Biaryl substituted triazoles as sodium channel blocators

FIELD: pharmacology.

SUBSTANCE: described are novel derivatives of triazole of general formulas (I) or (II) or their pharmaceutically acceptable salts, where R1 represents H, C1-C6-alkyl, or group CONRaRb, Ra represents hydrogen or C1-C6-alkyl; R2 represents H or C1-C6-alkyl; R3 represents H or F, CI, Br or I; R4 represents H; R5 represents CF3 or O-(C1-C4)alkyl, three times substituted with F; R6 and R7 each independently represents H, F or CF3, on condition that one of R6 and R7 always represents H.

EFFECT: application of said compounds for preparing medication for treatment and prevention of pain or pain-induced disturbances; pharmaceutical composition containing novel compounds, and method of their obtaining.

9 cl, 20 ex

 

This invention relates to billsimmons triazole derivatives. In particular, this invention relates to billsimmons triazolam, which are blockers of sodium channels and is suitable for the treatment of chronic and neuropathic pain. The compounds of this invention are also suitable for treating other conditions, including disorders of the Central nervous system (CNS), such as epilepsy, manic depression, bipolar disorder, depressive syndrome, a state of fear and diabetic neuropathy.

This invention relates to billsimmons triazolam, which are blockers of sodium channels and is suitable for the treatment of chronic and neuropathic pain. The compounds of this invention are also suitable for treating other conditions, including disorders of the Central nervous system (CNS), such as epilepsy, depressive syndrome, a state of fear, manic depression and bipolar disorder. This invention also relates to pharmaceutical compositions comprising a compound of the present invention, either individually or in combination with one or more therapeutically active compounds, and pharmaceutically acceptable filler.

The invention also includes methods of treatment of acute pain, chronic pain, visceral the pain Oh, inflammatory pain, neuropathic pain and CNS disorders, including but not limited to them alone, epilepsy, depressive syndrome, a state of fear, manic depression and bipolar disorder, by administering the compounds and pharmaceutical compositions of the present invention. The invention also relates to a method for data connections.

Detailed description of the invention

This invention includes compounds represented by formula (I) or (II)

or their pharmaceutically acceptable salt,

where R1represents a

(a) N;

(b) C1-C6-alkyl, C2-C4alkenyl,2-C4-quinil,3-C6-cycloalkyl or1-C4-alkylen-[C3-C6-cycloalkyl], any of which is optionally substituted by one or more of the following substituents: F, CF3HE,-(C1-C4)alkyl, O-CONRaRb, NRaRbN (Ra)CONRaRb, COO-(C1-C4)alkyl, COOH, CN, CONRaRb;

(c) -C0-C4-alkylen-C1-C4-perfluoroalkyl;

(d) NRaRb, -N(CORaRb, -N(SO2RaRb, -N(Ra)CON(Ra)2, -N(Ra)SO2Ra, -N(ORa)CONRaRbor-N(Ra)SO2N(Rsup> a)2;

(e) -CH(ORaRa, -C(ORbCF3, -CH(otherbRa, -C(=O)RaC(=O)CF3, -SOCH3, -SO2CH3, COORa, CN, CONRaRb, -COCONRaRb, -SO2NRaRb, -CH2O-SO2NRaRb, SO2N(RaORa, -C(=NH)NH2, -CRa=N-ORaCH=CHCONRaRb;

(f) -CONRa(CH2)0-2C(Ra)(Rb)(CH2)0-2CONRaRb;

(g) -C(Ra)=C(Rb)-COORaor-C(Ra)=C(Rb)-CONRaRb;

Rarepresents a

(a) H;

(b) (C1-C4-alkyl, optionally substituted by one or more of the following substituents: F, CF3HE,-(C1-C4)alkyl, S(O)0-2-(C1-C4)alkyl, -OCONH2, -OCONH(C1-C4alkyl), -OCON (C1-C4alkyl) (C1-C4alkyl), -OCONH(C1-C4alkylaryl), -OCON(C1-C4alkyl)(C1-C4alkylaryl), NH2, NH(C1-C4alkyl), N(C1-C4alkyl)(C1-C4alkyl), NH(C1-C4alkylaryl), N(C1-C4alkyl)(C1-C4alkylaryl), NHCONH2, NHCONH(C1-C4alkyl), NHCONH(C1-C4alkylaryl), -NHCON (C1-C4alkyl)(C1-C4alkyl), NHCON(C1-C4alkyl)(C1-C4alkylaryl), N(C1-C4Alki is)CON(C 1-C4alkyl)(C1-C4alkyl), N(C1-C4alkyl)CON(C1-C4alkyl)(C1-C4alkylaryl), COO-(C1-C4alkyl), COOH, CN, CONH2, CONH(C1-C4alkyl), CON(C1-C4alkyl)(C1-C4alkyl);

(c)0-C4-alkylene-(C1-C4)-perfluoroalkyl; or

(d) -C1-C4alkylaryl, where aryl represents phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl or oxadiazolyl, any aryl of which is optionally substituted by 1-3 substituents selected from i) F, Cl, Br, I, ii) -CN, iii) -NO2iv) -C(=O)(C1-C4alkyl), v)- (C1-C4alkyl), vi) -N(C1-C4alkyl)(C1-C4alkyl), xiii) -C1-10alkyl and (xiv) -C1-10alkyl, where one or more carbon atoms in the alkyl may be replaced by-O-, -S(O)1-2-, -O-C(O), -C(O)-O-, -C(O)-, -CH(OH)-, -C=C - or-C≡C-;

Rbrepresents a

(a) N or

(b) C1-C6-alkyl, optionally substituted by one or more of the following substituents: F, CF3HE,-(C1-C4)-alkyl, S(O)0-2-(C1-C4)alkyl, -OCONH2, -OCONH(C1-C4alkyl), NH2, NH(C1-C4alkyl), N(C1-C4alkyl)(C1-C4alkyl), NHCONH2, NHCONH(C1-C4alkyl), -NHCON(C1 -C4alkyl)(C1-C4alkyl), COO-(C1-C4alkyl), COOH, CN or CONH2;

R2represents a

(a) N;

(b) -C1-C4-alkyl, -C3-C6-cycloalkyl or-C1-C4-alkylene-(C3-C6)cycloalkyl, optionally substituted by one or more of the following substituents: F, CF3HE,-(C1-C4)alkyl, S(O)0-2-(C1-C4)alkyl, O-CONRaRb, NRaRbN(Ra)CONRaRb, COO-(C1-C4)alkyl, COOH, CN, CONRaRb;

(c) -C0-C4-alkylen-C1-C4-perfluoroalkyl;

(d) -C(=O)(Ra), -CONRaRb, -COO-(C1-C4)alkyl, -SO2Ra, -SO2N(Ra)(Rb);

R3and R4each independently represents a

(a) N;

(b)- (C1-C6-alkyl, -C2-C6alkenyl or-C2-C6-quinil or-C3-C6cycloalkyl, any of which is optionally substituted by one or more of the following substituents: F, CF3, -O-(C1-C4)alkyl, CN, -N(Ra)(Rb), -N(Ra)- (C1-C4)alkyl, COORb, CON(Ra)(Rbor phenyl;

(c) -C0-C4-alkylen-C1-C4-perfluoroalkyl or-O-C0-C4-alkylen-C1-C4-perfluoroalkyl; or

(d) CN, NH2, NO2, F, Cl, Br, I,OH, OCON(Ra)(Rb), O(C1-C4-alkylene)CONRaRb, -OSO2N(Ra)(Rb), COORb, CON(Ra)(Rbor aryl, where aryl optionally substituted by 1-3 substituents selected from i) F, Cl, Br, I, ii) -CN, iii) -NO2iv) -C (=O)(Ra), v) ORavi) -NRaRbvii) -C0-4alkylene-CO-ORaviii) -(C0-4alkylene)-NH-CO-ORaix) -(C0-4alkylen)CO-N(Ra)(Rb), x) -S(O)0-2Ra, xi) -SO2N(Ra)(Rb), xii) -NRaSO2Raxiii) -C1-10alkyl and (xiv) -C1-10alkyl, where one or more carbon atoms in the alkyl may be replaced by-NRa-, -O-, -S(O)1-2-, -O-C(O)-, -C(O)-O-, -C(O)-N(Ra)-, -N(Ra)-C(O) -, -N(Ra)-C(O)-N(Ra)-, -C(O)-, -CH(OH)-, -C=C - or-C≡C-; and

R5, R6and R7each independently represents a

(a) N;

(b) C1-C6-alkyl, C2-C4alkenyl, or-C2-C4-quinil, or-C3-C6-cycloalkyl, any of which is optionally substituted by one or more of the following substituents: F, CF3HE,-(C1-C4)alkyl, OCON(Ra)(Rb), NRaRb, COORa, CN, CONRaRbN(RaRb)CONRaRb;

(c) -O-C1-C6-alkyl or-O-C3-C6-cycloalkyl, -S-C1-C6-alkyl or-S-C3-C6-cycloalkyl, any of which neoba is consequently substituted by one or more of the following substituents: F, CF3HE, O-(C1-C4)alkyl, NH2, NH(C1-C4alkyl), N(C1-C4-alkyl)2, COOH, CN, CONH2, CONH(C1-C4alkyl), CON(C1-C4alkyl)2, SO2NH2, SO2NH(C1-C4-alkyl), tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl, pyrrolidinyl or piperazinil;

(d) -C0-C4-alkylen-C1-C4-perfluoroalkyl or-C0-C4-alkylen-C1-C4-perfluoroalkyl;

(e) CN, N(Ra)(Rb), NO2, F, Cl, Br, I, -ORa, -SRa, -OCON(Ra)(Rb), -OSO2N(Ra)(Rb), COORb, CON(Ra)(Rb), -N(Ra)CON(Ra)(Rb), -N(Ra)SO2N(Ra)(Rb), -C(ORbRa, -C(ORaCF3, -C(otheraCF3, -C(=O)Ra, -C(=O)CF3, -SOCH3, -SO2CH3, -NHSO2(C1-6-alkyl), NHSO2-aryl, SO2N(Ra)(Rb), -CH2OSO2N(Ra)(Rb), SO2N(Rb)-ORa, -C(=NH)NH2, -CRa=NORaCH=CH2or aryl, where aryl optionally substituted by 1-3

substituents selected from i) F, Cl, Br, I, ii) -CN, iii) -NO2iv) -C(=O)(Ra), v) ORavi) -NRaRbvii) -C0-4alkylene-CO-ORavii) -(C 0-4alkylene)-NH-CO-ORaix) -(C0-4alkylene) -CO-N(Ra)(Rb), x) -S(O)0-2Ra, xi) -SO2N(Ra)(Rb), xii) -NRaSO2Raxiii) -C1-10alkyl and (xiv) -C1-10alkyl, where one or more carbon atoms in the alkyl may be replaced by-NRa-, -O-, -S(O)1-2-, -O-C(O)-, -C(O)-O-, -C(O)-N(Ra)-, -N(Ra)-C(O)-, -N(Ra)-C(O)-N(Ra)-, -C(O)-, -CH(OH)-, -C=C - or-C≡C-.

This invention also includes compounds of formula III

or their pharmaceutical salts, where each R1-R7takes the values defined above.

The following compounds are excluded from the present invention:

1-methyl-3-(2-chlorophenyl)-5-[3-(4-triptoreline)phenyl]-1,2,4-triazole,

1-methyl-3-(2-chloro-6-forfinal)-5-[3-(4-triptoreline)-phenyl]-1,2,4-triazole,

1-methyl-3-(2,6-differenl)-5-[3-(4-triptoreline)-phenyl]-1,2,4-triazole,

1-methyl-3-(2,6-differenl)-5-[3-(4-trifloromethyl)-phenyl]-1,2,4-triazole,

1-(3-phenyl)phenyl-1,2,4-triazole.

In the first aspect of this invention relates to the compound represented by the chemical formula (I)or its pharmaceutically acceptable salts, where R5takes a value other than N, and all other variables take the values defined above.

In the embodiment, the specified first aspect of this invented the e refers to the connection, represented by the chemical formula (I)or its pharmaceutically acceptable salts, where R5represents-ORaand all other variables take the values defined above.

