Hetero-aryl derivatives as super ligands for nociceptin orl-1 receptor

FIELD: chemistry.

SUBSTANCE: invention pertains to new hetero-aryl derivatives of 8-azabicyclo-[3.2.1]-octan-3-ol with general formula I where R-R4 represent hetero-aryl. The hetero-aryl is in form of a cyclic aromatic group with C5-C6 or a bicyclic group with C9-C10, which contain 1, 2 or 3 hetero atoms, independently O, S or N, or a residue of , R1-H, C1-C6-akyl, R2 and R3 independently CH3, -OCH3, F, Cl, Br, J, R4 - from 1 to 4 substitutes, -H, halogen, C1-C6alkyl, -CF3, -OCF3, -(CH2)n-OR5, -(CH2)n-NR5R6, -(CH2)n-NHSO2R5, -(CH2)n-NH(CH2)2NR5R6, -(CH2)n-NHC(O)NR5R7, -(CH2)n-NH(CH2)2OR5, or 1-piperazinyl; n - 0, 1, 2, 3; R5 and R6 - H, C1C3alkyl, R7-H, C1-C3alkyl, aminoalkyl C1-C3, or to their pharmaceutical salts. The compounds are antagonists of the nociceptin ORL-1 receptor.

EFFECT: obtaining of compounds that are useful in the treatment of cough.

10 cl, 22 ex, 1 tbl

 

The present invention relates to agonists of the receptor nociceptin ORL-1 - 8-(bis(halogenfree)-methyl)-3-heteroaryl-8-azabicyclo-[3.2.1]-Octan-3-ol and its derivatives, used in the treatment of cough, pain, anxiety, asthma, alcohol addiction or depression. Also disclosed are pharmaceutical compositions comprising these compounds and combinations of the claimed compounds with other drugs intended for the symptomatic treatment of cough, Allergy or asthma.

8-(Bis(halogenfree)-methyl)-3-heteroaryl-8-azabicyclo-[3.2.1]-octane-3-Ola in General, but not specifically disclosed in U.S. patent US 6262066 B1 and in the international application WO 01/07050, as used in the treatment of cough, pain, anxiety, asthma, alcohol addiction or depression. Compounds corresponding to the present invention are selective to the invention in comparison with the U.S. patent US 6262066 B1 and WO 01/07050.

Compounds of the present invention represented by formula I

or its pharmaceutically acceptable salts, where:

R means R4-heteroaryl or;

R1means hydrogen or alkyl with 1-6 carbon atoms;

R2and R3independently from each other selected from the group comprising methyl, methoxy, fluorine, chlorine, bromine and iodine;

R4means on the 1 to 4 substituents, independently selected from the group comprising hydrogen, halogen, alkyl with 1-6 carbon atoms, cyano, trifluoromethyl, triptoreline, -(CH2)n-OR5, -(CH2)n-NR5R6, -(CH2)n-NHSO2R5, -(CH2)n-NH(CH2)2NR5R6, -(CH2)n-NHC(O)NR5R7, -(CH2)n-NH(CH2)2OR51-piperazinil;

n is 0, 1, 2 or 3;

R5and R6independently from each other selected from the group comprising hydrogen and alkyl with 1-3 carbon atoms; and

R7denotes hydrogen, alkyl with 1-3 carbon atoms or aminoalkyl with 1-3 carbon atoms.

In another embodiment the present invention relates to pharmaceutical compositions comprising at least one compound of formula I and a pharmaceutically acceptable carrier.

Compounds corresponding to the present invention are agonists of the receptor ORL-1 and therefore in another embodiment the present invention relates to a method of treatment of pain, anxiety, cough, asthma, alcohol addiction or depression, including the appointment of a mammal in need of such treatment, an effective amount of at least one of the compounds of formula I.

In another embodiment the present invention relates to a method for treatment of cough, including the appointment of milk is itausa, in need of such treatment: (a) an effective amount of at least one compound of formula I; and (b) an effective amount of one or more additional drugs for symptomatic treatment of cough, Allergy or asthma selected from the group including: antihistamines, inhibitors of 5-lipoxygenase, leukotriene inhibitors, inhibitors of N3, agonists β-adrenergic receptor, xanthine derivatives, agonists α-adrenergic receptor, stabilizers fat cells, antitussive drugs, expectorants drugs, receptor antagonists tachykinin NK1NK2and NK3and agonists GABAB.

In yet another embodiment the present invention relates to pharmaceutical compositions comprising at least one compound of formula 1 and one or more additional drug selected from the group including: antihistamines, inhibitors of 5-lipoxygenase, leukotriene inhibitors, inhibitors of N3, agonists β-adrenergic receptor, xanthine derivatives, agonists α-adrenergic receptor, stabilizers fat cells, antitussive drugs, expectorants drugs, receptor antagonists tachykinin NK1NK2and NK3and agonists GABAB.

According to the above form is s 1, the preferred compounds of the present invention are such in which R2and R3are in the 2-position of the phenyl rings. Also preferred are compounds in which R2and R3choose the same halogen atom. More preferred are compounds in which R2means chlorine and R3means chlorine, and most preferred are compounds in which R2means of 2-chloro and R3means 2-chloro.

Also preferred are compounds in which R means R4-heteroaryl where heteroaryl means pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl or indolyl, in particular, 2-pyridyl or 2-pyrimidinyl. The preferred values of R4is hydrogen, alkyl with 1-6 carbon atoms, -OR51-piperazinil. The preferred values of R are 2-pyrimidinyl, 5-ethyl-2-pyrimidinyl, 4-(1-piperazinil)-2-pyrimidinyl, 2-pyridyl and 6-methoxy-2-pyridyl.

R1preferably means hydrogen or methyl, and more preferred is hydrogen.

Especially preferred are the following specific compounds:

,,.

and

Preferred compounds of formula I is their use of the tion for the treatment of cough.

If not stated otherwise, when used in the present invention the following terms have the following values:

Halogen means fluorine, chlorine, bromine and iodine.

Heteroaryl means a cyclic aromatic group containing from 5 to 6 atoms or a bicyclic group containing from 9 to 10 atoms, including 1, 2 or 3 heteroatoms, independently selected from the group comprising oxygen, sulfur and nitrogen, said heteroatom (specified heteroatoms) is included in the carbocyclic ring structure and has a number of delocalized π-electrons sufficient to impart aromatic character, provided that the cycles do not include adjacent oxygen atoms and/or sulfur. The nitrogen atoms can form N-oxides. Includes all regioisomers, for example, 2-pyridyl, 3-pyridyl and 4-pyridyl. A typical 6-membered heteroaryl groups are pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and their N-oxides. Typical 5-membered heteroaryl cycles are furyl, thienyl, pyrrolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl and isoxazolyl. Typical bicyclic groups are condensed with the benzene ring cycle system formed of the above heteroaryl groups, for example, hinely, phthalazine, hintline, benzofuranyl, benzothiazol and indolyl. Heteroaryl cycle may as will replace the lei contain 1-4 groups R 4and any available and capable of substitution of the carbon atoms or nitrogen in the specified heteroaryl group can be optionally and independently substituted.

Some compounds of the present invention may exist in different stereoisomeric forms (e.g., enantiomeric, diastereoisomeric and athropogenic). The present invention includes all such stereoisomers in pure form and in mixtures, including racemic mixtures.

Some compounds in nature are acidic (e.g., compounds which contain carboxyl or phenolic hydroxyl group). These compounds can form pharmaceutically acceptable salts. Examples of such salts may include salts of sodium, potassium, calcium, aluminum, gold and silver. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines followed, hydroxyethylamine, N-methylglucamine and the like

Some basic compounds also form pharmaceutically acceptable salt, e.g. an acid additive salt. For example, the pyridine nitrogen atoms may form salts with strong acids, whereas compounds containing basic substituents such as amino groups, also form salts with weaker acids. Examples of acids suitable for the formation of salts are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methansulfonate and other mineral and carboxylic acids well known to specialists in this field of technology. Salt is produced by the interaction of the free base with a sufficient amount of the desired acid with formation of salts. The free base can be distinguished by treating the salt with a suitable dilute aqueous solution of a base, such as dilute aqueous NaOH solution, potassium carbonate, ammonia and sodium bicarbonate. Free base differs from the corresponding salts by some physical characteristics, such as solubility in polar solvents, however, for the objectives of the present invention for other characteristics of salt is equivalent to the corresponding free base.

In accordance with the scope of the present invention, it is assumed that all such acidic and basic salts are pharmaceutically acceptable and objectives of the present invention all acidic and basic salts are considered equivalent to the free forms of the corresponding compounds.

Compounds of the present invention can be obtained by known methods from the original substances or known in the art, or obtained by methods known the in the art.

A typical method of producing compounds of the formula Ia, in which R1means hydrogen, includes the interaction of 8-[bis-(halogenfree)-methyl]-8-azabicyclo-[3.2.1]-Octan-3-one of formula II with the lithium derivative of heteroaryl:

Starting material of formula II can be obtained by the following reaction scheme:

The compound of formula II can be obtained by alkylation piperidino III derived derived diphenylmethane IV in the presence of a base, such as2CO3in a solvent such as CH3CN, at 80°C. Compounds of formulas III and IV are known in the art or can be obtained by known methods.

Compounds of the present invention and source materials for their production, are given below as examples, should not be considered as limiting the scope of the present disclosure.

