Piperidine derivative or its pharmaceutical salt

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new piperidine derivative, with the following general formula (I) where R1 - R4 each stands for any of the univalent groups, indicated below: R1 stands for a hydrogen atom, halogen atom, inferior alkyl, which can be substituted with a halogen atom or OH; -O-inferior alkyl, which can be substituted with a halogen atom; -O-aryl, aryl, -C(=O)-inferior alkyl, COOH, -C(=O)-O-inferior alkyl, -C(=O)-NH2, -C(=O)NH-inferior alkyl, -C(=O)N-(inferior alkyl)2, OH, -O-C(=O)-inferior alkyl, NH2, -NH-inferior alkyl, -N-(inferior alkyl)2, NH-C(=O)- inferior alkyl, CN or NO2; R2 and R3 each stands for a hydrogen atom; and R4 stands for any of the univalent groups (a), (b) and (c), shown below in formula 2 where in the above indicated groups (a), (b) and (c), A stands for a pyrrolidine, piperidine, morpholine, piperizine or oxazepane ring; B stands for a pyrrolidine or piperidine ring; R5 and R8-R11 can be identical or different from each other and each stands for a hydrogen atom, -C(=O)-O-inferior alkyl, cycloalkyl or tetrahydropyrane; R6 stands for a hydrogen atom, -C(=O)-O-inferior alkyl, OH, -inferior alkylene-OH or -C(=O)-pyridine; and R7 stands for a hydrogen atom. The invention also pertains to pharmaceutical salts of the piperidine derivative, as well as medicinal compositions.

EFFECT: obtaining new biologically active compounds and a medicinal composition, based on these compounds, which is a sodium channel inhibitor.

10 cl, 91 ex, 22 tbl

 

The technical field to which the invention relates

The present invention relates to a new piperidinol derivative or its pharmaceutically acceptable salts, as well as medical composition. More specifically the present invention relates to a new piperidinol derivative or its pharmaceutically acceptable salt, as they both have excellent effect of inhibiting sodium channels and excellent analgesic action, as well as medical composition containing the above piperidine derivative or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, and more particularly to a pharmaceutical composition having an analgesic effect, with reduced side effects, in particular neuropathic pain, which acts as an inhibitor of sodium channels.

The level of technology

Voltage controlled sodium channel is a protein responsible for the initiation and propagation of action potentials in neurons. Voltage controlled sodium channel subunit consists of α larger with four domains, each composed of six transmembrane segments, as the overall structure, and two subunits β smaller size. The main part of the function of the channel implementation is aetsa through subunit α . To date, it is known from more than 10 different subtypes subunits α (Goldin AL, Annals of New York Academy of Sciences 868:38-50, 1999). Each subtype of voltage-controlled sodium channel shows different distribution in tissues of the Central and peripheral nerves. These subtypes regulate nervous anxiety and play an important role in the regulation of physiological functions in individual tissues. It is also assumed that they are deeply associated with various pathological States (Goldin AL, Annual Review of discrimination 63:871-894, 2001).

In recent years it has become clear that the voltage controlled sodium channels deeply involved in neural pain transmission, and, as expected, inhibitors of sodium channels will be excellent therapy for pain, in particular therapeutic means from neuropathic pain (Taylor CP, Current Pharmaceutical Design, 2: 375-388, 1996).

Neuropathic pain means pain that occurs as a result of dysfunction in the Central or peripheral neurons, and refers to painful diabetic neuropathy, pain and cancer pain, trigeminal neuralgia, phantom limb pain, post herpetic neuralgia, thalamic pain, and the like. The clinical picture of neuropathic pain include shooting pain, burning pain, hyperalgesia, allodynia, and the like. In medical cases, for the purpose of relieving pain, used non-steroidal anti-inflammatory drugs, narcotic analgesics, such as morphine, and the like. Recently antiarrhythmic drugs and anticonvulsants, which are inhibitors of sodium channels, also start to be used for the purpose of relieving pain.

Nonsteroidal anti-inflammatory drugs are not completely satisfactory because of the analgesic effect and, in addition, have the problem of side effects (such as gastrointestinal disorders and renal disorders). Narcotic analgesics (eg, morphine) are highly effective mainly for nociceptive pain but can have large adverse effects on the digestive system, respiratory system and Central nervous system. Moreover, these medicines are usually small beneficial effects on neuropathic pain. Conventional inhibitors of sodium channels, such as antiarrhythmic medicines (eg, lidocaine and meksiletin) and anticonvulsant drugs (eg, carbamazepine), begin also be used for pain relief. However, these inhibitors of sodium channels have side effects on the Central nervous system (eg, convulsions, and with the justice and adverse effects on the peripheral nervous system (for example, brachycardia), and for this reason they have problems due to the fact that the introduction in a large enough dose is complex, making it difficult to obtain a sufficient analgesic effect.

As described above, have not yet found an analgesic that is effective for the treatment of neuralgic pain and with high security. For this reason it is desirable a new inhibitor of sodium channels, which is highly effective, particularly for neuropathic pain and has low side effects. A brief description of the application for international patent WO 01/53288 (hereinafter referred to as patent literature 1) describes the inhibitor of sodium channels, represented by the following General formula:

Formula 1

where in the above formula, the symbol (W) is a C1-6alkylenes group which may be substituted, or the like; the symbol Z represents a C6-14aromatic hydrocarbon ring group which may be substituted, or the like; the symbol (l) represents 0 or an integer from 1 to 6; the symbol (R1) and (R2represent each a hydrogen atom or something like that. The details of these characters specified in patent literature 1. The connection described in the patent literature is the temperature 1, represents a connection in which piperidine ring linked through the lower alkylenes group or something like that [W] the aromatic hydrocarbon ring group or something like that [the symbol (Z)], and 1-position piperidino ring linked through the lowest alkylen with oxopiperidine ring. At the same time the connection of the present invention differ from the compounds described in patent literature 1, the basic skeleton, in which the 4-position piperidino ring communicates through vinile monosubstituted with (-R1or unsubstituted benzene ring and the 1-position piperidino ring has an acyl group [-C(=O)-R4].

A brief description of the application for international patent WO 01/53288, WO 94/13291 (hereinafter referred to as patent literature 2) describes nitrogen-containing heterocyclic ring derivative having a sterile group (-CH=CH-benzene ring)represented by the following General formula:

Formula 2

where in the above formula, the symbol (W) is a -(CH2)4-, -(CH2)5-, -(CH2)2O(CH2)2- or -(CH2)2S(CH2)2-; the symbol (A)represents a bond, -CH=CH-, O, S, NR1or something like that; the symbol (R1represents a hydrogen atom, a C 1-3alkyl or phenyl-C1-3alkyl; symbol (Ar) represents aryl or heteroaryl; the symbol (n) is an integer from 0 to 6; and the symbol (m) is an integer from 0 to 3. In this regard, the details of these characters is given in patent literature 2.

A brief description of the application for international patent WO 01/53288 WO 97/19059 (hereinafter referred to as patent literature 3) describes nitrogen-containing heterocyclic ring derivative represented by the following General formula:

Formula 3

where in the above formula, the symbol (B) is not present or represents a lower alkylene, cycloalkyl or something like that; the symbol (D) represents-O-, -S-, -C(O)-, -C(O)-O-, -S(O)-, -S(O)2or something like that; the symbol (E) is a lower alkylene or something like that; the symbol (X) is not present or represents-O-, -S - or something like that; the symbols (R1) - (R5represent each a hydrogen atom, halogen or the like; the symbol (RDrepresents a hydrogen atom, lower alkyl or the like; the symbol (n) is an integer from 0 to 3; and the symbol (m) is an integer from 0 to 2. In this regard, the details of these characters is given in patent literature 3.

In patent literature 2 and 3, however, no descriptions, and assumptions about the connection, such as piperidine derivative of the present invention, in which the 4-position piperidino ring linked through vinile, monosubstituted with (-R1or unsubstituted benzene ring, and 1-position piperidino ring has an acyl group [-C(=O)-R4]. In addition, the use of compounds of the patent literature 2 and 3 is an antagonist calcium channel (patent literature 2) and the promoter of the release of acetylcholine (patent literature 3), and in this patent literature, there is neither consideration nor assumptions about the action on the inhibition of sodium channels or analgesic actions.

Description of the invention

The present invention aims at the creation of new piperidinol derivative or its pharmaceutically acceptable salt having an excellent effect of inhibiting sodium channels and excellent analgesic action, and medical compositions containing the new piperidine derivative or its pharmaceutically acceptable salt; in particular, the compounds for inhibition of sodium channels, demonstrating a high analgesic effect on nerve pain and has low side effects, and medical compositions containing the compound as an active ingredient.