In another embodiment, the specified first aspect of this invention relates to the compound represented by the chemical formula (I)or its pharmaceutically acceptable salts, where R1represents an optionally substituted C1-C6-alkyl, optionally substituted C3-C6-cycloalkyl, -C(=O)Raor CONRaRband all other variables take the values defined above.

In the second aspect of this invention relates to the compound represented by the chemical formula (II), or its pharmaceutically acceptable salts, where R5takes a value other than N, and all other variables take the values defined above.

In the embodiment, the specified second aspect of this invention relates to the compound represented by the chemical formula (II), or its pharmaceutically acceptable salts, where R5represents-ORaand all other variables take the values defined above.

In another embodiment, the specified second aspect of this invention relates to the compound represented by Henichesk the th formula (II), or its pharmaceutically acceptable salts, where R1represents an optionally substituted C1-C6-alkyl, optionally substituted C3-C6-cycloalkyl, -C(=O)Raor CONRaRband all other variables take the values defined above.

In the third aspect of this invention relates to the compound represented by chemical formula (III), or its pharmaceutically acceptable salts, where R5takes a value other than N, and all other variables take the values defined above.

In the embodiment, the specified third aspect of this invention relates to the compound represented by chemical formula (III), or its pharmaceutically acceptable salts, where R5represents-ORaand all other variables take the values defined above.

In another embodiment, the implementation of the third aspect of this invention relates to the compound represented by chemical formula (III), or its pharmaceutically acceptable salts, where R1represents an optionally substituted C1-C6-alkyl, optionally substituted C3-C6-cycloalkyl, -C(=O)Raor CONRaRband all other variables take the values defined above.

The invention is also relative to the fast method of obtaining compounds of formula (I) or its pharmaceutically acceptable salt, including the interaction of the compounds of formula 34 or 35:

with the compound of the formula 36:

where each R1-R7takes the values defined above, in the presence of a base to obtain the compounds of formula (I) or its pharmaceutically acceptable salt.

In the first aspect of the proposed method this invention relates to a method for obtaining compounds of formula (I) or its pharmaceutically acceptable salt, where

R1represents H, -C(=O)Ra, COORa, CONRaRbC1-C6alkyl or C3-C6cycloalkyl where the specified alkyl or cycloalkyl optionally substituted by one or more F, OH or NRaRb,

R2represents H,

R5, R6and R7each independently represents H, F, -ORaC1-C6-alkyl or-O-C1-C6-alkyl, where the specified alkyl optionally substituted by one or more F, CF3or-O-(C1-C4)alkyl, and all other variables take the values defined above.

In the second aspect of the proposed method this invention relates to a method for obtaining compounds of formula (I) or its pharmaceutically acceptable salt, where the base is a metal acetate, metal carbonate, or tertiary is minutes

In the third aspect of the proposed method this invention relates to a method for obtaining compounds of formula (I) or its pharmaceutically acceptable salt, where the base is a potassium acetate.

This invention also relates to a method for obtaining compounds of formula (I) or its pharmaceutically acceptable salts, including the interaction of the compounds of formula 34 or 35:

with the compound of the formula 36:

where each R1-R7takes the values defined above, in the presence of a base and optionally in an alcohol solvent, and optionally with heating, to obtain the compounds of formula (I) or its pharmaceutically acceptable salt.

Used in this description, the term “alkyl” as well as other groups that contain the prefix “ALK”such as, for example, alkoxy, alkanoyl, alkenyl and quinil, means carbon chains which may be linear or branched or a combination of both. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec - and tert-butyl, pentyl, hexyl and heptyl. The terms “alkenyl”, “quinil” and other similar terms include carbon chain containing at least one unsaturated C-C bond.

The term “cycloalkyl” means carbon cycles not containing g is teratomas, and includes mono-, bi - or tricyclic saturated carbon cycles, as well as condensed cyclic system. Such condensed cyclic system may include one ring that is a partially or fully unsaturated, such as a benzene ring to form a condensed cyclic systems, such as benzododecinium carbon cycles. Cycloalkyl include condensed cyclic system, as pyrocondensation cyclic system. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl and 1,2,3,4-tetrahydronaphthalen.

The term “aryl” includes, without limitation aromatic Deputy, which is a single ring or multiple rings fused together. If you have many rings, at least one of the constituent rings is aromatic. The term “aryl”, unless otherwise noted, also includes heteroaryl and, thus, includes a stable 5-7-membered monocyclic and stable 9-10-membered condensed bicyclic heterocyclic ring system containing carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, where the heteroatoms nitrogen and sulfur optionally could the t to be oxidized and the nitrogen heteroatoms may not necessarily be quaternity. Suitable aryl groups include phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl and oxadiazolyl.

The term “cycloalkane”unless otherwise stated, includes cycloalkyl group attached via short1-2alkyl linking to the oxygen atom.

The term “C0-6alkyl” includes alkali that contain 6, 5, 4, 3, 2, 1 carbon atoms, or do not contain them. Alkyl lack of carbon atoms is a Deputy in the form of a hydrogen atom when a is a terminal alkyl group, or directional communication, when the alkyl is a linking group.

The term “amine”unless otherwise stated, includes primary, secondary and tertiary amines.

The term “carbonyl”, if not specified otherwise, includes C0-6alkyl substituent, when the carbonyl is a terminal.

The term “halogen” includes fluorine atoms, chlorine, bromine and iodine.

The term “optionally substituted” is intended to include both substituted and unsubstituted fragments. So, for example, optionally substituted aryl can be a pentafluorophenyl or phenyl. In addition, optionally substituted compound of structural fragments, such as, for example, alkylaryl indicate that the alkyl and aryl groups, not necessarily for what emeny. If only one of the constituent fragments is optionally substituted, it will be specially marked so as alkylaryl, and aryl, optionally substituted with halogen or hydroxyl”.

Compounds described in the description can contain one or more double bonds and, therefore, can form CIS/TRANS-isomers as well as other conformational isomers. The invention includes all such possible isomers, as well as mixtures of such isomers, unless specifically provided otherwise.

Compounds described in the description can contain one or more asymmetric centers and therefore, can form diastereoisomers and optical isomers. This invention includes all possible diastereoisomers as well as their racemic mixtures, their essentially pure separated enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts. The above chemical formula shown without indicating the stereochemistry at certain positions. This invention includes all stereoisomers of the chemical formula and their pharmaceutically acceptable salts. Also included are mixtures of stereoisomers, as well as selected specific stereoisomers. When carrying out the synthetic procedures used to prepare such compounds, or the use of p is ocedur racemization or epimerization, well-known experts in this field, the products of such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. If the compounds of this invention are acid, their corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts of such inorganic bases include salts of aluminum, ammonium, calcium, copper (two - and monovalent), iron (three - and divalent), lithium, magnesium, manganese (four-, three - and divalent), potassium, sodium, zinc and the like salts. Salts of pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, and cyclic amines and substituted amines, such as amines naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which can be formed salts include ion exchangers, such as, for example, arginine, betaine, caffeine, choline, N,N'-dibenziletilendiaminom, diethylamin, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucose is min, histidine, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine polymers, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine and tromethamine.

If the compounds of this invention are basic, their corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzosulfimide, benzoic, camphorsulfonic, lemon, econsultancy, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate acid, etc.

The pharmaceutical compositions of this invention contain the compound represented by formula I, II or III (or its pharmaceutically acceptable salt as an active ingredient, a pharmaceutically acceptable excipient, and optionally one or more additional therapeutic agents or adjuvants. Such additional therapeutic agents can include, for example, (i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) agonists NT receptor or antagon the texts (iv) sodium channel antagonists, v) agonists of the NMDA receptor or antagonists, vi) selective inhibitors SOH-2, vii) NK1 antagonists, viii) non-steroidal anti-inflammatory drugs (NSAIDs, “NSAID”), (ix) selective inhibitors of serotonin reuptake (“SSRI”) and/or selective inhibitors of reuptake of serotonin and norepinephrine (“SSNRI”), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) Li, xiii) valproate and (xiv) neurontin (gabapentin). Corresponding compositions include compositions suitable for oral, rectal, local and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable way in any particular case will depend on the private recipient, the nature and severity of the conditions under which introduces the active ingredient. The pharmaceutical compositions may be conveniently presented in the form of a standard dosage form and prepared by any method well known in the field of pharmacy.

These compounds and compositions suitable for the treatment of chronic, visceral, inflammatory and neuropathic pain syndromes. They are suitable for the treatment of pain resulting from traumatic injury of nerve compression or infringement nerve, post herpetic neuralgia, trigeminal of neural and and diabetic neuropathy. These compounds and compositions suitable for the treatment of chronic lumbar pain, phantom pain, chronic pelvic pain, neuromas pain, complex regional pain syndrome, chronic arthritic pain and related neuralgia, pain associated with cancer, chemotherapy, HIV and neuropathy caused by HIV treatment. The compounds of this invention can also be used as local anesthetics. The compounds of this invention are suitable for the treatment of irritable bowel syndrome and related disorders, as well as Crohn's disease.

These compounds have clinical application for the treatment of epilepsy and partial and generalized tonic seizures. They are also suitable for neurotoxity in ischaemic conditions caused by stroke or trauma to the nerves, and for the treatment of multiple sclerosis. The compounds of this invention are suitable for treatment of depression, fear, bipolar disorder and tachyarrhythmias.

In addition, it is understood that the compounds of this invention can be introduced into prophylactically effective dosage amounts to prevent the above conditions and disorders, as well as to prevent other conditions and disorders associated with the activity of sodium channels.

Paste, ointment, gel-like form, solutions or suspen the AI, containing these compounds, can be applied for local use. Solutions and liquid for rinsing the oral cavity are included within the local application for the purposes of this invention.

A metered amount of from about 0.01 mg/kg to about 140 mg/kg of body weight per day is suitable for the treatment of inflammatory and neuropathic pain, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammatory pain can be effectively treated by the introduction of from about 0.01 mg to about 75 mg of compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day. Neuropathic pain can be effectively treated by the introduction of from about 0.01 mg to about 125 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 5.5 g per patient per day.

The amount of active ingredient that may be combined with materials such as fillers to create a single dosage form will vary depending on the recipient being treated and the particular route of administration. For example, a drug intended for oral administration to humans may simply contain from about 0.5 mg to about 5 g of the active ingredient mixed with an appropriate and suitable number m of the material of the filler, which may vary from about 5 to about 95 percent of the total composition. Standard dosage forms for the most part will contain from about 1 mg to about 1000 mg of the active ingredient, usually 25, 50, 100, 200, 300, 400, 500, 600, 800 or 1000 mg

Implied, however, that the specific level of dosage for any particular patient will depend on many factors. These factors related to the patient include age, body weight, General health, sex and diet of the patient. Other factors include the time and route of administration, rate of excretion, combination of drugs and the severity of the particular disease undergoing therapy.

Practically compounds represented by formula I, II, and III, or their pharmaceutically acceptable salts can be combined as the active ingredients into a homogeneous mixture with a pharmaceutical excipient according to conventional pharmaceutical techniques of mixing. The filler may be in various forms depending on the form of the drug intended for administration, e.g. oral, or parenteral (including intravenous). Thus, the pharmaceutical compositions of this invention may be presented as discrete units suitable for oral administration such as capsules, starch wafers or tablets, each of which is contains a predetermined amount of the active ingredient. In addition, the compositions can be presented in the form of powder, granules, solution, suspension in an aqueous liquid, non-aqueous liquid, emulsion, oil-in-water or emulsion water-in-oil. In addition to the above the usual dosage forms, the compounds represented by formula I, II, and III, or their pharmaceutically acceptable salts can also be introduced by means of a controlled release of the active substance and/or devices for his release. The composition can be prepared by any of the methods of pharmacy. Essentially, these include the stage of introduction of the active ingredient into Association with a carrier which contains one or more necessary ingredients. Essentially, the composition is prepared at a constant and homogeneous mixing of the active ingredient with liquid excipients or finely ground solid fillers or by both jointly. The product can then be made convenient to the desired shape.