The following solvents and reagents in the present invention designated by the abbreviations: tetrahydrofuran (THF); ethanol (EtOH); methanol (Meon); ethyl acetate (EtOAc); diisopropylamide lithium (LDA); triethylamine (Et3N) and N,N-dimethylformamide (DMF).

Preparation 1

8-Azabicyclo-[3.2.1]-Octan-3-one, hydrochloride

To a solution of tropinona (10 g, 71,84 mmol) in dichloroethane (200 ml) until the NML at 0° With the add α-chloroethylphosphonic (15,4 g, 108 mmol). The reaction mixture is refluxed for 2 hours. The solvent is evaporated and get a brown residue. The residue is dissolved in Meon (200 ml) and refluxed for 2 hours. Meon is evaporated and the solid is stirred in EtOAc, filtered, collecting the solid and washed with ether and receive the product (7 g). The crude product is used without further purification.1H NMR (CDCl3) δ of 4.45 (s, br, 2H), 3,35 (dd, 2H), 2,58 (d, 2H), 2.49 USD (dd, 2H), 2,0 (m, 2H).

Preparation of 2

Bis-(2-chlorophenyl)-bromatan

Stage 1:

To a solution of 2,2'-dichlorobenzophenone (5 g, to 19.9 mmol) in Meon (40 ml) at room temperature was added NaBH4(1.5 g, 39,82 mmol) and stirred for 2 hours. The reaction is stopped using H2O, neutralized with 1 N HCl and remove the Meon. The residue is extracted with EtOAc, washed with brine, dried over MgSO4and concentrate and get the desired compound (5 g) as a white solid, which is used in the next stage of the reaction without purification.1H NMR (CDCl3) δ was 7.45 (m, 4H), 7,35 (m, 4H), 6,60 (d, 1H), 2,58 (d, 1H, HE).

Stage 2:

The product obtained in stage 1 (20,36 g, 80,47 mmol)in CH2Cl2treated with SOBr2(30,11 g, 144,85 mmol) at 0°and AC who're asked at room temperature over night. The reaction is stopped with ice and NaHCO3(aqueous solution), extracted with CH2Cl2, dried and filtered. Remove the solvent and obtain the desired bromide (23,6 g).1H NMR (CDCl3) δ and 7.6 (d, 2H), and 7.4 (d, 2H), 7,13 (m, 4H), 7,0 (s, 1H).

Preparation of 3

8-[Bis-(2-chlorophenyl)-methyl]-8-azabicyclo-[3.2.1]-Octan-3-one

The mixture of products obtained in Synthesis 1 (26 g, 161 mmol) in Preparation 2 (53 g, 168 mmol), and K2CO3(110 g, 796 mmol) is heated in anhydrous CH3CN (410 ml) at 80°C for 80 hours. The reaction mixture is cooled to room temperature and filtered. The solvent is evaporated and the solid is purified using flashmemory in column (4%, 7% EtOAc/hexane) and get the desired product.1H NMR (CDCl3) δ to 7.9 (d, 2H), and 7.3 (m, 4H), 7,2 (m, 2H), 5,7 (s, 1H), 3,35 (s, br, 2H), and 2.7 (dd, 2H), 2,3 (m, 2H), 2,2 (d, 2H), 1,65 (dd, 2H).

Example 1

8-[Bis-(2-chlorophenyl)-methyl]-3-(2-pyrimidinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

Stage 1: 2-Tributylstannyl

This connection receive according to the method described in Sandosham et al., Tetrahedron (1994), 50, 275-284). From Diisopropylamine (25 ml, 178 mmol) and n-BuLi (2.5 M, 70 ml, 175 mmol) in THF (230 ml) of freshly prepared LDA. A solution of LDA dropwise at 0°treated With a solution of tributyltinhydride (142 ml, 156 mmol) in THF (30 ml) and after added the I stirred for a further 15 minutes. The reaction mixture was cooled to -78°With added dropwise a solution of 2-chloropyrimidine (15 g, 131 mmol) in THF (100 ml) and stirred the reaction mixture for 3 hours at -78°C, then the reaction mixture is allowed to warm to 0°C for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layers are combined, dried and concentrated. The residue is purified by chromatography on a column and get the desired compound as a pale yellow oil.1H NMR (CDCl3) δ 8,65 (d, 2H), and 7.1 (t, 1H), 1,6 (m, 6H), 1,3 (m, 6H), 1,1 (m, 6H), 0.85 (t, 9H).

Stage 2:

n-BuLi (2.5 M in hexane, to 16.5 ml, 41.2 mmol) are added dropwise to a solution of the product obtained in stage 1 (15 g, to 40.6 mmol)in THF (80 ml) at -78°and the reaction mixture was kept at this temperature for 45 minutes. To this solution is added dropwise a solution of the product obtained in Preparation 3 (6 g, and 16.7 mmol)in THF (30 ml) and stirred the reaction mixture for a further 3 hours at -78°C. the Reaction mixture was warmed to room temperature for 1.5 hours. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layers are combined and dried koncentriruiutsia residue by chromatography on a column gives the desired compound in the form of a white solid matter what. 1H NMR (CDCl3) δ is 8.75 (d, 2H), of 7.96 (d, 2H), 7,30 (m, 4H), 7,20 (t, 1H), 7,15 (m, 2H), 5,59 (s, 1H), a 4.86 (s, 1H, HE), 3,20 (m, br, 2H), 2,60 (dd, 2H), 2.40 a (dd, 2H), 2,24 (m, 2H), 1,68 (d, 2H).

Example 2

8-[Bis-(2-chlorophenyl)-methyl]-3-(5-ethyl-2-pyrimidinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

Stage 1: 5-Ethyl-2-tributylstannyl

Using the techniques described in Example 1, step 1, using LDA, tributylamine tin (23,8 g, 81,78 mmol) and 2-chloro-5-ethylpyrimidine (10 g, 70 mmol)) to obtain the desired compound (6 g).1H NMR (CDCl3) δ 8,55 (s, 2H), 2,60 (q, 2H), 1.55V (m, 6H), of 1.35 (m, 6H), 1,25 (t, 3H)and 1.15 (t, 6H), of 0.85 (t, 9H).

Stage 2:

n-BuLi (2.5 M, 6.5 ml, 16,33 mmol) are added dropwise to a solution of the product obtained in stage 1 (5.9 g, 14,85 mmol), in THF at -78°With the temperature of the reaction mixture supports equal -78°C for 30 minutes. It added to the product obtained in Preparation 3 (5.34 g, 14,85 mmol). The reaction mixture is slowly warmed to room temperature and stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layers are combined, dried and concentrated. Purification of the residue by chromatography on a column gives the desired compound as a white solid.1H NMR (CDCl3) δ and 8.6 (s, 2H), and 8.0 (d, 2H), 7,25 (m, 4H), to 7.15 (m, 2H), 5,6 (s, 1H), around 4.85 (s, 1H, HE), 3,2 (s, br, 2H), 2,65 (q, 2H), 2,60 (d, 2H), 2.40 a (m, 2H), 2,25 (m, 2H), 1,65 (d,2H), of 1.30 (t, 3H).

Example 3

8-[Bis-(2-chlorophenyl)-methyl]-3-[4-(1-piperazinil)-2-pyrimidinyl]-8-Aza-bicyclo-[3.2.1]-Octan-3-ol

Stage 1: 4-Chloro-2-tributylstannyl

Using the techniques described in Example 1, step 1, using LDA, tributylamine tin (10.8 g, is 37.2 mmol) and 2,4-dichloropyrimidine (5,2 g, is 34.9 mmol)) to obtain the desired compound (6.3 g).1H NMR (CDCl3) δ charged 8.52 (d, 1H), 7,18 (d, 1H), 1,58 (m, 6H), 1,30 (q, 6H), of 1.18 (t, 6H), 0,86 (t, 9H).

Stage 2: 8-[Bis-(2-chlorophenyl)-methyl]-3-(4-chloro-2-pyrimidinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

n-BuLi (2.5 M, 8.0 ml, 20.0 mmol) are added dropwise to a solution of the product obtained in stage 1 (6.3 g, 16.2 mmol)in THF (30 ml) at -78°and the reaction mixture was kept at this temperature for 30 minutes. It added to the product obtained in Preparation 3 (4.0 g, 11.1 mmol). The reaction mixture is slowly warmed to room temperature and stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layers are combined, dried and concentrated. Purification of the residue by chromatography on a column gives the desired compound as a light brown foam substance.1H NMR (CDCl3) δ 8,61(d, 1H), to 7.93 (d, 2H), 7,25 (m, 5H), ,12 (m, 2H), the 5.65 (s, 1H), 4,33 (s, 1H, HE), 3,18 (s, br, 2H), 2,58 (dd, 2H), 2,33 (m, 2H), 2.13 in (m,2H), 1,65(d,br,2H).

Stage 3:

To a solution of the product obtained in stage 2 (25 mg, 0.05 mmol)in EtOH (4 ml) at room temperature was added piperazine (20 mg, 0.23 mmol). The reaction mixture was stirred at 80°With during the night. Extraction and purification gives the desired compound (20 mg).1H NMR (CDCl3) δ 8,24 (d, 1H), to 7.93 (d, 2H), 7,26 (d, 2H), 7,22 (t, 2H), 7,10 (t, 2H), 6,33 (d, 1H), 5,64 (s, 1H), to 3.67 (s, br, 4H), 3.15 in (s, br, 2H), 2.95 and (m, 4H), 2,59 (dd, 2H), 2,34 (m, 2H), 2,17 (m, 2H), of 1.57 (d, br, 2H).

