retigabine is particularly effective in models of drug resistant epilepsy. Retigabine also active in some other models of seizures. Because of the wide spectrum of activity retigabine and unusual molecular mechanism, it is hoped that retigabine will be effective in the treatment of several types of seizures, including complex partial seizures, and in the treatment of hitherto incurable forms of epilepsy. Porter, Roger J., Nohria, Virinder, and Rundfeldt, Chris, of neurotherapeutics, 2007, vol.4, 149-154.

Recognition retigabine as m is of dulator potassium channels contributes to the search for other - and, hopefully, the best - modulators of potassium channels from among compounds with structural features similar to the features retigabine.

Disclosure of inventions

In one embodiment, this invention provides a compound of formula I

where the dotted line represents an optional double bond; where R1represents phenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl, imidazolyl, Persil, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl or isothiazole, optionally substituted by one or two substituents, independently selected from halogen, C1-C6of alkyl, mono-halo, C1-C6of alkyl, di-halo, C1-C6of alkyl, CF3CN, S-C1-C6the alkyl or O-C1-C6of alkyl; R2represents H, methyl, or halogen; R3and R4represent, independently, CF3, OCF3OC1-C3alkyl, halo, or C1-C3alkyl, where C1-C3alkyl groups are optionally substituted by one or more halogen atoms; X=O or S; Y is O or S; q=1 or 0; R5represents a C1-C6alkyl, where C1-C6the alkyl group optionally is substituted with one or two groups independently selected from HE, OMe, OEt, F CF 3, Cl or CN; (CHR6)wC3-C6cycloalkyl, (CHR6)wCH2C3-C6cycloalkyl, CH2(CHR6)wC3-C6cycloalkyl, CR6=CH-C3-C6cycloalkyl, CH=CR6-C3-C6cycloalkyl, (CHR6)wC5-C6cycloalkenyl, CH2(CHR6)wC5-C6cycloalkenyl,2-C6alkenyl,2-C6quinil, Ar1, (CHR6)wAr1CH2(CHR6)wAr1or (CHR6)wCH2Ar1where w=0-3, Ar1represents phenyl, pyridyl, pyrrolyl, thienyl or furyl, and R6represents hydrogen, methyl, halogen or methoxy group; where all cyclic groups optionally are substituted by one or two substituents, independently selected from C1-C3of alkyl, halogen, HE, OMe, SMe, CN, CH2F and trifloromethyl; or its pharmaceutically acceptable salt. Such compounds are modulators of potassium channels.

In another embodiment, the invention provides a composition comprising a pharmaceutically acceptable carrier and one or more of the following: a pharmaceutically effective amount of the compounds of formula I; a pharmaceutically effective amount of its pharmaceutically acceptable salts, pharmaceutically eff is active, the number of its pharmaceutically acceptable ether complex.

In the following embodiment, the invention provides a method of prophylaxis or treatment of a disease or disorder that affects the modulation of voltage-dependent potassium channels, comprising the administration to a patient in need, a therapeutically effective amount of the compounds of formula I or its salt, or a complex ester.

In another embodiment, this invention provides or is considering a composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of the compounds of formula I; (ii) its pharmaceutically acceptable salt; (iii) pharmaceutically acceptable ester; iv) its pharmaceutically acceptable MES.

In another embodiment, this invention provides or is considering a method of treatment or prevention of a disease or disorder that is affected by the strengthening of neuronal M-currents, comprising the administration to a patient in need this, one or more of the following: i) a pharmaceutically effective amount of the compounds of formula I; (ii) its pharmaceutically acceptable salts; (iii) pharmaceutically acceptable ether complex and iv) its pharmaceutically acceptable MES.

In the following embodiment, this invention predostavlyaetsya prevention or treatment of a disease or disorder, which is influenced by the activation of voltage-dependent potassium channels, comprising the administration to a patient in need this, one or more of the following: i) a pharmaceutically effective amount of the compounds of formula I; (ii) its pharmaceutically acceptable salts; (iii) pharmaceutically acceptable ether complex and iv) its pharmaceutically acceptable MES.

In another embodiment, this invention provides or is considering a method of treatment or prevention of epileptic disorders in humans comprising the administration to a patient, the affected or potentially affected by such a disorder, one or more of the following: i) a pharmaceutically effective amount of the compounds of formula I; (ii) its pharmaceutically acceptable salts; (iii) pharmaceutically acceptable ether complex; (iv) its pharmaceutically acceptable MES.

In another embodiment, this invention provides or is considering a pharmaceutical preparation for oral administration containing a therapeutically effective amount of the compounds of formula I and/or a suitable substance for tabletting or a suitable syrup for use in Pediatrics.

In another embodiment, this invention provides or is considering a tablet for oral administration containing terapevticheskii effective amount of the compounds of formula I and a suitable substance for tableting.

In another appropriate embodiment, this invention provides or is considering syrup for pediatric use, containing a solution or dispersion or suspension of the compounds of formula I and a suitable syrup.

In another embodiment, this invention considers a pharmaceutical preparation for administration to animals, including animal companions (dogs and cats) and cattle containing a therapeutically effective amount of the compounds of formula I and a carrier suitable in veterinary medicine.

In another embodiment, this invention considers a method of prevention or treatment of a disease or disorder that affects the activation of voltage-dependent potassium channels, including the introduction of an animal in need, one or more of the following: i) a pharmaceutically effective amount of the compounds of formula I; (ii) its pharmaceutically acceptable salts; (iii) pharmaceutically acceptable ether complex; (iv) its pharmaceutically acceptable MES.

In another embodiment, the invention regards a method for the treatment of epilepsy (seizure) disorders in an animal, comprising the introduction of an animal affected or potentially affected by such a disorder, one or more of the following: (i) the pharmaceutical is Eski effective amount of the compounds of formula I; ii), its pharmaceutically acceptable salts; (iii) pharmaceutically acceptable ether complex; (iv) its pharmaceutically acceptable MES.

This invention includes all tautomers, salts and stereoisomeric forms of the compounds of the formula I. This invention also includes all the compounds of this invention where one or more atoms replaced by their radioactive isotopes.

This invention provides or is considering the compounds of formula I above, where each NH-C(=X)-(Y)q-R5represents the following: NHC(=O)R5, NHC(=O)OR5, NHC(=S)R5, NHC(=S)SR5, NHC(=S)OR5and NHC(=O)SR5.

Thus, in one embodiment, this invention provides or is considering a compound of formula I, where NH-C(=X)-(Y)q-R5represents NHC(=O)R5.

In another embodiment, this invention provides or is considering a compound of formula I, where NH-C(=X)-(Y)q-R5represents NHC(=S)R5.

In another embodiment, this invention provides or is considering a compound of formula I, where NH-C(=X)-(Y)q-R5represents NHC(=S)SR5.

In another embodiment, this invention provides or is considering a compound of formula I, where NH-C(=X)-(Y)q-R5represents NHC(=O)OR5.

q-R5represents NHC(=S)OR5.

In another embodiment, this invention provides or is considering a compound of formula I, where NH-C(=X)-(Y)q-R5represents NHC(=O)SR5.