The authors of this image is the shadow has carried out research on nitrogen-containing heterocyclic ring derivatives. In the result it was found that piperidine derived, in which the 4-position piperidino ring linked through vinile, monosubstituted with (-R1or unsubstituted benzene ring and the 1-position piperidino ring has an acyl group [-C(=O)-R4], or its pharmaceutically acceptable salt, shows high inhibitory effect (activity) relative to sodium channels and, in addition, demonstrates good analgesic effect on mice with streptozotocin-induced diabetic nerve disorder, as animal models of painful condition. This discovery leads to the completion of the present invention. In accordance with the present invention provides a new connection and a medical composition containing the compound as an active ingredient, both described below.

[1] Piperidine derivative represented by the following further by formula (I)

Formula 4

where in the above formula (I), the symbols R1- R4represent, each, any of the monovalent groups shown below.

R1represents a hydrogen atom, halogen atom, lower alkyl which may be substituted, -O-lower alkyl which may be substituted, -O-aryl, aryl, cycloalkyl, -C(=O)-lower alkyl, COOH, -(=O)-O-lower alkyl, -C(=O)-NH2, -C(=O)NH-lower alkyl, -C(=O)N(lower alkyl)2,OH, -O-C(=O)-lower alkyl, NH2, -NH-lower alkyl, -N(lower alkyl)2, -NH-C(=O)-lower alkyl, CN or NO2;

R2and R3may be the same or different from each other and represent each a hydrogen atom, lower alkyl or halogen atom; and

R4represents lower alkyl which may be substituted, -O-lower alkyl which may be substituted, nitrogen-containing heterocyclic ring group which may be substituted, aryl which may be substituted, NH2, -NH-lower alkyl which may be substituted, or-N(lower alkyl which may be substituted)2],

or its pharmaceutically acceptable salt.

[2] Piperidine derivative or its pharmaceutically acceptable salt p.[1], where, in the formula (I), the monovalent group represented by the symbol R4represents any monovalent group (a), (b) and (c)shown below

Formula 5

where in the above groups (a), (b) and (c) the symbols A and B represent, each, ring, shown below, and the symbols R5- R11represent, each, any of the monovalent groups shown below. A and B represent, each, a nitrogen-containing heterocyclic ring; R5and R - R11may be the same or different from each other and represent each a hydrogen atom, a lower alkyl, -C(=O)-O-lower alkyl which may be substituted, a lower alkylene-O-lower alkyl, cycloalkyl, or saturated or unsaturated 5 - or 6-membered heterocyclic ring group having 1-3 heteroatoms selected from N, S and O;

R6represents a hydrogen atom, a lower alkyl, -O-lower alkyl, -O-lower alkylene-O-, which is bound to one carbon atom of ring A, with the formation of the ring, -C(=O)-O-lower alkyl which may be substituted, OH, -lower alkylene-OH or-C(=O)-heteroaryl; and

R7represents a hydrogen atom, a lower alkyl, -O-lower alkyl, -C(=O)-O-lower alkyl, OH, -lower alkylene-OH, or-C(=O)-heteroaryl.

[3] Piperidine derivative or its pharmaceutically acceptable salt p.[2], where the symbol R4represents a monovalent group (a) and nitrogen-containing heterocyclic ring represented by the symbol A represents a pyrolidine, piperidine, morpholine, pieperazinove or oxazepam ring.

[4] Piperidine derivative or its pharmaceutically acceptable salt p.[2], where the symbol R4represents a monovalent group (b) and nitrogen-containing heterocyclic ring represented by the symbol B represents pyrrolidino the second or piperidino ring.

[5] Piperidine derivative or its pharmaceutically acceptable salt p.[2], where the symbol R4represents a monovalent group (c) and R9- R11in group (c) may be the same or different from each other and represent each a hydrogen atom, a lower alkyl, -C(=O)-O-lower alkyl which may be substituted, a lower alkylene-O-lower alkyl, cycloalkyl, or saturated or unsaturated 5 - or 6-membered heterocyclic ring group having 1-3 heteroatoms selected from N, S and O.

[6] Piperidine derivative or its pharmaceutically acceptable salt p.[5], where at least one of R9- R11in group (c) is cycloalkyl, and the other (others) may be the same or different and represents (represent each a hydrogen atom, a lower alkyl, -C(=O)-O-lower alkyl which may be substituted, a lower alkylene-O-lower alkyl, cycloalkyl or saturated or unsaturated 5 - or 6-membered heterocyclic ring group having 1-3 heteroatoms selected from N, S and O.

[7] Piperidine derivative or its pharmaceutically acceptable salt according to any one of paragraphs. [1]-[6], where piperidine derivative represented by the formula (I)represents at least one compound selected from the group consisting of 4-(2-{4-[(E)-2-(2-were)vinyl]piperidine-1-yl}-2-ox is ethyl)research, 4-(2-{4-[(E)-2-(4-isopropylphenyl)vinyl]piperidine-1-yl}-2-oxoethyl)research, 4-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)of the research, N-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)cyclohexanamine and N-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)-N-methylcyclohexylamine.

[8] the Medical composition containing piperidine derivative or its pharmaceutically acceptable salt according to any one of paragraphs. [1]-[7], and a pharmaceutically acceptable carrier.

[9] the Medical composition according to [7], which is an inhibitor of sodium channels.

Piperidine derivative or its pharmaceutically acceptable salt according to the present invention, as confirmed, has an excellent effect of inhibiting sodium channels and excellent analgesic action and demonstrates a high analgesic effect, in particular, neuralgic pain. For this reason, this compound is suitable for use as an inhibitor of sodium channels with low side effects.

The best way of carrying out the invention

Piperidine derivative or its pharmaceutically acceptable salt according to the present invention is described specifically. It describes the definition of each symbol used in the General formula (I) and monovalent groups (a), (a) and (c), as well as in the specific examples of each character.

The term "lower" refers, unless otherwise specified, in the hydrocarbon chain, straight chain or branched chain having 1-6 carbon atoms. As "lower alkyl" may be considered, for example, C1-6alkali, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl and the like; and preferable are methyl, ethyl, propyl, butyl and tert-butyl.

As "lower alkylene" can be considered, for example, methylene, ethylene, propylene and isopropylene; and methylene and ethylene are preferred. The term "cycloalkyl" refers to a mono - to tricyclic, saturated aliphatic hydrocarbon ring group having 3-14 carbon atoms, and may be considered, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloheptene, bicycloalkyl, bicycloalkyl, bicycloalkyl, tricyclene, tricyclodecane, tricyclodecane and tricyclodecane, and are preferred cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "aryl" refers to a mono - to tricyclic aromatic hydrocarbon group having 6-14 carbon atoms; and may be considered, for example, Fe is Il, naphthyl, antril and tenantry, and phenyl and naphthyl are preferred.

The term "heteroaryl" indicates heteroaryl having 1-3 heteroatoms selected from N, S and O, and preferably represents pyridyl and pyrimidyl. The term "nitrogen-containing heterocyclic ring" refers to mono - or disilicate, nitrogen-containing heteroaryl ring having 5-10 atoms including 1-3 nitrogen atom, and may in addition contain 1-3 oxygen atom or sulfur, in addition to atom (atoms) of nitrogen. Can be considered, for example, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazin, triazine, indolin, isoindoline, benzimidazolyl, benzopyranones, pyrrolopyridine, imidazopyridine, quinoline, isoquinoline and cinoxacin. The term "nitrogen-containing heterocyclic ring" also indicates mono - or disilicate nitrogen containing heteroseksualci having 3-10 atoms including 1-3 nitrogen atom, and may be considered, for example, aziridine, azetidine, pyrrolidine, piperidine, piperazine, hexahydroazepin, Hinkley, azabicycloalkanes (for example, azabicyclo[3.2.1]octane), diazabicyclo, azabicycloalkanes and azabicycloalkanes. May include, in addition to atom (atoms) nitrogen, 1-3 oxygen atom or sulfur, and can be considered morpholine, oxazepam, oxazol, isooctanol, thiazole, isothiazol, furazan, and the like. "Attester is ASEE heterocyclic ring preferably is a pyrolidine, piperidino, morpholino or oxazepam ring. As the "nitrogen-containing heterocyclic ring group" can be considered a monovalent group of the above "nitrogen-containing heterocyclic ring".

As a "saturated or unsaturated 5 - or 6-membered heterocyclic ring group having 1-3 heteroatoms selected from N, S and O can be considered tetrahydropyranyl, furanyl, thiophenyl, pyrrolyl and morpholyl. The group includes the part above the "nitrogen-containing heterocyclic ring group, and preferably represents tetrahydropyranyl or morpholinyl.