Example 4

8-[Bis-(2-chlorophenyl)-methyl]-3-(2-pyridinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

n-BuLi (2.5 M in hexane, 1.5 ml, 3.8 mmol) are added dropwise to a solution of 2-bromopyridine (0.50 g, 3.10 mmol) in THF (1 ml) at -78°C and stirred for 1 hour. To it was added a solution of the product obtained in Preparation 3 (0.5 g, 1.4 mmol) in THF (1.5 ml) dropwise and the reaction mixture is stirred for a further 3.5 hours at -78°C. the Reaction mixture is heated to 0°C for 1 hour, pour the reaction mixture into saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layers are combined, dried and concentrated. Purification of the residue by chromatography on a column gives the desired compound in the form of a pale yellow solid (400 mg).1H NMR (CDCl3) δ 8,49 (d, 1H), 7,92 (d, 2H), 7,76 (t, 1H), to 7.61 (d, 1H), 7,28 (m, 4H), 7,16 (m, 3H), 5,65 s, 1H), 5,54 (s, 1H, HE), 3,18 (s, br, 2H), 2,41 (m, 2H), 2,32 (dd, 2H), of 2.21 (m, 2H), 1,72 (d, br, 2H).

Example 5

8-[Bis-(2-chlorophenyl)-methyl]-3-(6-methoxy-2-pyridinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

n-BuLi (2.5 M in hexane, 1.5 ml, 3.8 mmol) are added dropwise to a solution of 2-bromo-6-methoxypyridine (700 mg, 3.7 mmol) in THF (2 ml) at -78°C and stirred for 0.5 hour. To it are added dropwise a solution of the product obtained in Preparation 3 (600 mg, 1.7 mmol)in THF (3 ml) and stirred the reaction mixture for a further 1 hour at -78°C. the Reaction mixture is heated to 0°C for 2.5 hours. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layers are combined, dried and concentrated. Purification of the residue by chromatography on a column gives the desired compound (0.5 g).).1H NMR (CDCl3) δ of 7.90 (d, 2H), 7,65 (t, 1H), 7,31 (d, 2H), 7,26 (t, 2H), 7,13 (m, 3H), 6,63 (d, 1H), 5,64 (s, 1H), 5,15 (s, 1H, HE), of 3.96 (s, 3H), 3,17 (s, br, 2H), 2,33 (m, 4H), of 2.21 (m, 2H), 1,74 (d, br, 2H).

Example 6

8-[Bis-(2-chlorophenyl)-methyl]-3-methoxy-3-(2-pyrimidinyl)-8-azabicyclo-[3.2.1]-octane

The product obtained in Example 1 (300 mg, of 0.68 mmol)in THF (3 ml) and DMF (1 ml) is treated with NaH (30 mg, 0.75 mmol) at 0°C for 30 minutes. Add CH3l and the reaction mixture is heated to room temperature. After stirring during the course the e night reaction stop using H 2O, extracted with EtOAc, washed with brine, dried and concentrated. The resulting residue is purified by chromatography on a column and get the desired compound (0,25 g).1H NMR (CDCl3) δ 8,77 (d, 2H), 7,83 (d, 2H), 7,27 (d, 2H), 7,18 (m, 3H), 7,10 (t, 2H), 5,54 (s, 1H), 3.15 in (s, br, 2H), 2,99 (s, 3H), of 2.38 (dd, 2H), 2,12 (m, 6H),

Example 7

8-[Bis-(2-chloranil)-methyl]-3-(1H-pyrazole-5-yl)-8-azabicyclo-[3.2.1]-Octan-3-ol

The pyrazole (0.68 g, 10 mmol) in water (4 ml) at room temperature was added formaldehyde (37 wt.%, 1.5 ml, 50 mmol), stirred at room temperature overnight. Extracted with CH2Cl2, dried (Na2SO4) and concentrate and get 1-hydroxymethyluracil. To a solution of 1-hydroxymethylimidazole (129 mg, 1,31 mmol) in THF (2 ml) at -78°With added freshly prepared LDA (2,63 mmol) in THF, stirred at -20°C for 40 minutes and cooled to -78°C. thereto are added dropwise a solution of the product obtained in Preparation 3 (236 mg, of 0.65 mmol)in THF (3 ml) and stirred the reaction mixture for a further 2 hours at -78°C. the Reaction mixture warmed to room temperature and stirred over night. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with ether. The organic layers are combined, dried, filtered and concentrated. Purification of the residue with OSU preparative thin-layer chromatography and HPLC gives the desired compound (25 mg). 1H NMR (CDCl3) δ 8,2 (s, br, 2H), with 8.05 (d, 2H), 7,25-7,40 (m, 6H), 7,20 (t, 2H), 6,2 (s, br, 1H), 5,9 (s, 1H), 3,2 (s, br, 2H), by 2.55 (d, 2H), 2,41 (dd, 2H), 2,3 (m, 2H), 1,95 (d, 2H).

Example 8

8-[Bis(2-chlorophenyl)-methyl]-3-(1-methyl-pyrazole-5-yl)-8-azabicyclo-[3.2.1]-Octan-3-ol

To a solution of the product obtained in Example 8 (70 mg, 0,164 mmol)in THF at 0°With added NaH (9,84 mg, 0,246 mmol) and stirred for 30 minutes. Add CH3I (34,89 mg, 0,246 mmol), warmed to room temperature and stirred over night. The reaction is stopped with a saturated aqueous solution of NH4Cl, extracted with EtOAc, dried (Na2SO4), filtered and concentrated. Purification of the residue using preparative thin-layer chromatography gives the desired compound (51 mg).1H NMR (CDCl3) δ a 7.85 (d, 2H), and 7.3 (m, 6H), to 7.15 (t, 2H), 6,21 (s, 1H), 5,6 (s, 1H), 3,85 (s, 3H), 3.15 in (s, br, 2H), 2,6 (s, 1H), 2,2-2,4 (m, 6H), of 1.85(d,2H).

Example 9

8-[Bis(2-chlorophenyl)-methyl]-3-(1-methyl-1H-indol-2-yl)-8-azabicyclo-[3.2.1]-Octan-3-ol

n-BuLi (1.6 M in hexane, of 0.32 ml, 0.51 mmol) are added dropwise to a solution of 1-methylindole (67 mg, 0.51 mmol) in THF (2 ml) at -20°C, warmed to room temperature, stirred for 3.5 hours and cooled to -78°C. To it was added a solution of the product obtained in Synthesis 3 (92 mg, 0.26 mmol)in THF (2 ml). The reaction mixture is heated to room the first temperature and stirred for 1.5 hours. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layers are combined, dried and concentrated. Purification of the residue using preparative thin-layer chromatography gives the desired compound (5 mg).1H NMR (CDCl3) δ 7,80 (d, 2H), 7,60 (d, 1H), 7,05-7,35 (m, 9H), of 6.45 (s, 1H), of 5.55 (s, 1H), 3,20 (s, br, 2H), by 2.55 (dd, 2H), 2,15 (br, s, 4H), 2,1 (d, 2H).

Example 10

8-[Bis(2-chlorophenyl)-methyl]-3-(1-methyl-1H-imidazol-2-yl)-8-azabicyclo-[3.2.1]-Octan-3-ol

n-BuLi (2.5 M in hexane, to 0.60 ml, 1.50 mmol) are added dropwise to a solution of 1-methylimidazole (0.15 g, 1.88 mmol) in THF (2 ml) at -78°C and stirred for 1.5 hours. To it are added dropwise a solution of the product obtained in Preparation 3 (0.20 g, 0.55 mmol)in THF (2 ml) and the reaction mixture is stirred for a further 2 hours at -78°C. the Reaction mixture was warmed to room temperature for overnight, the reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layers are combined, dried and concentrated. Purification of the residue by chromatography on a column gives the desired compound in the form of a pale yellow solid (80 mg).1H NMR (CDCl3) δ 7,79 (d, 2H), 7,27 (d, 2H), 7,18 (t, 2H), 7,10 (t, 2H), 6,63 (d, 2H), 5,48 (s, 1H), 3,74 (s, 3H), is 3.08 (br s, 2H), 2,45 (d, 2H),and 2.14(m,4H), of 1.81 (d, 2H).

Example 11

8-[Bis(2-chlorophenyl)-mate the]-3-(3-pyridazinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

n-BuLi (2.5 M in hexane, 4.8 ml, of 12.0 mmol) are added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (1,67 g, to 11.9 mmol) in THF (40 ml) at -78°C and stirred for 0.5 hour. The reaction mixture is heated to 0°C for 0.5 hour. The reaction mixture was cooled to -78°With added dropwise a solution of pyridazine (0,94 g, 11.7 mmol) in THF (5 ml) and stirred the reaction mixture for 15 minutes at -78°C. To it is added dropwise a solution of the product obtained in Preparation 3 (1.0 g, 2.8 mmol)in THF (5 ml) and stirred the reaction mixture for a further 1 hour at -78°C. the Reaction mixture is heated to room temperature over night. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layers are combined, dried and concentrated. Purification of the residue by chromatography on a column gives the desired compound (300 mg).1H NMR (CDCl3) δ 9,10 (dd, 1H), 7,87 (d, 2H), 7,81 (dd, 1H), 7,53 (dd, 1H), 7,29 (d, 2H), 7,26 (t, 2H), 7,14 (t, 2H), 5,62 (s, 1H), 4,71 (br s, 1H), 3,20 (br s, 2H), of 2.38 (m, 4H), of 2.23 (m, 2H), 1,80 (d, 2H).