In a more specific embodiment, this invention provides or is considering a compound of formula I, where R5represents a C1-C6alkyl, (CHR6)wC3-C6cycloalkyl, (CHR6)wCH2C3-C6cycloalkyl or CH2(CHR6)wC3-C6cycloalkyl.

In another more specific embodiment, this invention provides or is considering a compound of formula I, where R5 is a C5-C6 alkyl, (CH2)wC5-C6cycloalkyl or (CHR6)wCH2C5-C6cycloalkyl.

In another more specific embodiment, this invention provides or is considering a compound of formula I, where R5 is a C5-C6 alkyl, optionally substituted with one or two Oh groups.

In another subrtova embodiment, this invention provides or is considering a compound of the formula IA below.

In another subrtova embodiment, the invention provides and considers the compound of formula IB below.

In another subrtova embodiment, this invention provides or is considering a compound of formula IC below.

In another subrtova embodiment, this invention provides or is considering a compound of formula ID below.

In another subrtova embodiment, this invention provides or is considering a compound of formula IA, IB, IC or ID, where R3and R4independently represent methyl, chlorine or methoxy group.

In another more specific subrtova embodiment, this invention provides or is considering a compound of formula IA, IB, IC or ID, where R3and R4both represent methyl.

In another more specific subrtova embodiment, this invention provides or is considering a compound of formula IA, IB, IC or ID, where R1represents phenyl, substituted with halogen, cyano, CF3or a methoxy group, R2represents H or methyl, and R5represents a C5-C6alkyl or CH2-C3-C6cycloalkyl.

In another more specific subrtova embodiment, this invention provides or is considering a compound of formula IA, IB, IC or ID, where R1represents a substituted phenyl or unsubstituted phenyl.

In another more specific subrtova embodiment, this invention provides or is considering a compound of formula IA, IB, IC or ID, where R1represents phenyl, substituted with halogen.

In even more specific subrtova embodiment, this invention provides or is considering a compound of formula IA, IB, IC or ID, where R1is forfinal or differenl.

In another more specific subrtova embodiment, this invention provides or is considering a compound of formula IA, IB, IC or ID, where R1represents phenyl substituted by trifluoromethyl.

In another more specific subrtova embodiment, this invention provides or is considering a compound of formula IA, IB, IC or ID, where R1is halophenol, and R5represents a C5-C6alkyl or CH2-C5-C6cycloalkyl.

In another more specific subrtova embodiment, this invention provides or is considering a compound of formula IA, IB, IC or ID, where R1is halophenol, and R5represents CH2-C4-alkyl or CH2-C5-alkyl.

In another more concr the coherent subrtova embodiment, this invention provides or is considering a compound of the formula IA, IB, IC or ID, where R1is haloperidol.

In another more specific subrtova embodiment, this invention provides or is considering a compound of formula IA or IC, where R1is dihalogen or developerid; R2represents H; and R3and R4represent Cl, CF3or CH3.

In another more specific embodiment, this invention provides or is considering a compound of formula IB or ID, where R1is dihalogen or developerid; R2represents H; and R3and R4represent Cl, CF3or CH3.

In another more specific embodiment, this invention provides or is considering a compound of formula IB or ID, where R1is halophenol or haloperidol; R2represents H; and R3and R4represent Cl, CF3or CH3.

In another more specific embodiment, this invention provides or is considering a compound of formula IA or IC, where R1represents a 3,5-dichlorophenyl or 3,5-differenl.

In another more specific embodiment, this invention provides or is considering a compound of formula IB or ID, where R1isone 3,5-dichlorophenyl or 3,5-differenl.

In another embodiment, this invention provides or is considering a compound of the formula I, in which R5represents a C1-C6alkyl, where C1-C6alkyl group substituted by one or two groups independently selected from HE, OMe, OEt, F, CF3, Cl or CN.

In another embodiment, this invention provides or is considering a compound of the formula I, in which X represents S, q represents zero, R1is a substituted phenyl, R2represents N, and R5represents a C1-C6alkyl.

In another embodiment, this invention provides or is considering a compound of the formula I, in which X represents S, q represents zero, R1is a substituted phenyl, R2represents N, and R5represents a C1-C6alkyl.

In the following embodiment, this invention provides or is considering a compound of the formula I, in which X represents S, q represents 1, Y represents Oh, R1is a substituted phenyl, R2represents N, and R5represents a C1-C6alkyl.

In another embodiment, this invention provides or Russ is trivet compound of formula I, in which X represents S, q represents 1, Y represents S, R1is a substituted phenyl, R2represents N, and R5represents a C1-C6alkyl.

The implementation of the invention

During the development of compounds with therapeutic properties, superior therapeutic properties retigabine, shown below,

retigabine

and while searching for the optimum desired therapeutic properties of this connection, the present inventors discovered that the compounds of formula I possess unexpected and exceptional activity against potassium channels, which is confirmed by strong activity, measured through analysis of "exit" (Affleck) rubidium (Rb+), described below.

Moreover, the inventors have found that substitution in both 2 - and 6-positions of the Central benzene ring makes some desirable properties, including increased activity and increased stability in vivo. Thus, 2,6-diamesinae is the defining characteristic of some embodiments of the present invention.

Additionally, the inventors have found that, in particular, the alkyl substitution in both 2 - and 6 - positions of the Central benzene ring gives the desired properties, including increased activity and uvelichenie the stability in vivo. Thus, 2,6-dimethyl substitution is the defining characteristic of a variant of implementation of the present invention.

In addition, the inventors also found that the substitution alkoxide groups in both 2 - and 6-positions of the Central benzene ring also gives a number of desirable properties, including increased activity and increased stability in vivo. Thus, such a substitution is the defining characteristic of another variant implementation of the invention.

Moreover, the inventors also discovered that substitution at the 2 - and 6-positions of the Central benzene ring substituents selected from halogen, trifloromethyl and metoxygroup, also gives a number of desirable properties, including increased activity and increased stability in vivo. Thus, such a substitution is the defining characteristic of another variant implementation of the invention.

Among the embodiments of the present invention, the most active compounds demonstrate improvement from 40 to 400 times compared to retigabine, in the presence of the most promising compounds, demonstrating performance EC50one nanomolar range. The activity of several compounds of this invention listed in the following Table 1. Activity retigabine at the Eden for comparison.

When used herein, the term "potassium channel modulator" refers to a compound that can cause an increase in potassium currents in the channels. It also refers to a compound capable of increasing the open probability of KCNQ2/3 channels. For preliminary testing compounds for the ability to modulate potassium channels inventors used the test of "exit" of rubidium ions, described below.

As proposed by this invention, the compounds of formula I are intended for oral or intravenous dosing approximately up to 2000 mg per day. Thus, this invention considers the solutions or suspensions of the compounds of formula I developed for intravenous administration. Similarly, also discusses solutions or suspensions containing the syrup, such as sorbitol or propylene glycol, among many other examples, in addition to the compounds of formula I, suitable for oral pediatric use. Also reviewed and chewing and Nerevarine tablets containing the compounds of formula I together with pharmaceutically acceptable substances for tableting and other pharmaceutically acceptable carriers and excipients.