As the "halogen atom" may be considered fluorine, chlorine, bromine and iodine; and fluorine and chlorine are preferred.

The term expressing the Deputy of the "lower alkyl which may be substituted", the "nitrogen-containing heterocyclic ring group which may be substituted, or aryl which may be substituted", the expression "which may be substituted" indicates that, "which may be substituted by 1-3 identical or different substituents". As examples of the nitrogen-containing heterocyclic ring group which may be substituted, can be considered piperazinil, morpholinyl and imidazolyl, all of which may have substituents, such as OH, lower alkyl-O, NH2, lower alkyl-NH-, (lower alkyl) 2-N-, aryl, lower alkyl and the like; however, the group is not limited. In any case, as examples of preferred substituents can be considered phenyl, methoxy, amino and dimethylamino. "Lower alkyl which may be substituted" is preferably a substituted methyl group represented by the following further by the formula

Formula 6

"Nitrogen-containing heterocyclic ring group which may be substituted" is preferably a nitrogen-containing heterocyclic ring group represented by the following further by the formula

Formula 7

where in the above formula, each symbol has the same definition as given above.

In compound (I) of the present invention are the optical isomers (for example, optically active compounds and diastereomer) or geometrical isomers, depending on the kinds of substituents. For this reason, the present compound (I) includes mixtures of these optical isomers or geometrical isomers and dedicated connections.

Also present compound (I) can form acid or basic additive salt. As such salts can be considered, for example, addition the e salt with inorganic acid, such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid, phosphoric acid or the like; additive salts with organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonate acid, econsultancy acid, glutamic acid or the like; salts with an inorganic base, such as salts of sodium, potassium, magnesium, calcium, aluminum or the like; and salts with organic base such as methylamine, ethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine, lysine, ornithine or the like. In addition, the present compound (I) or its pharmaceutically acceptable salt may form, in some cases, hydrate, MES (for example, MES with ethanol) or polymorphic connection.

In addition, compound (I) of the present invention include all compounds (prodrugs)that can be metabolized and converted in vivo in the present compound (I) or its pharmaceutically acceptable salt. As the group capable of forming a prodrug according to the present compound (I)may be considered, for example, the groups described in Prog. Med. 5:2157-2161 (1985), and the groups described in "Development of Drugs" (Hirokawa Shoten in 1990) Vol. 7 (Molecular Design) 163-198. These groups, in particular, are those which can be converted into primary amine, secondary amine, OH, HOC(=O)- or something like that, according to the present invention, by hydrolysis or solvolysis or under physiological conditions. As prodrugs OH can be considered, for example, lower alkyl-COO-, which may be substituted, aryl-C(=O)O-, which may be substituted, ROC(=O)-substituted or unsubstituted lower alkylene-C(=O)O-(R represents H or lower alkyl. This applies hereinafter), ROC(=O)-substituted or unsubstituted lower albaniles-C(=O)O-, ROC(=O)-lower alkylene-O-lower alkylene-C(=O)O-, ROC(=O)-C(=O)O-, ROS(=O)2substituted or unsubstituted lower albaniles-C(=O)O-, phthalidyl-O - and 5-methyl-1,3-dioxolan-2-he-4-yl-metiloksi.

The following is a description of representative methods of obtaining this compound (I), synthesis of source materials and recipes.

Ways to get

The present compound (I) can be obtained by various synthesis methods, using the characteristics based on the basic skeleton or types of substituents. Here, we describe two ways to get (the first is the method of obtaining and second production method).

The first way to obtain

The first method of obtaining is a way to obtain the present compound (I) in accordance with by the reaction shown below.

Formula 8

In the above reaction path characters (R1)-(R4indicate the above monovalent group. The symbol (P) indicates a phosphorus atom; the symbol (Ph) indicates a phenyl group, and the symbol (Y) indicates a protective group for amino. The same applies next.

In accordance with a first method of obtaining the compound (I) of the present invention can easily be obtained through the implementation, in the usual way, the Wittig reaction between postnasal salt (1) and the aldehyde or ketone (2) [Org. React., 14, 270-490 (1965); the application for international patent WO 01/53288], to obtain the compound (3), remove aminosidine group of the compound (3), to obtain the compound (4), and the implementation of amidation between the compound (4) and carboxylic acid (5). As solvent for the reaction of Wittig can be used an organic solvent not participating in the reaction, such as tetrahydrofuran, dioxane, dimethyl sulfoxide, toluene or something like that. As the base can be sodium hydride, tert-piperonyl potassium, ethoxide sodium, diisopropylamide lithium or something like that. Reclamare be carried out at a temperature of from -70° C to the temperature of reflux distilled. As aminosidine group can be considered tert-butoxycarbonyl group, benzyloxycarbonyl group and the like. Removing protection (removal of protective group) can be performed by conventional removal protection (Protective Group in Organic Synthesis, second ed., JOHN WILEY & SONS, INC.). Subsequent amidation can be carried out by usual method.

The second way to obtain

The second way of obtaining presents a way to obtain the present compound (I) in accordance with by the reaction shown below.

Formula 9

In the above reaction path characters (R1) - (R4indicate the above monovalent group; the symbol (M) indicates Li, MgCl or the like; and the symbol (Y) indicates aminosidine group. The same applies next.

In accordance with the second method of obtaining, the present compound (I) can be obtained through the normal reaction between Arimathea (for example, abilities or aryl-Grignard) (6) and carbonyl compound (7) [Org. Synth. III, 200 (1955); Org. React., 6, 339-366 (1964); Org. React., 8, 258-304 (1967)]. As the reaction solvent may be used an organic solvent not participating in the reaction, such as a simple diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, AWOL or something like that. The reaction may be carried out at a temperature of from -70°C to the temperature of reflux distilled. Subsequent removal aminosidine group and amidation can be carried out in the same manner as in the first method of receipt.

The present compound (I) can be also obtained by reactions other than the above-mentioned reactions, such as reactions Peterson [Org. React., 38, 1-223 (1990)], and formation of a triple bond, with subsequent partial recovery [J. Am. Chem. Soc, 77, 3378 (1955); J. Am. Chem. Soc, 99, 2805 (1977); Synthesis, 1973, 457; and Tetrahedron 30, 3817 (1974)].

Synthesis of starting materials

The source materials for the present compound (I) can easily be obtained in accordance with the methods of synthesis described in the above literature [Org. React., 14, 270-490 (1965); WO 01/53288; Org. React., 16, 1-438 (1968); Org. Synth., III, 200 (1955); Org. React., 6, 339-366 (1964); Org. React., 8, 258-304 (1967)] and Org. Chem. 43, 4099 (1978).

Thus obtained compound (I) of the present invention excreted in the free form or in the form of its pharmaceutically acceptable salts. Salt of the present compound (I) can be obtained by acting on the present compound (I) (which is a free base) conventional salt formation reaction.

Also present compound (I) or its pharmaceutically acceptable salt is allocated and cleared in the form of its hydrate, MES or polymorphic joint is. Isolation and purification are carried out by conventional chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various types of chromatography and the like.

Various isomers can be separated through the use of appropriately selected source materials or through the use of differences in physical or chemical properties between the isomers. For example, optical isomers can be purified to pure stereochemical isomers through the use of appropriately selected source materials or by racemic resolution of racemic compounds (e.g., racemic compounds converted in diastereomeric salt using conventional optically active acid, followed by optical resolution).

Recipes

The present compound (I) can be used in various recipes used usually. Representative recipes that are applicable to the present compound (I)are described below.

The medical composition of the present invention, containing at least one species of the present compound (I) or its pharmaceutically acceptable salt according to the present invention may contain a pharmaceutically acceptable carrier. By using the Oia media filler and other additives, all of them are commonly used in pharmaceutical preparations, a real medical composition is in the form of tablets, powder, candy, granules, capsules, pills, solutions, preparation for injection, suppository, ointment, paste or the like and is administered orally (including sublingual administration) or parenteral.

Clinical dose of the present compound (I) or its pharmaceutically acceptable salt for a person is determined appropriately in each individual case, taking into account the symptom, weight, age and sex of the individual patient, the route of administration, and the like; however, it is usually the introduction is carried out orally in a total amount of from 1 mg to 1000 mg, preferably from 10 mg to 200 mg, for once or several times per day for an adult, or intravenously, in an amount of from 1 mg to 500 mg for once or several times per day for an adult, or is administered intravenously way a slow release over a period of from 1 hour to 24 hours per day. Because the dose varies depending on various conditions, as described above, a quantity that is smaller than the above dose may be sufficient.