Thus, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable excipient and a compound or pharmaceutically acceptable salt of formula I, II or III. The compounds of formula I, II and III or their pharmaceutically acceptable salts can also be included in pharmaceutical compositions in combination with one or more tera is efticiency active connections.

Applied pharmaceutical filler may constitute, for example, solid, liquid or gas. Examples of particulate fillers include lactose, gypsum, sucrose, talc, gelatin, agar, pectin, Arabic gum, magnesium stearate and stearic acid. Examples of liquid fillers are a sugar syrup, peanut butter, olive oil and water. Examples of gaseous fillers include carbon dioxide and nitrogen.

In the preparation of compositions for oral administration of the dosage form can be applied in any convenient pharmaceutical environment. For example, water, glycols, oils, alcohols, corrigentov, preservatives, coloring tools, etc. can be applied to formation of liquid preparations for oral administration such as suspensions, elixirs and solutions; while the extenders, such as starches, sugars, microcrystalline cellulose; diluents, granulating agents, sizing, binders and dezintegriruetsja agents can be applied for the formation of oral solid preparations such as powders, capsules and tablets. Due to ease their administration tablets and capsules are the preferred standard dosages for oral administration, so use solid pharmaceutical excipients. Optional, but tabla the key can be coated, made according to standard aqueous and non-aqueous methods.

Tablet containing composition of this invention may be prepared by compression or molding, optionally with one or more additional ingredients or adjuvants. Compressed tablets can be prepared in a suitable machine by pressing the active ingredient in free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be prepared in a suitable machine by forming a mixture of the powdered compound moistened inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each starch wafer or capsule preferably contains from about 0.1 mg to about 500 mg of the active ingredient. Thus, tablet, starch wafer or capsule typically contains 0,1, 1, 5, 25, 50, 100, 200, 300, 400 or 500 mg of the active ingredient to be taken as one or two tablets, starch wafers or capsules one, two or three times a day.

The pharmaceutical compositions of this invention suitable for parenteral administration may be prepared in the form of rest the ditch or suspensions of the active ingredient in water. Suitable surfactant can be, for example, hydroxypropylcellulose. Can also be prepared dispersions in glycerol, liquid polyethylene glycols and their mixtures in oils. In addition, may include a preservative to prevent harmful microbial growth.

The pharmaceutical compositions of this invention suitable for injection include sterile aqueous solutions or dispersions. In addition, the composition can be in the form of sterile powders, prepared for immediate admission of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively liquid for easy injection with a syringe. Pharmaceutical compositions must be stable under conditions of manufacture and storage and must therefore be preserved from the contaminating action of microorganisms, such as bacteria and fungi. The filler can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures based on them.

The pharmaceutical compositions of this invention may have a form suitable for topical application, such as, for example, an aerosol, cream, ointment, lotion and powder is to spray. In addition, the composition can be in the form suitable for transdermal application methods. These preparations can be prepared using the compounds of formula I, II or III or pharmaceutically acceptable salts using conventional techniques. For example, a cream or ointment is prepared by mixing the hydrophilic material and water together with from about 5 wt.% up to about 10 wt.% connection to obtain a cream or ointment desired consistency.

The pharmaceutical compositions of this invention may have a form suitable for rectal administration, where the filler is a solid substance, for example, when the mixture forms a standard dose in the form of suppositories. Suitable fillers include cocoa butter and other materials commonly used in this field. Suppositories can be prepared first by mixing the composition with the softened or melted(and) filler(s), then cooling and molding.

In addition to the aforementioned ingredients-excipients, the pharmaceutical preparations described above, may include, if appropriate, one or more additional ingredients such as fillers, such as diluents, buffers, corrigentov, binders, surfactants, thickeners, oil and preservatives (including antioxidants). In addition to the CSO, may include other adjuvants to give the drug isotonicity with the blood of the intended recipient. Compositions containing a compound described by formula I, II or III, or pharmaceutically acceptable salt, can also be prepared in powder or concentrated liquid form.

The pharmaceutical compositions of this invention are used to block sodium channels. Accordingly, this invention relates to the treatment of diseases in mammals, the intensity of which can be reduced through blocking neuronal sodium channels, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain and neuropathic pain, the introduction of an effective amount of the compounds of this invention. The term “mammal” includes humans and animals, such as dogs, cats, horses, pigs and cattle. Accordingly, it is understood that the treatment of mammals, other than humans, refers to the treatment of clinical conditions in warm-blooded animals other than humans, but they correlate with the above conditions.

As used in the description for the purposes of the method according to the invention, the term “base” includes, acetates, metals, metal carbonates and tertiary amines. Examples of the acetates of the metals include azatadine and sodium acetate. Examples of carbonates of metals include potassium carbonate and sodium carbonate. The base of the tertiary amines include trialkylamines, such as triethylamine.

As stated in the description for the purposes of the method according to the invention, the term “alcoholic solvent includes, for example, methanol, ethanol, isopropanol and 1-butanol.

When the method according to the invention is heated, the method can be carried out in the temperature range from about 40°to about 150°C, vklyuchaem intervals from about 50°to about 140°C., from about 50°to about 130°C., from about 60°to about 120°C., from about 65°to about 100°C., or from about 65°to about 85°C.

As used in the description, the term “solvent/co-solvent” includes mixtures of solvents, such as toluene/tetrahydrofuran, tetrahydrofuran/diethyl ether, toluene/diethyl ether, tetrahydrofuran/methyl tert-butyl ether, toluene/methyl tert-butyl ether, toluene/dioxane and tetrahydrofuran/dioxane.

Abbreviations used in the description have the following meanings (abbreviations not listed here, have common values, unless noted): AC (acetyl), AIBN (2,2'-azobis(isobutyronitrile)), BINAP (1,1'-bis-2-naphthol), Bn (benzyl), camp (cyclic adenosine-3',5'-monophosphate), DAST ((diethylamino)sulfur TRIFLUORIDE), DEAD (diethylazodicarboxylate), DBU (1,8-disabili the lo[5.4.0]undec-7-Yong), DIBAL (diisobutylaluminium), DMAP (4-(dimethylamino)pyridine), DMF (N,N-dimethylformamide), Dppf (1,1'-bis(diphenylphosphino)ferrocene), EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), Et3N (triethylamine), GST (glutationtransferase), HMDS (hexamethyldisilane), LDA (sitedisability),m-CPBA (metachlorobenzoic acid), MMR (monoperoxyphthalic acid), Ms (methanesulfonyl; mesyl or SO2Me), MsO (methanesulfonate or mesilate), NBS (N-bromosuccinimide), NSAID (non-steroidal anti-inflammatory drugs),aboutTol (ortho-tolyl), OXONE® (2KHSO5•KHSO4•K2SO4), PCC (pyridine chlorproma), Pd2(dba)3(bis(dibenzylideneacetone)palladium(0)), PDC (pyridine dichromate), PDE (phosphodiesterase), Ph (phenyl), Phe (bersoldier), RMV (pair-methoxybenzyl), ROI (pyridinyl), r.t. or RT (room temperature), Rac (racemic), SAM (aminosulfonyl; sulfonamide or SO2NH2), SEM (2-(trimethylsilyl)ethoxyethoxy), SPA (scintillation approximate analysis), TBAF (Tetra-n-butylammonium fluoride), Th (2 - or 3-thienyl), TFA (triperoxonane acid), TFAA (anhydride triperoxonane acid), THF (tetrahydrofuran), Thi (theoffender), TLC (thin layer chromatography), TMC-CN (trimethylsilylethynyl), TMSI (trimethylsilylmethyl), Tz (1H(or 2H)-tetrazol-5-yl), XANTPHOS (4,5-bis-diphenylphosphanyl-9,9-dimethyl-N-Xanten)3H5(allyl), Me (methyl), Et (e) - Rev. Il), n-Pr is normal propyl),i-Pr (isopropyl),n-Bu (normal butyl),i-Butyl (isobutyl),s-Bu (secondary butyl),t-Bu (tertiary butyl)-Pr (cyclopropyl)-Bu (cyclobutyl)-Pen (cyclopentyl)-Hex (cyclohexyl).

The following in vitro and in vivo studies were conducted to evaluate the biological activity of these compounds.

Evaluation of compounds (in vitro assays)

Identification of inhibitors of the sodium channel based on the ability of sodium channels cause depolarization of the cells, when sodium ions penetrate through the channels, modified agonist. In the absence of inhibitors effect on the channel, modified agonist, sodium ions will cause a depolarization of the cell. Inhibitors of sodium channels will prevent depolarization of the cells, caused by the movement of sodium ions through sodium channels, modified agonist. Changes in membrane potential can be determined using a sensitive voltage fluorescent resonance energy transfer (FRET) dye pair using two components, where the donor is coumarin (SS2DMPE) and the acceptor oxanol (DiSBAC2(3)). Oksana is a lipophilic anion and distributed along the membrane according to the membrane potential. In the presence of agonist sodium channel, but in the absence of sodium within the indoor portion of the cell is negative relative to the outer part, oxanol accumulates on the outer part of the membrane and the excitation of the coumarin is the reason for FRET. Adding sodium will cause membrane depolarization, leading to the redistribution of oxanol on the inner part of the cell and, as consequence, to decrease in FRET. Thus, attitude change (donor/acceptor) increases after membrane depolarization. In the presence of an inhibitor of sodium channel depolarization of the cells will not occur and therefore the distribution of Akinola and FRET will remain unchanged.

Cells stably transfetsirovannyh sodium channel subtype PN1 (HEK-PN1), were grown in 96-well tablets, coated polylysine, with a density of approximately 140,000 cells/well. Wednesday aspirated, cells were washed in PBS buffer and incubated with 100 μl consisting of 10 µm CC2-DMPE in 0.02% of pluronic acid. After incubation at 25°C for 45 min, the medium was removed and cells were washed 2 times with buffer. Cells were incubated with 100 µl DiSBAC2(3) in TMA buffer containing 20 μm veratridine, 20 nm of brevetoxin-3 and the test sample. After incubation at 25°C for 45 min in the dark the tablets were placed in VIPR apparatus and record the fluorescence emission of both components, CC2-DMPE and DiSBAC2(3)within 10 seconds At this point in the wells was added 100 μl of saline (physiological) buffer for definition wide-angle is dependent on sodium depolarization of cells and record the fluorescence emission of both dyes additionally within 20 C. The ratio CC2-DMPE/DiSBAC2(3) before adding salt buffer is 1. In the absence of inhibitors of this relationship after adding salt buffer is >1.5 to. When sodium channel fully Engibarov or known standard or the test compound, then this ratio is equal to 1. Therefore, it is possible to chitravati activity inhibitor of the sodium channel by monitoring changes dependent on the concentration, in fluorescence.

Electrophysiological tests (in vitro)

Preparation of cells: used own cell line SOME-293 stably expressing the sodium channel subtype PN1. Cells were cultured in the medium for growth MEM (Gibco) with 0.5 mg/ml G418, 50 units/ml Pen/Strep and 1 ml V / V heat inactivated fetal bovine serum at 37°C and 10% CO2. For electrophysiological register cells were placed on a 35 mm Cup, coated with poly-D-lysine.

General register cells: cells of SOME 293 stably expressing subtype PN1 sodium channel was investigated using the full consolidation cell voltage (Hamill, et al. Pfluegers Archives 391:85-100 (1981)) using amplifier EPC-9 and pulse software (Pulse software, HEKA Electronics, Lamprecht, Germany). The experiments were conducted at room temperature. The electrodes were melted to the resistance of 2-4 MΩ. Errors on the order were minimized by a series of compensatory resistance, and a false signal electric capacity was removed using an EPC-9 component in an electrical circuit. Data were acquired at 50 kHz and filtered at 7-10 kHz. The solution for washing consisted of 40 mm NaCl, 120 mm NMDG Cl, 1 mm KCl, 2.7 mm CaCl2, 0.5 mm MgCl2, 10 mm NMDG HEPES, pH 7.4 and internal (pipetochnoe) solution contained 110 mm Cs-methanesulfonate, 5 mm NaCl, 20 mm CsCl, 10 mm CsF, 10 mm VARTA (Tetra Cs salt), 10 mm Cs-HEPES, pH 7,4.