Example 12

8-[Bis(2-chlorophenyl)-methyl]-3-(2-pyrazinyl)-8-azabicyclo[3.2.1]Octan-3-ol

t-BuLi (of 1.7 M in pentane, 6,0 ml, 10.2 mmol) are added dropwise to a solution of godperson (1.0 g, 4.9 mmol) in diethyl ether (20 ml) at -50°C and stirred for 0.5 hour. To it is added dropwise a solution of the product, obtained in Preparation 3 (1.0 g, 2.8 mmol)in THF (4 ml) and the reaction mixture is stirred for a further 1.5 hours at -50°C. the Reaction mixture was warmed to room temperature for over night. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layers are combined, dried and concentrated. Purification of the residue by chromatography on a column gives the desired compound (400 mg).1H NMR (CDCl3) δ 8,96 (s, 1H), of 8.47 (m, 2H), 7,89 (d, 2H), 7,29 (d, 2H), 7,27 (t, 2H), 7,14 (t, 2H), 5,63 (s, 1H), 4,34 (s, 1H), 3,20 (br s, 2H), is 2.37 (m, 4H), 2,22 (m, 2H), 1,76 (d, 2H).

Example 13

8-[Bis(2-chlorophenyl)-methyl]-3-(4-pyrimidinyl)-8-azabicyclo[3.2.1]Octan-3-ol

Stage 1: 8-[Bis(2-chlorophenyl)methyl]-3-(5-bromo-4-pyrimidinyl)-8-azabicyclo-[3.2.1]Octan-3-ol

To a solution of 5-bromopyridine (450 mg, 2.77 mmol) and the product obtained in Preparation 3 (1 g, 2.77 mmol)in THF (5 ml) added dropwise pre-cooled (using solid carbon dioxide), freshly prepared LDA (2.77 mmol) in THF (5 ml) and stirred at room temperature overnight. The reaction is stopped with ice-N2O, extracted with EtOAc, dried, filtered and concentrated. Purification of the residue by chromatography on a column gives the desired compound (187 mg).

Stage 2:

The product obtained in stage 1 (22 mg)in CH3HE-tOAc (1:1,10 ml) and NH 3/CH3HE (7, N, 1 ml) hydronaut in the presence of Lindlar catalyst at a pressure of 1 ATM for 2 hours, filter and concentrate and get the desired connection.1H NMR (CDCl3) δ to 9.15 (s, 1H), to 8.70 (d, 1H), 8,00 (m, 2H), 7,80 (d, 1H), 7,25 (m, 4H), 7,19 (t, 2H), 5,61 (s, 1H), 3.15 in (br s, 2H), 2,50 (dd, 2H, in), 2.25 (m, 4H), of 1.65 (d, 2H).

Example 14

8-[Bis(2-chloranil)-methyl]-3-(5-bromo-2-pyridinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

BuLi (of 1.6 M in hexane, to 1.59 ml, 2.54 mmol) was added to 2,5-dibromopyridine (501 mg, 2,12 mmol) in toluene (13 ml) at -78°C and stirred for 2 hours. Add the product obtained in Preparation 3 (501 mg, 2,12 mmol)in toluene (2 ml) at -78°C and stirred for 3 hours. Warmed to room temperature, the reaction stopped with a saturated aqueous solution of NH4Cl, extracted with CH3Cl2, dried and concentrated. Purification of the residue using preparative thin-layer chromatography and HPLC gives the desired connection.1H NMR (CDCl3) δ 8,59 (s, 1H), a 7.85 (m, 3H), 7,50 (d, 1H), 7,25 (m, 4H), 7,19 (t, 2H), 5,61 (s, 1H), around 4.85 (s, 1H), 3,20 (br s, 2H), 2,15-to 2.40 (m,4H), of 1.75(d,2H).

Example 15

1,1-Dimethylethyl-[2-[[[[[6-[8-[bis(2-chlorophenyl)methyl]-3-hydroxy-8-Aza-bi-cyclo[3.2.1]-Oct-3-yl]-2-pyridinyl]methyl]amino]carbonyl]-amino]-ethyl]-carbamate

Stage 1: 2-bromo-6-hydroxymethyluracil

NaBH4(1,46 g, 38,58 mmol) is riboulet to 6-bromo-2-pyridine-carboxaldehyde (5.32 g, 28,58 mmol) in CH3HE is at 0°C and stirred at 0°C for 1 hour, extracted with CH2Cl2, dried over Na2SO4and concentrate and get the desired connection.

Stage 2: 2-bromo-6-(tert-butyldimethylsiloxy)pyridine

To a solution of the product obtained in stage 1 (5,54 g, 29,46 mmol), and tert-butyldimethylsilyl (equal to 4.97 g, 32,99 mmol) in CH2Cl2(60 ml) at room temperature is added imidazole (3,01 g, 44,19 mmol) and stirred over night. Filter the reaction mixture and concentrate the filtrate. The residue is purified using chromatography and get the desired connection.

Stage 3: 8-[Bis(2-chlorophenyl)-methyl]-3-(6-(tert-butyldimethylsiloxy)-2-pyridinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

n-BuLi (1.6 M in hexane, to 7.2 ml, 11,49 mmol) was added to the product obtained in stage 2 (3,29 g, 10,88 mmol)in THF (5 ml) at -78°C and stirred for 1 hour. Add the product obtained in Preparation 3 (1.84 g, 5,11 mmol)in THF (14 ml) at -78°slowly heated to 0° (˜2 hours). The reaction is stopped with a saturated aqueous solution of NH4Cl, extracted with EtOAc, dried and concentrated. The residue is purified by chromatography on a column and get the desired connection.

Stage 4: 8-[Bis(2-chlorophenyl)-methyl]-3-(6-hydroxymethyl)-2-pyridinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

the solution of the product obtained in stage 3 (2,34 g, 4,01 mmol)in THF (30 ml) at room temperature was added tetrabutylammonium (2.1 g, of 8.04 mmol) and stirred over night. The reaction is stopped with a saturated aqueous solution of NaHCO3, extracted with EtOAc, dried over Na2SO4and concentrate. The residue is purified by chromatography on a column and get the desired connection.

Stage 5: 3-[6-(Azidomethyl)-2-pyridinyl]-8-[bis-(2-chlorophenyl)-methyl]-8-azabicyclo-[3.2.1]-Octan-3-ol

To the product obtained in stage 4 (404 mg, 0.86 mmol), at 0°add diphenylphosphinite (272 mg, 0,99 mmol) and 1,8-diazabicyclo-[5,4,0]undec-7-ene (150 mg, 0,99 mmol), stirred for 20 minutes, warmed to room temperature, then stirred at 50°C for 1 hour. Cooled to room temperature and stirred over night. The reaction is stopped using H2O and saturated aqueous solution of NH4Cl, extracted with CH2Cl2, dried and concentrated. The residue is purified by chromatography on a column and get the desired connection.

Step 6: 3-[6-(Aminomethyl)-2-pyridinyl]-8-[bis-(2-chlorophenyl)-methyl]-8-azabicyclo-[3.2.1]-Octan-3-ol

To a suspension of the product obtained at stage 5 (279 mg)in a mixture of EtOAc and CH3HE is in the presence of 7 N NH3in CH3HE (1 ml) was added Lindlar catalyst (44 mg). With the ect hydronaut at 1 ATM for 1.5 hours, filtered through celite, rinsing with NH3/CH3HE (3,5 N) and concentrate and get the desired connection.

Step 7:

To a solution of the product obtained at stage 7 (157 mg, 0,335 mmol)in toluene (10 ml) at room temperature in an argon atmosphere is added triphosgene (34.8 mg, 0,117 mmol) and diisopropylethylamine (222 mg, 1,675 mmol). Heated to 120°C and stirred for 2.5 hours. Cooled to room temperature, was added N-Boc-Ethylenediamine (65 mg, 0.42 mmol) and stirred over night. The reaction is stopped with a saturated aqueous solution of NH4Cl, extracted with EtOAc, dried over N2SO4and concentrate. The residue is purified using preparative thin-layer chromatography and get the desired connection.1H NMR (CDCl3) δ to 7.9 (d, 2H), of 7.75 (t, 1H), 725 (d, 1H), and 7.1 to 7.4 (m, 4H), 5,65 (s, 1H), 5.25 in (b, s, 1H), 4,45 (d, 2H), 3,25 (m, 2H), 3,1 (m, 4H), of 2.15-2.45 (m, 6H), of 1.65 (d, 2H).

Example 16

N-(2-(Aminoethyl)-N'-[[6-[8-[bis-(2-chlorophenyl)-methyl]-3-hydroxy-8-azabicyclo-[3.2.1]-Oct-3-yl]-2-pyridinyl]-methyl]-urea

To a solution of the product obtained in Example 15 (53 mg)in CH2Cl2and CH3HE at room temperature was added HCl (1 N in ether, 1.0 ml) and stirred until LC-MS (liquid chromatography-mass spectroscopy) will not indicate full use of the product obtained in Example 15, and receive the have the desired compound as hydrochloride. MS-IER (mass spectrometry with ionization by elektrorazpredelenie) 554,1 (100, M+).