As a solid composition according to the present invention for oral administration are tablets, powder, granules and the like. In such a firm is th composition of one or more active substances are mixed, at least one inactive diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate or something like that. The composition may contain, in accordance with a customary method, additives other than the inactive diluent, for example a lubricant such as magnesium stearate, baking powder, such as starch or cellulose calcium glycolate, stabilizer type lactose and a solubilizer, such as glutamic acid or aspartic acid. Tablets or pills may be coated with sugar or covered with a film soluble in the stomach or in the intestine, using sucrose, gelatin, hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate and the like.

Liquid composition for oral administration contains emulsifier, solvent, suspendisse agent, syrup, elixir and the like, which all are pharmaceutically acceptable, and further comprises an inactive diluent commonly used, such as purified water, ethanol or the like. This composition may contain, along with the inactive diluents, auxiliary agent, such as a solubilizer, wetting agent or suspendisse agent, sweetening agent, aromatic the dominant agent, the perfume, preservative and the like.

The preparation for injection for parenteral administration contains a solubilizer, suspendisse agent or emulsifier, which all are sterile and are aqueous or non-aqueous solutions. An aqueous solution of a solubilizer or a suspending agent includes, for example, distilled water for injection and physiological saline. Nonaqueous the solubilizer or suspendisse agent include, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohol such as ethanol and Polysolvate 80 (trade name). Such a composition may further contain additives such as an isotonic agent, preservative, wetting agent, emulsifier, dispersing agent, a stabilizer such as lactose, auxiliary agent for solubilization and dissolution, and the like. The composition is sterilized, for example by filtration through a bacterial filter or by mixing with sterilizers, or irradiation. Alternative it can also be obtained in the form of an aseptic solid composition, and the resulting aseptic composition is provided for use after dilution before use in aseptic water or aseptic solvent for injection. Now with the unity (I) can be used in combination with a therapeutic drug for diseases, described above, or with other drugs suitable for use against pain, through a mechanism other than blockade of sodium channels. Drug, suitable for use against pain, which is used in combination, includes narcotic analgesics, antipyretic analgesics, non-steroidal anti-inflammatory drugs and the like.

Examples

The present invention is described below in more detail by means of examples [examples obtain the present compound (I)]. However, the present invention is by no means the case is not limited to these examples. First, the examples get the source materials used in the following examples, described as comparative examples.

Comparative example 1

To 15.0 ml of N,N-dimethylformamide suspension containing 2.38 g (2 chlorbenzyl)(triphenyl)phosphonylated add to 0.63 g of tert-butoxide potassium. The mixture is stirred at room temperature for 10 minutes. To the resulting orange suspension is added to 1.00 g of tert-butyl 4-formylpiperidine-1-carboxylate, and the mixture was stirred for 15 minutes to interact. The resulting reaction mixture is then poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer is washed us is placed a solution of salt, and then dried over anhydrous sodium sulfate. After filtration the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexanitrate), with 1.45 g of tert-butyl 4-[2-(2-chlorophenyl)vinyl]piperidine-1-carboxylate as a colourless oil.

Comparative examples 2-32

The compounds shown in tables 1-3, receive the same manner as in comparative example 1.

Comparative example 33

To 1.45 g of tert-butyl 4-[2-(2-chlorophenyl)vinyl]piperidine-1-carboxylate add 2,10 g p-toluensulfonate acid. The mixture is stirred at 150°C for 5 hours to communicate. To the obtained reaction mixture was added 10.0 ml of water. The mixture is brought to about pH 11 with 10% aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is washed with water and saturated saline solution and then dried over anhydrous sodium sulfate. After filtration, the filtered material is concentrated under reduced pressure, to obtain 0.97 g of 4-[(E)-2-(2-chlorophenyl)vinyl]piperidine as a yellow oil.

Comparative examples 34-40

Compounds shown in table 3, receive the same manner as in comparative example 33.

Comparative example 41

5.0 ml chloroformate solution containing 0.55 g of 4-[(E)-2-(3-chlorphen is)vinyl]piperidine and 0.5 ml of triethylamine, add 5.0 ml chloroformate solution containing 0.2 ml of chloroacetanilide, and the resulting mixture was stirred at room temperature for 20 minutes to interact. The reaction mixture was poured into 10% hydrochloric acid. The organic layer is separated and washed with saturated aqueous sodium bicarbonate and saturated saline solution and then dried over anhydrous sodium sulfate. After filtration the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexanitrate), with the receipt of 0.42 g of 1-(chloroacetyl)-4-[(E)-2-(3-chlorophenyl)vinyl]piperidine as a yellow oil.

Comparative examples 42-45)

The compounds shown in tables 3 and 4 receive the same manner as in comparative example 41.

Example 1

To 10.0 ml of N,N-dimethylformamide solution containing 0.45 g of 4-[(E)-2-(2-chlorophenyl)vinyl]piperidine add 0,37 g monohydrochloride morpholine-4-yl-acetic acid, 0.39 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide of monohydrochloride, 0.27 g of 1-hydroxybenzotriazol monohydrate and 0.28 ml of triethylamine. The mixture is stirred at room temperature for 2 days to communicate. The resulting reaction mixture was poured into 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and Ishenim salt solution, and then dried over anhydrous sodium sulfate. After filtration the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (ethyl acetate), to obtain 0.56 g of 4-(2-{4-[(E)-2-(2-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)the research in the form of pale yellow crystals. These crystals get in a solution of 3.0 ml of ethanol and 1.0 ml of tetrahydrofuran. To it add 2.0 ml of an ethanol solution containing 0.14 g of oxalic acid. The resulting crystals are collected by filtration and recrystallized from ethanol, to obtain 0.52 g of 4-(2-{4-[(E)-2-(2-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)the research oxalate as colorless powdery crystals.

Examples 2-54

The compounds shown in tables 5-13 receive the same manner as in example 1.

Example 55

To 10.0 ml of N,N-dimethylformamide solution containing 0,80 g of 1-(chloroacetyl)-4-[(E)-2-(4-chlorophenyl)vinyl]piperidine add 0,41 g piperidine-3-ol and 0.74 g of potassium carbonate, and the resulting mixture was stirred at room temperature for 6 hours to interact. The resulting reaction mixture was poured into 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. After filtration, the filtrate concentration of irout under reduced pressure. The residue is purified by column chromatography on silica gel (ethyl acetate-ethanol), with the receipt of 0.92 g of 1-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)piperidine-3-ol as a colourless oil. This oil was dissolved in 5.0 ml of ethanol. To it add 5.0 ml of an ethanol solution containing 0,23 g of oxalic acid. The resulting crystals are collected by filtration and recrystallized from ethanol-ethyl acetate, to obtain 0.96 g of 1-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)piperidine-3-ol oxalate as colorless powdery crystals.

Examples 56-65

The compounds shown in tables 13-15, receive the same manner as in example 55.

Example 66

To 20,0 ml of N,N-dimethylformamide solution containing 2.00 g of 1-(chloroacetyl)-4-[(E)-2-(4-chlorophenyl)vinyl]piperidine add 1.86 g of phthalimide potassium, and the resulting mixture was stirred at 50°C for 3 hours to interact. The resulting reaction mixture was poured into 10% aqueous potassium carbonate solution, extracted with chloroform. The organic layer is washed with water and saturated saline solution and then dried over anhydrous sodium sulfate. After filtration the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (chloroform-acetone), with the receipt of 2.46 g of 2-(2-{4-[(E)-2-(4-chlorophenyl)VI is Il]piperidine-1-yl}-2-oxoethyl)-1H-isoindole-1,3(2H)dione as colorless powdery crystals.

Example 67

To a 50.0 ml methanol suspension containing the 2.46 g of 2-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)-1H-isoindole-1,3(2H)-dione, add 0,65 ml of hydrazine monohydrate, and the mixture was heated under reflux for 1.5 hours. The resulting reaction mixture is cooled to room temperature and concentrate under reduced pressure. To the residue add to 100.0 ml of 5% aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is washed with water and saturated saline solution and then dried over anhydrous sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, obtaining of 1.80 g of 2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxetanone in the form of a colorless oil.

Example 68

To 5.0 ml of an ethanol solution containing 0.71 g of tert-butyl 4-(2-{4-[(E)-2-(3-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)piperazine-1-carboxylate, add 10.0 ml of 35% hydrochloric acid - ethanol. The mixture is stirred at room temperature for 2 hours to interact. The reaction mixture is concentrated under reduced pressure. The residue three times azeotropic distil together with 5.0 ml of ethanol. The remainder will recrystallized from ethanol, to obtain and 0.46 g of 1-(2-{4-[(E)-2-(3-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)piperazine dihydrochlor is Yes in the form of colorless crystals.