The following protocols were used to assess sustainable affinity of the compounds alone and inaktivirovannoj the state of the channel (Krand Kirespectively):

1. 8 MS (millisec) experienced the pulses applied to depolarizing voltages from -60 mV to +50 mV from an initial potential of -90 mV to build dependencies current - voltage (IV curves). The voltage is close to the peak of the IV-curve (typically -10 or 0 mV), were used as experimental pulse voltage throughout the remainder of the experiment.

2. Curves equilibrium inactivation (ability), built by the measurement current, activated through 8 experienced MS pulse with a subsequent 10 sec pulses to potentials in the range from -120 mV to -10 mV.

3. Compounds were applied at the source potential, in which 20-50% of the channels were inactivated and the blockade of sodium channels was controlled within 8 MS experienced pulses with an interval of 2 sec.

4. After installation is flowed balance for connections determined dependent on the equilibrium voltage inactivation in the presence of compounds according to the above Protocol 2). Compounds that block the rest of the channel, reduce amperage identified during the pilot pulses from all of the source potentials, while compounds that essentially block inaktivirovannoj condition, move the middle point of the curve of equilibrium inactivation. The maximum current at the negative source potential (Imaxand the difference in the median points of the curves is the equilibrium inactivation (ΔV) in the control and in the presence of compounds used for the calculation of Krand Kiin the following equations:

If the connection is not affecting the rest, Kiwas calculated by the following equation:

Formalin test in the rat paw (analysis in vivo)

Compounds were evaluated for their ability to inhibit behavioral response caused a 50 μl injection of formalin (5%). The metal strip was fixed on the left hind paw of male rats Sprague-Dawley (Charles River, 200-250 g) and each rat was kept with the band within 60 minutes inside a plastic cylinder (diameter 15 cm). The rats were given a dose of either filler or test compounds before (local) or PEFC is (system) injection of formalin. For the local introduction of the compounds were prepared in ethanol as a filler, PEG400 and saline (EPEGS) at a ratio of 1:4:5 and was administered by injection subcutaneously into the dorsal surface of the left hind legs for 5 min before formalin. For systemic injections of the compounds were prepared either in the filler EPEGS or filler Tween 80 (10%)/sterile water (90%) and was administered by intravenous injection (via the lateral tail vein 15 min after the injection of formalin) or oral (for 60 min before the injection of formalin). The number twitching from the pain felt continuously for 60 min using an automatic analyzer of pain reception (UCSD Anesthesiology Research, San Diego, CA). Statistical significance was determined by comparing the total number of spasms in the early (0-10 min) and late (11-60 min) phases with unpaired t-test.

Analysis of in vivo using the model CFA rat

Unilateral inflammation caused by the injection of 0.2 ml complete adjuvant's adjuvant (CFA: Mycobacterium tuberculosis Sigma; suspended in the emulsion oil/saline (1:1); 0.5 mg of Mycobacterium/ml) in the plantar surface of the left hind paws. This dose of CFA caused significant swelling of the hind legs, but the animals showed normal behavior for cleaning of the body and the increase in weight throughout the experiment. Mechanical hyperalgesia was assessed by the via 3 days after tissue injury using test Randall-Selitto. Re-did the analysis of variants (ANOVA), followed Dunnet''s Post Hoc test.

SNL: Mechanical allodynia (analysis in vivo)

Tactile allodynia was assessed using calibrated Frey filaments using the effect of the rise-fall before and after the two weeks following nerve damage. Animals were placed in a plastic cage with a bottom of the wire holes and allowed to acclimate for 15 min before each experiment. To determine the 50% threshold of the reaction was used Frey filaments (interval intensity from 0.4 to 28.8 g) to sredneoblastnoy surface within 8 or until until the reaction was abstinence. After a positive response was evaluated significantly weaker stimulus. If there is no response to a stimulus, then take a much stronger stimulus. After the initial threshold crossing procedure was repeated to represent the four stimuli per animal for the experiment. Mechanical sensitivity was assessed 1 and 2 hours after oral administration of the test compounds.

Compounds described in this invention show activity by blocking sodium channels in concentrations of from about less than 0.05 microns to about less than 50 μm in the in vitro experiments described above. The advantage is that Dan is haunted compounds exhibit activity by blocking sodium channels in concentrations smaller than about 5 microns, in vitro. A greater advantage is that these compounds exhibit activity by blocking sodium channels in concentrations less than about 1 μm in the in vitro tests. An even greater advantage is that these compounds exhibit activity by blocking sodium channels in concentrations less than about 0.1 μm, in vitro. The biggest advantage is that these compounds exhibit activity by blocking sodium channels in concentrations less than approximately 0.05 μm in the in vitro tests.

These compounds may be prepared according to the General scheme shown below, and in accordance with the methods described in the examples. The following schemes and examples additionally reveal, but do not limit the scope of the invention.

Unless otherwise stated, the experimental procedures were performed under the following conditions. All operations were carried out at room temperature or at ambient temperature, i.e. in the temperature range of 18-25°C. Evaporation of the solvent was performed using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5 to 30 mm Hg) with a bath temperature up to 60°C. the reaction Course was accompanied by thin-layer chromatography (TLC, TLC), and the time of reaction are given only what to illustrate. The melting temperature are unadjusted, and 'd' indicates decomposition. Data melting point represent the melting temperature obtained for the materials prepared as described. Polymorphism in some preparations may be the result of selection of materials with different melting points. The structure and purity of all target products was confirmed by at least one of the following techniques: TLC (TLC), mass spectrometry, spectrometry, nuclear magnetic resonance (NMR (NMR)or microanalytical data. If the outputs, they are only an illustration. Data of NMR, if they are presented in the form (δ) values for most diagnosed proton dimension in parts per million (ppm) relative to tetramethylsilane (TMS)as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventional abbreviations used for the configuration signals are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broadening etc. Additionally, “Ar” signifies an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), l (liter(s)), ml (milliliters), g (gram(s)), mg (milligrams(s)), mol (say what), mmol (mmol), eq (equivalent(s)).

The synthesis methods

The compounds of this invention can be prepared according to the General scheme shown below, and in accordance with the methods described in the examples. The substituents are the same as in the above formulas, except where defined otherwise, or otherwise obvious to the ordinary specialists preparation.

The new compounds of this invention can be readily synthesized using techniques known to experts in this field, such as, for example, described inAdvanced Organic Chemistry, March, 4thEd., John Wiley and Sons, New York, NY, 1992;Advanced Organic Chemistry. Carey and Sundberg, Vol. A and B, 3rdEd., Plenum Press, Inc., New York, NY, 1990;Protective groups in Organic SynthesisGreen and Wuts, 2ndEd., John Wiley and Sons, New York, NY, 1991;Comprehensive Organic Transformations, Larock, VCH Publishers, Inc., New York, NY, 1988;Handbook of Heterocyclic Chemistry, Katritzky and Pozharskii, 2ndEd., Pergamon, New York, NY, 2000, and in the references cited in them. The source materials for these compounds can be prepared by applying standard synthetic transformations of chemical precursors that are readily available from commercial sources including Aldrich Chemical Co. (Milwaukee, WI); Sigma Chemical Co. (St. Louis, MO); Lancaster Synthesis (Windham, N.H.); Ryan Scientific (Columbia, S. C.); Maybridge (Cornwall, UK); Matrix Scientific (Columbia, S. C.); Arcos, (Pittsburgh, PA) and Trans World Chemicls (Rockville, MD).

The techniques described in the description for the synthesis of compounds can include one or several stages on the manipulation of the protecting group or purification such as recrystallization, distillation, column chromatography, flash chromatography, thin layer chromatography (TLC, TLC) and high performance liquid chromatography (HPLC, HPLC). The products can be characterized using various methods well known in the field of chemistry, including proton and carbon-13 nuclear magnetic resonance (1H and13With NMR), infrared and ultraviolet spectroscopy (IR and UV), x-ray crystallography, elemental analysis and HPLC and mass spectrometry (LC-MS). Methods of removing the protective group, purification, identification of patterns and quantification are well known to every expert in the field of chemical synthesis.

Assume that the functional groups present in the compounds represented in the diagrams below, can be further transformed when appropriate, using standard methods of transformation of functional groups available for specialists in this field, to obtain the target compounds described in this invention.

Other changes or modifications which will be obvious to experts in the area covered by the volume and the copy-book this is subramania. This invention should not be limited, except as summarized in the following claims.

Scheme 1:

In one of the protocols 3-bromobenzoyl acid1enter into interaction with tert-BUTYLCARBAMATE activated with HOBt (hydroxybenzotriazole) in the presence of a suitable carbodiimide, such as EDC [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide], and diisopropylethylamine (DIEA)in dichloromethane or THF to obtain a protected hydrazide2. There are a number of other suitable ways of activation of carboxylic acids for interaction (see March J. “Advanced Organic Chemistry”, 5thed., John Wiley & Sons, New York, pp. 506-512 (2001). Connection2can be turned into a number of asymmetric biphenylene intermediate products3through a variety of binding interactions. One of them is a Suzuki reaction, where bromine, iodine or triflate derived2subjected to interaction with arylboronic acid in the presence of palladium catalyst such as palladium acetate, triphenylphosphine and aqueous sodium carbonate in a solvent such as toluene, and the co-solvent, such as n-propanol (see Suzuki, et al. Chem. Rev., 95, 2457, 1995). Various arylboronic acids are commercially available or can be conveniently prepared from the corresponding the corresponding Allbreed or iodide into organolithium derived [Baldwin, J.E., et al. Tetrahedron Lett. 39, 707-710 (1998)] or Grignard reagent followed by treatment with trialkylborane [Li, J.J. et al. J. Med. Chem., 38: 4570-4578 (1995) and Piettre, S.R., et al. J. Med. Chem., 40: 4208-4221 (1997)]. Arylboronic can also be used as an alternative arylboronic acids in these binding interactions catalyzed by Pd [Giroux, A., et al., Tetrahedron Lett., 38, 3841 (1997)]. Boronate can be easily prepared from the approach formulated above, iodides and triftormetilfullerenov according to the method described Murata, M., et al. [J. Org. Chem. 65: 164-168 (2000)]. The BOC-protective group of the compound3removed under standard conditions - triperoxonane acid in dichloromethane, the resulting TFA salt hydrazide4,which can be desalted aqueous solution of NaOH.

Scheme 2

Figure 2 illustrates the method of preparation of derivatives of 5-biphenyl-3-substituted-1,2,4-triazole, where substitution may represent the remains of esters, acids, amides, etc. (Catarzi, et al. J. Med. Chem., 38, 2196-2201, 1995). Interaction hydrazide4with tetrafluoroborate carbethoxy-S-methylthiopyrimidine and triethylamine in dichloromethane gives examinational7that cyclists in triadology ether8.The reagent carbethoxy-S-methylthiopyrimidin of tetrafluoroborate was obtained by interaction of ethyl-2-thiooxamate with trimethyloxonium tetrafluoroborate (see Catarzi et al., above) in dichloromethane. Ether8maybe PR is rotation system-easy installation in the amide by heating it with an appropriate amine, in this case, with ammonia, in a solvent such as methanol. Ether8may be subjected to hydrolysis to the corresponding acid under standard conditions, and the resulting acid can be converted into amide in various conditions, such as described in scheme 1. In addition, ether8can be restored to the primary alcohol, for example, with sodium borohydride (NaBH4) to obtain the compounds of formula (I), where R1represents hydroxymethyl. Alternatively, the ether8can be converted into the secondary alcohol interaction with a mixture of borohydride lithium and Grignard reagent in an aprotic solvent such as THF. Such primary or secondary alcohol obtained from ether8can then be transformed into derived by using several methods, including oxidation to ketone oxidizing reagent, such as chromium reagent. This alcohol can be converted to ftoroproizvodnykh, for example, the interaction of Diethylenetriamine sulfur (DAST) in dichloromethane at low temperatures.