Example 17

3-[3-(Aminomethyl)-2-pyridinyl]-8-[bis-(2-chlorophenyl)-methyl]-8-sabicic-lo[3.2.1]-Octan-3-ol

Stage 1: 2-Bromo-3-hydroxymethyluracil

To a solution of 2-bromo-3-pyridineboronic acid (5,63 g, 27,89 mmol) and Et3N (2,96 g, 29,28 mmol) in toluene (150 ml) at room temperature was added ethylchloride (3,17 g, 29,28 mmol) and stirred for 1 hour, filtered and concentrated. The residue is dissolved in THF (93 ml)at -78°With added dropwise to a suspension of LiAIH4(1,11 g, 29,28 mmol) in THF (37 mmol) and stirred for 30 minutes. The reaction is stopped with a saturated aqueous solution of NH4Cl, stirred at room temperature for 1 hour, filtered through celite, extracted with EtOAc, dried over Na2SO4and concentrate. Purification of the residue by chromatography on a column gives the desired connection.

Stage 2: 2-bromo-3-(tert-butyldimethylsiloxy)pyridine

According to the method described in stage 2 of Example 15, using 2-bromo-3-hydroxymethylbilane (3,66 g, 19,48 mmol), tert-butyldimethylsilyloxy (by 5.87 g, 38,97 mmol) and imidazole (of 3.31 g, 48,71 mmol) to obtain the desired compound (6,38 g).

Stage 3: 8-[Bis(2-chlorophenyl)-methyl]-3-(3-(tert-butyldimethylsiloxy)-2-pyridinyl)-8-azab the cyclo-[3.2.1]-Octan-3-ol

According to the method described in stage 3 of Example 15, using the product obtained in stage 2 (6,38 g, 21.1 mmol), n-BuLi (1.6 M in hexane, to 14.5 ml, 21.1 mmol) and the product obtained in Preparation 3 (of 7.60 g, 21.1 mmol), get the required product.

Stage 4: 8-[Bis-(2-chlorophenyl)-methyl]-3-(3-hydroxymethyl)-2-pyridinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

According to the method described in stage 4 of Example 15, using the product obtained in stage 3 (12.3 g, 21.1 mmol), and tetrabutylammonium (11 g, 42,2 mmol) get the desired connection.

Stage 5: 3-[3-(Azidomethyl)-2-pyridinyl]-8-[bis(2-chlorophenyl)-methyl]-8-azabicyclo-[3.2.1]-Octan-3-ol

According to the method described in stage 5 of Example 15, using the product obtained in stage 4 (for 95.2 mg, 0,213 mmol), diphenylphosphinite (67,4 mg, 0,245 mmol) and 1,8-diazabicyclo-[5,4,0]-undec-7-ene (52,96 mg, 0.32 mmol) as contained in fewer product get the desired connection.

Step 6:

According to the method described in stage 6 of Example 15, using the product obtained at stage 5 (69 mg) and Lindlar catalyst (7 mg) receive the desired connection.1H NMR (CDCl3) to 8.40 (d, 1H), 7,95 (d, 2H), 775 (d, 1H), 7,05-to 7.15 (m, 7H), ceiling of 5.60 (s, 1H), 5.25 in (b, s, 1H), and 4.40 (s, 2H), 3,20 (s, br, 2H), 2,50 (dd, 2H), 2,3 (m, 4H), of 1.75 (d, 2H).

Example 18

8-[Bis(2-chlorophenyl)-methyl]-3-[4-(methylamino)-2-pyridinyl]-8-azabicyclo-[3.2.1]-Octan-3-ol

Stage 1: 2-bromo-4-(tert-butoxycarbonylamino)pyridine

A mixture of 4-amino-2-bromopyridine (1,00 g, 5,79 mmol), Et3N (1,75 g, 17,37 mmol) and di-tert-BUTYLCARBAMATE (1.90 g, 8.69 mmol) in CH2Cl2(20 ml) was stirred at room temperature overnight. Diluted with CH2Cl2(10 ml), washed with saturated aqueous NaHCO3, dried over MgSO4and concentrate. The residue is purified by chromatography on a column and get the desired connection.

Stage 2: - Dimethylethyl-[2-[8-[bis(2-chlorophenyl)-methyl]-3-hydroxy-8-Aza-bicyclo-3.2.1]-Oct-3-yl]-4-pyridinyl]-carbamate

n-BuLi (1.6 M in hexane, 1,12 ml of 1.81 mmol) was added to the product obtained in stage 1 (237 mg, 0.87 mmol)in THF (2.7 ml) at -78°C and stirred for 2 hours. Add the product obtained in Synthesis 3 (337 mg, of 0.94 mmol)in THF (1 ml) at -78°C and stirred for 3 hours, warmed to room temperature and stirred over night. The reaction is stopped with a saturated aqueous solution of NH4Cl, extracted with EtOAc, dried and concentrated. The residue is purified by chromatography on a column and get the desired product.

Stage 3:

To a solution of the product obtained in stage 2 (48,4 mg, 0,087 mmol), in dioxane (0.5 ml) at room temperature was added LiAlH4(1 M in ether, of 0.26 ml, 0.26 mmol) in dioxane (0.5 ml) and re is eshivot boiling under reflux overnight. Cooled to room temperature, was added LiAlH4(1.0 M in ether, 0.2 ml) and stirred at the boil under reflux for 5 hours. The reaction is stopped using H2About (0.05 ml), aqueous NaOH (15%, 0.1 ml) and N2About (0.05 ml). Diluted with EtOAc, filtered and concentrated. The residue is purified by chromatography on a column and get the desired connection.1H NMR (CDCl3) 8,10 (d, 1H), 7,95 (d, 2H), 7,05-to 7.15 (m, 6H), 6.75 in (s, 1H), 6,39 (d, 2H), 5,70 (s, 1H), 3,20 (s, br, 2H), 2.95 and (s, 3H), 2,35 (m, 4H), 2,2 (m, br, 2H), 1,65 (d, 2H).

Example 19

3-[6-[(2-amino-ethyl)-amino]-2-pyridinyl]-8-[bis-(2-chlorophenyl)-methyl]-8-azabicyclo-[3.2.1]-Octan-3-ol

Stage 1: 8-[Bis(2-chlorophenyl)methyl]-3-(6-bromo-2-pyridinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

n-BuLi (of 1.6 M in hexane, to 26.8 ml, 42,92 mmol) was added to 2,6-dibromopyridine (12.2 g, 51,5 mmol) in THF (150 ml) at -78°C and stirred for 2 hours. Add the product obtained in Synthesis 3 (9.28 are g, 25,75 mmol)in THF (50 ml) at -78°C and stirred for 3 hours, warmed to room temperature and stirred over night. The reaction is stopped with a saturated aqueous solution of NH4Cl, extracted with EtOAc, dried and concentrated. The residue is purified by chromatography on a column and get the desired product.

Stage 2: 1,1-Dimethylethyl-[2-[6-[8-[bis(2-chlorophenyl)-methyl]-3-hydroxy-8-AZ is bicyclo-[3.2.1]-Oct-3-yl]-2-pyridinyl]-amino-ethyl]-carbamate

A solution of the product obtained in stage 1 (and 64.5 mg, 0,128 mmol), N-Boc-Ethylenediamine (123 mg, 0.77 mmol) and pyridine (12 mg, 0,154 mmol) was stirred at 110°C in a sealed tube for 3.5 hours. Cooled to room temperature, was added N-Boc-Ethylenediamine (0.3 ml) and heated at 140°With during the night. Cooled to room temperature, the reaction is stopped using H2O, extracted with EtOAc, dried and concentrated. The residue is purified by chromatography on a column and get the desired product.

Stage 3:

To a solution of the product obtained in stage 2 (11 mg, 0.018 mmol)in CH2Cl2at room temperature for 24 hours was added HCl (1 N in ether, 0,36 ml). Add HCl (1 N in ether, 0,36 ml) and stirred at room temperature for 24 hours. Add more of 0.36 ml HCl (1 N in ether) and stirred at 30°C for 24 hours. Concentrated, treated with ether and filtered and receive the desired compound as a white solid. MS-IER 497,1 (100, M+).

Example 20

8-[Bis-(2-chlorophenyl)-methyl]-3-(1,4,5,6-tetrahydro-2-pyrimidinyl)-8-azabicyclo-[3.2.1]-Octan-3-ol

To a solution of the product obtained in Example 1 (160 mg)in ethanol (10 ml) at room temperature was added Raney Nickel. Heated to 80°C and stirred for 20 hours, filtered and the concentration of irout. The residue is purified by chromatography on a column and get the desired connection.1H NMR (CDCl3) a 7.85 (d, 2H), 7,25 (m, 4H), to 7.15 (t, 2H), of 5.55 (s, 1H), 3,40 (dd, 4H), 3,10 (s, br, 2H), 2.05 is to 2.35 (m, 6H), to 2.75 (q, 2H), 1.55V (d, 2H).

The compounds of formula I are more than 50-fold selectivity with respect to the classical opioid receptors. Receptor ORL-1 is characterized by a high degree of gomologichnosti with classical opioid receptors (i.e., μ, κ and δ), but the receptor ORL-1 is not activated by endogenous opioids and endogenous opioids do not activate the receptor ORL-1. It is known that codeine and other opioids, used to suppress coughs, activate opioid receptor μ, leading to side effects such as respiratory depression, constipation, tolerance and physical dependence. Agonists of the receptor ORL-1 does not activate opioid receptor μ and therefore presumably lead to a superior safety profile compared with opioids.

The activity of compounds of the formula I, as agonists of the receptor ORL-1, and their effect on the cough and breathing can be quantitatively determined using the following studies.