Examples 69-74

The compounds shown in tables 15-16, receive the same manner as in example 68.

Example 75

To 10.0 ml of N,N-dimethylformamide suspension containing 0,70 g of 1-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)piperazine dihydrochloride add and 0.46 ml of triethylamine and 0.56 g of chloride monohydrochloride nicotinic acid. The mixture is stirred at room temperature for 2 hours to interact. The resulting reaction mixture was poured into 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexane - ethyl acetate), to obtain 0.73 g of 1-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)-4-(pyridine-3-ylcarbonyl)piperazine as a pale yellow oil. To 3.0 ml of an ethanol solution containing it, add 2.0 ml of an ethanol solution containing 0.15 g of oxalic acid. The resulting crystals are collected by filtration and recrystallized from ethanol, to obtain 0.66 g of 1-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)-4-(pyridine-3-ylcarbonyl)piperazine oxalate in the form of a hazy white powdery crystals.

Example 7

To 20,0 ml methylenchloride solution containing 1.80 g of 2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxetanone add to 0.67 ml of cyclohexanone and 0.35 ml of acetic acid, to obtain the solution at about pH 5. The solution was stirred at room temperature for 15 minutes. To it add to 1.37 g triacetoxyborohydride sodium, and the resulting mixture is stirred for 10 minutes to interact. The resulting reaction mixture was poured into 10% aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. After filtration the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (chloroform-ethanol)to obtain 1.73 g of N-2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)cyclohexanamine in the form of light brown crystals. 10.0 ml of an ethanol solution get by dissolving 0.88 g of the compound. To the solution add 5.0 ml of an ethanol solution containing 0,22 g of oxalic acid. The resulting crystals are collected by filtration and recrystallized from ethanol-ethyl acetate, to obtain 1.0 g of N-2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)cyclohexanamine oxalate as colorless powdery crystals.

Example 77

Connection, shown in table 17, receive the same manner as in example 76.

Example 78

To 10.0 ml acetonitrile solution containing 0,81 g N-2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)cyclohexanamine, at room temperature, add 1.0 ml of 37% formaldehyde solution, and the mixture was stirred for 5 minutes. To it was added 0.15 ml of acetic acid and stirred for 10 minutes to interact. Add 0,85 g triacetoxyborohydride sodium, the mixture is stirred for 10 minutes. The resulting reaction mixture was poured into 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. After filtration the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on aluminium oxide (n-hexane-ethyl acetate), obtaining 0,69 g N-2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)-N-methylcyclohexylamine in the form of a colorless oil. After receiving it in 5.0 ml of an ethanol solution is added 5.0 ml of an ethanol solution containing 0.16 g of oxalic acid. The resulting crystals are collected by filtration and recrystallized from ethanol-ethyl acetate, obtaining 0,72 g N-2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)-N-is ethylcyclohexylamine oxalate as colorless powdery crystals.

Example 79

Compounds shown in table 17, receive the same manner as in example 78.

Example 80

6 ml of 20% aqueous sodium hydroxide solution is added to 30 ml of a methanol solution containing 2.85 g of methyl 3-{(E)-2-[1-(morpholine-4-ylacetic)piperidine-4-yl]vinyl}benzoate. The mixture is heated under reflux for 1 hour, distil under reduced pressure to remove solvent. To the residue is added to neutralize 10% hydrochloric acid. The resulting mixture was extracted with chloroform, and the extract is dried over anhydrous sodium sulfate. The dried extract distil under reduced pressure to remove solvent. Then the obtained crystals suspended in ethyl acetate, the resulting suspension is filtered, collecting 1,91 g of 3-{(E)-2-[1-(morpholine-4-ylacetic)piperidine-4-yl]vinyl}benzoic acid.

Examples 81-82

Compounds shown in table 17, receive the same manner as in example 80.

Example 83

To 8 ml acetonitrile suspension containing 589 mg of 4-{(E)-2-[1-(morpholine-4-ylacetic)piperidine-4-yl]vinyl}benzoic acid, add 943 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide of monohydrochloride, 556 mg of 1-hydroxybenzotriazole and 1.5 ml of 50% aqueous dimethylamine. The mixture is heated under reflux for 1.5 hours. After cooling the reaction mixture to the center under reduced pressure. To the residue is added saturated aqueous sodium bicarbonate solution, and the resulting mixture extracted with chloroform. The extract was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The dried extract distil under reduced pressure to remove solvent. The residue is purified by column chromatography on silica gel (chloroform-methanol), to obtain 315 mg of N,N-dimethyl-4-{(E)-2-[1-(morpholine-4-ylacetic)piperidine-4-yl]vinyl}benzamide as a pale yellow oil. After receiving from him 8 ml of an ethyl acetate solution is added 4 ml of an ethanol solution containing 74 mg of oxalic acid. The resulting crystals are collected by filtration and recrystallized from ethanol-ethyl acetate, to obtain 290 mg of N,N-dimethyl-4-{(E)-2-[1-(morpholine-4-ylacetic)piperidine-4-yl]vinyl}benzamide oxalate.

Examples 84-88

Compounds shown in table 18, receive the same manner as in example 83.

Example 89

6.5 1 ml,2M solution motility - simple diethyl ether is added at -78°C to 20 ml of tertrahydrofuran ring solution containing 824 mg of methyl 4-{(E)-2-[1-(morpholine-4-ylacetic)piperidine-4-yl]vinyl}benzoate. The mixture was stirred at the same temperature for 3 hours. To it was added 20 ml of a saturated aqueous solution of ammonium chloride, and the mixture was heated to room is based temperature. The reaction mixture is extracted with chloroform. The extract was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The dried extract distil under reduced pressure to remove solvent. The residue is purified by column chromatography on silica gel (ethyl acetate-methanol), to obtain 283 mg 2-4-{(E)-2-[1-(morpholine-4-ylacetic)piperidine-4-yl]vinyl}phenyl)propan-2-ol as a pale yellow oil. Then it transforms to 5 ml of an ethyl acetate solution is added 1 ml of an ethanol solution of 68 mg of oxalic acid. The resulting crystals are collected by filtration and recrystallized from ethanol, to obtain 219 mg 2-4-{(E)-2-[1-(morpholine-4-ylacetic)piperidine-4-yl]vinyl}phenyl)propan-2-ol oxalate.

Example 90

To 20 ml of a methanol solution containing 667 mg of 4-(2-{4-[(E)-2-(4-nitrophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)of the research, add 5 ml of water, 0.5 g of ammonium chloride and 0.5 g of zinc powder. The mixture is heated under reflux for 30 minutes. After cooling, the reaction mixture is filtered. The filtrate is concentrated under reduced pressure. To the residue water is added and extracted with ethyl acetate. The extract was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The dried extract distil under reduced pressure. The residue is purified using the column chromatography on silica gel (ethyl acetate-methanol), to obtain 600 mg of 4-{(E)-2-[1-morpholine-4-ylacetic]piperidine-4-yl}vinyl}aniline as a pale yellow oil. 250 mg get connection in solution in 2 ml of ethyl acetate and 1 ml of ethanol through its dissolution. To the resulting solution was added 1 ml of an ethanol solution containing 68 mg of oxalic acid. The resulting crystals are collected by filtration and recrystallized from ethanol, to obtain 231 mg of 4-{(E)-2-[1-morpholine-4-ylacetic]piperidine-4-yl}vinyl}aniline oxalate.

Example 91

0.5 ml of acetic anhydride is added to 5 ml of a pyridine solution containing 500 mg of 4-{(E)-2-[1-morpholine-4-ylacetic)piperidine-4-yl]vinyl}aniline. The resulting mixture was stirred at room temperature for 6 hours to interact. The reaction mixture was concentrated under reduced pressure. To the residue add 5% aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract is washed with water and saturated saline solution and then dried over anhydrous sodium sulfate. The dried extract distil under reduced pressure to remove solvent. To the residue is added ethyl acetate, and the resulting mixture is stirred. The resulting crystals are collected by filtration, to obtain 520 mg of N-4-{(E)-2-[1-(2-morpholine-4-ylacetic)piperidine-4-yl]vinyl}phenyl)ndimethylacetamide in the form of pale yellow powdery crystals. C is the added solution of 3 ml of ethyl acetate and 3 ml of ethanol, contains 450 mg of the compound, 1 ml of an ethanol solution containing 110 mg of oxalic acid. The resulting crystals are collected by filtration and recrystallized from ethanol, to obtain 470 mg of N-4-{(E)-2-[1-(2-morpholine-4-ylacetic)piperidine-4-yl]vinyl}phenyl)ndimethylacetamide oxalate.