When used herein, the term "pharmaceutically acceptable carrier" includes such excipients, binders, lubricant is s, substances for tabletting and dezintegriruetsja substances that are commonly used in the concluding part of medicines. Examples of such agents include, but are not limited to, microcrystalline cellulose, lactose, starch and dicalcium phosphate and provide. However, due to the incompatibility of primary amines with lactose, the invention does not consider the composition in which the active ingredients with groups of primary amines combined with lactose. In addition, it also discusses dezintegriruetsja substances such as sodium salt glycolate, starch, lubricants such as stearic acid and SiO2and substances that enhance solubility, such as cyclodextrins, among many other examples for each group. Such substances and methods of their use are well known in the pharmaceutical field. Additional examples are provided in the work Kibbe, Hubook of Pharmaceutical Excipients, London, Pharmaceutical Press, 2000.

The invention also considers pharmaceutical preparations for administration to animals, containing a therapeutically effective amount of the compounds of formula I and a carrier acceptable for veterinary use. Any animal that is susceptible to epilepsy (seizure) disorders included in the scope of this invention.

Methods synthesis

Section I. formation of compounds of formula XIV p is estaline in figure 1.

Scheme 1

where:

Quinoline - quinoline

Reflux is the backward flow

Raney Ni-Ni Raney

Section II. Obtaining compounds of formula IX are presented in Scheme 2.

Scheme 2

where:

Raney Ni-Ni Raney

Section III. Obtaining compounds of formula XIX is shown in figure 3.

Scheme 3

Section IV. Obtaining compounds of formula XX are presented in figure 4.

Scheme 4

where:

Base - base

Section V. Obtaining the compounds of formula XXI is presented in Scheme 5.

Scheme 5

where:

Lawesonn''s reagent is the reagent of Lawesson

Section VI. Obtaining compounds of formula XXII presented in figure 6.

Scheme 6

where:

Lawesonn''s reagent is the reagent of Lawesson

Section VII. Obtaining compounds of formula XXIII are presented in figure 7.

Scheme 7

where:

Lawesonn''s reagent is the reagent of Lawesson

Section VIII. Obtaining compounds of formula XXIV presented in figure 8.

Scheme 8

where:

Lawesonn''s reagent is the reagent of Lawesson

Section IX. Obtaining compounds of formula XXVI is presented in Scheme 9.

Scheme 9

Section X. Obtaining compounds of formula XXVII, not only the but in Scheme 10.

Scheme 10

4,6-dimethyl-1H-indole-2-carboxylato acid ethyl ester (2)

Monohydrate p-toluensulfonate acid (132 g, 0.69 mol) in 500 ml of benzene was boiled under reflux for 2 hours in a flask equipped with a nozzle Dean-stark. Then added a solution of 3,5-dimethylphenethylamine hydrochloride (34,5 g; 0.2 mol), atilirovanie (23,2 g; 0.2 mol) and monohydrate p-toluensulfonate acid (0.85 grams; of 0.005 mol) in 500 ml of benzene, which was boiled under reflux for 2 hours, whereby the water is removed through the office of Dean-stark. The resulting mixture was boiled under reflux and stirred overnight. After cooling, the solution was treated with saturated sodium bicarbonate solution and diluted with methylene chloride. The organic fraction is washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified via ISCO (hexane/EtOAc, 0-30%, 40 min) with the formation of a hard yellow substance, which was recrystallized from hexane/ethyl acetate (10%) with the formation of colorless crystals (35,6 g; 82%).1H NMR (DMSO-d6, 400 MHz): δ 11,68 (brs, 1H, interchangeable D2O, NH), 7,12 (s, 1H), 7,05 (s, 1H), of 6.71 (s, 1H), 4,33 (q, J=6.8 Hz, 2H), 2,44 (s, 3H), of 2.35 (s, 3H), of 1.34 (t, J=6.8 Hz, 3H).

4,6-dimethyl-1H-indole-2-carboxylic acid (3)

The mixture is delovogo ether 4,6-dimethyl-1H-indole-2-carboxylic acid (22 g; 0.1 mol) and lithium hydroxide (4.8 g; 0.2 mol) in 400 ml of ethanol was boiled under reflux overnight. The solvent was removed under reduced pressure, and the residue was dissolved in water and neutralized using 10% HCl until pH<3. The obtained precipitation was filtered, washed with water and dried under vacuum at 40°C with the formation of solid white (18 g; 95%).1H NMR (DMSO-d6, 400 MHz): δ of 12.73 (brs, 1H, interchangeable D2O, NH), 11,55 (brs, 1H, interchangeable D2O, NH), 7.06 (s, 1H), 7.03 (s, 1H), 6.69 (s, 1H), 2.44 (s, 3H), 2.35 (s, 3H).

4,6-dimethyl-1H-indole (4)

Method a: a Mixture of 4,6-dimethyl-1H-indole-2-carboxylic acid (3,61 g; KZT 19.09 mmol, 1 equiv.), of copper powder (850 mg; made 13.36 mmol; 0.7 equiv.) and freshly distilled quinoline (50 ml) was heated under reflux for 2 hours. The mixture was cooled and filtered through celite. The filtrate was poured onto ice, the pH of the solution was brought to pH 4 with concentrated HCl and was extracted with ethyl acetate (3×100 ml). The combined extracts were washed with 2 N HCl (3×100 ml), saturated NaHCO3and brine. The organic solution was dried over MgSO4and concentrated. The residue was subjected to flash chromatography on silica gel using hexane-AcO-Et (85-15) with formation of a solid white color (2.6 g; 94%).1H NMR (DMSO-d6, 400 MHz): δ 10.8 (brs, 1H, interchangeable D2O, NH), 7.19 (t, J=2 Hz, 1H), 6.99 (s, 1H), 6.62 (s, 1H), 6.36 (t, J=2 Hz, 1H), 2.41 (s, 3H),2.34 (s, 3H).

Method 2: This indol also obtained by heating 26 g (0.14 mol) of 4,6-dimethyl-1H-indole-2-carboxylic acid up to 230°C within 3 hours. After cooling, the reactant was distilled under reduced pressure (a 2.9-4.4 mm Hg) at 130-135°C with the formation of the pure product as a colourless oil (15.6 g; 77%).

4,6-Dimethylindoline (5) and 1-Acetyl-4,6-dimethylindoline (6) receive the following method.

4,6-Dimethylindole (1.08 g) was dissolved in acetic acid (20 ml) and portions added cyanopolyyne sodium (2.3 g) at 15°C. the Mixture was stirred at the same temperature for 1 hour and poured into ice-cold water. To neutralize the mixture was added saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent is evaporated at reduced pressure. The residue was dissolved in benzene and added acetic anhydride (840 mg), then stirred at room temperature for one hour. The reaction mixture was washed with saturated aqueous sodium bicarbonate and saturated brine and dried over sodium sulfate. The solvent is boiled away under reduced pressure. The residue was subjected to chromatography (ISCO, hexane/EtOAc, 0-40%, 40 min) with the formation of 1.3 g of 1-acetyl-4,6-dimethylindoline.1H-NMR (CDCl3) δ: 2.18 (6N, s), 2.30 (3H, s), 3.00 (2H, t, J=8.3 Hz), 4.03 (2H, t, J=8.3 Hz), 6.66 (1H, s), 7.89 (1H, s).