Scheme 3

Figure 3 describes the method of preparation of the unsubstituted 3-triazolone cyclic system (Lin, et al., J. Org. Chem., 44(23), 4160-4165, 1979). Ethyl-3-bromobenzoate10subjected to interaction with arylboronic acid, as described n the scheme 1, to obtain biphenylenes ether11. Ether11provides preliminary education biphenylenes intermediate product, which can then be converted into a compound4or related derivatives, as described in earlier schemes 1-2. Scheme 3 ether11converted into amide12under standard conditions. In particular, ether11hydrolized to the corresponding acid, which then activate the carbonyl diimidazol (CDI) in DMF (DMF) c followed by the addition of ammonia as ammonium acetate, getting amide12.Amide12heated dimethylacetal of dimethylformamide, receiving the intermediate product13which when heated with hydrazine in acetic acid gives triazole14.

Scheme 4

In the Protocol for the preparation of derivatives of 1-biphenyl-3-substituted-1,2,4-triazole, original bromaniline22where the amino group is protected with a BOC group, and arylboronic acid is converted into a series of asymmetrical biphenylene intermediate products23as shown in figure 1. The BOC protective group of the compound23delete, as described earlier, and turned into its diazonium salt24the standard interaction with sodium nitrite and HCl in water. The add connection24to a mixture of methylisocyanate and sodium acetate in methanol and water leads to three the ash ether 25. Key intermediate connection25can then be converted into a number of useful derivatives using methods presented in schemes 1-3.

Scheme 5

In a variant of the protocols described above in schemes 1, 3 and 4, aniline26protected BOC-group and contains the group Bronevoy acid or brunatnego ether, and arilbred, iodide or triflate turned in a number of asymmetric biphenylene intermediate products23as shown in figure 1.

Scheme 6

In accordance with scheme 6,31and32can be turned into biphenylyl intermediate product33for example, the reaction of the Suzuki-Miyaura c application of catalytic system of palladium acetate/triphenylphosphine. Biphenylyl intermediate product33can be converted into HCl salt of imidate34in standard conditions of Pinner, for example, using concentrated hydrochloric acid in ethanol. Imidate34can be converted to triazole37the alkalization using bi-phase mixture, such as EtOAc and NaOH, through the receipt of eiliminate35with subsequent treatment of the hydrazide examinados acid36, an alcohol solvent such as ethanol, and any relevant grounds, one of many, including metal acetate, such to the to potassium acetate, tertiary amine or carbonate of the metal, when heated.

Scheme 7

Option to scheme 6, the intermediate product34make triazole37direct addition of the hydrazide examinados acid36, an alcoholic solvent, such as ethanol, and any relevant grounds, one of many, including metal acetate such as potassium acetate, tertiary amine or carbonate of the metal, when heated.

Scheme 8

In accordance with scheme 8, compounds of formula (I) or (II)where R2represents H,38can be transformed by deprotonization with the base of the metal alkoxide, such as tert-piperonyl or potassium tert-piperonyl sodium, in an appropriate mixture of solvent/co-solvent in the Sol39.

EXAMPLE 1

3-[3-(2-Trifloromethyl)phenyl]-1,2,4-triazole

Stage A: 2-Triftormetilfullerenov acid

To a stirred solution of 2 g (9.5 mmol) of 1-bromo-2-cryptomaterial in 28 ml of tetrahydrofuran (THF, THF) at -78°C. was carefully added to 5.9 ml of a 1.7 M solution of tert-utility in hexane (9.5 mmol). The reaction mixture was stirred 45 min at -78°C. To the reaction mixture at -78°C was added 2,58 ml (11.1 mmol) of triisopropylsilane and this mixture was slowly heated when anatoy temperature (RT) for 16 hours. The reaction mixture was diluted with water and was treated with 2N NaOH to pH. The reaction mixture was washed with EtOAc. The aqueous fraction was acidified with a solution of 2N HCl and stirred for 1 hour at RT. The reaction mixture was extracted with EtOAc and the organic fraction washed with water, saturated NaCl solution (brine), dried over Na2SO4and filtered. The filtrate was concentrated, obtaining mentioned in the title compound as a white solid.1H NMR (CDCl3) (δ, ppm): of 7.96 (DD, J=7,2, 1,6 Hz, 1H), 7,53 (DDD, J=9,1, to 7.3, 1.8 Hz, 1H), 7,38 (TD, J=7,3, 0.7 Hz, 1H), 7,28 (d, J=8,2 Hz, 1H), 5.25-inch (USS, 2H), MS (M+H): 206,9.

Stage b: Ethyl-3-(2-trifloromethyl)benzoate

To a solution of 0.94 g (4,58 mmol) ethyl-3-bromobenzoate 14.5 ml of toluene at RT was added 0.25 g (0,218 mmol) tetrakis(triphenylphosphine)palladium(0), 0,94 g (4,58 mmol) 2-triftormetilfullerenov acid, 2,22 ml (of 4.45 mmol) of aqueous 2M sodium carbonate solution and 7 ml of ethanol. The reaction mixture was heated under reflux for 18 hours. The reaction mixture was cooled and was diluted with ethyl acetate and water. The organic fraction was separated and washed with saturated NaCl solution (brine), dried over MgSO4was filtered and the filtrate was concentrated to obtain oil, which was purified by chromatography (silica, 1%, 5%, 30% sequentially ethyl acetate:hexane), receiving specified in the header of the connection.1/sup> H NMR (CD3OD) (δ, ppm): 8,02 (s, 1H), of 7.97 (DD, J=7,8, 1.2 Hz, 1H), 7,60 (DD, J=7,7, 1.3 Hz, 1H), 7,50-7,33 (m, 5H), or 4.31 (q, 2H), 1,31 (t, 3H). Mass spectrum (ESI) m/e (M+1): 311,2.

Stage C: 3-(2-Trifloromethyl)benzoic acid

A solution of 0.3 g (4,19 mmol) ethyl-3-(2-trifloromethyl)benzoate and 8.3 ml (8.3 mmol) of 1N NaOH solution in 12.5 ml of methanol was stirred 18 h at RT. The reaction mixture was concentrated and brought to pH 2 using 1N HCl solution. The mixture was extracted with ethyl acetate (EtOAc) and the organic fraction was dried over MgSO4was filtered and the filtrate was concentrated, obtaining mentioned in the title compound as a white solid, which was used without further purification.

Stage D: 3-(2-Trifloromethyl)benzamid

To a solution of 0.94 g (3,36 mmol) 3-(2-trifloromethyl)benzoic acid in 17 ml of DMF (DMF) was added 0.55 g (3,36 mmol) carbonyldiimidazole (CDI) and the reaction mixture was stirred at RT 4 h. To the reaction mixture was added 2.6 g (33.6 mmol) of ammonium acetate and the mixture was stirred for overnight at RT. The reaction mixture was distributed between etiracetam and water and the organic fraction was washed with saturated saline solution, dried over MgSO4was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30%, 50% sequentially EtOAc:hexane), receiving specified in the header connection. Mass spectrum (ES) m/e (M+1): 282,2.

Stage E: 3-[3-(2-Trifloromethyl)phenyl]-1,2,4-triazole

The solution 0,137 g (0.48 mmol) of 3-(2-trifloromethyl)benzamide in 1 ml of dimethylacetal N,N-dimethylformamide was heated for 2 hours at 120°C, while the reaction mixture was concentrated in vacuum. This product was 2.3 ml of acetic acid was added 0,028 g (0.55 mmol) of hydrazine hydrate is added and the reaction mixture was heated for 2 hours at 90°C. Then the reaction mixture was concentrated and distributed between EtOAc and a saturated solution of NaHCO3. The organic fraction was washed with saturated saline solution, dried over MgSO4was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30:1, 9:1, 3:1 consistently CH2Cl2:acetone)to give specified in the header of the connection.1H NMR (CD3OD) (δ, ppm): 8,32 (s, 1H), of 8.06 (s, 1H), 7,98 (m, 1H), 7,50 (m, 3H), 7,39 (m, 3H). Mass spectrum (ESI) m/e (M+1): 306,1.

EXAMPLE 2

3-[3-(2-(2,2,2-Triptracker)phenyl]-1,2,4-triazole

Stage A: 2-(2,2,2-Triptoreline)phenylboronic

A solution of 0.35 g (2 mmol) of 2-bromophenol, 0,63 g (3 mmol) of 2,2,2-triptoreline, 0.55 g (4 mmol) of potassium carbonate in 2 ml of DMF was subjected to interaction at 150°C in a microwave system (Personal Chemistry, Smithcreator) 30 minutes After cooling to RT, the reaction mixture was diluted with water and extracted with ethyl acetate. Organic coat the Oia was dried over MgSO 4was filtered and the filtrate was concentrated. The residue was purified by chromatography (5%, 10% sequentially EtOAc:hexane), receiving specified in the header of the connection.

Stage b: Ethyl 3-(2-(2,2,2-triptracker)benzoate

To a solution of 2.5 g (9.8 mmol) of 2-cryptgetkeyparam in 33 ml of toluene at RT was added 0,57 g (0.49 mmol) of tetrakis(triphenylphosphine)palladium(0), 0,2 g (10.3 mmol) of 3-ethoxycarbonylphenyl acid, 5,9 ml (to 11.8 mmol) of a 2M aqueous solution of sodium carbonate and 17 ml of ethanol. The reaction mixture was heated under reflux for 18 hours. The reaction mixture was cooled and was diluted with ethyl acetate and water. The organic fraction was separated and washed with saturated NaCl solution (brine), dried over MgSO4was filtered and the filtrate was concentrated to obtain oil, which was purified by chromatography (silica, 1%, 5%, 30% sequentially ethyl acetate:hexane), receiving specified in the header connection. Mass spectrum (ESI) m/e (M+1): 325,1.

Stage C: 3-[3-(2-(2,2,2-Triptracker)phenyl]-1,2,4-triazole

Specified in the title compound can be prepared using procedures similar to the procedures described in example 1, stage C-E.

EXAMPLE 3

3-[3-((2-(2,2,2-Triptoreline)phenyl)-(4-fluoro)phenyl]-1,2,4-triazole

Mass spectrum (ESI) m/e (M+1): 338,0.

Stage A: Methyl 3-((2-hydroc and)phenyl)-4-perbenzoate

To a solution of 2 g (8,45 mmol) of methyl 3-bromo-4-perbenzoate in 28 ml of toluene at RT was added 0,49 g (0.42 mmol) of tetrakis(triphenylphosphine)palladium(0), 1,95 g (8.9 mmol) of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 5,1 ml (10,15 mmol) of a 2M aqueous solution of sodium carbonate and 14 ml of n-propanol. The reaction mixture was heated under reflux for 18 hours. The reaction mixture was cooled and was diluted with ethyl acetate and water. The organic fraction was separated and washed with saturated NaCl solution (brine), dried over MgSO4was filtered and the filtrate was concentrated to an oil, which was purified by chromatography (silica, 90:1, 30:1 consistently CH2Cl2:acetone)to give specified in the header connection. Mass spectrum (ESI) m/e (M+1): 247,0.

Stage b: Methyl 3-((2-(2,2,2-triptoreline)phenyl)-4-perbenzoate

A mixture of 1.7 g (7.1 mmol) of methyl 3-((2-hydroxy)phenyl)-4-perbenzoate, 2,46 g (10.6 mmol) of 2,2,2-triptorelin triftoratsetata and 3.45 g (10.6 mmol) of cesium carbonate in 35 ml of DMF was stirred 18 h at 60°C. the Cooled reaction sies was distributed between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic fractions were washed with water, saturated NaCl solution, dried over MgSO4and filtered. The filtrate was concentrated and purified by chromatography (silica, 5%, 30% sequentially EtOAc:hexane), receiving specified in C is the cylinder connection. Mass spectrum (ESI) m/e (M+1): 329,0.

Stage C: 3-[3-((2-(2,2,2-Triptoreline)phenyl)-(4-fluoro)phenyl]-1,2,4-triazole

Specified in the title compound can be prepared using procedures similar to the procedures described in example 1, stage C-E.