The analysis of binding nociceptin

Preparation of cell membranes of Chinese hamster ovary expressing the receptor ORL-1 (2 mg), incubated with [125I][Tyr14]nociception in various concentrations (3-500 PM) in buffer Rast is ora, containing 50 mM HEPES (pH 7.4), 10 mm NaCl, mm MgCl2, 2.5 mm CaCl21 mg/ml bovine serum albumin and 0.025% bacitracin. In a number of research tests conducted in a buffer solution containing 50 mm tris-HCl (pH 7.4), 1 mg/ml bovine serum albumin and 0.025% bacitracin. The samples incubated for 1 hour at room temperature (22°). Labeled ligands associated with the membrane are collected on filters, GF/B, pre-soaked in 0.1% polyethylenimine, using the device to collect cells Brandell and washed 5 times with 5 ml of cold distilled water. Nonspecific binding is determined in parallel with similar analyses carried out in the presence of 1 μm nociceptin. Analyses at every conditions perform twice, specifying the full and nonspecific binding.

Calculation of Ki values carried out by methods well known in the art.

For compounds of the present invention obtained Ki values are in the range from 0.6 to 30 nm, and the preferred are compounds with Ki values equal to less than 10 nm.

The Ki values for some common compounds presented in the Table below:

Example No.Ki (nm)Example No.Ki (nm)
16,286,0
27,6117,0
34,0122,0
44,0141,3
6of 5.4

Using the techniques described in European Journal of Pharmacology, 336 (1997), p.233-242, it is determined activity of the compounds of the present invention, as agonists. Measured activity as agonists (EC50) of these compounds is in the range of 20-200 PM.

The study cough

The effects of agonist nociceptin estimated using induced by capsaicin cough in Guinea pigs according to the methods proposed Bolser et al. British Journal of Pharmacology (1995) 114, 735-738 (see also McLeod et al., British Journal of Pharmacology (2001) 132,1175-1178). This model is a widely used technique for assessment of activity possible antitussive drugs. Starving during the night of male Hartley Guinea pigs (350-450 g, Charles River, Bloomington, MA, USA) placed in a transparent chamber 12×14 inches. To create the cough reflex in animals exposed to aerosol of capsaicin (300 μm, for 4 minutes), the obtained inkjet dispenser (Puritan Bennett, Lenexa, KS, USA). Each Guinea pig is exposed to caps what izina only once. The number of cough registers microphone placed in the camera, and checks the trained observer. The signal from the microphone is fed to a polygraph, which registers the number of coughs. 2 hours before exposure to capsaicin aerosol injected or filler (methylcellulose, 1 ml/kg, orally) or investigational compounds. As a positive control, also determine the antitussive activity of baclofen (3 mg/kg, orally).

Studies of breath

Studies conducted on male Hartley Guinea pigs weighing between 450 to 550, Animals starve during the night, but they give unlimited water. Guinea pigs head out placed in plethysmograph to register the change of volume of the body and on the animal's head is placed a rubber collar and get a tight seal between the Guinea pig and plethysmography. The air flow is measured by the differential pressure on the wire mesh covering the 1-inch hole in the wall plethysmograph. The signal of the air flow is integrated in the signal, proportional to the volume, using the pre-amplifier and a computer, registering lung function (Buxco Electronics, Sharon, CT., model XA). To pletismography attach the head to the camera and throughout the study through the head chamber circulates the air coming from the source of compressed air is (21% O 2rest N2). All studies of respiration is carried out with Guinea pigs inhaling this circulating air,

The signal about the volume coming from each animal, directed to the storage system/data analysis (Buxco Electronics, model XA), which calculates the tidal volume and the respiratory rate for periods between successive breaths. These signals are displayed on the monitor screen. Tidal volume and respiratory rate as average values are recorded every minute.

Guinea pigs give to calm down in pletismography within 30 minutes. Measure baseline values carried out at the end of this 30-minute period. Then Guinea pigs extract from plethysmograph and orally administered investigational compound (10 mg/kg, orally), baclofen (3 mg/kg, orally) or filler methylcellulose placebo (2 ml/kg, orally). Immediately after injection of Guinea pigs placed in plethysmograph, re-attach the head chamber and circulating the air and after 30, 60, 90 and 120 minutes after injection to measure respiratory parameters (tidal volume (VT), breathing frequency (f) and minute volume (MV=VT×f)). This study conducted by the ACUC Protocol #960103.

In the methods of the present invention can enter from one to three compounds of the formula I, preferably one connection.

Connection is about the present invention possess antitussive activity that makes them applicable as a cough suppressant in mammals. Mammals, which treat cough, at least one agonist nociceptin receptor ORL-1 can be assigned in conjunction with one or more additional drugs for symptomatic treatment of cough, Allergy or asthma, selected from the group including antihistamines, inhibitors of 5-lipoxygenase, leukotriene inhibitors, inhibitors of N3, agonists β-adrenergic receptor, xanthine derivatives, agonists α-adrenergic receptor, stabilizers fat cells, antitussive drugs, expectorants drugs, receptor antagonists tachykinin NK1NK2and NK3and agonists GABAB. Preferably, the combination of the present invention include one compound of formula I and 1-3 additional drug, preferably 1-2 additional drug, and more preferably 1 extra drug.

Non-limiting examples of antihistamines include astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine (also known as SCH-34117), doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, lorat the Dean, levocabastine, mizolastine, Aquitain, mianserin, doberstyn, meclizine, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

Non-limiting examples of antagonists of the receptor N3histamine include: typename, impromidine, burimamide, closedprofit, impactmin, mepetidine, S-supremity, R-supremity, SKF-91486, GR-175737, GT-2016, UCL-1199 and clozapine. Other compounds can be easily examined to determine activity against receptors N3using known methods, including analysis of the brain membranes of Guinea pigs and analysis of the nervous contraction of the ileum of Guinea pigs, which are described in U.S. patent US 5352707. In another useful method of analysis used membranes of rat brain and it is described in the work of West et al., "Identification of Two-H3-Histamine Receptor Subtypes," Molecular Pharmacology, Vol.38, pages 610-613 (1990).

The term "leukotriene inhibitor" includes any agent or compound that inhibits, restricts or otherwise affects the action or activity of leukotrienes. Non-limiting examples of inhibitors include leukotriene montelukast [R-(E)]-1[[[1-[3-[2-(7-chloro-2-chinoline)-ethynyl]phenyl]-3[2-(1-hydroxy-1-methylethyl)phenyl]propyl]-thio]-methyl]-cyclopropanecarbonyl acid and its sodium salt, is described in European patent application EP 0480717; 1-((()-(3-(2-(6,7-debtor-2-chinoline)ethynyl)phenyl)-3-(2-(2-hydroxy-2-propyl)-phenyl)-thio)-methylcyclopropane acid and its sodium salt, described in the international application WO 97/28797 and U.S. patent US 5270324; 1-(((1(R)-3(3-(2-(2,3-dichlorethene-[3,2-b]-pyridine-5-yl)-(E)-ethynyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)-phenyl)propyl)-thio)-methyl)-cyclopropanecarbonyl acid and its sodium salt, is described in international application WO 97/28797 and U.S. patent US 5472964; pranlukast, N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-n-(4-phenylmethoxy)-benzamide), described in international application WO 97/28797 and European patent application EP 173516; zafirlukast (cyclopentyl-3-[2-methoxy-4-[(o-tamilselvan)-carbarnoyl]-benzyl]-1-methyl-indol-5-carbamate), described in the international application WO 97/28797 and European patent application EP 199543; and [2-[[2(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]-hydroxy-methyl]-phenyl]-acetic acid, described in U.S. patent US 5296495 and Japanese patent JP 08325265 A.

The term "inhibitor of 5-lipoxygenase" or "inhibitor of 5-LO" includes any agent or compound that inhibits, retards or otherwise affect the enzymatic action of 5-lipoxygenase. Non-limiting examples of inhibitors of 5-lipoxygenase include zileuton, docebenone, periost, ICl-D2318 and AUTHOR 761.

Non-limiting examples of agonists β-adrenergic receptor include albuterol, bitolterol, isoetharine, metaproterenol, pirbuterol, salmeterol, terbutaline, isoproterenol, ephedrine and epinephrine.

A non-limiting example of production is underwater xanthine is theophylline.

Non-limiting examples of agonists α-adrenergic receptor include arylalkylamine (for example, phenylpropanolamine and pseudoephedrine), imidazoles (for example, nafazolina, Oxymetazoline, tetrahydrozoline and Xylometazoline) and cyclooctylamine (for example, propylhexedrine).

A non-limiting example of a stabilizer of mast cells is the sodium salt of nedocromil.

Non-limiting examples of antitussive drugs include codeine, dextromethorphan, benzonatate, chlophedianol and escarpin.

A non-limiting example of an expectorant drug, is guaifenesin.

Non-limiting examples of receptor antagonists tachykinin NK1NK2and NK3include CP-99,994 and SR 48968.

Non-limiting examples of agonists GABABinclude baclofen and 3-aminopropylphosphonic acid.

In the manufacture of pharmaceutical compositions from the compounds described in this invention, inert, pharmaceutically acceptable carriers can be solid or liquid. The solid form preparations include powders, tablets, dispergirujutsja granules, capsules, pills and suppositories. The powders and tablets may contain from about 5 to about 70% of the active component. Suitable solid carriers are known in the art and include, for example, magnesium carbonate, magnesium stearate, that is RC, sugar, lactose. Tablets, powders, pills and capsules can be used as solid dosage forms suitable for oral administration.

For preparing suppositories low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, is first melted and evenly dispersed active component, for example, by stirring. The molten homogeneous mixture is then poured into the form of a standard size, allow it to cool and thereby solidify.