1-Acetyl-4,6-dimethyl-5-nitroindoline (7) was obtained in the following way.

1-Acetyl-4,6-dimethylindoline (2.6 g) was dissolved in acetic anhydride (35 ml) and dropwise added nitric acid (d=1.5, the 0,92 ml), dissolved in acetic anhydride (15 ml) at 0°C. the Mixture was stirred at room temperature for 1 hour and poured into ice-cold water. For neutralization to the mixture was added saturated aqueous sodium bicarbonate, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over sodium sulfate. The solvent is boiled away under reduced pressure. The precipitate was chromatographically (ISCO, hexane/EtOAc, 0-40%, 40 min) with the formation of 2.4 g of a solid substance of white color.1H NMR (DMSO-d6, 400 MHz): δ 6.95 (s, 1H), 4.19 (t, J=8.0 Hz, 2H), 3.04 (t, J=8.0 Hz, 2H), 2.26 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H).

4,6-Dimethyl-5-nitroindoline (8) was prepared by the following method.

1-Acetyl-4,6-dimethyl-5-nitroindoline (2.4 g) was dissolved in methanol (25 ml). Added 6N hydrochloric acid (20 ml), and then boiled under reflux for 15 hours. After completion of the reaction the solvent evaporated at reduced pressure. The residue was dissolved in chloroform, the mixture was washed with saturated aqueous sodium bicarbonate and saturated brine and dried over sodium sulfate. The solvent is boiled away under reduced pressure. The precipitate was chromatographically (ISCO, hexane/EtOAc, 0-40%, 40 min) on the education of 1.8 g of 4,6-dimethyl-5-nitroindoline in a solid yellow color. 1H NMR (DMSO-d6, 400 MHz): δ 6.36 (brs, 1H, interchangeable D2O, NH), 6.20 (s, 1H), 3.54 (t, J=8.0 Hz, 2H), 2.91 (t, J=8.0 Hz, 2H), 2.17 (s, 3H), 2.10 (s, 3H).

4,6-Dimethyl-5-nitro-1-(4-trifluoromethyl-benzyl)-indolin (9): R=CF3

4,6-Dimethyl-5-nitroindoline (0.33 g; 1.7 mmol) was dissolved in dimethylformamide (10 ml) and added sodium hydride (CA. 60% in oil suspension, 136 mg) at 0°C. the Mixture was stirred at 0°C for 0.5 hour, the reaction mixture was added 4-triftormetilfosfinov (0,48 g; 2 mmol), then stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent is evaporated at reduced pressure. The precipitate was chromatographically (ISCO, hexane/EtOAc, 0-40%, 40 min) with the formation of solids in yellow (0.55 g; 92%).1H NMR (DMSO-d6, 400 MHz): δ 7.73 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 6.41 (s, 1H), 4.52 (s, 2H), 3.50 (t, J=8.0 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H), 2.20 (s, 3H), 2.11 (s, 3H).

The following compounds were obtained using the above method:

4,6-Dimethyl-5-nitro-1-(4-terbisil)-indolin

4,6-Dimethyl-5-nitro-1-(3-Chlorobenzyl)-indolin

4,6-Dimethyl-5-nitro-1-(4-bromobenzyl)-indolin

4,6-Dimethyl-5-nitro-1-(3,4-diferensial)-indolin

4,6-Dimethyl-5-nitro-1-(naphthalene-2-ylmethyl)-indolin

4,6-Dimethyl-5-nitro-1-(pyridine-4-ylmethyl)-indolin

4,6-Dimethyl-5-NITR is-1-(pyridine-3-ylmethyl)-indolin

4,6-Dimethyl-5-nitro-1-(4-(trifluoromethyl)benzyl)-1H-indole (12): R=CF3

A solution of 4,6-dimethyl-5-nitro-1-(4-trifluoromethyl-benzyl)-indoline (350 mg, 1 mmol) and DDQ (454 mg, 2 mmol) in 30 ml of anhydrous dioxane was stirred at 50°C for 2 days. After cooling, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (ISCO, hexane/EtOAc, 0-40%, 40 min) with the formation of yellow crystals (300 mg, 86%).

The following compounds were obtained using the above method:

4,6-Dimethyl-5-nitro-1-(4-terbisil)-1H-indole

4,6-Dimethyl-5-nitro-1-(4-Chlorobenzyl)-1H-indole

4,6-Dimethyl-5-nitro-1-(4-bromobenzyl)-1H-indole

4,6-Dimethyl-5-nitro-1-(3,4-diferensial)-1H-indole

4,6-Dimethyl-5-nitro-1-(3,5-diferensial)-1H-indole

1-(4-Trifluoromethyl-benzyl)-4,6-dimethyl-5-aminoindole (10): R=CF3

1-(4-Trifluoromethyl-benzyl)-4,6-dimethyl-5-nitroindoline (1.0 g) was dissolved in methanol (40 ml) and added catalytic amount of Nickel (Ni) Raney, in order to provide the ability to hydrogenation at room temperature under normal pressure. After completion of the reaction the catalyst was filtered, and the filtrate evaporated at reduced pressure with the formation of a solid white product, which was pure enough for the next stage without additional purification.

The following connection is obtained using the above method:

1-(4-Terbisil)-4,6-dimethyl-5-aminoindole

1-(3-Chlorobenzyl)-4,6-dimethyl-5-aminoindole

1-(4-Bromobenzyl)-4,6-dimethyl-5-aminoindole

1-(3,4-Diferensial)-4,6-dimethyl-5-aminoindole

1-(Naphthalene-2-ylmethyl)-4,6-dimethyl-5-aminoindole

1-(Pyridine-4-ylmethyl)-4,6-dimethyl-5-aminoindole

1-(Pyridine-3-ylmethyl)-4,6-dimethyl-5-aminoindole

4,6-Dimethyl-5-amino-1-(4-(trifluoromethyl)benzyl)-1H-indole

4,6-Dimethyl-5-amino-1-(4-terbisil)-1H-indole

4,6-Dimethyl-5-amino-1-(4-Chlorobenzyl)-1H-indole

4,6-Dimethyl-5-amino-1-(4-bromobenzyl)-1H-indole

4,6-Dimethyl-5-amino-1-(3,4-diferensial)-1H-indole

4,6-Dimethyl-5-amino-1-(3,5-diferensial)-1H-indole

N-[1-(4-Trifluoromethyl-benzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

(11): R=CF3

To a solution of 5-amino-4,6-dimethyl-1-(4-trifloromethyl)indoline (0.26 g; 0.82 mmol) of the above and triethylamine (125 mg, 1,24 mmol) in anhydrous methylene chloride (20 ml) was dropwise added tert-butylcatechol (135 mg, 1 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 18 hours. To the reaction mixture was added water, and the mixture was washed with saturated brine and dried over sodium sulfate. The solvent is evaporated at reduced pressure. The residue was purified by the method of column chromatography on silica gel (ISCO, hexane/EtOAc, 0-40%, 40 min) and recrystallize from g is Xan/EtOAc (5:1) with the formation of 290 mg (85%) solid white. 1H NMR (DMSO-d6, 400 MHz): δ 8.80 (brs, 1H, interchangeable D2O, NH), 7.72 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 6,29 (s, 1H), 4.34 (s, 2H), 3.28 (t, J=8.0 Hz, 2H), 2.82 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.96 (s, 3H), 1.07 (s, 9H). MS: 419 (M+1).