Chemical structural formulas and physical and chemical properties of the compounds obtained in the above comparative examples and examples are shown in tables 1-19. In addition to the compounds described in the examples, the compounds listed in tables 20, can be obtained through the methods described above, the methods described in comparative examples and examples of the methods known to experts in this field, and their modifications, without the need for any special experiments.

Symbols in the tables indicate the following.

Rf: No. comparative example, EX: No. of example, Me: methyl group, MC: mass spectrum (if not stated otherwise, FAB or ESI) m/z NMR spectrum, nuclear magnetic resonance (unless otherwise indicated, 400 MHz,1H-NMR, DMSO-d6, internal standard TMS) δ (ppm)

Table 1
Srpr No.StructureDataSrpr No.StructureData
1MS: 321(EI)2MS: 301(EI)
3MS: 315(EI)4MS: 345(EI)
5MS: 332(EI)6MS: 347(EI)
7MS: 305(EI)8MS: 365(EI)
9MS: 301(EI)10MS: 343(EI)
11MS: 345(EI)12MS: 332(EI)
13MS: 303(EI)14MS: 347(EI)

Data
Table 2
Srpr No.StructureSrpr No.StructureData
15MS: 305(EI)16MS: 321(EI)
17MS: 365(EI)18MS: 301(EI)
19MS: 329(EI)20MS: 343(EI)
21MS: 363(EI)22MS: 312(EI)
23MS: 345(EI)24MS: 355(EI)
25MS: 332(EI)26MS: 303(EI)
27MS: 317(EI)28MS: 379(EI)

Table 3
Srpr No.StructureDataSrpr No.StructureData
29MS: 371(EI)30MS: 305(EI)
31MS: 321(EI)32MS: 365(EI)
33MS: 22234MS: 222
35MS: 26436MS: 218
37MS: 28038MS: 206
39MS: 22240MS: 265(EI)
41MS: 297(EI)42 MS: 297(EI)

Table 4
Srpr No.StructureDataSrpr No.StructureData
43MS: 27844MS: 297(EI)
45MS: 343(EI)

Table 5
Ave., No.StructureData
1NMR: 1,21 (1H, m)of 1.41 (1H, m), is 1.81 (2H, m)of 2.50 (1H, m), 2,65 is 2.80 (5H, m), 3.45 points-of 3.80 (7H, m), 3,90 (1H, m), 4,37 (1H, m), 6,34 (1H, DD), 6,69 (1H, d), 7,20-to 7.35 (2H, m), 7,40 (1H, d), 7,66 (1H, d) MS: 349
2MS: 315
3NMR: 1,24 (1H, m)of 1.40 (1H, m), is 1.81 (2H, m), 2,28 (3H, c), 2,47 (1H, m), 2,71 (1H, t), 2,80 (4H, m), 3,10 (1H, t), 3,51-of 3.80 (6H, m)to 3.89 (1H, d), 4,37 (1H, d), 6,11 (1H, DD), 6,59 (1H, d), 7,12 (3H, m), 7,42 (1H, m) MS: 329
4 MS: 343
5MS: 343
6MS: 360

Table 6
Ave., No.StructureData
7MS: 331
8MS: 345
9MS: 359
10MS: 373
11MS: 333
12MS: 395
13MS: 329

Table 7
Ave., No.StructureData
14MS: 371

MS: 373
15
16MS: 360
17MS: 331
18MS: 345
19MS: 359

Table 8
Ave., No.StructureData
20MS: 373
21MS: 333
22NMR: 1,24 (1H, m)to 1.37 (1H, m), of 1.78 (2H, m), 2,42 (1H, m), 2,60 is 2.80 (5H, m), is 3.08 (1H, m), of 3.57 (1H, m), 3,60 of 3.75 (5H, m), 3,90 (1H, m), 4,35 (1H, m), 6,38 (2H, m), 7.23 percent (3H, m), of 7.48 (1H, s) MS: 349
23MS: 395
24NMR: 1,21 (1H, m)to 1.37 (1H, m)to 1.87 (2H, m), and 2.27 (3H, s)to 2.41 (1H, m), 2,70 (1H, t), 2,85 (4H, m)to 3.09 (1H, t), 3,68-a 3.87 (7H, m), 4,34 (1H, d), 6,18 (1H, DD), 6,34 (1H, d), 7,11 (2H, d), 7,28 (2H, d) MC: 329
25MS: 343

Table 9
Ave., No.StructureData
26NMR: of 1.18 (6H, t), 1,17-of 1.39 (2H, m), of 1.78 (2H, m), is 2.40 (1H, m), 2,67-is 2.88 (6H, m), is 3.08 (1H, t), 3,60-3,70 (6H, m), a 3.87 (1H, d), 4,34 (1H, d), 6,18 (1H, DD), 6.35mm (1H, d), 7,16 (2H, d), 7,29 (2H, d) MS: 357
27NMR: 1.26 in (9H, s), 1,26-of 1.39 (2H, m), of 1.78 (2H, m), 2,42 (1H, m), 2,70 (1H, t), and 2.79 (4H, m), is 3.08 (1H, t), 3,64-to 3.89 (7H, m), 4,34 (1H, d), 6,18 (1H, DD), 6.35mm (1H, d), 7,31 (4H, s) MS: 371
28MS: 391
29MS: 340

30MS: 373
31MS: 383

Table 10
Ave., No.StructureData
32MS: 360
33MS: 331
34 MS: 345
35MS: 359
36MS: 373
37NMR: 1,20-of 1.26 (1H, m), 1,34-of 1.42 (1H, m), of 1.78 (2H, m), 2,42 (1H, m), 2,70 (1H, m)of 2.75 (4H, m), is 3.08 (1H, m), of 3.57 (1H, m), 3,68-to 3.73 (5H, m)to 3.89 (1H, m)to 3.36 (1H, m), to 6.19 (1H, DD), 6,40 (1H, d), 6,95 (2H, d), of 6.99 (2H, DD), 7,13 (1H, t), of 7.36-the 7.43 (4H, m) MS: 409

Table 11
Ave., No.StructureData
38MS:399
39MS:333
40NMR: 1,16-of 1.26 (1H, m), 1,33-of 1.42 (1H, m), of 1.78 (2H, m), 2,42 (1H, m), 2,70 (1H, m), and 2.79 (4H, m), with 8.05 (1H, m), to 3.58 at 3.69 (6H, m)to 3.89 (1H, m), 4,36 (1H, m), 6,30 (1H, DD), 6,41 (1H, d), of 7.36 (2H, d), 7,43 (2H, d) MS: 349
41MS: 395
42MS: 315
43MS: 373
44MS: 360

Table 12
Ave., No.StructureData
45MS: 333
46MS: 395
47MS: 357
48MS: 371
49MS: 391
50MS: 409
51MS: 333

Table 13
Ave., No.StructureData
52MS: 349
53MS: 418(EI)
54MS: 399

55 NMR: 1,20-of 1.45 (3H, m)of 1.64 (1H, m), of 1.80 (4H, m), of 2.45 (1H, m), is 2.74 (2H, m)to 3.09 (3H, m), 3,70-4,10 (4H, m), 4,36 (1H, m), 6,30 (1H, DD), 6,41 (1H, d), of 7.36 (2H, d), the 7.43 (2H, d) MS: 363
56MS: 447(EI)
57MS: 447(EI)

Table 14
Ave., No.StructureData
58MS: 385
59MS: 428
60MS: 447(EI)
61MS: 493(EI)
62MS: 359
63MS: 379

Table 15
Ave., No.StructureData
64MS: 343
65MS: 363
66MS: 408(EI)
67MS: 278(EI)
68NMR: 1,26 (1H, m)of 1.41 (1H, m), of 1.80 (2H, m), 2,46 (1H, m), 2,78 (1H, m), 3,11 (1H, m), 3,15-4,00 (10H, m), 4,35 (2H, m), 6,40 (2H, d), 7,27 (1H, d), 7,35 (2H, m), 7,49 (1H, s), 9,60-10,00 (1H, m) MS: 348
69MS: 348
70MS: 328

