The compound, pharmaceutical composition

 

Disclosed are compounds of formula (I) or their acceptable from a pharmaceutical point of view salts, in which: the dotted line indicates an optional double bond; X1means optionally substituted (C1-C12)-alkyl, (C3-C12)-cycloalkyl, phenyl, fornillo, thienyl, pyridyloxy, thiazolidine, 1H-indolering group; X2means-CHO, -CN, -(CH2)vOR13, -(CH2)vNR21R22or -(CH2)vNHC(O)R21v is 0 or 1 or X1means optionally substituted condensed with a benzene ring heterocyclic group, and X2means hydrogen; or X1and X2together form an optional condensed with a benzene ring spiroheterocyclic group; R1, R2, R3and R4independently mean H, and (C1-C6)-alkyl group, or (R2and R4together can form Allenby bridge of 1 to 3 carbon atoms; Z1means substituted phenyl, Z2means substituted phenyl, Z3means hydrogen; or Z1, Z2and Z3together with the carbon atom to which they are attached, form a bicyclic saturated ring; fromseptember receptor ORL-1 and can be used for the treatment of cough. 2 C. and 8 C.p. f-crystals, 2 ill., 13 table.

By model studies on animals showed that nociceptin receptor ORL-1 is involved in the modulation of pain. ORL-1 (nociceptive receptor) was found in the form of the opioid receptor types with unknown affinity", i.e., receptor ligands is unknown. Nociceptive receptor is a receptor associated G-protein. Although the structure it is very similar to the three classical opioid receptors, i.e., targets of traditional analgesics, it is not activated by endogenous opioids. Similarly, endogenous opioids do not activate nociceptive receptor. As with classical opioid receptors, nociceptive receptors are widely distributed in the Central nervous system.

Nociceptin was opened in late 1995 and it has been shown that there is an endogenous peptide ligand that activates nociceptive receptor. The data contained in the first publications, testified that nociceptin and its receptor are part of a new public road that is involved in the perception of pain stimulation. Further studies carried out in several laboratories have shown that when intra the activity of endogenous opioid peptides. Recent data show that when introduced directly into the brain of rodents nociceptin acts as an anxiolytic. When studies standard models of anxiety in animals efficiency nociceptin was similar to that detected for the classical benzodiazepine anxiolytics. This data show that a small molecule agonist nociceptin receptor may have a significant analgesic or anxiolytic activity.

More recent data (Rizzi, et. al, Life Sci., 64, (1999), R. 157-163) showed that activation nociceptive receptors on isolated bronchi Guinea pigs inhibits tajikenergostroy neadrenergicheskoy-neholinergichesky reduction, indicating that receptor agonists nociceptin can be used in the treatment of asthma. Also reported (Ciccocioppo et. al, Psyschopharmacology. 141 (1999), R. 220-224) that nociceptin reduces the useful properties of ethanol in rats msP accustomed to alcohol, indicating that the introduction nociceptin may be useful in the treatment of alcohol abuse. In EP 856514 disclosed substituted in position 8 derivatives 1,3,8-diazaspiro[4,5]Decan-4-it is as agonists and/or antagonists orphanin FQ, (i.e. nociceptin) applicable for treatment according to the in WO 98/54168, Earlier in US 3318900 described benzamidopiperidine having analgesic activity.

The use of potent analgesics, such as traditional opioids, such as morphine, is associated with significant side effects. Important from a clinical perspective, side effects include tolerance, physical dependence, respiratory depression and weakening of the peristalsis of the gastrointestinal tract. For many patients, especially those who are constantly treated with opioids, such as patients with cancer, these side effects limit prescribed dose of opioid. Clinical data show that more than a third of patients suffering from cancer, there is pain that is poorly removed existing drugs. The data obtained for nociceptin indicate its possible advantages in comparison with opioids. With consistent use nociceptin unlike morphine does not cause habituation in rodents. In addition, continuous treatment with morphine does not cause cross-tolerance with respect to nociceptin; this shows that these drugs are characterized by different exposure routes.

Due manifested at the present time interest in the objectives of the modification impact nociceptin, which is the natural ligand for the ORL-1 and therefore suitable for the treatment of pain and anxiety. This contribution introduces the present invention.

Summary of invention

Compounds corresponding to the present invention are substances of the formula I

or acceptable from a pharmaceutical standpoint salt or solvate,

where a dotted line indicates an optional double bond;

X1means R5-(C1-C12)alkyl, R6-(C3-C12)cycloalkyl, R7is aryl, R8-heteroaryl, or R10-(C3-C7)geterotsyklicescoe group;

X2means-Cho, -CN, -NHC(=NR26)Other26, -CH(=NOR26), -NHOR26, R7is aryl, R7aryl(C1-C6)alkyl, R7aryl(C1-C6)alkenylphenol, R7aryl(C1-C6)alkylamino, -(CH2)vOR13, -(CH2)vCOOR27, -(CH2)vCONR14RL5, -(CH2)vNR21R22or -(CH2)vNHC(O)R21group, where v is zero, 1, 2 or 3;

or X1means

and X2means hydrogen;

or X1and X2together they form avno 1, R16or R17means C(O)R28;

p is 0 or 1;

Q means-CH2-, -O-, -S-, -SO-, -SO2- or-NR17-;

R1, R2, R3and R4independently selected from the group comprising hydrogen and (C1-C6)alkyl group, or (R1and R4), or (R2and R3), or (R1and R3), or (R2and R4together can form Allenby bridge of 1-3 carbon atoms;

R5means from 1 to 3 substituents independently selected from the group comprising N, R7is aryl, R6-(C3-C12)cycloalkyl, R8is heteroaryl, R10-(C3-C7)geterotsyklicescoe, -NR19R20, -OR13and-S(O)0-2R13groups;

R6means from 1 to 3 substituents independently selected from the group comprising H, (C1-C6)alkyl, R7-aryl, -NR19R20, -OR13and-SR13groups;

R7means from 1 to 3 substituents independently selected from the group comprising hydrogen, halide, (C1-C6)alkyl, R25-aryl, (C3-C12)cycloalkyl, -CN, -CF3, -OR19-(C1-C6)alkyl-or SIG19, -F3, -NR19R20, -(C1-C6)alkyl-NR2, -CONR19R20, -NR20COR19, -COR19, -F3, -OCOR19, -OCO2R19, -COOR19, -(C1-C6)alkyl-NHCOOC(CH3)3, -(C1-C6)alkyl-NF3, -(C1-C6)alkyl-NHSO2-(C1-C6)alkalay-(C1-C6)alkyl-NHCONH-(C1-C6)alkyl group, or

where f is from 0 to 6; or the substituents R7the adjacent cyclic carbon atoms may together form methylenedianiline or ethylendiamine ring;

R8means from 1 to 3 substituents independently selected from the group comprising hydrogen, halide, (C1-C6)alkyl, R25-aryl, (C3-C12)cycloalkyl, -CN, -CF3, -OR19-(C1-C6)alkyl-or SIG19, -F3, -NR19R20, -(C1-C6)alkyl-NR19R20, -NHSO2R19, -SO2N(R26)2, -NO2, -CONR19R20, -NR20COR19, -COR19, -OCOR19, -OCO2R19and-COOR19groups;

R9means hydrogen, (C1-C6)alkyl, halide, -OR19, -NR19R20, -NHCN, -SR19or -(C1-C6)alkyl-NR19R20group;

R101-C6)alkyl-NR19R20group;

R11independently selected from the group comprising H, R5-(C1-C6)alkyl, R6-(C3-C12)cycloalkyl -(C1-C6)alkyl(C3-C12)cycloalkyl -(C1-C6)alkyl-or SIG19, -(C1-C6)alkyl-NR19R20group and

where q and as such, as defined above;

R12means H, (C1-C6)alkyl, halide, -NO2, -CF3, -F3, -OR19, -(C1-C6)alkyl-or SIG19, -NR19R20or -(C1-C6)alkyl-NR19R20group;