The following compounds were obtained using the above method.

N-[1-(4-Terbisil)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

1H NMR (DMSO-d6, 400 MHz): δ 8.78 (brs, 1H, interchangeable D2O, NH), 7.37 (dd, J=8.8 and 5.7 Hz, 2H), 7.16 (t, J=8.8 Hz, 2H), 6.32 (s, 1H), 4.22 (s, 2H), 3.22 (t, J=8.0 Hz, 2H), 2.79 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.95 (s, 3H), 1.05 (s, 9H). MS: 369 (M+1).

N-[1-(3-Chlorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

1H NMR (DMSO-d6, 400 MHz): δ 8.79 (brs, 1H, interchangeable D2O, NH), 7.34 (m, 4H), 6.29 (s, 1H), 4.25 (s, 2H), 3.26 (t, J=8.0 Hz, 2H), 2.81 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.96 (s, 3H), 1.05 (s, 9H). MS: 385 (M+1).

N-[1-(4-Bromobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

1H NMR (DMSO-d6, 400 MHz): δ 8.78 (brs, 1H, interchangeable D2O, NH), 7.54 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 6.29 (s, 1H), 4.21 (s, 2H), 3.24 (t, J=8.0 Hz, 2H), 2.80 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.02 (s, 3H), 1.95 (s, 3H), 1.05 (s, 9H). MS: 429 (M+1).

N-[1-(3,4-Diferensial)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

1H NMR (DMSO-d6, 400 MHz): δ 8.79 (brs, 1H, interchangeable D2O, NH), 7.41 (m, 2H), 7.19 (m, 1H), 6.30 (s, 1H), 4.22 (s, 2H), 3.25 (t, J=8.0 Hz, 2H), 2.80 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.03 (s, 3 is), 1.96 (s, 3H), 1.05 (s, 9H). MS: 387 (M+1).

N-(4,6-Dimethyl-1-(naphthalene-2-ylmethyl)indolin-5-yl)-3,3-dimethylbutyramide

1H NMR (DMSO-d6, 400 MHz): δ 8.79 (brs, 1H, interchangeable D2O, NH), 7.89 (m, 4H). 7.50 (m, 3H), 6.35 (s, 1H), 4.39 (s, 2H), 3.29 (t, J=8.0 Hz, 2H), 2.84 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.97 (s, 3H), 1.05 (s, 9H). MS: 401 (M+1).

N-(4,6-Dimethyl-1-(pyridine-4-ylmethyl)indolin-5-yl)-3,3-dimethylbutyramide

1H NMR (DMSO-d6, 400 MHz): δ 8.80 (brs, 1H, interchangeable D2O, NH), 8.52 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 6.25 (s, 1H), 4.28 (s, 2H), 3.30 (t, J=8.0 Hz, 2H), 2.84 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.02 (s, 3H), 1.97 (s, 3H), 1.05 (s, 9H). MS: 352 (M+1).

N-(4,6-Dimethyl-1-(pyridine-3-ylmethyl)indolin-5-yl)-3,3-dimethylbutyramide

1H NMR (DMSO-d6, 400 MHz): δ 8.79 (brs, 1H, interchangeable D2O, NH), 8.57 (d, J=2.0 Hz, 1H), 8.49 (dd, J=2.0 and 4.4 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.38 (dd, J=8.0 and 4.4 Hz, 1H), 6.36 (s, 1H), 4.27 (s, 2H), 3.24 (t, J=8.0 Hz, 2H), 2.79 (t, J=8.0 Hz, 2H), 2.17 (s, 2H,), 2.04 (s, 3H), 1.95 (s, 3H), 1.05 (s, 9H). MS: 352 (M+1).

N-(4,6-Dimethyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)-3,3-dimethylbutyramide

1H NMR (DMSO-d6, 400 MHz): δ 9.00 (brs, 1H, interchangeable D2O, NH), 7.67 (d, J=8.0 Hz, 2H), 7.41 (d, J=3.2 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.09 (s, 1H), 6.50 (d, J=3.2 Hz, 1H), 5.50 (s, 2H), 2.29 (s, 2H), 2.22 (s, 3H), 2.19 (s, 3H), 1.07 (s, 9H). MS: 417 (M+1).

N-(4,6-Dimethyl-1-(4-(tormentil)-1H-indol-5-yl)-3,3-dimethylbutyramide

1H NMR (DMSO-d6, 400 MHz): δ 8.99 (brs, 1H, interchangeable D2O, NH), 7.39 (d, J=3.2 Hz, 1H), 7.21 (dd, J=8.8 and 5.7 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 7.12 (s, 1H), 6.46 (d, J=3.2 Hz, 1H), 5.36 (s, 2H), 2.28 (s, 2H), 2.22 (s, 3H), 2.20 (s, 3H), of 1.07 (s, 9H). MS: 367 (M+1).

N-(4,6-Dimethyl-1-(3,4-diferensial)-1H-indol-5-yl)-3,3-dimethylbutyramide

1H NMR (DMSO-d6, 400 MHz): δ 9.00 (brs, 1H, interchangeable D2O, NH), 7.41 (d, J=3.2 Hz, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.14 (s, 1H), 6.95 (m, 1H), 6.48 (d, J=3.2 Hz, 1H), 5.36 (s, 2H), 2.28 (s, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 1.07 (s, 9H). MS: 385 (M+1).

N-(4,6-Dimethyl-1-(3,5-diferensial)-1H-indol-5-yl)-3,3-dimethylbutyramide

1H NMR (DMSO-d6, 400 MHz): δ 9.01 (brs, 1H, interchangeable D2O, NH), 7.43 (d, J=3.2 Hz, 1H), 7.13 (s, 1H), 7.10 (m, 1H), 6.81 (m, 2H), 6.49 (d, J=3.2 Hz, 1H), 5.40 (s, 2H), 2.29 (s, 2H), 2.22 (s, 3H), 2.21 (s, 3H), 1.08 (s, 9H). MS: 385 (M+1).

N-(4,6-Dimethyl-1-(3-Chlorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutyramide

1H NMR (DMSO-d6, 400 MHz): δ 9.00 (brs, 1H, interchangeable D2O, NH), 7.41 (d, J=3.2 Hz, 1H), 7.31 (m, 2H), 7.19 (s, 1H), 7.12 (s, 1H), 7.03 (m, 1H), 6.95 (m, 1H), 6.49 (d, J=3.2 Hz, 1H), 5.39 (s, 2H), 2.29 (s, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 1.08 (s, 9H). MS: 383 (M+1).