Liquid form compositions include solutions, suspensions and emulsions. As an example, you can specify water or water-propylene glycol solutions for parenteral injection.

To liquid form compositions can also include solutions for vnutripuzarnogo introduction.

Aerosol compositions suitable for inhalation may include solutions and solids in powder form, which can be combined with a pharmaceutically acceptable carrier, such as a compressed inert gas.

In the scope of the present invention also includes a solid form compositions which are intended for conversion into liquid form compositions intended for oral or parenteral administration, which is shortly before use. Such liquid forms include solutions, suspensions and emulsions.

Connect the ment of the present invention can also be entered percutaneous. Percutaneous composition can be creams, lotions, aerosols and/or emulsions and can be included in the matrix patch percutaneous exposure or patch reservoir type that is commonly used in the art for such purpose.

The compound of the present invention are preferably administered orally.

Preferably, the pharmaceutical composition is contained in a single dosage form. In this form, the composition is divided into single doses of appropriate size containing appropriate quantities of the active component, for example, the effective amount is sufficient to achieve the desired goals.

The number of active compound of formula I contained in one dose of the drug, in accordance with the specific case of application may be changed or adjusted from about 0.1 to about 1000 mg, more preferably from about 1 to about 300 mg

Used active dose may vary depending on the needs of the patient and severity at treatment of a pathological condition. Determination of appropriate dosing regime for a specific case holds a specialist in this field of technology. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Then increase the dose small the steps, until you reach the optimum under these circumstances the effect. For convenience, the total daily dose, if necessary, you can divide and assign portions during the day.

The amount and frequency of administration of compounds of the present invention and/or their pharmaceutically acceptable salts will be regulated in accordance with the decision of the attending physician, taking into account such factors as age, condition and weight of the patient, and the severity of the symptoms treated. A typical recommended daily dosage regime by oral administration may include the introduction of from 10 to 2000 mg/day, preferably from 10 to 1000 mg/day, administered by two to four divided doses, and to ensure the elimination of pain, anxiety, depression, asthma or alcohol dependence. With the introduction of this range of doses of the compounds are non-toxic.

When the agonist nociceptin receptor ORL-1 of the formula I is assigned with one or more additional drugs, the compound of formula I and the additional drug (more drugs) is preferably administered in a combined dosage form (e.g. a tablet), although they can be assigned individually. Additional drugs are administered in effective amounts and ensures the elimination of symptoms is s cough allergies or asthma, assigning preferably from about 0.1 to 1000 mg, more preferably from about 1 to 300 mg in one dose. Typical recommended dosing regime for more of the drug is from 1 to 2000 mg/day, preferably from 1 to 1000 mg/day in two to four divided doses. Typical values of the doses of other medicines can be taken from literature data, for example from the directory the Physicians''s Desk Reference.

The following are examples of pharmaceutical dosage forms, containing a compound of the present invention. Experts in the art should understand that such dosage forms can be easily modified with the inclusion of one or more active components. Scope of the present invention in its embodiment in the form of pharmaceutical compositions is not limited to the given examples.

Examples of pharmaceutical dosage forms

EXAMPLE AS Tablets

No.Componentsmg tabletmg tablet
1.Active connection100500
2.Lactose United States Pharmacopeia122113
3.Corn starch, food, in the form of 10% PA who you are in purified water 3040
4.Corn starch food4540
5.Magnesium stearate37
Only300700

A method of manufacturing

In a suitable mixer for 10-15 minutes mix components # 1 and # 2. The mixture granularit component No. 3. If necessary, the wet granules are passed through a coarse sieve (for example, 1/4 inch, 0,63 cm). The wet granules are dried. If necessary, dry granules are sieved and mixed with component No. 4 and stirred for 10-15 minutes. Add component # 5 and stirred for 1-3 minutes. The mixture is pressed into tablets of appropriate size and weight on a suitable teletrauma machine.

The EXAMPLE IN Capsules

No.Componentm g/capsulemg/capsule
1.Active connection100500
2.Lactose United States Pharmacopeia106123
3.Corn starch food4070
4.Magnesium stearate National is farmacevticheskogo directory 77
Only253700

A method of manufacturing

In a suitable mixer for 10-15 minutes mix components 1, 2 and 3. Add component # 4 and stirred for 1-3 minutes. The mixture is filled into the corresponding two capsules of hard gelatin on a suitable kapsulirujushchej machine.

Although the present invention is described in connection with specific variants of implementation of the above, for professionals with a common training in the art should be obvious, many alternatives, modifications, and changes. It is implied that all such alternatives, modifications and changes are included in the scope and essence of the present invention.

1. Heteroaryl compounds of General formula (I)

or its pharmaceutically acceptable salt,

where R means R4heteroaryl, and heteroaryl is a cyclic aromatic group with 5 or 6 carbon atoms, or a bicyclic group with 9 or 10 carbon atoms, comprising 1, 2 or 3 heteroatoms, independently selected from the group comprising oxygen, sulfur and nitrogen;

or;

R1means hydrogen or alkyl with 1-6 carbon atoms is kind;

R2and R3independently selected from the group comprising methyl, methoxy, fluorine, chlorine, bromine and iodine;

R4means from 1 to 4 substituents, independently selected from the group comprising hydrogen, halogen, alkyl with 1-6 carbon atoms, cyano, trifluoromethyl, triptoreline, -(CH2)n-OR5, -(CH2)n-NR5R6, -(CH2)n-NHSO2R5, -(CH2)n-NH(CH2)2NR5R6, -(CH2)n-NHC(O)NR5R7, -(CH2)n-NH(CH2)2OR5or 1-piperazinil;

n is 0, 1, 2 or 3;

R5and R6independently selected from the group comprising hydrogen and alkyl with 1-3 carbon atoms; and

R7denotes hydrogen, alkyl with 1-3 carbon atoms or aminoalkyl with 1-3 carbon atoms.

2. Heteroaryl compound according to claim 1, where R is 2-pyrimidinyl, 5-ethyl-2-pyrimidinyl, 4-(1-piperazinil)-2-pyrimidinyl, 2-pyridyl or 6-methoxy-2-pyridyl.

3. Heteroaryl compound according to claim 1, where R1means hydrogen or methyl.

4. Heteroaryl compound according to claim 1, where R2means of 2-chloro and R3means 2-chloro.

5. Heteroaryl compound according to claim 1, selected from the group comprising compounds of the formula

,,.

and

6. Heteroaryl compound according to claim 1, which represents a compound of formula

7. Pharmaceutical composition having the properties of the ligand of the receptor nociceptin ORL-1, comprising therapeutically effective amount of at least one compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, additionally comprising a therapeutically effective amount of one or more active substances selected from the group including: antihistamines, inhibitors of 5-lipoxygenase, leukotriene inhibitors, inhibitors of N3, agonists β-adrenergic receptor, xanthine derivatives, agonists α-adrenergic receptor, stabilizers fat cells, antitussive drugs, expectorants drugs, receptor antagonists tachykinin NK1NK2and NK3and agonists GABAB.

9. A method of treating cough, comprising introducing to a mammal in need of such treatment, the compounds according to claim 1.

10. The method according to claim 9, including additional introduction 1-3 active substances intended for the symptomatic relief of cough.



 

Same patents:

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

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The invention relates to derivatives of 3-(piperidinyl-1)-chroman-5,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)alkanol General formula I or their pharmaceutically acceptable salts accession acid, in which (a) R2and R5taken individually and R1, R2, R3and R4independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7and R5represents methyl; or (b) R2and R5taken together form a ring chroman-4-ol, a R1, R3and R4each independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7; R7represents methyl; and R6represents a substituted piperidinyl or 8-azabicyclo[3,2,1]octenidine derived; provided that (a) if R2and R5taken separately, at least one of R1, R2, R3and R4is not hydrogen; and (b) if R2and R5taken together, at least one of R1, R3and R4is not hydrogen, with the property that the NMDA antagonist

FIELD: organic chemistry, medicine.

SUBSTANCE: invention proposes using aryl(or heteroaryl)azolylcarbinol of the general formula (I) wherein Ar means possibly substituted phenyl or thienyl; R means hydrogen atom or alkyl; R2 means dialkylaminoalkyl or azaheterocyclylalkyl; Het means unsubstituted azol of substituted with one or two substitutes, and their salts. Proposed derivatives can be used as an agent for treatment of chronic obstructive pulmonary diseases (cough, bronchitis, allergic rhinitis and asthma). Proposed compound depresses cough being without sedative effect.

EFFECT: valuable medicinal properties of compounds.

4 cl, 1 tbl, 3 ex

FIELD: medicine, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to a medicinal formulation of tramadol with delayed-release. Proposed medicinal formulation possesses the high effectiveness in treatment of pains of different etiology and can be used in treatment of diseases chosen from the following group: enuresis, cough, inflammatory processes and/or allergic responses, depression states, abuse and/or alcoholism, gastritis, diarrhea, cardiovascular diseases, diseases of respiratory ways, psychic diseases, epilepsy.

EFFECT: improved and valuable medicinal and pharmaceutical properties of formulation.

38 cl, 11 tbl, 4 dwg, 11 ex

FIELD: medicine, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to pharmaceutical salts of the biologically active substance tramadol and at least one sugar substitute chosen from a group comprising saccharin, cyclamate or acesulfam, and a medicament comprising these salts, and its using in treatment of enuresis and pains. The claimed tramadol pharmaceutical salt and sugar substitute possesses the delayed release that provides prolonged curative effect.