R13means H, (C1-C6)alkyl, R7-aryl, -(C1-C6)alkyl-or SIG19-(C1-C6)alkyl-NR19R20-(C1-C6)alkyl-SR19or aryl(C1-C6)alkyl group;

R14and R15independently selected from the group comprising H, R5-(C1-C6)alkyl, R7-aryl group, and

where q and a are such as defined above;

R16and R17independently selected from the group comprising hydrogen, R5-(C1-C6)alkyl, R7-aryl, (C3-C12)ub>)alkyl(C3-C7)geterotsyklicescoe -(C1-C6)alkyl-or SIG19and -(C1-C6)alkyl-SR19groups;

R19and R20independently selected from the group comprising hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, aryl or aryl(C1-C6)alkyl groups;

R21and R22independently selected from the group comprising hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, (C3-C12)cycloalkyl(C1-C6)alkyl, (C3-C7)geterotsyklicescoe -(C1-C6)alkyl(C3-C7)geterotsyklicescoe, R7is aryl, R7aryl(C1-C6)alkyl, R8-heteroaryl(C1-C12)alkyl, -(C1-C6)alkyl-or SIG19, -(C1-C6)alkyl-NR19R20-(C1-C6)alkyl-SR19, -(C1-C6)alkyl-NR18-(C1-C6)alkyl-O-(C1-C6)alkyl and -(C1-C6)alkyl-NRl8-(C1-C6)alkyl-NR18-(C1-C6)alkyl groups;

R18means hydrogen or (C1-C6)alkyl group;

Z1means R5-(C1-C12)alkyl, R7is aryl, R82(C1-C6)alkyl, CN or-C(O)NR19R20group; Z2means hydrogen or Z1; Z3means hydrogen or (C1-C6)alkyl group; or Z1, Z2and Z3together with the carbon atom to which they are attached, form the group of

or

where r is from 0 to 3; w and u are equal to 0 to 3 provided that the sum of w and u is 1-3; and d independently is 1 or 2; s is 1 to 5; and ring a represents a condensed R7is phenyl, or R8-heteroaryl ring;

R23means from 1 to 3 substituents independently selected from the group comprising H, (C1-C6)alkyl, -OR19-(C1-C6)alkyl-or SIG19, -NR19R20and -(C1-C6)alkyl-NR19R20groups;

R24means from 1 to 3 substituents independently selected from the group comprising R23, -CF3, -F3, -NO2or halide group, or the substituents R24the adjacent cyclic carbon atoms may together form methylenedianiline or ethylendiamine ring;

R25means from 1 to 3 substituents independently selected from the group comprising H, (C1-C6)al the surrounding N, (C1-C6)alkyl and R25-C6H4-CH2groups;

R27means H, (C1-C6)alkyl, R7aryl(C1-C6)alkyl or (C3-C12)cycloalkyl group;

R28means (C1-C6)alkyl, -(C1-C6)alkyl(C3-C12)cycloalkyl, R7is aryl, R7aryl(C1-C6)alkyl, R8-heteroaryl, -(C1-C6)alkyl-NR19R20-(C1-C6)alkyl-OR19or -(C1-C6)alkyl-SR19group;

provided that, if X1means

or X1and X2together mean

and Z1means R7is phenyl, Z2means not hydrogen or (C1-C3)alkyl group;

provided that, if Z1, Z2and Z3together with the carbon atom to which they are attached, form a

and X1and X2together mean

R11means not hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)hydroxyalkyl group;

provided that, Estoria they are attached, not mean

and provided that when X1means

and Z1means R6-(C3-C12)cycloalkyl group, Z2means not.

The preferred compounds disclosed in this invention are those in which Z1and Z2mean R7-aryl group, in particular, R7is a phenyl group. Preferred substituents R7are (C1-C6)alkyl and halide, and more preferred is a substitution in the ortho-position.

Preferred are compounds in which all R1, R2, R3and R4mean hydrogen, and compounds in which R1and R3mean hydrogen, and R2and R4mean Allenby bridge with 2 or 3 carbon atoms.

Preferred are compounds in which X1means R7-aryl group, for example, R7is a phenyl group, and X2IT means (for example, X2means -(CH2)vOR13where v is 0 and R13means N) or NC(O)R28, compounds in which X1means

where R12means hydrogen and R1-C6)alkyl-or SIG19or -(C1-C6)alkyl-NR19R20group; and compounds in which X1and X2together form spirocyclic group

where m is 1, R17means phenyl group, and R11means -(C1-C6)alkyl-OR19or -(C1-C6)alkyl-NR19R20group, or

In another embodiment, the present invention relates to pharmaceutical compositions comprising a compound of formula I and acceptable from a pharmaceutical point of view of the media.

Compounds corresponding to the present invention are agonists and/or antagonists of the receptor ORL-1 and for this reason, in another embodiment, the present invention relates to a method of treatment of pain, anxiety, cough, asthma, alcohol abuse and depression, which is to assign to a mammal in need of such treatment, an effective amount of the compounds of formula I.

In another embodiment, the present invention relates to a method for treatment of cough, which is to assign to a mammal in need of such treatment: (a) an effective amount of agonist Entomol cough, allergies or asthma and selected from the group including: antihistamines, inhibitors of 5-lipoxygenase, leukotriene inhibitors, inhibitors of N3, agonists-adrenergic receptor, xanthine derivatives, agonists-adrenergic receptor, stabilizers mastocytes, antitussives, expectorants, antagonists NK1NK2and NK3thickening and receptor agonists GABAIn(GABA - gamma-aminobutyric acid).

In yet another embodiment of the invention the present invention relates to a pharmaceutical composition comprising the agonist nociceptin receptor ORL-1 and a second drug selected from the group including: antihistamines, inhibitors of 5-lipoxygenase, leukotriene inhibitors, inhibitors of N3, agonists-adrenergic receptor, xanthine derivatives, agonists-adrenergic receptor, stabilizers mastocytes, antitussives, expectorants, antagonists NK1NK2and NK3thickening receptor and agonists DAWAIn.

In other words, the present invention relates to the use of compounds on p. 1 I and to the use of agonist nociceptin receptor ORL-1 as single drug or in combination with a second drug to treat the symptoms of cough, allergies or asthma.

In yet another embodiment, the present invention relates to a new compound not described by the structure represented by formula I, with the specified connection is:

Brief description of drawings

In Fig.1 is mapped to the effects of compounds a and b (see Example 12) and baclofen for cough in Guinea pigs caused by capsaicin.

In Fig.2A and 2B shows the changes in tidal volume after administration of the compounds a and baclofen, and Fig.2C shows changes in breathing rate after administration of the compounds a and baclofen.

Detailed description of the invention

If not stated otherwise, the following terms are used in the present invention, in accordance with the definitions:

M+means the molecular ion is present in the mass spectrum, and MH+means the molecular ion with a hydrogen atom that is present in the mass spectrum.