EXAMPLE 4

5-Methyl-3-[3-((2-triptoreline)phenyl)phenyl]-1,2,4-triazole

Stage A: 3-Brompheniramine-(N-tert-butoxycarbonyl)hydrazide

A solution of 1 g (equal to 4.97 mmol) 3-bromobenzoyl acid, 0,59 g (to 4.52 mmol) of tert-BUTYLCARBAMATE, 0.95 g (equal to 4.97 mmol) of EDC [1-(3-dimethylaminopropyl)3-ethylcarbodiimide), of 0.67 g (equal to 4.97 mmol) of hydroxybenzotriazole (HOBt) and 3.15 ml (18,1 mmol) diisopropylethylamine in 23 ml of CH2Cl2was stirred 18 h at RT. The reaction mixture was diluted with CH2Cl2and washed with 1N HCl solution, a saturated solution of NaHCO3and saturated NaCl solution. The solution was dried over MgSO4was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30:1, 9:1, 3:1 consistently CH2Cl2:acetone)to give specified in the header connection. Mass spectrum (ESI) m/e (M): 314,0 (M+2): 316,0.

Stage b: 3-((2-Triptoreline)phenyl)phenylhydrazide

The solution is 0.22 g (1.07 mmol) of 2-triftormetilfullerenov acid and 0.32 g (1,02 mmol) 3-brompheniramine-N-tert-butoxycarbonylmethyl in 5 ml of toluene and 2.5 ml of n-propanol displaced ivali 30 minutes To the reaction mixture were added 0,0007 g (0,003 mmol) of palladium acetate, 0.0024 g (0,009 mmol) of triphenylphosphine and 0.61 ml (1.2 mmol) of 2M aqueous sodium carbonate solution and the mixture was heated under reflux for 18 hours. The reaction mixture was cooled and diluted with EtOAc and water. The organic fraction was dried over Mg2SO4was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30:1, 9:1 consistently, CH2Cl2:acetone)to give the protected hydrazide, which was then dissolved in a mixture of 2.1 ml of TFA and 2.1 ml of CH2Cl2. The reaction mixture was stirred 2 hours, after which it was concentrated, dissolved in CH2Cl2and washed with 1N NaOH solution. The organic fraction was dried over Mg2SO4was filtered and the filtrate was concentrated, obtaining mentioned in the title compound as a white solid. Mass spectrum (ESI) m/e (M+1): 297,1.

Stage C: 5-Methyl-3-[3-((2-triptoreline)phenyl)phenyl]-1,2,4-triazole

To a solution of 0,093 g (0.98 mmol) of the hydrochloride of acetamidine 1.1 ml of ethanol was added to 0.22 ml (0.98 mmol) of a 25% solution of sodium methylate in methanol and the reaction mixture was stirred 30 min, after which it was filtered. To the filtrate was added to 0.19 g (0.66 mmol) of 3-((2-triptoreline)phenyl)phenylhydrazide and the reaction mixture was stirred over night. The reaction mixture was concentrated and PTS is attended by chromatography (silica, 3%, 10%, 30% sequentially, methanol:CH2Cl2), getting a white solid. White solid was heated (caution) when the melting point of 30 minutes, the Reaction mixture was cooled to RT, dissolved in CH2Cl2and concentrated. The residue was purified by chromatography (silica, 3%, 10%, sequentially, methanol:CH2Cl2), getting mentioned in the title compound as a white solid.1H NMR (CD3OD) (δ, ppm): 8,00 (s, 1H), to 7.93 (m, 1H), 7,49-7,34 (m, 6N), is 2.41 (s, 3H). Mass spectrum (ESI) m/e (M+1): 320,5.

EXAMPLE 5

3-[3-((2-Triptoreline)phenyl)phenyl]-1,2,4-triazole-5-carboxamide

Stage A: Ethyl N1-3-(2-triptoreline)benzoyl-N2-examinational

To a solution of 0.45 g (1.54 mmol) of 3-(2-trifloromethyl)phenylhydrazide (example 4, step A) in 20 ml of CH2Cl2added 0.54 g (2.3 mmol) of tetrafluoroborate carbethoxy-S-methylthiopyrimidine and 0.43 ml (is 3.08 mmol) of triethylamine and the reaction mixture was heated under reflux with stirring 4 hours. The reaction mixture was cooled to RT, washed with water, dried over Na2SO4was filtered and the filtrate was concentrated until solidification. Was added 2 ml of CH2Cl2and the formed solid product was isolated by filtration. Mass spectrum (ESI) m/e (M+1): 396,1.

Stage b: Ethyl 3-[3-((2-t is aftermatket)phenyl)phenyl]-1,2,4-triazole-5-carboxylate

Solid ethyl N1-3-(2-triptoreline)benzoyl-N2-examinational with stage A (0.25 g, 0,616 mmol) was heated on an oil bath at a temperature above its melting point of 20 minutes After cooling to RT, the residue was dissolved in CH2Cl2and concentrated, obtaining a yellow solid. It was purified by chromatography (silica, 10%, 30%, 50% sequentially, EtOAc:hexane), getting a white solid. Mass spectrum (ESI) m/e (M+1): 378,1.

Stage C:3-[3-((2-triptoreline)phenyl)phenyl]-1,2,4-triazole-5-carboxamide

A solution of 0.13 g (0.34 mmol) of ethyl 3-[3-((2-triptoreline)phenyl)phenyl]-1,2,4-triazole-5-carboxylate (from step B) in 2 ml of methanol in a test tube was saturated with ammonia. The tube was sealed and the reaction mixture was heated at 60°C over night. The reaction mixture was then concentrated and the residue was purified by chromatography (silica, 3%, 10%, 20% sequentially, methanol:CH2Cl2), receiving specified in the header of the connection.1H NMR (CD3OD) (δ, ppm): 8,10 (s, 1H), 8,02 (m, 1H), 7,54 and 7.36 (m, 6N). Mass spectrum (ESI) m/e (M+1): 349,2.

EXAMPLE 6

3-[3-((2-(2,2,2-Triptoreline)phenyl)-4-forfinal]-1,2,4-triazole-5-carboxamide

Stage A: 3-((2-(2,2,2-Triptoreline)phenyl)-4-Formentera acid

To a solution of 0.75 g (to 2.29 mmol) of methyl 3-((2-(2,2,2-triptoreline)phenyl)-4-perbenzoate (example 3, the stud is I) in 11.5 ml of a mixture of THF:water 3:1) was added 0,164 g (6,86 mmol) LiOH and the reaction mixture was stirred 18 h at RT. The reaction mixture was concentrated and brought to pH 2 using 1N HCl solution. The mixture was extracted with EtOAc and the combined organic fractions were washed with saturated NaCl solution, dried over MgSO4was filtered and the filtrate was concentrated, obtaining mentioned in the title compound, which was used without further purification.

Stage b: 3-[3-((2-(2,2,2-Triptoreline)phenyl)-4-forfinal]-1,2,4-triazole-5-carboxamide

Specified in the title compound was obtained from 3-((2-triptoreline)phenyl)-4-fermenting acid in accordance with the techniques described in example 4, stage A and B, and example 4.1H NMR (CD3OD) (δ, ppm): 8,02 (m, 2H), 7,99 (m, 1H), 7,39 (m, 1H), 7,30 (m, 1H), 7,16 (m, 2H), 4,45 (kV, J=8.5 Hz, 2H). Mass spectrum (ESI) m/e (M+1): 381,0.

The following examples 7-10 were performed in accordance with the methods described in examples 5 and 6.

ExampleStructureMass spectrum (M+1)
7333,1
8363,1
9 367,0
10351,0

EXAMPLE 11

3-[3-((2-Triptoreline)phenyl)-(4-fluoro)phenyl]-1,2,4-triazole-5-carboxamide

Mass spectrum (ESI) m/e (M+1): 367,0.

Stage A: Preparation of 4-fluoro-3-(2-trifloromethyl)benzonitrile

3-Bromo-4-perbenzoate (1.0 equivalent), 2-(triptoreline)bendovervideo acid (1.25 equivalents), palladium acetate (0.005 equivalents) and triphenylphosphine (0.01 equivalent), was loaded into a flask with a few holes. After blowing off the flask with nitrogen was added toluene (5 ml/g 3-bromo-4-perbenzoate) and the resulting suspension was stirred, barbotine nitrogen into the reaction mixture for about 20 minutes. In a separate flask was prepared an aqueous solution of potassium phosphate dissolving solid potassium phosphate (2.0 equivalents) in water (2 ml/g of potassium phosphate). The resulting solution was desoxyribose by bubbling nitrogen into the reaction mixture under stirring for approximately 30 minutes. An aqueous solution of potassium phosphate were added to a toluene suspension and the reaction mixture was heated at 60-65°C with steam heating. The course of the reaction was monitored by HPLC and the temperature of the reaction mixture was maintained in the range 63-69°C. When 3-bromo-4-perbenzoate was spent, heating the tion was stopped and the reaction mixture was cooled to RT in an ice bath. The aqueous layer was ciphervalue from the vessel and added to the reaction vessel Ecosorb C-941 (0.5 g/g 3-bromo-4-perbenzoate, commercially available from graver carving Technologies, Glasgow, Delaware). The resulting black suspension was stirred at RT for 15 hours. The charcoal was removed by filtering the suspension through a porous layer Soloflex on the filter crucible. The filter cake was washed with toluene (4 ml/g of 3-bromo-4-perbenzoate). The combined filtrates metered concentrated (40-50°C) to obtain bikinicollege product as a thick light orange oil (yield 94%).

Stage b: Preparation:

Absolute ethanol (1.8 ml/g bikinifree) were placed in a round bottom flask. Mix the ethanol was cooled in a bath of ice/acetone and barbotirovany into a solution of gaseous hydrogen chloride, while the internal temperature was maintained below 20°C. the Addition of HCl controlled by proton titration using a Metrohm 808 Titrando (commercially available from Metrohm Ltd.) to determine the concentration of HCl in ethanol. The addition was stopped after the HCl concentration was reached 38% (7.5 equivalents). Barillari from step A (1.0 quivalent) was added in the form of undiluted oil to the cooled ethanol solution of HCl and the reaction solution was allowed to warm to RT with stirring overnight (>15 h). The midrange response is Tali completed, when HPLC analysis showed the presence of the original bikinifree. The reaction mixture then was diluted with toluene (8 ml/g bikinifree). In order to cause crystallization, loading solvent switched to toluene joint distillation with ethanol (<35°C internal temperature), which azeotrope was removed ethanol. This procedure was performed until such time as the ethanol content in the mother liquor was less than 1 mol.%, with respect to toluene. This endpoint was determined by proton NMR uterine fluid in CDCl3. A solid substance was separated by filtration, washed with toluene (2.3 ml/g bikinifree). White crystalline HCl salt ethylimidazole product was dried in a stream of nitrogen.

Stage C: Preparation

HCl salt of imidate from step C (1.0 equivalent) and EtOAc (4 ml/g of HCl salt of imidate) was added into the flask, followed by stirring for formation of a heterogeneous suspension. This suspension was cooled to 10°C, followed by slow addition of 5,0N NaOH solution (3.3 equivalents). The speed of addition of the NaOH solution was periodically adjusted to establish the temperature of the reaction mixture below 15°C. After complete addition of NaOH biphasic reaction mixture was allowed to warm to ambient temperature, at which all solids were dissolved (PR is approximately 30 min). The stirring was stopped and left two coats for full separation. The lower aqueous layer was removed and discarded. Into the flask containing the organic layer was added water (2 ml/g of HCl salt of imidate) and the resulting biphasic mixture was stirred for 5 minutes. The layers were left to separate and the lower aqueous layer was removed and discarded. Followed by adding to the flask 10% aqueous solution of NaCl (2 ml/g of HCl salt of imidate). The resulting two layers were stirred for 5 minutes and the lower aqueous layer was removed and discarded. The upper organic layer was transferred into a round bottom flask which was attached to the periodic hub. Then there was the replacement of the solvent with EtOAc in EtOH removing EtOAc joint distillation with EtOH. After solvent exchange (<3% EtOAc according to the1H NMR, the concentration of imidate approximately 185 mg/ml) ethanol solution containing free primary imidate, was transferred to a new flask.