N-(4,6-Dimethyl-1-(4-bromobenzyl)-1H-indol-5-yl)-3,3-dimethylbutyramide

1H NMR (DMSO-d6, 400 MHz): δ 8.99 (brs, 1H, interchangeable D2O, NH), 7.49 (d, J=8.4 Hz, 2H), 7.38 (d, J=3.2 Hz, 1H), 7.08 (s, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.47 (d, J=3.2 Hz, 1H), 5.36 (s, 2H), 2.28 (s, 2H), 2.19 (s, 3H), 2.17 (s, 3H), 1.07 (s, 9H). MS: 427 (M+1).

Biological results

The connection is of this inventive formulas were evaluated as modulators of potassium channels by measuring the release of rubidium ions in the following method of analysis.

Methods: Cells PC-12 were grown at 37°C and 5% CO2in the DMEM/F12 with the addition of 10% horse serum, 5% fetal bovine serum, 2 mm glutamine, 100 U/ml penicillin, 100 U/ml streptomycin. Cells were seeded in covered with poly-D-lysine 96-well microplates for cell culture with a density of 40,000 cells/well and differentiated under the effect of 100 ng/ml NGF-7 within 2-5 days. To study the medium was removed by aspiration and cells were washed once in 0.2 ml of wash buffer (25 mm HEPES, pH 7,4, 150 mm NaCl, 1 mm MgCl2; 0.8 mm NaH2PO4, 2 mm CaCl2). Then the cells were added 0.2 ml Rb+boot buffer (wash buffer plus 5.4 mm RbCl2, 5 mm glucose) and incubated at 37°C for 2 hours. Attached cells were rapidly washed with buffer three times (the same buffer as Rb+boot buffer, but containing 5.4 mm KCl instead of RbCl) to remove extracellular Rb+. Immediately after washing, 0.2 ml of buffer for depolarization (wash buffer plus 15 mm KCl) with connections or no connections added to the cells in order to activate the "output" through potassium ion channels. After incubation for 10 minutes at room temperature, the supernatant was carefully removed and collected. Cells were literally by adding 0.2 ml lyse buffer (buffer for depolarization plus 0.1% of Triton X-100), and the tile is cnie lysates were also collected. If samples are not analyzed immediately on the contents of Rb+using atomic absorption spectroscopy (see below), they were stored at 4°C without negative effects on subsequent analysis Rb+.

The concentration of Rb+in supernatant (Rb+Sup) and cell lysates (Rb+Lys) quantitatively determined using a spectrometer ICR8000 plasma atomic absorption (Aurora Biomed Inc., Vancouver, B.C.) under conditions established by the manufacturer. Samples of 0.05 ml of titration microplate automatically processed by dilution with equal volumes of buffer for analysis of the sample Rb+and injection into an air-acetylene flame. The quantity Rb+the sample was measured by absorption at 780 nm using a lamp with a hollow cathode as a light source and RMT detector. The calibration curve, including the limit of 0-5 mg/l Rb+in the buffer for analysis of the sample was made for each set of tablets. The percentage of "exit" Rb+(F) was determined using the

F=[Rb+Sup/(Rb+Sup+Rb+Lys)]×100%.

The effect (E) of the compounds was determined by the formula:

E=[(Fc-Fb)/(Fs-Fb)]×100%,

where Fcis an "exit" in the presence of compounds in the buffer for depolarization, Fbis an "exit" in the basal buffer and F sis an "exit" in the buffer for depolarization. The effect (E) and the concentration was plotted on a graph, to calculate the value EC50, the concentration is at the maximum output Rb+50%. The results are shown below. Legend: A: EU50=1 nm-50 nm; In: EU50=50 nm-100 nm; (C: EC50=100 nm-200 nm; D: EU50=200 nm-500 nm.

Table 1
The activity of illustrative compounds
ConnectionActivity
And
And
And
And
And
And

Table-continuation
The activity of illustrative compounds
ConnectionActivity
D
A
A
A
A
A

Table 1 - continued
The activity of illustrative compounds
ConnectionActivity
A
A

1. The compound of the formula I

where the dotted line submitted the optional double bond; where R1represents phenyl, naphthyl, or pyridyl, optionally substituted by one or two substituents, independently selected from halogen, C1-C6of alkyl, mono-halo1-C6of alkyl, di-halo1-C6the alkyl or CF3; R2represents H, methyl, or halogen; R3and R4represent, independently, CF3, halo, or C1-C3alkyl, where C1-C3alkyl groups are optionally substituted by one or more halogen atoms; X=O; q=0; R5represents a C1-C6alkyl, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1is a para-halophenol or differenl.

3. The compound according to claim 1, where R1is replaced by stands or trifluoromethyl.

4. The compound according to claim 1 of formula IA

5. The compound according to claim 1 of formula IC

6. The compound according to any one of claims 4 or 5, where R3and R4represent, independently, methyl, or chlorine.

7. The compound according to any one of claims 4 or 5, where R2represents H, and R3and R4both represent methyl.

8. The compound according to any one of claims 4 or 5, where R3and R4both represent methyl; R1represents phenyl, naphthyl or pyridyl, optionally alseny halogen or trifluoromethyl; and R5represents a C5-C6alkyl.

9. The composition having modulating activity against potassium channels, which contains a compound of the formula I according to claim 1 and a pharmaceutically acceptable carrier.

10. The composition having modulating activity against potassium channels, which contains a pharmaceutically acceptable carrier and one or more of the following: a compound of formula I according to claim 1, or its pharmaceutically acceptable salt.

11. The method of prevention or treatment of a disease or disorder that affects the modulation of potassium channels, comprising the administration to a patient in need, a therapeutically effective amount of a composition containing one or more of the following: a compound of formula I according to claim 1, or its pharmaceutically acceptable salt.

12. The compound according to claim 4, where R3and R4both represent methyl, and R5represents a C5-C6alkyl.

13. The connection section 12, where R1represents a monosubstituted phenyl.

14. The connection indicated in paragraph 13, where R1is a para-forfinal or para-triptoreline.

15. The connection section 12, where R1represents 3,5-differenl or 3-forfinal.

16. The compound according to claim 5, where R3and R4both represent methyl, and R5represents a C 5-C6alkyl.

17. Connection P16, where R1represents pyridyl or phenyl, optionally substituted one additional Deputy selected from halogen, C1-C6of alkyl, mono-halo, C1-C6of alkyl, di-halo, C1-C6the alkyl or CF3.

18. The connection 17, where R1is a para-forfinal or para-triptoreline.

19. Connection P16, where R1represents 3,5-differenl or 3-forfinal.

20. The composition having modulating activity against potassium channels, which contains a compound of the formula IA according to claim 4 and a pharmaceutically acceptable carrier.

21. The composition having modulating activity against potassium channels, which contains one or more of the following: a compound of formula IA according to claim 4; or a pharmaceutically acceptable salt of the compounds of formula IA.

22. The method of prevention or treatment of a disease or disorder that affects the modulation of voltage-dependent potassium channels, comprising the administration to a patient in need, a therapeutically effective amount of a composition containing one or more of the following: a compound of formula IA according to claim 4 and a pharmaceutically acceptable salt of the compounds of formula IA.