VI means boutelou group; Et means ethyl group; Me means methyl group, and Ph means phenyl group;

an alkyl group (including alkyl fragments CNS, alkylamino and dialkylamino group means linear and branched carbon chains containing from 1 to 12 carbon atoms is optimum, isopentanol, hexoloy group, etc;

Alchemilla group means an alkyl chain containing from 2 to 6 carbon atoms and one or two double bonds in the chain, such as vinyl, propanolol or butenyloxy group;

Alchemilla group means an alkyl chain containing from 2 to 6 carbon atoms and one triple bond in the chain, for example etinilnoy or propenyloxy group;

CNS group means alkyl fragment that is associated with the adjacent structural element of the covalent bond via an oxygen atom, for example metaxylene, amoxilina, propoxyimino, betaxolol, pentoxil, exocrine group, etc;

aryl group (including alkyl fragment arylalkyl group) means a carbocyclic group containing from 6 to 15 carbon atoms and including at least one aromatic ring (e.g., aryl group is a phenyl group), and mentioned aryl group optionally may be condensed with aryl, (C3-C7)cycloalkenyl, heteroaryl or hetero(C3-C7)cycloalkyl rings; and R7-aryl group means any of the available capable of substitution of carbon atoms and nitrogen in the specified aryl group and/or casesto 1-3 substituents of the group R7. Examples of aryl groups are phenyl, naftalina and antenna groups;

arylalkyl group means certain higher alkyl group in which one or more hydrogen atoms of the alkyl fragment substituted with one to three aryl groups, and aryl group such as defined above;

arrochela group means defined above aryl group in which the aryl group is linked to the adjacent structural element of the covalent bond via an oxygen atom, such as phenoxyl group;

cycloalkyl group means a saturated carbocyclic ring containing from 3 to 12 carbon atoms, preferably from 3 to 7 carbon atoms, a R6- cycloalkyl group means any of the available capable of substitution of the carbon atoms in the specified cycloalkyl group can be optionally and independently substituted and that cycloalkyl ring contains as Vice-1-3 group, R6;

cycloalkylation group means certain higher alkyl group in which one or more hydrogen atoms of the alkyl fragment is substituted by one to three cycloalkyl group, and cycloalkenyl group such as defined above;

halide of groupgroup, containing one to three heteroatoms selected from the group comprising O, S and N, and said heteroatom (heteroatoms) are included in the structure carbocyclic cycle and have a sufficient number of delocalized PI electrons to give aromatic character, with the aromatic heterocyclic groups contain from 5 to 14 carbon atoms, and the said heteroaryl group optionally may be condensed with one or more aryl, cycloalkyl, heteroaryl or heterocyclicamines ring and that any available capable of substitution of the carbon atoms or nitrogen in the specified heteroaryl group and/or condensed specified cycle (cycles) may be optionally and independently substituted and that the heteroaryl ring may contain as substituents are 1 to 3 groups of R8; typical heteroaryl groups can include, for example, fornillo, thienyl, imidazolidinyl, pyrimidinyl, triazolyl, 2-, 3 - or 4-pyridyloxy or 2-, 3 - or 4-pyridyl-N-oxide, where the pyridyl-N-oxide can be represented in the form:

heteroallyl group means certain higher alkyl group in which one or more atoms of water is recycleability group means a saturated ring, containing from 3 to 7 carbon atoms, preferably from 4 to 6 carbon atoms, which contains 1 to 3 heteroatoms selected from the group comprising-O-, -S - and-NR21-, in which R21is the same as defined above, and in which the specified ring optionally may contain one or two unsaturated relationships that do not attach to the ring of aromatic character; and in which any of the available capable of substitution of the carbon atoms of the ring may be substituted; and in which heterocycle-alkyl ring may contain as substituents are 1 to 3 groups of R10; typical heterocytolysine groups include 2 - or 3-tetrahydrofuranyl, 2-or 3-tetrahydrocannibinol, 1-, 2-, 3 - or 4-piperidinyl, 2 - or 4 - dioxolo, morpholinyl,

where R17is the same as defined above, a t is 0, 1 or 2.

If piperidinium ring of formula I has an optional double bond, then one of X1or X2forms a bond with the carbon atom located at position 3, and the second of the X1or X2is not hydrogen.

If X1and X2form defined above Spiro group, a wavy line in the structure shown in the definitions, ukazyvayutsya connection represented by the following formula:

Some compounds corresponding to the present invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The present invention includes all such stereoisomers in pure form and in mixtures, including racemic mixtures.

Some compounds in nature are acidic, for example such compounds, which have a carboxyl or phenolic hydroxyl group. These compounds can form acceptable from a pharmaceutical point of view of salt. Examples of such salts may include salts of sodium, potassium, calcium, aluminum, gold and silver. Also included are salts with acceptable pharmaceutical point of view amines, such as ammonia, alkylamines followed, hydroxyethylamine, N-methylglucamine, etc.

Some basic compounds also form acceptable from a pharmaceutical point of view salts, such as molecular salts with acids. For example, the nitrogen atoms of the pyridine type can form salts with strong acids, whereas compounds containing basic substituents such as amino groups, also form salts with weaker acids. Examples kiveleva, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methansulfonate and other inorganic and carboxylic acids well known to specialists in this field of technology. Salt is prepared in the usual manner by reacting the free base with an amount of acid sufficient to obtain salt. The free base can be selected, processing salt diluted aqueous solution of a suitable base, such as dilute aqueous NaOH solution, potassium carbonate, ammonia and sodium bicarbonate. Free base differ slightly from the corresponding salts by some physical characteristics, such as solubility in polar solvents, but for the purposes of this invention, salts of acids and bases in other respects equivalent to the corresponding free bases.

Assume that, as such, salts of acids and bases are acceptable from a pharmaceutical point of view salts in accordance with the present invention and the present invention all salts of acids and bases are considered equivalent to the free forms of the corresponding compounds.

Compounds corresponding to the present invention can be prepared by salami, known in the art. Below are examples of common procedures and specific examples of the synthesis.

Usually X1X2-substituted piperidine alkylate Z1,Z2,Z3-substituted halogenmethyl in the presence of an excess of bases, such as2CO3and Et3N, in solvents such as DMF (dimethylformamide), THF (tetrahydrofuran) or CH3JV at room temperature or at elevated temperatures.

X1X2-Substituted piperidine or are corrupt, or synthesized using known procedures. For example, 4-hydroxy-4-phenylpiperidine can be turned into a 4-tB-amino-4-phenylpiperidine according to the following reaction scheme, where PG denotes a benzyl, Ph means phenyl and tc means tert-butoxycarbonyl, aq means an aqueous solution, RT means room temperature:

Sales 4-phenyl-4-piperidinol protect benzyl group and the resulting intermediate product is treated with IU3SiN hydrolyzing the resulting product with a solution of aqueous Hcl in CH3HE was getting 4-amino derivatives. The amino protecting using tBoc, a N-benzyl group is removed by hydrogenolysis with getting the required the/sup>,Z2,Z3-halogenmethyl and remove the protective group. To obtain derivatives Amin Amin (i.e. the connection to the X2meaning-NH2) can be subjected to various standard transformations. For example, the amine of formula I can enter into reaction with R22-carboxaldehyde in the presence of a mild reducing reagent, such as Na(OAc)3BH, or with the compound of the formula R22-L, where L means useplease group, such as CL or Br, in the presence of a base such as Et3N

An alternative method of synthesis of compounds of formula I, in which X1means R7-aryl group, and X2IT means, includes alkylation of the hydrochloride of 4-piperidone with Z1,Z2,Z3-halogenmethyl and the subsequent interaction of the ketone with an appropriately substituted R7-phenylmagnesium or a compound of the formula X1-L1where L1means, Br or I, and n-butyllithium.

X1X2-Substituted compounds of formula I can be converted into other compounds of formula I by holding with substituents X1and/or X2reactions are well known in the art. For example, a piperidine with carboxaldehyde substituent (i.e.2oz shown on the following scheme for the compounds of formula I, in which X1means phenyl group, Z1and Z2mean phenyl group, and R1, R2, R3and R4and Z3mean N:

Lansley piperidine (for example, when X2means-CN) can be converted into substituted piperidine, where X2means R21R22N-CH2or X2means R28C(O)NH-CH2- as shown in the following scheme for the compounds of formula I, in which X1means phenyl group, R1, R2, R3and R4and Z3mean N, and L means useplease group, such as CL or Br:

The compounds of formula I, in which X denotes a nitrogen-containing heterocycle condensed with a benzene core and comprising a substituent R11non-hydrogen receive the reaction of the corresponding compounds in which R11means hydrogen, with a compound of formula R11L (R11does not mean N, and L is as defined above).

Alternatively, using similar procedures before carrying out the reaction with Z1,Z2,Z3-replaced by halogenation original X1X2-substituted piperidine can be turned into other X1

and R4different form alkylene bridges, selling 4-substituted piperidone protected on the N atom, is treated with phenyllithium and from the resulting intermediate product to remove the protective group, receiving the desired connection, for example, according to the scheme:

where WG - protective group atom N, Ph means phenyl group, and z is 1-2.