EFFECT: improved and valuable medicinal and pharmaceutical properties of salts.

12 cl, 8 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes an orally administrated liquid composition used in treatment of respiratory diseases and comprising from 2% to 40% of guaifenesin and a filling agent comprising from 5% to 25% of polyoxyalkylene block-copolymer, from 30% to 90% of hydrophilic solvent, and from 5% to 45% of water. The composition shows high physical stability in delivery of the concentrated doses of pharmaceutically active component, in particular, the active component doesn't show precipitation from solution for the prolonged times. Also, the composition remains in a liquid form in the mouth cavity that provides the effect of the pharmaceutically active agent of the composition on large areas in the mouth cavity mucosa.

EFFECT: enhanced effectiveness and valuable medicinal properties of agent.

6 cl, 16 tbl, 1 dwg, 16 ex

FIELD: pharmaceutical technology.

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EFFECT: improved preparing method.

2 cl, 5 ex

FIELD: pharmaceutical industry.

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EFFECT: improved reliability during tableting and storage.

3 cl, 1 tbl, 16 ex

The invention relates to pharmaceutical
The invention relates to medicine, namely to therapy, and for the treatment of cough

The invention relates to new carboxyterminal cyclic carboxamide derivative of formula 1

< / BR>
where G1- CH2; G2- C(O); m = 2 or 3, n is 0 or 1; R1is 1-3 substituent, independently selected from H, G, C1-C6alkoxy; R2is 1-3 substituent, independently selected from H, C1-C6alkoxy; R3means N or

< / BR>
< / BR>
< / BR>
R4- H; Ar1means

< / BR>
< / BR>
R8means 1-3 substituent, independently selected from H, G; R9means N;

And means

< / BR>
< / BR>
< / BR>
where p = 1, 2, 3, or 4; X is-O-, -CH2-; R10-H, C1-C6alkyl or

< / BR>
">< / BR>
< / BR>
< / BR>
where q = 2 or 3; R5- C1-C4alkyl, (CH2)2HE; R6- C1-C4alkyl, -(CH2)2HE, (CH2)2N(CH3)2; R5', R6' - C1-C4alkyl; R7- C1-C6alkyl, and the stereoisomers and pharmaceutically acceptable salts
The invention relates to medicine, in particular, pharmacology, and can be used for treatment of cough syndrome

FIELD: medicine; pharmacology.

SUBSTANCE: invention can be applied for treatment of asthma and associated disorders, specifically for treatment of chronic obstructive lungs disease. This composition contains specific anticholinergic agents, antagonists of β-2 and corticosteroids.

EFFECT: favourable and improved asthma treatment.

33 cl, 43 ex

FIELD: medicine, phthisiology.

SUBSTANCE: it is necessary to introduce ipratropium bromide per 2 dosages at 6 a.m., 5 p.m. and 11 p.m. The innovation enables to change the mode of introducing chinolytics at taking into account the onset of the greatest bronchial obstruction during 24 h.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: chemistry of polymers.

SUBSTANCE: invention relates to a method for preparing medicinal polymers used in producing nicotine-containing preparations used for smoking lose the habit and possessing stimulating effect, and to nicotine-containing preparations. Invention describes a method for preparing copolymer of N-vinylpyrrolidone with lauryl methacrylate used for the transdermal administration of nicotine. Method involves radical copolymerization of co-monomers of N-vinylpyrrolidone and lauryl methacrylate in the presence of an emulsifying agent, hydrogen peroxide as a initiating agent, ammonium hydroxide and sodium metabisulfite at temperature 70-75°C. As an emulsifying agent nonylphenoxy-(ethoxy)9-sulfoacid ammonium salt is used. The process is carried out by preliminary preparing a mixture of ammonium hydroxide, co-monomers, initiating agent, sodium metabisulfite and water and administration of this mixture to the polymerization reactor containing preliminary prepared solution of emulsifying agent. Emulsifying agent solution is prepared by successive administration water to the polymerization reactor, nitrogen bubbling, water heating to temperature 80-85°C, cooling to a polymerization point after saturation of water with nitrogen and administration of emulsifying agent in the mass ratio of water amount used in preparing the mixture containing monomers and amount of water used in preparing solution of emulsifying agent from 20:80 to 40:60, and the polymerization process is carried out at constant bubbling of nitrogen. Increase of prolonged effect of the preparation used for the transdermal administration of nicotine is provides by mixing a prepared copolymer, propylene glycol, cellulose derivative, isopropylmyristate, stearic acid, aerosil, cetyl alcohol, nicotine and ethanol that involves preliminary dissolving water-insoluble copolymer of N-vinylpyrrolidone with unsaturated organic acid ester in ethanol followed by successive addition of propylene glycol and ethanol, and stirring. Then other components are added to the prepared mixture at constant stirring followed by addition of nicotine solution in remained amount of ethanol.

EFFECT: improved preparing method.

4 cl, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a novel drug based on anti-cholinergic agents and inhibitors of EGFR kinase, capsules containing inhalation powder and to using a drug designated for treatment of inflammatory and obstructive diseases of respiratory ways. Invention describes a novel medicinal agent useful in using in diseases of respiratory ways.

EFFECT: valuable medicinal and biochemical properties of compositions.

32 cl, 1 dwg, 19 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out patient premedication with Phenozepam tablets at a dose of 0.0005-0.001 g, Sibazon intramuscularly introduced at a dose of 10 mg 30 min before operation on the eve and in the morning at operation day and Dimedrol at a dose of 10 mg. Then the patient is placed on operational table on mattress heated to temperature of 37-39°C and connected to monitor. The central vein is punctured and catheterized and preoperative patient infusion preparation is started by intravenously dropping 500 ml of crystalloid solutions heated to temperature of 37-42°C like Ringer solution or Acesol, or Trisol, or Lactasol, and the same quantity of colloid solutions HES 6% or HES 10%. Then epidural space is punctured at Th7-L1 level with subsequent catheterization following so that with catheter top being arranged at Th5-Th11 level. 4 ml of 0.5% Bupivacaine hydrochloride solution test-dose is epidurally introduced in bolus mode into the epidural space with its action being estimated. Then anesthetic is fractionally introduced in 4-5 ml large portions under arterial blood pressure and pulse control with the total amount reaching 15-20 ml with earlier entered test-dose quantity being taken in account. Oxygen inhalation is carried out through narcosis apparatus mask at a rate of 5-8 l/min on the background of independent patient breathing. Then intravenous bolus 0.1% atropine injection is introduced at a dose of 0.005 mg/kg. Anesthesia induction of 2% sodium thiopental solution is carried out at a dose of 4-5 mg/kg, and also 0.005% Phentanyl solution at a dose of 0.0025-0.0035 mg/kg as intravenous bolus injection into the central vein. Trachea intubation is carried out on the precurarization background by introducing Arduan at a dose of 1-2 mg or Esmeran at a dose of 10-20 mg. The patient is transferred to artificial lung ventilation on the background of a muscular relaxation by introducing 2% Ditiline solution at a dose of 1.5-2 mg/kg, and body temperature control gauge is arranged in the middle one-third of patient esophagus. Anesthesia is supported at all stages of operation under artificial lung ventilation conditions by carrying out inhalation with nitrous oxide and oxygen mixture with their proportion being from 2:1 up to 3:1 using flow-reversing respiratory contour having respiratory ventilation volume of 7-8 ml/kg and minute ventilation of 100-120 ml/kg. 0.5% Bupivacaine hydrochloride solution is also introduced into the epidural space every 120-150 min at a dose of 3-5 ml, Arduan is intravenously introduced every 40-60 min at a dose of 2-4 mg or Esmeron every 25-35 min at a dose of 10-20 mg. Intravenous dropping infusion of crystalloid solutions heated to temperature of 37-42°C is carried out at a rate of 10-20 ml/kg/h at neoplasm removal stage. 500 ml of colloid solutions heated to temperature of 37-42°C or 400 ml of 20% albumin solution heated to temperature of 36-37°C is intravenously introduced 25-35 min prior to the beginning of chemotherapy. Transfusion of 400-450 ml of fresh frozen blood heated to temperature of 36-37°C is carried out. The warming up mattress is switched off at chemotherapy preparation stage. Patient head occipital part and main cervical blood vessel passage area is compulsorily cooled with ice packages at the beginning of chemotherapy stage, with intravenous heated crystalloid and colloid solutions, albumin and blood plasma introduction being simultaneously terminated and crystalloid solutions introduction at room temperature being continued with patient body temperature controlled not to be above 38.5°C according to esophageal gauge indications. Sodium bicarbonate and electrolytes are intravenously introduced in planned amount after having finished the chemotherapy treatment. Anesthesia is stopped at operation finish stage by stopping introducing the preparations into the epidural space and intravenously introducing relaxants, continuing artificial lung ventilation using oxygen and air mixture with FiO2 equal 0.4-0.6.

EFFECT: maximum nociceptive pulsation blockade from surgical intervention zone; patient body temperature supported at the level of 36-37°C; prevented brain hyperthermia.

4 cl

FIELD: pharmaceutical chemistry and urology.

SUBSTANCE: invention proposes treatment of frequent vesical tenesmus and incontinence with combination of tramadol, its derivatives, and derivatives of 1-phenyl-3-dimethylaminopropane compounds of formula I: with antimuscarine agents, in particular combination of (+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentane-3-ol and oxybutynine. Invention also relates to drug form of this combination.

EFFECT: enlarged choice of incontinence treatment agents.

2 cl, 1 tbl, 2 ex

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