23. The composition having modulating activity against CA is yevich channels, which contains a compound of the formula IC according to claim 5 and a pharmaceutically acceptable carrier.

24. The composition having modulating activity against potassium channels, which contains one or more of the following: a compound of the formula IC according to claim 5; or its pharmaceutically acceptable salt.

25. The method of prevention or treatment of a disease or disorder that affects the modulation of voltage-dependent potassium channels, comprising the administration to a patient in need, a therapeutically effective amount of a composition containing one or more of the following: a compound of the formula IC according to claim 5, and a pharmaceutically acceptable salt of the compounds of formula IC.

26. Connection, which is one of the following:
N-[1-(4-Trifloromethyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
N-[1-(4-Terbisil)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
N-[1-(3-Chlorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
N-[1-(4-Bromobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
N-[1-(3,4-Diferensial)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
N-(4,6-Dimethyl-1-(naphthalene-2-ylmethyl)indolin-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(pyridine-4-ylmethyl)indolin-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(pyridine-3-ylmethyl)indolin-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)-3,3-dimethy butanamide
N-(4,6-Dimethyl-1-(4-(tormentil)-1H-indol-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(3,4-diferensial)-1H-indol-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(3,5-diferensial)-1H-indol-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(3-Chlorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutyramide and
N-(4,6-Dimethyl-1-(4-bromobenzyl)-1H-indol-5-yl)-3,3-dimethylbutyramide.

27. The composition having modulating activity against potassium channels, which contains a pharmaceutically acceptable carrier and any compound selected from one of the following or its pharmaceutically acceptable salt:
N-[1-(4-Trifloromethyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
N-[1-(4-Terbisil)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
N-[1-(3-Chlorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
N-[1-(4-Bromobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
N-[1-(3,4-Diferensial)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
N-(4,6-Dimethyl-1-(naphthalene-2-ylmethyl)indolin-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(pyridine-4-ylmethyl)indolin-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(pyridine-3-ylmethyl)indolin-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(4-(tormentil)-1H-indol-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(3,4-diferensial)-1H-indol-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(3,5-differenze is)-1H-indol-5-yl)-3,3-dimethylbutyramide
N-(4,6-Dimethyl-1-(3-Chlorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutyramide and
N-(4,6-Dimethyl-1-(4-bromobenzyl)-1H-indol-5-yl)-3,3-dimethylbutyramide.

28. Method for the treatment or prevention of a disease or condition that affects the modulation of potassium channels, comprising the administration to a patient in need of this treatment an effective amount of the compound according to item 27.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to obtaining cPLA2 inhibitors of formula (A1): , where Ar, R, z, R10, n1, n3, X2, R12, R13 and R14 have values, given in invention formula, or pharmaceutically acceptable salts of said compound, which includes reaction of corresponding compound of formula II: [Ar-(R)2-SO2-1]qM, where M and q have values, given in formula of invention, with reagent, carrying substituting halogen atom, in presence of catalytic amount of water and cocatalyst with formation of corresponding compound of formula III: Ar-(R)z-SO2-X, where X represents halogen; and reaction of formula III compound with corresponding compound of formula (B1): , where R12 represents phenyl, substituted with group -(CH2)n4-COOH, where carboxyl group is protected by protective group, with obtaining of sulfonamide; and if necessary, conversion of obtained compound into form of its pharmaceutically acceptable salt. In addition, claimed invention relates to novel intermediate compounds for obtaining cPLA2 inhibitors and to methods of obtaining intermediate compounds for obtaining cPLA2 inhibitors.

EFFECT: method improvement.

26 cl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to an economical method for synthesis of compounds of formula 1: by reacting compounds of formulae 2 and 3: to obtain a compound of formula 4: where: R1, R2, R3 and R4 each independently denotes H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -NO2, -C1-6-alkyl, -C1-6-alkoxy, -NH2, -NH(C1-6-alkyl), -N(C1-6-alkyl)2, and -NHC(O)-C1-6-alkyl; R5 denotes H,-C(O)O- C1-6-alkyl; and the reaction takes place in the presence of a base, a palladium catalyst and a copper catalyst; with subsequent reaction of the obtained formula 4 compound with copper to obtain a compound of formula 5: which reacts with a compound of formula 6: to obtain a compound of formula 7: and subsequent reaction with the base to remove the ether C1-6alkyl group.

EFFECT: economical method of obtaining the said compounds.

36 cl, 3 dwg, 16 ex

FIELD: chemistry.

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EFFECT: obtaining compounds, demonstrating activity in inhibiting plasminogene activator inhibitor which allows using them in pharmacology.

23 cl, 1 dwg, 1 tbl, 13 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

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EFFECT: valuable medicinal properties of compounds and compositions.

6 cl, 2 dwg, 3 tbl, 9 ex

The invention relates to N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which IGN="ABSMIDDLE">

where R7denotes phenyl or pyridinyl; R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids

The invention relates to new hydroxyindole General formula

< / BR>
where R1- C1-C12-alkyl, linear or branched, if necessary monosubstituted monocyclic saturated or polyunsaturated carbocycles with 6 ring members, WITH6-aryl group and closed carbocyclic substituents on its part, if necessary, can be mono - or polyamidine R4; R5- monocyclic polyunsaturated carbocycles with 6 ring members, mono - or politeley atoms, halogen or a monocyclic polyunsaturated heterocycles with 6 ring members, one of which is N as heteroatom, mono - or politeley atoms of halogen; R2and R3can be hydrogen or HE, and at least one or both of the Deputy should be-HE; R4means-H, -OH, -F, -Cl, -J, -Br, -O-C1-C6-alkyl, -NO2; A -, or a bond, or -(CHOZ)m-(C= 0)-, and m= 0

The invention relates to new indole derivative of the formula I

< / BR>
in which R1is hydrogen, (NISS

The invention relates to 1H-indol-3-acetamide General formula I where X is oxygen; R1selected from groups (i), (iii), where (i)6-C20-alkyl, C4-C12-cycloalkyl; (iii) - (CH2)n-(R80), where n is 1-8 and R80is the group specified in (i); R2is hydrogen, halogen, C1-C3-alkyl, C1-C2-alkylthio,1-C2-alkoxy; R3each independently is hydrogen or methyl; R4- R7each independently - C1-C10-alkyl, C2-C10alkenyl,3-C8-cycloalkyl,1-C10-alkoxy,

WITH4-C8-cycloalkane, phenoxy, halogen, hydroxy, carboxyl, -C(O)O(C1-C10-alkyl), hydrazide, hydrazino, NH2, NO2, -C(O)NR82R83where R82and R83independently is hydrogen, C1-C10-alkyl or a group of formula (a), where R84and R85independently is hydrogen, C1-C10-alkyl; p= 1 to 5; z is a bond, -O-, -NH-; Q is-CON(R82R83), -SO3H, phenyl, a group of formula b), C), (d), where R86independently selected from hydrogen, C1-C10-alkyl, and their pharmaceutically acceptable salts or their esters, or Amida

Chemical method // 2481331

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula II from a compound of formula III: , where R1 and R2 are independently Cl, Br, F, I, via reaction thereof with an ester of formula (IV) , where R3 is C1-6alkyl; to obtain a compound of formula V: , which reacts with a hydroxyl ion in the presence of an aryl-alkyl ammonium salt or tetra-alkyl ammonium salt, to obtain a compound of formula VI , followed by treatment thereof to obtain a compound of formula VII: , which is reduced to obtain a compound of formula II.