Z1,Z2,Z3-Halogenosilanes derivatives in which Z1and Z2mean R7is a phenyl group, or are commercially available, or can be obtained by using the procedure shown in the following reaction scheme:

Similar procedures, or other procedures known in the art, can be used to produce compounds in which the substituents Z are phenyl groups.

Compounds corresponding to the present invention, or source materials for their production are described in the following examples, which should not be construed as limiting the scope of the present invention.

The following solvents and reagents indicated by these abbreviations: tetrahydrofuran (THF), ethanol (EtOH), methanol (Meon), acetic acid (SPLA or Asón), ethyl acetate (EtOAc),

A mixture of 4-hydroxy-4-phenylpiperidine (1.5 g, of 8.47 mmol) and K2CO3(3.0 g, 21,73 mmol) in CH3CN was stirred at RT. It added to-bromodiphenylmethane (2.5 g, 10,12 mmol) and the reaction mixture was stirred over night. The reaction mixture was concentrated, re-dissolved in CH3CL2, washed with water, dried (MgSO4and focusing, chromatography was carried out (SiO2, 9: 1 hexane/EtOAc) gives the desired compound (2.6 g, 90%).1H NMR (Dl3):of 1.80 (m, 2H), by 2.55 (m, 2H), 2,42 (m, 2H), 2,90 (m, 2H), 4.40 (s, 1H), 7,2-7,6 (m, 15H).

Example 2

Stage 1: a Solution of the hydrochloride monohydrate of 4-piperidone (5 g, with a 32.6 mmol) in CH3CN alkylate using the procedure described in Example 1. Chromatography-grafirovanija residue on silica (95:5 hexane/EtOAc) gives the desired connection.

Stage 2: To a solution of the product obtained in Stage 1 (191 mg, to 0.72 mmol) in THF at 0With added dropwise 4-methylphenylamine (solution 0.5 M in THF, 1.75 ml, 0.87 mmol). The solution is stirred for 2 h at 0With sharply cooled mixture with ice water, extracted with EtOAc, washed with water and brine, dried and concentrated. sup>1H NMR (CDCl3):to 7.5 (m, 6H, AGN), and 7.3 (t, 4H, AGN). 7,2 (t, 4H, ArH), 4,35 (s, 1H), and 2.8 (d, 2H), 2,4 (m, 5H), 2,2 (td, 2H), 1,75 (d, 2H): MC (mass spectroscopy) (HEE [chemical ionization]) 358 (M+1); Elemental analysis for C25H27NO1,2 H2O: Calculated: 79,2, N Of 7.82, N of 3.69; found: 78,90, N 8,02, N 3,85.

Example 3

To a solution of 3-bromothiophene (0.15 g, 0.95 mmol) in Et2O at -70With added dropwise n-BuLi (solution 2.5 M of 0.38 ml, 0.95 mmol) and stirred for 2 hours To the reaction mixture was added a solution of the product obtained in Stage 1 of Example 2 (230 mg, 0.87 mmol) in Et2O (4 ml) for 3 h slowly heated to CT. the reaction is stopped aqueous solution of NH4Cl, chilled with ice, extracted with Et2O, washed with water and brine, dried and concentrated. The chromatography was carried out of the remainder (95:5 hexane/EtOAc) gives the desired compound (90 mg).1H NMR (CDCl3):to 7.5 (d, 2H), 7,35 (bt, 4H), 7,25 (m, 3H), 7,2 (m, 2H), 4,4 ('s. 1H), and 2.8 (d, 2H), 2.5 (t, 2H), 2,3 (dt, 2H), 2,0 (d, 2H): MC (HEE) 350 (M+1); Elemental analysis for C22H22NOS1,1 HCl0,9 H2O: Calculated: 65,11, N To 6.43, N 3,54, S 7,8, Cl being 9.61; found: 65,27, N Is 6.54, N 3,45, S 7,30, Cl 9,43.

Example 41H NMR (Dl3):is 2.40 (m, 6H), of 2.50 (m, 2H), 2,85 (m, 2H), 4,25 (s, 1H), 7,20 is 7.50 (m, 15H), 9,42 (s, 1H).

Stage 2: a solution of the product obtained in Stage 1 (3.0 g, to 8.45 mmol), cooled to 0C and treated with NaBH4(1.0 g, 26,32 mmol). After 0.5 h, the reaction mixture is treated with 1N. solution of Hcl and concentrated. The residue is extracted with CH2CL2, dried (MgSO4) and evaporated. Using column chromatography (4:1 hexane : EtOAc) receive the necessary primary alcohol.1H NMR (CDCl3):2,00 (m, 2H, in), 2.25 (m, 4H), to 2.65 (m, 2H), 3,65 (d, 2H), 4,20 (s, 1H), 4,25 (d, 1H), 7,2-7,6 (m. 15H).

Stage 3: the Product obtained in Stage 2, is treated with NaH in DMF at 0C for 0.5 hours Add CH3I and the reaction mixture is heated to CT. After stirring over night the reaction mixture was poured on ice, extracted with Et2O, dried (MgSO4) and evaporated. Using column chromatography of the residue receive the desired product.1H NMR (CDCl3):of 2.10 (m, 4H), 2.40 a (m, 2H), 2,78 (m, 2H), 2,90 (m, 2H), 3.00 for (s, 1H), to 4.38 (s, 1H), 7,21-7,52 (m, 15H).

Example 5

of 2.21 (m, 4H), 2.49 USD (t, J=12.3 Hz, 2H), 3,11 (d, J=12,5 Hz, 2H), 4,46 (s, 1H), 7,45 (m, 15H).

Stage 2: a solution of the product obtained in Stage 1 (6.0 g, 17 mmol), Et2O (40 ml) cooled to 0°C and added dropwise in a stream of nitrogen for 0.5 h, treated with 1M solution of lithium aluminum hydride (34,10 ml, 34 mmol). The reaction mixture is allowed to warm to CT and then refluxed for 4 hours, the Reaction mixture was cooled to 0C and treated with water (8 EQ.). The reaction mixture is allowed to warm to CT and then stirred for 1 h Obtained solid is filtered off, washed with Et2O and the filtrate is concentrated and receiving of 5.45 g (90%) of desired product.1H NMR (CD3OD):of 1.84 (m, 2H), 2,16 (m, 4H), of 2.56 (m, 2H), 2,68 (m, 2H), 4,07 (s, 1H), 7,25 (m, 15H).

Studyarea (0,078 ml, 0,673 mmol) and pyridine (0,045 g, 0,568 mmol) at RT in a stream of nitrogen for 18 hours, the Reaction mixture was concentrated, and then selectively extracted by distribution between H2Oh and CH2CL2. The organic layer was washed with water (twice) and brine, then dried (MgSO4), filtered and concentrated. The chromatography was carried out (SiO2, 3:1 hexane/EtOAc) to give 0.2 g (77%) of desired product.1H NMR (CD3D):to 2.13 (m, 6H), to 2.66 (m, 4H), 3,50 (s, 2H), 4,07 (s, 1H), 7.11-7.65 (m, 20H),

Stage 4: a solution of the product obtained in Stage 3 (0.075 g, 0.16 mmol) in THF (3 ml) with stirring, cooled to 0°C. In a stream of nitrogen added to alumoweld lithium (solid, 0.025 g, of 0.65 mmol) and continue stirring for a 0.25 h Then the reaction mixture was refluxed for 5 h and then stirred at RT for 18 h, the Reaction mixture was cooled to 0°C and the reaction stopped with water (8 EQ.) The reaction mixture is allowed to warm to room temperature and stirred for 1 h Obtained solid is filtered off, washed with Et2O and the filtrate is dried (MgSO4) and concentrate. The chromatography was carried out (neutral Al2About3CH2Cl2then 3:1 CH2Cl2: EtOAc) gives ,53 (s, 2H), 4,05 (s, 1H), 7,01 - 7,38 (m, 20H).