Hydrazide examinados acid (1.1 equivalent) and potassium acetate (5.0 equivalents) was added to the ethanol solution containing the above imidate. The resulting heterogeneous mixture was then heated in the range of 60-70°C on a steam bath with strong stirring. The reaction was monitored by HPLC analysis of the transformation of imidate in the target triadology product. After completion of the reaction, the reaction mixture was cooled to a tempera is URS environmental followed by slow addition of water (4 ml/g of HCl salt of imidate) in order to cause crystallization of the desired product from the reaction mixture. The target product was then separated by filtration under vacuum as not quite white solid (yield 85%).

Stage D: the Preparation

Triadology product stage (1.0 equivalent) was added to the reaction vessel followed by the addition of toluene (5.3 ml/g of triazole) and THF (1.7 ml/g of triazole). The resulting heterogeneous mixture was stirred at ambient temperature. To this suspension was added a solution of potassium tert-butylate (1.1 equivalent). The rate of addition of the base was periodically adjusted to establish the temperature of the reaction mixture below 35°C. as adding the reaction mixture became less heterogeneous. After complete addition, the Foundation obtained a homogeneous pale yellow solution was stirred at ambient temperature for 30 minutes In the moment for download slowly added (about 10 min), water (2.5 equivalent), with a slight exothermic effect. After about 15 minutes the reaction mixture became highly turbid and the temperature of the contents slowly began to rise. Approximately 20 min after the addition of water began to form solids, which indicated the beginning of crystallization. After about 30 min the temperature of the load has reached its maximum (24,9°C). Heterogeneous content was stirred an additional 30 minutes. The contents were filtered in the filter tank using mother liquor to obtain any residual solids in the reaction vessel. The wet precipitate was washed with cool toluene (4 ml/g of triazole). The load was transferred into a vacuum thermostat and dried at 45°C and 100 mm RT. Art. within 24 hours before receiving dihydrate potassium salt of the product as a white solid (yield 95%).

EXAMPLE 12

3-[3-((2,4-Bis(trifluoromethyl)phenyl)phenyl]-1,2,4-triazole-5-carboxamide

Mass spectrum (ESI) m/e (M+1): 401,0.

EXAMPLE 13

N-methyl-3-[3-((2-triptoreline)phenyl)phenyl]-1,2,4-triazole-5-carboxamide

To a solution of 0.083 g (0.24 mmol) of 3-[3-((2-triptoreline)phenyl)phenyl]-1,2,4-triazole-5-carboxylic acid (obtained from ethyl 3-[3-((2-triptoreline)phenyl)phenyl]-1,2,4-triazole-5-carboxylate of example 5, following the methods of example 6) in 1.2 ml DMF at RT was added 0,038 g (0.24 mmol) of carbonyldiimidazole (CDI) and the reaction mixture was stirred 3 hours. To the reaction mixture was added 1.2 ml (2.4 mmol) of a 2M solution of methylamine in THF and the reaction mixture was stirred over night at RT. The reaction mixture was concentrated and distributed between EtAc and water. The aqueous fraction was extracted with EtOAc and the combined organic fractions were washed with water and saturated saline solution, dried over MgSO4, filloval and the filtrate was concentrated. The residue was purified by chromatography (silica, 30%, 50% sequentially, EtOAc:hexane), getting mentioned in the title compound in the form of a foamy white solid. Mass spectrum (ESI) m/e (M+1): 363,0.

EXAMPLE 14

1-[3-((2-(2,2,2-Triptoreline)phenyl)phenyl]-1,2,4-triazole-3-carboxamide

Stage A: 3-((2-(2,2,2-Triptoreline)phenyl)aniline

To a solution of 1.0 g (3.93 mmol) of 2-(2,2,2-triptoreline)panelbased (example 2, step A) in 39 ml of toluene was added 0,136 g (amount of 0.118 mmol) tetrakis(triphenylphosphine)palladium(0), 0.56 g (or 4.31 mmol) 3-aminophenylarsonic acid (47 ml (94,1 mmol) of a 2M solution of sodium carbonate and 8 ml of ethanol and the reaction mixture was heated for 22 h at 90°C. the Reaction mixture was cooled to RT and distributed between water and EtOAc. The aqueous fraction was extracted with EtOAc and the combined organic fractions were washed with water and saturated saline solution, dried over Na2SO4was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 4:1 hexane:EtOAc)to give specified in the header connection. Mass spectrum (ESI) m/e (M+1): 268,1.

Stage b: Methyl 1-[3-((2-(2,2,2-triptoreline)phenyl)phenyl]-1,2,4-three is evil-3-carboxylate

To a solution of 0,923 g (of 3.45 mmol) of 3-((2-triptoreline)phenyl)aniline in 6 ml of 1N HCl solution at 0°C was added 0,238 g (of 3.45 mmol) of sodium nitrite and 1 ml of water and the reaction mixture was stirred 20 min, obtaining the solution of diazonium salt.

To a solution of 0.27 g (was 2.76 mmol) methylisocyanate in 15 ml of methanol and 2 ml of water at 0°C was added 1.8 g (22,08 mmol) of sodium acetate. To this reaction mixture was added dropwise a solution of diazonium salt and the reaction mixture was stirred 1 hour at 0°C. the Reaction mixture then was diluted with methanol and concentrated. The residue was diluted with EtOAc and 0,5N HCl solution. The aqueous layer was extracted with EtOAc and the combined organic fractions washed with 5% solution of NaHCO3saturated salt solution, dried over Na2SO4was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 1:1 EtOAc:hexane), receiving specified in the header connection. Mass spectrum (ESI) m/e M+1: 378,1.

Stage C: 1-[3-((2-(2,2,2-Triptoreline)phenyl)phenyl]-1,2,4-triazole-3-carboxylic acid

A solution of 0.29 g (0,769 mmol) methyl-1-[3-((2-triptoreline)phenyl)phenyl]-1,2,4-triazole-3-carboxylate and 2.2 ml (2.2 mmol) of 1M NaOH solution in water was stirred 18 h at RT. The reaction mixture was concentrated. The residue was diluted with water and the pH brought up to 2-4 1N HCl solution. The mixture was extracted with EtOAc and the combined organic fractions were washed us is on a salt solution dried over Na2SO4was filtered and the filtrate was concentrated, obtaining specified in the header connection. Mass spectrum (ESI) m/e M+1: 363,9.

Stage D: 1-[3-((2-(2,2,2-Triptoreline)phenyl)phenyl]-1,2,4-triazole-3-carboxamide

To a solution 0,225 g (0,619 mmol) 1-[3-((2-triptoreline)phenyl)phenyl]-1,2,4-triazole-3-carboxylic kilty 3.1 ml of DMF was added 0.1 g (0,19 mmol) CDI and the reaction mixture was stirred 4 h at RT. To the reaction mixture were added 0,477 g (to 6.19 mmol) of ammonium acetate and the reaction mixture was stirred 19 hours. The reaction mixture was diluted with water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic fractions were washed with saturated brine, dried over Na2SO4was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 1:1 EtOAc:hexane, 1% methanol:CH2Cl210% methanol:CH2Cl2), receiving specified in the header connection. Mass spectrum (ESI) m/e M+1: 363,1.

EXAMPLE 15

1-[3-((2-Triptoreline)phenyl)phenyl]-1,2,4-triazole-3-carboxamide

Stage A: 1-N-Tert-butoxycarbonylamino-3-Brabanthal

A solution of 10 g (58,13 mmol) 3-bromoaniline and 15.2 g (69,75 mmol) Vos2About 300 ml of toluene was heated overnight at 70°C. the Reaction mixture was concentrated and diluted with EtOAc and 0,5N HCl solution. The organic fraction was washed 0,5N Rast is a PR HCl and saturated salt solution. The fraction was dried over Na2SO4was filtered and the filtrate was concentrated. The residue was purified by chromatography (hexane, 9:1 hexane:EtOAc consistently), receiving specified in the header of the connection.

Stage b: 1-N-Tert-butoxycarbonyl-3-((2-triptoreline)phenyl)aniline

1-N-Tert-butoxycarbonylamino-3-Brabanthal were subjected to interaction with the 2-by-triftormetilfullerenov acid in accordance with the methods of example 14, step A.

Stage C: 3-((2-Triptoreline)phenyl)aniline

The solution 0,977 g (2.77 mmol) of 1-N-tert-butoxycarbonyl-3-((2-triptoreline)phenyl)aniline in 7 ml of TFA and 7 ml of CH2Cl2was stirred for 1 hour at RT. The reaction mixture was concentrated and the residue was diluted with 1N NaOH solution and EtOAc. The organic fraction washed with 1N NaOH solution and saturated saline solution, dried over Na2SO4was filtered and the filtrate was concentrated, obtaining specified in the header connection. Mass spectrum (ESI) m/e M+1 254,1.

Stage D: 1-[3-((2-Triptoreline)phenyl)phenyl]-1,2,4-triazole-3-carboxamide

Specified in the title compound was obtained from 3-((2-triptoreline)phenyl)aniline by following the procedures of example 14. Mass spectrum (ESI) m/e M+1 349,1.

The following examples 16-17 were obtained using the methods of examples 14 or 15.

EXAMPLE 16

1-[3-((2,4-Bis-triptoreline)phenyl)phenyl]-1,2,4-triazole-3-ka is boxlid

Mass spectrum (ESI) m/e M+1 401,1.

EXAMPLE 17

1-[3-((2-(2,2,2-Triptoreline-4-fluoro)phenyl)phenyl]-1,2,4-triazole-3-carboxamide

Mass spectrum (ESI) m/e M+1 381,2.

The following EXAMPLE 18 was obtained using the method of example 13, from 3-[3-((2-triptoreline)phenyl)phenyl]-1,3,4-triazole-5-carboxylic acid.

ExampleStructureMass spectrum (M+1)
18363,1

Example 19

3-[3-((2,6-Bis-trifluoromethyl)phenyl)phenyl]-1,2,4-triazole-5-carboxamide

Specified in the title compound was obtained using the methods of examples 5 and 6.

Example 20

Mass spectrum (ESI) m/e M+1 381.

1. The compound represented by formula (I) or (II)


or its pharmaceutically acceptable salt,
where R1represents H, C1-C6-alkyl, or a group CONRaRb, Rameans hydrogen, a Rbmeans hydrogen or C1-C6alkyl;
R2represents N or C1-C6-alkyl;
R3represents H or F, Cl, Br or I;br/> R4represents H;
R5is a CF3or O-(C1-C4) alkyl, three times substituted by F;
R6and R7each independently represents H, F, or CF3provided that one of R6and R7always represents N.

2. The compound according to claim 1 represented by the chemical formula (I)or its pharmaceutically acceptable salt, where R1-R7take the values defined above.

3. The compound according to claim 1 represented by the chemical formula (II), or its pharmaceutically acceptable salt, where R1-R7take the values defined above.

4. The compound according to claim 1, selected from


or their pharmaceutically acceptable salts.

5. The compound represented by formula (III)

or its pharmaceutically acceptable salt, where R1is a group CONRaRb, Rameans hydrogen, a Rbmeans hydrogen or C1-C6alkyl;
R2, R3, R4represents H;
R5is a CF3or O-(C1-C4)alkyl, three times substituted by F;
R6and R7each independently represents H, F, or CF3provided that one of R6and R7always represents N.

6. The compound according to claim 5, selected from


or their pharmaceutically acceptable salts.

7. The pharmaceutical composition, the active item is blocking sodium channels, containing a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable filler.

8. The use of compounds according to claim 1 for the preparation of drugs for treatment or prevention of pain or impairment caused by pain.