Table 16
Ave., No.StructureData
71MS: 348
72MS: 394
73MS: 299
74NMR: 1,20-1,50 (2H, m), 1.70 to 2.00 in (5H, m), of 2.45 (1H, m), 2,80 (1H, m), 3,10-to 3.35 (3H, m), a 3.87 (1H, m), 4,36 (1H, m), 4,50 with 4.65 (1H, m), of 6.31 (1H, DD), 6.42 per (1H, d), of 7.36 (2H, d), the 7.43 (2H, d), 8,43 (1H, m), 9,60-and 10.20 (1H, m) MS: 319
75MS: 453
76 NMR: 1,00-1,45 (7H, m)to 1.60 (1H, m), 1.70 to of 1.85 (4H, m), 2,04 (2H, m)2,44 (1H, m), 2,77 (1H, m), 2,89 (1H, m), 3,10 (1H, m), of 3.77 (1H, m), 3.95 to of 4.05 (2H, m), 4,37 (1H, m), of 6.29 (1H, DD), 6,41 (1H, d), of 7.36 (2H, d), the 7.43 (2H, d) MS: 361

Table 17
Ave., No.StructureData
77MS: 363
78NMR: 1,00-1,50 (7H, m)to 1.60 (1H, m), of 1.80 (4H, m)to 1.98 (2H, m)2,44 (1H, m)to 2.66 (3H, s), 2,77 (1H, m), 3.00 and is 3.15 (2H, m), with 3.79 (1H, m), 4,10 (2H, m), 4,37 (1H, m), 6,30 (1H, DD), 6,41 (1H, d), of 7.36 (2H, d), the 7.43 (2H, d)

MS: 375
79MS: 377
80MS: 359
81MS: 359
82MS: 359

Table 18
Ave., No.StructureData
83MS: 386
84 MS: 358
85MS: 386
86MS: 358
87MS: 386
88MS: 358

Table 19
Ave., No.StructureData
89MS: 373
90MS: 330
91MS: 372

Table 20

Pharmacological studies

For compound (I) of the present invention investigated the effect of inhibition of sodium channels and analgesic effects in animal models. Studies are described in detail below.

The study of inhibition of sodium channels

Action inhibition of sodium channels of representative compounds according to the present compound (I) is confirmed by examining the consumption of [14C] guanidine with what ispolzovaniem brain tissue of the rat. Studies of consumption of [14C] guanidine is implemented by the update method Bonisch et al. (British Journal of Pharmacology, 108, 436-442, 1993). [14C] guanidine is used as a tracer for sodium, and measured the inhibitory activity on the consumption of [14C] guanidine induced by veratridine, as activator sodium channels in primary neurons of the cerebral cortex of the rat.

a. Cooking system culture of primary neurons of the cerebral cortex of rats.

Pregnant rats (Wistar, female, term pregnancy = 19 days) anaesthetize simple diethyl ether and slaughtered by exsanguination through perestiani carotid artery. Fruits cut in pregnant rats and sterilized with ethanol for disinfection. Then the fruit separates the cerebral cortex. Cerebral cortex digested by papain and is dispersed in the culture medium. Then separated the neurons are placed in a 96-well white tablet coated with poly-L-lysine at a density of 2.5×106cells/well, and cultured for 2 days in CO2the incubator (37°C, 5% CO2).

b. Evaluation of the studied compounds

Each well is washed once with buffer for analysis (135 mm choline Cl, 5 mm KCl, 1 mm MgSO4, 5.5 mm glucose, 1 mg/ml BSA, 10 mm Hepes-Tris, pH 7,4). Buffer samples are added to each well and incubated at 25� C for 10 minutes. Then buffer for analysis replace the reaction solution (investigational compound, [14C] guanidine and 100 μm veratridine), and incubated at 25°C for 15 minutes. The reaction is stopped by three times washing with cold wash buffer (135 mm NaCl, 5 mm KCl, 1 mm MgSO4, 10 mm Hepes-Tris, pH 7,4). To each well add 17 ál of 0.1 n NaOH; carry out stirring; then add 100 ál of the scintillator to measure the radioactivity of each well using a liquid scintillation counter. In each study, the consumption of [14C] guanidine, inhibiting by 1 mm meksiletina, is accepted as part of the specific consumption through the sodium channel. The activity of the compounds on sodium channel is expressed as the concentration of 50% inhibition (IC50for specific consumption.

As shown in table 21, the present compound include compounds that demonstrate value IC50about 3-30 microns, and have a higher impact than meksiletin (about 70 μm).

Table 21
Etc.IC50(µm)Etc.IC50(µm)
1271016
26 253713
40235012
52246512
68257413
763,4783,1

Analgesic effect on diabetic neuropathy in streptozotocin-induced diabetic mice

Representative compounds for the compound (I) of the present invention are evaluated for analgesic effect on diabetic neuropathy in streptozotocin (STZ)-induced diabetic mice to confirm the impact on neuropathic pain. Assessment is made using the method Kamei et al. (Pharmacology Biochemistry &Behavior 39, 541-544, 1991) with some modifications.

Male ICR mice aged 4 weeks to receive intraperitoneal injection mass of 200 mg/kg STZ to obtain mice with diabetic neuropathy. Analgesic effect estimate by examining the crushing of the tail. Specifically analgesic action detects as prolongation of the reaction time (in seconds), i.e. the time before the animal shows the reaction of rotation of the head, after the tail is pinched by a clip. At day 14 after injection of STZ carry out preliminary is the first study to determine the latency of the response before the introduction of the investigated compounds. Only animals showing in the preliminary study, the latency of the reaction is not more than 3 seconds, is used to evaluate the compounds for the next day (day 15 after injection of STZ). When evaluating the compounds measured values of the latency of response after administration of the compounds. The investigated compound is administered orally at a dose of 30 mg/kg, 45 minutes prior to measurement of the latency of response. Analgesic effect of the compounds is expressed as a prolongation of the latency (in seconds)calculated by the formula:

(latency response after introduction of a test compound) - (latency response before the introduction of the tested compound).

As shown in table 22, these investigational compounds demonstrate prolongation of latency of approximately 2 to 4 seconds and have a good analgesic effect.

Table 22
Etc.The increase in latency time (sec)Etc.The increase in latency time (sec)
32,3262,3
403,4763,2
782,4

Given the i.i.d. above study confirmed that the present compound has an activity of inhibiting sodium channels, higher than mexiletine. It was confirmed also that the present connection, when injected oral, shows good analgesic activity in animal models of painful conditions, i.e. in mice with diabetic neuropathy. Thus, it is confirmed that the present compound is effective as an excellent inhibitor of sodium channels in pain, in particular neuropathic pain associated with diabetic neuropathy, and the like.

The study of the absence of side-effects

For drugs currently used to treat neuropathic pain, the difference between dose for pronounced analgesic exposure and dose for the Express side effects is small, and for this reason is often a side effect, making heavy use at high dose. Through research Rotarod, often used as a classic method for detecting a side impact, confirmed that a representative compound of the compounds of the present invention hardly cause side effects, even when injected at a dose considerably higher than the dose necessary to Express analytice the who action. The study of differences from dose side effects through partial modification of the method of Christensen et al. (Pain 93, 147-153, 2001). When studying the use of SD rats. In each experiment each of the studied animal is placed on a device that accelerates from 4 rpm to 40 rpm at a constant acceleration for 5 minutes, and measure the time (retention time, seconds) before the fall of the studied animal. On the day of the experience, at first, each of the investigated animal measured body weight, and they are subjected to the influence of three experiments before the introduction of drugs. For the study of pharmacological action select those studied animals that exhibit the longest retention time of 90 seconds or more, in three experiments. These selected investigational animals are divided into groups, so that differences in average retention time before the introduction of drugs between groups is minimal. Each drug administered orally together with the solvent (5 ml/kg). After the introduction of medicines carried out two experiments with the same time schedule as for studies to measure the impact against allodynia in mice with legirovannye spinal nerves L5/L6. For example, when the impact against allodynia measured 30 minutes after administration of medicinal environments is TBA, experiences after the introduction of medicines carried out within 30 minutes after administration of the medicinal product, and also in the study Rotarod. As the retention time after the introduction of drugs for investigational animal, take the average of two experiments. The retention time of each group is expressed as the average ± standard error. The significance of differences between group, where he introduced the solvent, and the group was administered the drug, analyze using test Dunnet, and the level of p<0,05 assessed as significant.

Compounds of the present invention include compounds having such a property that the side effects can hardly be called even when they are introduced at a dose considerably higher than the dose effective in the study to measure impact against allodynia in rats with legirovaniem spinal nerve L5/L6.