Example 6

The product obtained in Stage 2 of Example 5 (0.2 g, 0,561 mmol), acetic anhydride (3 ml) and Et3N (0,096 ml, 0.67 mmol) are combined and stirred at RT for 18 h, the Reaction mixture was concentrated and selectively extracted by distribution between H2Oh and CH2CL2. The organic layer was washed with water (twice) and brine, then dried (MgSO4), filtered and concentrated, obtaining 0,214 g (95%) of the desired compound.1H NMR (CD3D):to 1.87 (m, 5H), of 2.16 (m, 4H), 2,61 (m, 2H), and 3.31 (s, 2H), 4,07 (s, 1H), 7,12-7,40 (m, 20H).

Example 7

Stage 1: a Solution of 4-phenyl-4-hydroxypiperidine (10.0 g, of 56.4 mmol) in DMF (60 ml) is treated with Et3N (8,28 ml, a 59.2 mmol) and benzylbromide (7,37 ml, 62,10 mmol) and CT in a stream of nitrogen is stirred for 20 hours, the Reaction mixture was concentrated in vacuo, alkalinized to pH 8 with saturated solution of NaHCO3and selectively extracted by distribution between EtOAc and H2O. the Organic layer is washed twice with water, then brine and dried (MgSO4), filtered and concentrated. The chromatography was carried out (neutral Al2About3, hexane, then 1:1 hexane:EtOAc) gives 11,95 g (80%) required the 0,448 mmol), cooled to -15With in the bath etrange-Col/CO2in a stream of nitrogen added dropwise ice Asón (47 ml), maintaining the temperature of the mixture is equal to -15C. While maintaining the temperature of the mixture is equal to -15With and vigorous stirring, added dropwise concentrated H2SO4(47 ml, 0.34 mol). Then the cooling bath removed and the reaction mixture was stirred at RT for 18 h, the Reaction mixture was poured on ice and using 50% NaOH solution was adjusted pH value to 7, maintaining the temperature at approximately 25C. Then the reaction mixture was extracted with CH2CL2and the organic layer washed with water (twice), then with brine and dried (MgSO4), filtered and concentrated. Recrystallization from a mixture of EtOAc/hexane (1:10) gives to 22.35 g (68%) of the desired connection.1H NMR (CD3D):of 2.10 (m, 2H), 2.40 a (m, 4H), 2,82 (d, J=11,50 Hz, 2H), only 3.57 (s, 2H), 7,20 - the 7.43 (m, 10H), with 8.05 (s, 1H).

Stage 3: the Product obtained in Stage 2 (20 g, to 67.9 mmol) and 5% (wt./wt.) (concentrated aqueous solution of Hcl)/CH3HE (350 ml) is stirred in a stream of nitrogen for 48 hours the Mixture is concentrated to obtain foam, which is suspended in Et2O and giraut by vacuum filtration, washed with Et2O and dried in vacuum to obtain a desired product (23 g, 100%).1H NMR (CD3OD) dihydrochloride:at 2.59 (t, J=13.3 Hz, 2H). 2,93 (t. J=13.3 Hz, 2H), of 3.07 (d, J=13,50 Hz, 2H), to 3.58 (d, J=13 Hz, 2H), 4.26 deaths (s, 2H), 7,56 (m, 10H).

Stage 4: the Product obtained in Stage 3 (24,10 g, 71 mmol), CH2CL2(300 ml), (t)2O (17.0 g, 78,1 mmol) and Et3N (14,37 g, 0,142 mol) are combined and stirred at RT in a stream of nitrogen for 18 hours the Reaction mixture is selectively extracted by distributing among CH2Cl2and H2O and the aqueous layer was extracted with CH2CL2. The combined organic layers washed with water (twice), then with brine and dried (MgSO4), filtered and concentrated. The obtained solid is suspended in Et2O and treated with ultrasound, filtered and dried, obtaining the necessary connection (21,98 g, 90%).1H NMR (CD3OD):1,09 (bs, 2H), 1.39 in (s, 1H), 2.05 is (m, 2H), 2,34 (m, 4H), 2,65 (d, J=11.8 Hz, 2H), of 3.56 (s, 2H), 7.18 in-7,40 (m, 10H).

Stage 5: the Product obtained in Stage 4 (5,22 g of 14.2 mmol), CH3HE (430 ml), Pd(OH)2/C (3.0 g) and NH4COOH (18,86 g, 0,298 mol) are combined and refluxed in a stream of nitrogen for 8 hours, the Reaction mixture was filtered by using a target is (3,90 g, 97%).1H NMR (CD3OD):1,10 (bs, 2H), 1.39 in (s, 7H), 1,90 (m, 2H), and 2.26 (m, 4H), of 2.92 (m, 4H), 7,17-7,41 (m, 5H).

Step 6: the Product obtained in Stage 5 (2,74 g to 9.91 mmol), CH3CN (85 ml), Et3N (1.75 ml, 12,40 mmol) and bromodiphenylmethane (2.70 g, 10.9 mmol) are combined and stirred at RT in a stream of nitrogen for 18 hours the Mixture is concentrated and the resulting residue is selectively extracted by distribution between H2O and EtOAc. The layer containing EtOAc, washed with water (twice), brine, then dried (MgSO4), filtered and concentrated. The chromatography was carried out (neutral Al2About3, hexane, then 4:1 hexane:EtOAc) to give 2.85 g (65%) of desired product.1NAMR (CD3OD):1,07 (bs, 2H), 1,37 (s, 7H), of 2.23 (m, 2H), 2,24 (m, 4H), to 2.74 (d, J=12.1 Hz, 2H), 4,27 (s, 1H), 7,10 - 7,47 (m, 15H).

Stage 7: the Product obtained at Stage 6 (4.6 g, 10 mmol), 1,4-dioxane (38 ml) and 4 M Hcl solution in 1,4-dioxane (25 ml, 101 mmol) are combined and stirred at RT in a stream of nitrogen for 4 hours the Mixture is concentrated and the residue suspended in Et2O and concentrate again. The obtained solid is re-suspended in Et2O, treated with ultrasound and the product collected by vacuum filtration and dried, obtaining of 3.27 g (80%) of desired product.1H NMR (is a, received at Stage 7 (0.3 g, 0,722 mmol) in CH2Cl2(3 ml) in a stream of nitrogen at RT was added 2-thiophenecarboxaldehyde (of 0.133 ml, 1.44 mmol). With Et3N is the pH of the solution was adjusted to 6 and the mixture is stirred for 0.5 hours Then add PA(SLA)3NR (0,230 g at 1.08 mmol) and the reaction mixture was stirred at RT in a stream of nitrogen for 3 hours the Reaction abruptly stopped with a saturated aqueous solution of NaHCO3and selectively extracted by distributing among Et2O and H2O. the Organic layer washed with water (twice) and brine, then dried (MgSO4), filtered and concentrated. The chromatography was carried out (SiO2, toluene, and then 1:19 EtOAc:toluene) gives 0,158 g (50%) of the desired product.1H NMR (CD3OD):a 1.96 (m, 2H), 2,17 (m, 2H), 2,52 (m, 4H), of 3.45 (s, 2H), 4,24 (s, 1H), 6,76 (d, J=3.5 Hz, 1H), 6,85 (dd, J=3,6 Hz, 1H), 7,13-to 7.50 (m, 16H).

Example 8

Stage 1: using the procedure described in Stage 1 of Example 1, alkylate a solution of 4-(2-oxo-1-benzimidazolyl)-piperidine in CH3JV and receive the necessary connection.