EFFECT: high efficiency of the method.

5 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a compound of general formula VIII of enantiomeric purity min. 80% by a reaction of the compound according to general formula IV with enantiomeric pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid to produce a compound of general formula II to be reduced to prepare a compound for general formula I to be oxidated to form an aldehyde which then reacts with an aromatic amine of formula H2N-Ar to produce a respective imine which is then reduced to prepare a compound described by formula VIII in the enantiomeric pure form. Also, it refers to methods for preparing the compound of formula I, as well as to the compounds of formula I. In general formulas

, ,

, , X1, X2, X3 is specified in fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, trifluoromethyl, amino whereas the other groups X1, X2, X3 represent a hydrogen atom.

EFFECT: preparing the non-steroid anti-inflammatory drugs.

12 cl, 5 ex

Amide compound // 2479576

FIELD: chemistry.

SUBSTANCE: compounds exhibit antagonistic activity towards the EP4 receptor, which enables use thereof as an active ingredient in a pharmaceutical composition for treating chronic kidney disease or diabetic nephropathy.

EFFECT: high efficiency of the compounds.

27 cl, 228 tbl, 86 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted heteroaryl derivatives of general formula I: , wherein: A means N, CR7-10, with A at the most twice meaning N; W means O, S or NR4, the values B, C, R7-10 are presented in clause 1 of the patent claim. The method for preparing the compound I is described.

EFFECT: compounds show analgesic activity that enables using them for a variety of diseases, especially acute pain, neuropathic, chronic or inflammatory pain.

16 cl, 2 tbl, 307 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel substituted 2-phenylindole derivatives of general formula I: , where for R, R2 and R4=H and R1=OH, R3=CN,CF3, COOEt or SO2NH2; for R=Me and R1 and R3=H, R2=NO2 R4=OH; for R=Me and R1 and R3=H, R2=OH and R4=NO2; for R=Me and R2 and R3=H, R1=NO2 and R4=OH; for R=Me and R2 and R3=H, R1=OH and R4=NO2, which exhibit fungicidal activity, which allows for their use in preparing fungicide compositions. Described is a method of producing compounds where R=Me, R1 and R3=H, R2=NO2 R4=OH, for R=Me, R1 and R3=H, R2=OH, R4=NO2, for R=Me, R2 and R3=H, R1= NO2, R4= OH, for R=Me, R2 and R3=H, R1=OH, R4=NO2.

EFFECT: improved method.

4 cl, 3 dwg, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining derivatives of 2-aryl(hetaryl)-1H-indoles of general formula I:

IndexR1R2IaClIbОСН3IcHIdHIeНIfClIgCl

which is characterised by the fact that derivatives of 4-(1H-indol-3-yl)-but-3-en-2-ons II and phenylhydrazine hydrochloride are boiled in dimethylformamide for 2 min. Method ensures obtaining target products with output to 83%.

EFFECT: compounds can be used for synthesis of novel preparations of pharmaceutical purpose.

2 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (II-A) or pharmaceutically acceptable salt thereof: [in which symbols denote the following: R10-R12: are identical or different and each denotes halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, R13: R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, ring B: benzene ring or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from O, S and N, R14: R0, halogen or -OR0, R0: are identical or different and each denotes H or lower alkyl, Y1: a single bond, lower alkylene, lower alkenylene or O-lower alkylene-, and Z1: -CO2R0 or -C0-NH-SO2-lower alkyl]. The invention also relates to a pharmaceutical composition based on the said compound, having antagonistic effect on the EP1 receptor.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in a medicinal agent for treating lower urinary tract symptoms.

6 cl, 56 tbl, 231 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of structural formula IIIm: or pharmaceutically acceptable salt thereof, where: R81 is selected from a group comprising hydrogen, halogen, possibly substituted C1-6alkyl, possibly substituted C2-6alkenyl, possibly substituted C2-6alkynyl, possibly substituted cycloalkyl, possibly substituted heterocycloalkyl, possibly substituted aryl, possibly substituted heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR68, -SR68, -NR69R68, -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR69R68, -C(S)NR69R68, -S(O)2NR69R68; -NR69C(O)R68, -NR69C(S)R68, -NR69S(O)2R68, -NR69C(O)NH2, -NR69C(O)NR69R68, -NR69C(S)NH2, -NR69C(S)NR69R68, -NR69S(O)2NH2, -NR69S(O)2NR69R68, -S(O)R68 and -S(O)2R68, R83 is selected from a group comprising hydrogen, fluro and chloro; R112 is selected from a group comprising possibly substituted C2-6alkyl, possibly substituted aryl, possibly substituted heteroaryl and -NR79 R80; R68 is selected from a group comprising possibly substituted C1-6alkyl, possibly substituted C2-6alkenyl, but provided that when R68 is possibly substituted C2-6alkenyl, then one of its alkene carbons is not bonded with N, S, O, S(O), S(O)2, C(O) or C(S) from -OR68, -SR68, -NR69R68, -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR69R68, -C(S)NR69R68, -S(O)2NR69R68, -NR69C(O)R68, -NR69C(S)R68, -NR69S(O)2R68, -NR69C(O)NH2, -NR69C(O)NR69R68, -NR69C(S)NH2, -NR69C(S)NR69R68, -NR69S(O)2NH2, -NR69S(O)2NR69R68, -S(O)R68 or -S(O)2R68, possibly substituted C2-6alkynyl, but provided that when R68 is possibly substituted C2-6alkynyl, then one of its alkyne carbons is not bonded with N, S, O, S(O), S(O)2, C(O) or C(S) from -OR68, -SR68, -NR69R68, -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR69R68, -C(S)NR69R68, -S(O)2NR69R68, -NR69C(O)R68, -NR69C(S)R68, -NR69S(O)2R68, -NR69C(O)NH2, -NR69C(O)NR69R68, -NR69C(S)NH2, -NR69C(S)NR69R68, -NR69S(O)2NH2, -NR69S(O)2NR69R68, -S(O)R68 or -S(O)2R68, possibly substituted cycloalkyl, possibly substituted heterocycloalkyl, possibly substituted aryl and possibly substituted heteroaryl; R69 is selected from a group comprising hydrogen and possibly substituted C1-6alkyl; and R79 and R80 independently denote hydrogen or possibly substituted C1-6alkyl or R79 and R80 together with the nitrogen atom to which they are bonded form a possibly substituted 5-7-member heterocycloalkyl. Described also is a composition and a set for modulating protein kinase based on said compounds and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds which are active towards protein kinase are obtained and described.

71 cl, 59 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim.

EFFECT: there are presented the compounds of formula (I) as corticotropin-releasing factor (CRF) receptor antagonists.

20 cl, 2 dwg, 2 tbl, 51 ex

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