The impact against allodynia in rats with legirovaniem spinal nerve L5/L6

One of the main symptoms of neuropathic pain represents a significantly lower threshold of response to tactile stimulation (allodynia). The impact against allodynia representative compounds of the compounds of the present invention is confirmed by evaluating the analgesic action in rats with leagues the management of spinal nerve L5/L6. Assessments are carried out by the method of Kim and Chung (Pain50, 355-363, 1992) with some modifications. Under anesthesia with phenobarbital, male SD rats aged 5 or 6 weeks to undergo surgery for ligation of lumbar spinal nerves, left, as L5, and L6, tight, silk threads. For evaluation of the analgesic action is applied hair research background Freya. That is, the rear paw of the animal prick with hairs, and the least effort on the thread for responses limb is denoted as the reaction threshold (log g) for mechanical stimulation. As in the previous study confirmed that the reaction threshold hind legs of the animal, the lower legs on the side of ligation, is clearly low for 7-14 days after surgery (in the state of allodynia), the impact against allodynia of the studied compounds assess any day between days 7 and 14 after surgery. The day before the evaluation of the compounds measured the threshold of the reaction before the introduction of the investigated compounds. Animals are divided into 4-5 groups, so that differences in the mean values of the threshold reaction prior to introduction between the groups and the variance within groups becomes small. When evaluating the compounds measured threshold reactions after administration of the compounds. Studied the the group administered orally 30 minutes prior to the measurement threshold of the reaction. Selenocystine action against allodynia of the studied compounds is expressed as U50. When calculating the ED50the rapids are located on one side and on the opposite side, with respect to legirovanie, paws in the group, where he introduced the solvent, denoted by 0% and 100%, respectively.

The present compound includes those compounds that demonstrate excellent ED50. At the same time, U50meksiletina is approximately 70 mg/kg

1. Piperidine derivative represented by the following formula (I):

Formula 1

where the symbols R1-R4each represents any monovalent group shown below

R1represents a hydrogen atom, halogen atom, lower alkyl which may be substituted by a halogen atom or HE; -O-lower alkyl which may be substituted by a halogen atom; -O-aryl, aryl, -C(=O)-lower alkyl, COOH, -C(=O)-O-lower alkyl, -C(=O)-NH2-C(=O)NH-lower alkyl, -C(=O)N(lower alkyl)2HE, -O-C(=O)-lower alkyl, NH2, -NH-lower alkyl, -N(lower alkyl)2, -NH-C(=O)-lower alkyl, CN or NO2;

R2and R3each represents a hydrogen atom; and

R4represents any monovalent group (a), (b) and (C)shown below

Formula is 2

where in the above groups (a), (b) and (C)

But a pyrolidine, piperidine, morpholine, pieperazinove or oxazepine ring;

Represents a pyrolidine or piperidino ring;

R5and R8-R11may be the same or different from each other and each represents a hydrogen atom, -C(=O)-O-lower alkyl, cycloalkyl or tetrahydropyran;

R6represents a hydrogen atom, -C(=O)-O-lower alkyl, HE is the lowest alkylen-IT or-C(=O)-pyridine; and

R7represents a hydrogen atom;

or its pharmaceutically acceptable salt.

2. Piperidine derivative or its pharmaceutically acceptable salt according to claim 1, where the symbol R4represents a monovalent group (a) and nitrogen-containing heterocyclic ring represented by the symbol a, is a pyrolidine, piperidine, morpholine, pieperazinove or oxazepine ring.

3. Piperidine derivative or its pharmaceutically acceptable salt according to claim 1, where the symbol R4represents a monovalent group (b) and nitrogen-containing heterocyclic ring represented by the symbol, is pyrrolidin is the first or piperidino ring.

4. Piperidine derivative or its pharmaceutically acceptable salt according to claim 1, where the symbol R4represents a monovalent group (s) and R9-R11in group (C) may be the same or different from each other and represent each a hydrogen atom, -C(=O)-O-lower alkyl, cycloalkyl or tetrahydropyran.

5. Piperidine derivative or its pharmaceutically acceptable salt according to claim 4, where at least one of R9-R11in group (C) is cycloalkyl, and the other (others) may be the same or different and represents (represent each a hydrogen atom, -C(=O)-O-lower alkyl, cycloalkyl or tetrahydropyran.

6. Piperidine derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 5, where piperidine derivative represented by the formula (I)represents at least one compound selected from the group consisting of

4-(2-{4-[(E)-2-(2-were)vinyl]piperidine-1-yl}-2-oxoethyl)of the research,

4-(2-{4-[(E)-2-(4-isopropylphenyl)vinyl]piperidine-1-yl}-2-oxoethyl)of the research,

4-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)of the research,

N-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)cyclohexanamine and

N-(2-{4-[(E)-2-(4-chlorophenyl)vinyl]piperidine-1-yl}-2-oxoethyl)-N-methylcyclohexylamine.

7. Medical to the position, which is an inhibitor of sodium channel containing piperidine derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. The medical composition according to claim 7, which represents an analgesic agent.

9. The medical composition according to claim 7, which represents an analgesic agent for neuropathic pain.

10. The medical composition according to claim 7, which represents an analgesic agent for neuropathic pain associated with diabetic neuropathy.



 

Same patents:

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13 cl, 2 tbl, 5 ex

FIELD: chemistry.

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8 cl, 743 ex

FIELD: chemistry.

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11 cl, 3 ex, 1 tbl

FIELD: organic chemistry.

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4 cl, 1 tbl, 3 ex

FIELD: organic chemistry, chemical technology, medicine.

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33 cl, 69 ex

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4 cl, 1 tbl, 3 ex

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7 cl, 5 tbl, 5 ex

FIELD: organic chemistry, chemical technology, virology.

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EFFECT: improved method of synthesis.

2 cl, 1 ex

The invention relates to methods for producing compounds of formula (XVIIb):

where

R1represents optionally protected or modified iminomethylene group, optionally protected or modified hydroxymethylene group; and

R4is-H; or

R1and R4together form a group of the formula (IV), (V), (VI) or (VII):

R5represents-H or-IT;

R7represents-och3and R8is HE, or R7and R8together form a group-O-CH2-O-;

R14aand R14bthey are both-H or one is-H and the other represents-OH, -och3or-och2CH3or R14aand R14btogether form ketogroup; and R15

and derivatives of 21-cyanocobalamine formula (XVIb):

The invention also relates to new compounds:

These compounds possess both antibacterial and antitumor activity

The invention relates to pharmaceutical industry and relates to new compounds of the hydrochloride of N-(-hydroxyethyl)tsitizina formula (I) exhibiting high antiarrhythmic activity and low toxicity

FIELD: chemistry.

SUBSTANCE: invention concerns compounds with inhibition effect on thrombocyte aggregation, their pharmaceutically acceptable salts, particularly compounds of general formula (I) (where R1 is C1-C6 alkyl etc., R2 is hydrogen, C2-C7 alkanoyl, C7-C11 arylcarbonyl, group of formula R4-(CH2)1- etc., R3 is C6-C10 aryl etc., X1, X2, X3, X4 and X5 are independently hydrogen, halogen etc., and n is an integer from 0 to 2), its pharmaceutically acceptable salts. Invention claims pharmaceutical compositions inhibiting thrombocyte activation and containing claimed compounds as agent.

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26 cl, 272 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to the cycloalkyl derivative of 3-hydroxy-4-pyridinine with general formula , where R1 represents X with the condition that, R2 is Y; or R1 is T with the condition that, R2 is W; or R1 is X with the condition that, R2R5N taken together, form a heterocyclic ring, formed from morpholinyl or piperazinyl, where the morpholinyl or piperazinyl group is either unsubstituted or substituted with between one to three C1-C6 alkyl groups; X is C3-C6 cycloalkyl; Y is chosen from a group consisting of C3-C6 cycloalkyl, C1-C6 alkyl and C1-C6 alkyl, monosubstituted with C3-C6 cycloalkyl; T represents C1-C6 alkyl; W represents C3-C6 cycloalkyl; R3 represents hydrogen; R4 is chosen from a group consisting of hydrogen and C1-C6 alkyl. The invention also relates to the method of obtaining the derivative as well as to pharmaceutical compositions based on these compounds and use of these compounds in making medicinal preparations.

EFFECT: obtaining new compounds, which can be used in removing surplus iron from patients suffering from diseases related to iron oversaturation.

17 cl, 17 ex, 8 tbl, 9 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: compounds of this invention possess properties of protein kinase inhibitors. In the general formula p means integer within 0 to 2; R and R1 mean O; A1 and A2 mean single bond, (C1-C6)alkyl; B2 means monocyclic or bicyclic, saturated or unsaturated heterocyclic radical including 1 to several identical or different heteroatoms, chosen among O, S, N and NR7, probably substituted with one or several identical or different substitutes.

EFFECT: inhibiting effect on protein kinase, effective application of compounds of formula for medical products.

49 cl, 1 tbl, 6 dwg, 334 ex

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