Stage 2: To a solution of 3-[1-(diphenylmethyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazo-1-she (2.5 mg, 6.6 mmol) in DMF (25 ml) was added NaH and stirred at RT during 1 h To a mixture at Kew tO, washed with water and brine, dried (MgSO4) and concentrate. The chromatography was carried out of the residue on silica (1:9 EtOAc/hexane) gives the desired compound (2.35 g). The desired compound was dissolved in Et2O added a solution of Hcl in Et2O (8 ml, 1 M), stirred for 1 h and filtered, obtaining hydrochloric acid salt.1H NMR (CDCl3):at 7.55 (m, 4H, AGN), 7,35 (m, 5H, AGN), 7,25 (m, 2H, AGN), to 7.15 (m, 2H, AGN) and 7.1 (m, 1H, AGN), 4,4 (m, 2H), 3,95 (t, 2H), 3.15 in (d, 2H), 2,6 (dq, 2H), 2,1 (t, 2H), 1.8 m (m, 4H), 1,5 (m, 2H), 1,0 (t, 3H): ERIE-MS (ERI - electron spray ionization) 440 (M+1); Elemental analysis for C29H33N3OHClH2O: Calculated: 70,5, N 7,3, 8,5 N, Cl 7,18; found: 70,48, N 7,28, N 8,49, Cl 7,49.

Example 9

To a solution of 2-(chlorophenyl)-phenylmethanol (300 mg, 1.38 mmol) in CH2CL2at RT was added SOCl2(247 mg, 2,07 mmol), stirred at RT for 5 h and concentrated. The residue is dissolved in CH3JV, add2CO3, 4-hydroxy-4-phenylpiperidine and NaI. The solution is refluxed under stirring over night, filtered and concentrated. The chromatography was carried out of the residue on silica (9:1 hexane/EtOAc) gives the desired connection.dd, 2H), 2,5 (dq, 2H), 2,2 (dt, 2H). of 1.75 (d, 2H). The desired compound is dissolved in ether, was added HCl/Et2O (1 M) and receive a hydrochloric acid salt. MS HEE 378 (M+1); Elemental analysis for C24H24NOClHCl0,2 H2O: Calculated: 68,97, N 6,13, N 3,35, Cl 16,96; found: 68,87, N 6,04, N 3,35, Cl 17,00.

Example 10

Stage 1: use nitrile almond acid (1 g, 7,51 mmol) by the procedure described in Example 9, alkylate solution of the hydrochloride monohydrate of 4-piperidone (880 mg, 5 mmol) in CH3The JV. The chromatography was carried out of the residue on silica followed by recrystallization (EtOAc) gives the desired compound (630 mg).

Stage 2: To a solution of the product obtained in Stage 1 (330 mg, 1,185 mmol) in THF at 0To add a solution of 2-methoxyphenylacetamide in THF (24 ml, 0.5 M, 11,85 mmol). Remove the bath with ice and boiling under reflux stirred the mixture for 6 hours the Reaction is stopped aqueous solution of NH4Cl, extracted with EtOAc, washed with brine, dried and concentrated. The chromatography was carried out of the remainder (95:5,9:1 hexane/EtOAc) gives the desired compound (330 mg),1H NMR (Dl3):7,76 (d, 1H), 7.62mm (d, 1H), 7,55 (d, 1H)tion dissolved in Et2O added a solution of Hcl in Et2O, stirred for 1 h and filtered to obtain hydrochloric acid salt. MS of the Belarusian library Association (fast atom bombardment) 374,1 (M+1); Elemental analysis for C25H27NO2HCl0,15 H2O: Calculated: 72,77, N 6,91, N 3,39, Cl 8,59; found: 72,76, N 7,02, N 3,59, CL 8,83.

Example 11

Stage 1: using the procedure described in Stage 1 of Example 1, alkylate a solution of 1-phenyl-1,3,8-diazaspiro[4,5]Decan-4-she (0.5 g) in CH3CN and receive the necessary connection.

Stage 2: the Product obtained in Stage 1, 1-phenyl-8-(diphenylmethyl)-1,3,8-diazaspiro[4,5]Decan-4-one (0.4 g), alkylate using CH3I according to the procedure described in Stage 2 of Example 1, and obtain the desired compound (0.25 g).1H NMR (CDCl3):to 1.70 (d, 2H), 2,85 (m, 6N), was 3.05 (s, 3H), 4,50 (s, 1H), 4.72 in (s, 2H), 6,95 (t, 1H), 7,05 (d, 2H), 7,20-of 7.60 (m, 12H).

Compounds shown in table. 1-8, obtained using the procedures described in Examples 1 to 11, using the appropriate starting materials. Used the following abbreviations mass spectroscopic methods: CI chemical ionization; ESI - electron-spray ionization;

FAB - bombing quick comparat cell membranes of Chinese hamster ovary, expressing the receptor ORL-1 (2 mg), incubated with various concentrations of [125I][Tyr14]nociceptin (3-500 PM) in buffer solution containing 50 mm HEPES (N-2-hydroxyethylpiperazine-N-2-econsultancy acid) (pH 7.4), 10 mm NaCl, 1 mm MgCl2, 2.5 mm CaCl21 mg/ml serum albumin cattle and 0.025% bacitracin. In a number of research tests conducted in a buffer solution containing 50 mm hydrochloride trihydroxypyrimidine (pH 7.4), 1 mg/ml serum albumin cattle and 0.025% bacitracin. The samples incubated for 1 h at room temperature (22C). Radiolabelled ligand associated with the shell, collected on filters, GF/B, pre-soaked in 0.1% polyethylenimine, using the device for collecting cellular environments Branell and washed five times with portions of cold distilled water and 5 ml of Nonspecific binding study in parallel with similar analyses performed in the presence of 1 μm nociceptin. Under all conditions the tests conducted twice with the study of total and nonspecific binding.

Calculation of Ki values (constants of inhibition) is conducted by methods well known in the field as a technician,6 to 3000 nm, and the preferred are compounds with Ki values, less than 10 nm. For typical compounds of the present invention, the values of Ki are presented in tables 9, 10:

Using the procedures described in European Journal of Pharmacology. 336 (1997), R. 233-242, defined agonistic activity of the compounds of the present invention, is presented in table 11:

Example 12

Research cough

The effect of agonists nociceptin, connections, And (0,3 -10 mg/kg, orally) and compound B (10 mg/kg, orally)

research on Guinea pigs, causing them to cough with capsaicin, according to the methods Bolser et al. British Journal of Pharmacology (1995) 114, 735-738. This model is a widely used method of evaluating the activity of potential antitussive drugs. Not taking food during the night of male Hartley Guinea pigs (350-450 g, Charles River, Bloomington, MA, USA) placed in transparent boxes size 1214 inches. To cause a reflex cough, animals exposed to aerosol of capsaicin (300 μm, for 4 min), formed using an inkjet dispenser (Puritan Bennett, Lenexa, KS, USA). Each Guinea pig is affected by capsaicin only once. The number of kachlany recorded the multi-channel chart recorder, the registration number of kachlany. 2 hours before exposure to an aerosol of capsaicin animals give the filler (methylcellulose, 1 mg/kg, orally), or compound a, or compound C. as a positive control also investigated antitussive activity of baclofen (3 mg/kg, orally). The results are presented as histograms in Fig.1.

Example 13

Measuring characteristics of breathing

Studies of respiration is performed on the male Hartley Guinea pigs with a weight of from 450 to 550, during the night animals do not give food, but give unlimited amount of water. Guinea pigs are placed in plethysmograph to register the volume of the body, so that their head was located outside, and on the animal's head wear rubber cuff for sealing the Guinea pig in pletismography. The air flow rate measured by the differential pressure on the wire mesh covering the hole diameter of 1 inch in the wall of plethysmograph. With schema preamp and a computer to study the breathing characteristics (Buxco Electronics, Sharon, CT., model XA) signal of the air flow rate is converted into a signal proportional to volume. To plethysmograph attached the camera to the head and throughout the study via b>). When all the measurements of the breathing characteristics of the Guinea pig breathe circulating air.

The signal with the data about the volume coming from each animal served in the system of data collection and analysis (Buxco Electronics, model XA) in which tidal volume and respiratory rate are calculated for the periods from breath to breath. These signals are displayed on the monitor. Tidal volume and respiratory rate are recorded every minute in the form of averages.

For equilibrium Guinea pigs kept in plethysmography for 30 minutes At the end of this 30-minute period carry out the determination of a baseline. Then Guinea pigs extract from plethysmograph and orally administered compound a from Example 12 (10 mg/kg, orally), baclofen (3 mg/kg, orally) or placebo, representing a filler of methylcellulose (2 mg/kg, orally). Immediately after a dose Guinea pigs placed in plethysmograph, attach the camera to the head and connect air circulation and after 30, 60, 90 and 120 min after administration of the dose measured characteristics of the breath. This study was conducted in accordance with the ACUC Protocol #960103.

Analysis of the obtained data

The values of tidal volume (VT), breathing frequency (f) and minute obni after administration of a drug or excipient. The results are presented as mean values ± standard error. The results are shown in Fig.2A, 2B and 2C. In Fig.2A shows changes in minute volume, Fig.2B shows changes in tidal volume, and Fig.2C shows changes in the frequency of respiration.

We unexpectedly found that agonists nociceptin receptor ORL-1 possess antitussive activity, which makes them applicable as a cough suppressant in mammals. Non-limiting examples of agonists nociceptin receptor ORL-1 include compounds that are agonists nociceptin receptor ORL-1 described in the present invention. In the treatment of cough in mammals agonists nociceptin receptor ORL-1 can be assigned in combination with one or more additional drug intended for the treatment of symptoms of cough, Allergy or asthma, selected from the group including antihistamines, inhibitors of 5-lipoxygenase, leukotriene inhibitors, inhibitors of N3, agonists-adrenergic receptor, xanthine derivatives, agonists-adrenergic receptor, stabilizers mastocytes, antitussives, expectorants, antagonists NK1, NK include astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine at, carbinoxamine, descarboethoxyloratadine (also known as the SCH-34117), doxylamine, dimethindene, Bastin, epinastine, efletirizine, Fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, Aquitain, mianserin, doberstyn, meclizine, erastamisel, ecumest, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and three-palidin.

Non-limiting examples of antagonists histamine receptor H3include: typename, impromidine, burimamide, closedprofit, impactmin, mepetidine, S-apramycin, R-Aprotinin, SKF-91486, GR-175737, GT-2016, ULC-1199 and clozapine. Explore other compounds to determine their activity against receptors N3using known methods, including the study of brain shell of Guinea pigs and the study of neural contractions of the ileum of Guinea pigs; both of these methods are described in U.S. patent 5352707. Other useful methods of analysis that use membranes of rat brain, was described by West et al., Identification of Two H3-Histamine Receptor Subtypes, Molecular Pharmacology, Vol. 38, pages 610-613 (1990).

The term "leukotriene inhibitor" includes any or activity of leukotrienes. Non-limiting examples of inhibitors include leukotriene montelukast, [R-(E)]-[[[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 EP 0480717; 1-(((R)-(3-(2-(6,7-debtor-2-chinoline)-ethynyl)-phenyl)-3-(2-(2-hydroxy-2-propyl)-phenyl)-thio)-methylcyclopropane acid and its sodium salt, is described in WO 97/28797 and U.S. patent 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 WO 97/28797 and U.S. patent 5472964; pranlukast, N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-n-(4-phenylmethoxy)-benzamide), described in WO 97/28797 and EP 173516; zafirlukast, (cyclopentyl-3-[2-methoxy-4-[(o-tamilselvan)-carbarnoyl]-benzyl]-1-methylindol-5-carbamate), described in WO 97/28797 and EP 199543; and[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]-oxymethyl]-phenyl]-acetic acid, described in U.S. patent 5296495 and the Japan patent JP 08325265 A.

The term "inhibitor of 5-lipoxygenase", or "inhibitor of 5-LO" includes any agent or compound that inhibits, restrains, retards or otherwise affect the enzymatic action of 5-lipoxygenase. Pogranicze the living examples of antagonists-adrenergic receptor include albuterol, bitolterol, isoetharine, metaproterenol, pirbuterol, salmeterol, terbutaline, isoproterenol, ephedrine and epinephrine.

A non-limiting example of a derivative of xanthine is theophylline.

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

Non-limiting examples of the stabilizer of mastocytes is the sodium salt of nedocromil.

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

A non-limiting example of an expectorant is guaifenesin.

Non-limiting examples of antagonists NK1NK2and NK3thickening receptor include: CP-99,994 and SR 48968.

Non-limiting examples of antagonists DAWAIninclude baclofen and 3-aminopropylphosphonic acid.

For preparing pharmaceutical compositions from the compounds described in this invention, used inert appropriate farmaceut powders, tablets, dispersible granules, capsules, pills and suppositories. The powders and tablets may contain from about 5 to about 70% of the active component. In this area known in the art suitable solid carriers, such as magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, pills and capsules can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, first melt the low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, and then, for example, by mixing therein is dispersed active component. After that, the molten homogeneous mixture is then poured into the form of a standard size, allowed to cool and thereby solidify.

Liquid forms of medicinal preparations include solutions, suspensions and emulsions. As an example, we can point solutions in water and mixtures of water - propylene glycol, intended for parenteral injection.

Liquid forms of medications can include solutions for vnutripuzarnogo introduction.

Aerosol medications, suitable for inhalation may include solutions and solids in powder form, which can be see the solid forms of drugs, intended for conversion to liquid forms of medications, conducted shortly before use by oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

Compounds corresponding to the present invention may also be administered transdermally. Percutaneous composition can be in the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type in accordance with what is usually used for this purpose in the art.

Preferred oral administration of the compounds.

Preferably, the drug was a single dosage form. In such form the preparation is divided into doses containing appropriate quantities of the active component, for example a quantity effective to provide the necessary steps.

The number of active component in a single dose of a drug may change or be set equal to from about 0.1 to 1000 mg, More preferably from about 1 to about 300 mg, depending on the particular application.

Used in fact, the dosage may vary konkretnogo case performs a specialist in this field of technology. Usually begin treatment with smaller doses that are less than the optimum dose of the compound. Then to increase the dosage in small increments until the system is maximized under these circumstances the effect. For convenience, the total daily dose if necessary, you can split and take the parts during the day.

Dosage and frequency of administration of the compounds of the present invention, and their acceptable from a pharmaceutical point of view salts are determined by 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 to be treated. For the relief of pain, anxiety, depression, asthma or alcohol abuse typical recommended dosing regime is oral administration of from 10 to 2000 mg/day, preferably from 10 to 1000 mg/day in two to four divided doses. When you assign this range of doses, these compounds are not toxic.

For treatment of cough it is preferable that the number of agonist nociceptin receptor ORL-1 dose ranged from about 0.1 to 1000 mg, more preferably from about 1 to 300 mg Typical recommended dozer is - four divided doses. In the treatment of cough agonist nociceptin receptor ORL-1 may be administered in combination with one or more additional drugs intended for the treatment of symptoms of cough, Allergy or asthma, selected from the group including antihistamines, inhibitors of 5-lipoxygenase, leukotriene inhibitors, inhibitors of N3, agonists-adrenergic receptor, xanthine derivatives, agonists-adrenergic receptor, stabilizers mastocytes, antitussives, expectorants, antagonists NK1NK2and NK3thickening receptor and agonists DAWAIn. Preferably, the agonist nociceptin receptor ORL-1 and additional drugs were taken in a combined dosage form (e.g. a tablet), although they can be taken separately. Additional drugs are taken in amounts effective to alleviate the symptoms of cough, Allergy or asthma, preferably in an amount of 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 Pina examples of pharmaceutical dosage forms, which contain compounds corresponding to the present invention. The examples are not intended to limit the scope of the present invention that relates to pharmaceutical compositions.

Examples of pharmaceutical dosage forms

EXAMPLE A - Pill

The dosage of the components shown in table. 12.

The method of manufacturing In a suitable mixer for 10-12 minutes mix components 1 and 2. If necessary, the wet granules are passed through a large 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 10-12 minutes. Add component # 5 and stirred for 1-3 minutes. On a suitable tablet press machine, the mixture is pressed into tablets of the desired size and weight.

The EXAMPLE IN Capsule

The dosage of the components shown in table. 13.

The method of manufacturing In a suitable mixer for 10-12 minutes mix components 1, 2 and 3. Add component # 4 and stirred for 1-3 minutes. In a suitable machine for filling capsules, the mixture is placed in a suitable collapsible capsules of hard gelatin.

Although the present invention is described in connection with specific choices done by opochininyh alternatives modifications and alterations of the present invention. It is implied that all such alternatives, modifications and changes are included in the scope and essence of the present invention.

Claims

1. The connection formulas

or its pharmaceutically acceptable salt, where a dotted line indicates an optional double bond;

X1means R5-(C1-C12)alkyl, R6-(C3-C12)cycloalkyl, R7-phenyl, R8-heteroaryl from the group comprising R8-furanyl, R8-thienyl, R8-pyridyl, R8-thiazolyl and R8-1H-indolyl;

X2means-Cho, -CN, -(CH2zero or 1,

or X1means

X2means hydrogen or X1and X2together form spirograph formulas

m = 1;

p = 0;

Q means-CH2- or-O-;

R1, R2, R3and R4independently selected from the group comprising hydrogen and (C1-C6)alkyl, or R2and R4together can form Allenby bridge of 1-3 carbon atoms;

R5means from 1 to 3 substituents independently selected from the group comprising N, morpholinyl, tetrahydrofuryl, R7-phenyl, R10-pyrrolidinyl, -NR19R20and-OR13;

R6means hydrogen;

R7means from 1 to 3 substituents independently selected from the group comprising hydrogen, halogen, (C1-C6)alkyl, -CN, -CF3, -OR19-(C1-C6)alkyl-or SIG19, -NR19R20-(C1-C6)alkyl-NR19R20, -SR19, -COOR19, -COR19-(C1-C6)alkyl-N(CH3)3-(C1-C6)alkyl-NF3-(C1-C6)ALCO 3 substituents, independently selected from the group comprising hydrogen and (C1-C6)alkyl;

R9means halogen or-OR19,

R10means-OR19,

R11independently selected from the group comprising N, R5-(C1-C6)alkyl, -(C1-C6)alkyl(C3-C12)cycloalkyl -(C1-C6)alkyl-or SIG19-(C1-C6)alkyl-NR19R20-(C1-C6)alkyl-R18-(C3-C6)alkenyl -(C3-C6)quinil and

where q is from 2 to 4 and a is 1 or 2;

R12means N or19;

R13means H or (C1-C6)alkyl;

R17means R7is phenyl;

R19and R20independently selected from the group comprising hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, phenyl or phenyl(C1-C6)alkyl;

R21independently selected from the group comprising hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, (C3-C12)cycloalkyl -(C1-C6)alkyl, thienyl -(C1-C6)alkyl-piperidyl, R7-phenyl, R7-phenyl(C1-C6)alkyl, furyl-(C1-C12)alkyl, R8-thienyl(C1-C12)alkyl, pyridyl-(C1- the6)alkyl-SR19;

R22independently selected from the group comprising hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, (C3-C12)cycloalkyl -(C1-C6)alkyl, furyl, pyridyl, -(C1-C6)alkyl-piperidyl, R7-phenyl, R7-phenyl(C1-C6)alkyl, furyl-(C1-C12)alkyl, R8-thienyl(C1-C12)alkyl, pyridyl-(C1-C12)alkyl, -(C1-C6)alkyl-or SIG19-(C1-C6)alkyl-NR19R20and -(C1-C6)alkyl-SR19;

Z1means R7is phenyl;

Z2means R7is phenyl; Z3means hydrogen; or Z1, Z2and Z3together with the carbon atom to which they are attached, form the group of

where r is 1 or 2; w and u are equal to 0-2, provided that the sum of w and u are equal to 2; and ring a represents a condensed phenyl ring;

R23means from 1 to 3 substituents independently selected from the group comprising H and (C1-C6)alkyl,

R24means from 1 to 3 substituents independently selected from the group comprising H, -OR19and halogen;

R26independently selected from the group comprising H and (Sir> and X2together mean

and Z1means R7is phenyl and Z2means R7is phenyl, then at least one residue R7means halogen or (C1-C6)alkyl;

provided that, if Z1, Z2and Z3together with the carbon atom to which they are attached, form a

and X1and X2together mean

R11means (C1-C6)alkyl-NR19R20or

provided that, if R2and R4form Allenby bridge, Z1, Z2and Z3together with the carbon atom to which they are attached, do not mean

2. Connection on p. 1, in which Z1and Z2mean R7is phenyl.

3. Connection on p. 1, in which R7selected from the group comprising (C1-C6)and alkyl halide group.

4. Connection on p. 1, in which X1means R7-phenyl, and X2means the group HE or N(O)R21.

5. Connection on p. 1, in which X1means

and X<-C6)alkyl, -(C1-C6)alkyl(C3-C12)cycloalkyl -(C1-C6)alkyl-or SIG19or -(C1-C6)alkyl-NR19R20.

7. Connection on p. 1, in which X1and X2together form spirocyclic group,

8. Connection on p. 7, in which m is 1, R17means phenyl and R11means -(C1-C6)alkyl-or SIG19or -(C1-C6)alkyl-NR19R20.

9. Connection on p. 1, selected from the group including

10. Pharmaceutical composition having the properties of agonist nociceptin RES acceptable from a pharmaceutical point of view of the media.

 

Same patents:

The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione

The invention relates to a method for producing 7-aminopyrido[1,2-a][1,3]benzimidazole of the formula (1), which can be used as an intermediate in the synthesis of fluorescent and biologically active substances

The invention relates to 7-chloro-4-hydroxy-2(2-chloro-4-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione, its pharmaceutically acceptable salts, methods for treating pain, when administered pain relieving effective amount of this compound, and pharmaceutical compositions containing this compound

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to compounds of General formula I:

where n is 1, 2 or 3; R1and R2independently selected from hydrogen and alkyl; R3represents alkyl; R4-R7independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy, alkylthio, aaltio, alkylsulfonyl, alkylsulfonyl, arysulfatase, arylsulfonyl, amino, monoalkylamines, dialkylamino, nitro, cyano, carboxaldehyde, alkylcarboxylic, arylcarbamoyl, aminocarbonyl, monoalkylammonium, dialkylaminoalkyl, alkoxycarbonyl, aminocarbonyl, monoalkylammonium, dialkylaminoalkyl, monoalkylammonium, dialkylaminomethyl, or R5and R6together form a carbocyclic or heterocyclic ring, its pharmaceutically acceptable salts and prodrugs and a method of treatment and pharmaceutical compositions having the properties of agonist 5-HT2

The invention relates to the field of medicine and organic chemistry and relates to new derivatives of azobenzenes formula I, II or III, modulating the function of serine/threonine protein kinases, methods of modulating the function of serine/threonine protein kinases, the method of identifying compounds modulating the function of serine/threonine protein kinase, the method of treatment-related serine/threonine protein kinase pathological conditions using such compounds, methods of synthesis of the above on the basis of the compounds of formula I, II or III

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of 3-phenylpyridine formula (I)

in which R denotes hydrogen, C1-C7alkyl, C1-C7alkoxy, halogen or CF3, R1means H or halogen, or R and R1may together form-CH=CH-CH=CH-; R2means H, halogen, CF3, R3means H or C1-C7alkyl, R4means H or piperazine-1-yl; R5means H or C1-C7alkyl, X is-C(O)N(R5)-, -(CH2)mO-, -(CH2)mN(R5)-, -N(R5)C(O)- or N(R5)(CH2)m-; n is an integer from 0 to 4, m is 1 or 2, and their pharmaceutically acceptable acid additive salts

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity
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