9. The method of obtaining the compounds of formula (I):

or its pharmaceutically acceptable salts, where R1-R7take the values defined in claim 1,
namely, the compound of formula (34) or (35):

where R1-R7take the values defined above, is subjected to the interaction with the compound of the formula (36):

where R1and R2take the above meanings, in the presence of a base.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention claims substituted O-[ω-(azol-1-yl)alkyl]-N-phenylthiocarbamates of formula I: where Z=CH, N, R=H, Alk, AlkO, Hal etc., m=1, 2, 3, n=0-5, obtained by acylation of ω-(azol-1-yl)alkanols of formula II by substituted phenylisothiocyanates in polar aprotonic solvents in the presence if tertiary amines. Invention allows for more efficient suppression of phytopathogenic fungi in vitro than by such reference material as triadimefon, due to application of fungicide composition including substituted O-[ω-(azol-1-yl)alkyl]-phenylthiocarbamates I, such as O-(imidazole-1-ylmethyl)-N-(2-methyl-phenyl)thiocarbamates.

EFFECT: efficient suppression of phytopatogenic fungi growth.

4 cl, 5 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in substituted N-[ω-azol-1-yl)alkyl]benzolsulfamides , X and Y represent CH-group, n stands for 2 or 4, R - similar or different stand for alkyl group with number of carbon atoms from 1 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, n stands for 3, R - similar or different stand for alkyl group with number of carbon atoms from 2 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 2 to 4, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, where X stands for CH-group, Y stands for nitrogen atom, n stands for 2, R - similar or different stand for alkyl group with number of carbon atoms from 2 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, n stands for 3 or 4, R - similar or different stand for alkyl group with number of carbon atoms from 1 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, where X and Y simultaneously are chain C-CH=CH-CH=CH-C constituting together annelated with heterocycle ring, n stands for whole number from 2 to 4, R - similar or different stand for alkyl group with number of carbon atoms from 1 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, methods of their obtaining and application as anti-aggregation preparations. Anti-aggregation activity of N-[ω -azol-1-yl)alkyl]benzolsulfamides, of general formula I, for instance, hydrochloride of N-[4-(1H-triasol-1-yl)butyl]-n-methylbenzolsulfumide (35) is higher than of etalon dazoxyben.

EFFECT: increase of anti-aggregation activity.

4 cl, 5 tbl, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to substituted ω-azolylalkane anilides. Invention describes substituted ω-(1H-azol-1-yl)-N-phenylalkaneamides of the general formula (I): wherein Z and Y mean nitrogen atom of CH-group, or they represent the chain -C-CH=CH-CH=CH-C- simultaneously and forming in common an anellated ring; n means a whole number from 1 to 3; Rm are similar or different and mean hydrogen, halogen atom, alkyl group with number of carbon atoms from 1 to 4, alkoxy group, alkylenedioxy group, benzyloxy group, perfluoroalkyl group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group, carboxyl group, halogenphenylthio group, halogenbenzoyl group; m means a whole number from 0 to 5, their salts with acids. Also, invention describes methods for synthesis of compounds of the formula (I) and their using as anti-aggregative preparations. Invention provides synthesis of novel compounds possessing the useful biological properties.

EFFECT: valuable properties of compounds, improved method of synthesis.

8 tbl, 11 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-(azol-1-yl)ethaneamines that are used as the parent compounds in preparing biologically active compounds of medicinal and agriculture designation. Method for synthesis of 2-(azol-1-yl)ethaneamines of the general formula (I): wherein R1 means hydrogen atom or alkyl group comprising from 1 to 6 carbon atoms; each Z and X means independently -CH or nitrogen atom (N); or Z and X mean in common group -C-CH=CH-CH=CH-C that forms a system anellated with azole cycle involves the alkylation reaction of azole compounds wherein R1, Z and Y have the same values as in the formula (I) with oxazolines of the formula (II): wherein R2 means alkyl group comprising from 1 to 6 carbon atoms, phenyl, halogenphenyl group in the presence of Lewis acid or protonic acid to yield N-[2-(azol-1-yl)ethyl]alkaneamides of the formula (III): wherein R1, R2, Z and X have above given values followed by their hydrolysis in the presence of acids or bases in polar solvent medium at temperature 60-120°C.

EFFECT: improved method of synthesis.

5 cl, 17 ex

FIELD: organic chemistry, fungicides.

SUBSTANCE: invention describes substituted 1-(pyridinyl-2)-2-azolylethanols of the general formula (I): wherein R means hydrogen atom, direct or branched alkyl with 1 to 8 carbon atoms, cycloalkyl with from 3 to 8 carbon atoms; X means nitrogen atom or CH-group. Also, invention relates to a method for synthesis of these compounds and a fungicide composition that contains compound of the formula (I). Invention provides expanding assortment of fungicides for carrying out the effective control of harmful fungi.

EFFECT: valuable fungicide properties of compounds and composition.

5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel triazole derivative of the general formula (I): wherein R1 represents phenyl group optionally substituted with one or two groups chosen from (C1-C6)-alkyl group, (C1-C6)-halogenalkyl group, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkoxy-group, halogen atom, nitro-group or cyano-group, styrenyl group, (C1-C6)-alkoxystyrenyl-group or pyridyl group; R2 represents methyl or amino-group; A and B are carbon atoms; C and D represent independently carbon or nitrogen atom, and its nontoxic salt and pharmaceutical composition based on thereof. Also, invention relates to methods for synthesis of novel compounds, novel intermediate substances of the formula: wherein R2, A, B, C and D have above given values; n means a whole number from 0 to 2, and to a method for their synthesis. Compounds of the formula (I) possess anti-inflammatory activity and can be used potentially in treatment of fever, pain and inflammation.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 2 tbl, 50 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of adamantine, in particular, to a new method for preparing adamant-1-yl-containing azoles of the general formula I-VIII: wherein R1 means ; R2 means ; R3 means ; R4 means ; R5 means ; R6 means ; R7 means , and R8 means . Indicated derivatives of adamantine are semifinished products used in synthesis of biologically active substances. Proposed method for preparing these compounds involves using a new method for synthesis of adamant-1-yl-containing azoles that includes the addition reaction of azoles: 2-methylimidazole, 3(5)-methylpyrazole and 4-methylpyrazole, 3,4-dinitropyrazole, 1,2,4-triazole, 3-methylpyrazole, 3-nitro-1,2,4-triazole and 5-methyltetrazole to 1,3-dehydroadamantane in the mole ratio of 1,3-dehydroadamantane to azole = 1:1 in diethyl ether medium at temperature 100°C for 4-5 h.

EFFECT: improved preparing method.

8 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes a method for synthesis of fluconazole monohydrate of the formula (I): . Method involves hydrolysis of silyl ester derivative of the formula (II): wherein R2 means hydrogen atom, (C1-C10)-alkyl or phenyl group; R3 and R4 mean independently of one another (C1-C10)-alkyl or phenyl group at pH value below 3 or above 8 in an aqueous solution followed by cooling the prepared reaction mixture and isolation of the precipitated fluconazole monohydrate. Also, invention describes methods for synthesis of crystalline modification II of fluconazole of the formula (I). These methods involve dissolving anhydrous fluconazole or its monohydrate in (C1-C4)-alcohol of the linear or branched chain at the boiling point and cooling this solution at the rate 5-15°C/h, or fluconazole monohydrate is dried at 30-70°C. Except for, invention describes a method for synthesis of crystalline modification I of fluconazole of the formula (I) wherein fluconazole monohydrate is dried at 80°C. This invention provides preparing pure or easily purifying fluconazole in crystalline modifications allowing easy preparing the suitable medicinal formulations from them.

EFFECT: improved synthesis method.

16 cl, 1 tbl, 7 dwg, 8 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new compounds with formula (I), their esters, carbamates and pharmaceutically used salts, which can be used as inhibitors of p38 kinase, which means they can be used for curing diseases and conditions for which p38 is the mediator. In formula (I): Q represents -C(R1R2R3); R1 is chosen from hydrogen, C1-C8 alkyl, hydroxyC1-C8alkyl, and C1-C8alkoxy C1-C8alkyl; R2 and R3 are chosen: (i) independently from: (a) hydrogen, under the condition that, if R1 represents hydrogen, then only one of R2 and R3 can be chosen from hydrogen; (b) C1-C8alkyl; C1-C8alkyl, substituted with one or two radicals halogen, -OR8, -S(O)pR10;(c) -OR8; or (ii) R2 and R3 together with the carbon atom to which they are bonded, form optionally substituted C3-C7cycloalkyl or substituted heterocyclic ring system; R4 and R5 are independently chosen from halogen; R8 and R9 are independently chosen from hydrogen, C1-C8alkyl; R10 represents C1-C8alkyl; m equals 0, n equals 0; and p equals 2; where the term "substituted cycloalkyl" stands for a cycloalkyl group, containing one or two substitutes, which are independently chosen from a group, consisting of -Y-ORs, -Y-S(O)0-2RS, C(=O)ORs, where Y is absent; Rs is independently chosen from hydrogen, C1-C8alkyl, except when the said substitute represents -Y-S(O)1-2Rs, then RS represents hydrogen; the term "heterocyclic ring system" stands for a saturated non-aromatic monocyclic fragment, consisting of 5 to 6 atoms, which are part of the ring system, from which one atom, which is part of the ring system, is a heteroatom, chosen from N, O, and the rest of the atoms in the ring system are carbon atoms; the term "substituted heterocyclic ring system" stands for a heterocyclic fragment mentioned above, containing one substitute, chosen from the group, -Y-Rs, -Y-ORs, -Y-C(O)2Rs, -Y-S(O)0-2Rs, where Y is absent or represents a C1-C4alkylene group, Rs represents the same as was defined above for the substituted cycloalkyl group.

EFFECT: used for treating diseases and conditions.

13 cl, 2 dwg, 5 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula I, where R1 represents -(CHR')q-aryl or -(CHR')q-thiophen, which are unsubstituted or mono-, di- or tri-substituted with (inferior)alkyl, (inferior)alkoxy, CF3 or haloid, or represents (inferior)alkyl, (inferior)alkenyl, -(CH2)n-Si(CH3)3, -(CH2)n-O-(inferior)alkyl, -(CH2)n-S- (inferior)alkyl, -(CH2)q-cycloalkyl, -(CH2)n-[CH(OH)]m-(CF2)p-CHqF(3-q), or represents -(CH2)n-CR2-CF3, where two radicals R together with a carbon atom form a cycloalkyl ring; R' represents hydrogen or (inferior)alkyl; n is 1, 2 or 3; m is 0 or 1; p is 0, 1,2, 3, 4, 5 or 6; q is 0, 1, 2 or 3; R2 represents hydrogen or (inferior)alkyl; R3 represents hydrogen, (inferior)alkyl, CH2F, aryl, optionally mono-, di- or tri-substituted with a haloid, or represents -(CH2)nNR5R6, where R5 and R6 independently represent hydrogen or (inferior)alkyl; R4 represents one of the following groups a) or b), where R7 represents inferior)alkyl or -(CH2)ncycloalkyl; R8 and R9 independently represent hydrogen, (inferior)alkyl, -(CH2)n-cycloalkyl or -C(O)-phenyl. The invention also relates to pharmaceutically used acid addition salts of these compounds, optically pure enantiomers, racemates or diastereomeric mixtures, as well as compounds with general formula I-1, and medicinal agent.

EFFECT: obtaining new biologically active compounds, designed for inhibiting γ-secretase.

16 cl, 83 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new nitroxide compounds with formula I: where one of A, B and D represents N-O and others represent CR6; R1 represents alkyl, containing 1 to 4 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; R2 represents alkyl, containing 1 to 12 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; cycloalkylalkylk, containing 3 to 10 carbon atoms, which is unsubstituted or substituted once or several times with oxo, aryl, containing 6 to 14 carbon atoms, which is unsubstituted or substituted once or several times with OCF3; or a heterocyclic group, which is saturated, partially saturated or unsaturated, with 5 to 10 atoms in the ring, where at least 1 atom in the ring is an atom of N, O, or S; R3 represents cycloalkyl, containing 3 to 10 carbon atoms, which is unsubstituted once or several times with oxo, aryl, containing from 6 to 14 carbon atoms or which is unsubstituted or substituted once or several times with OCF3; or heteroaryl, with 5 to 10 atoms in the ring, in which at least 1 atom in the ring is a heteroatom; R represents H or alkyl, containing 1 to 4 carbon atoms. The invention also relates to pharmaceutically used salts of these compounds, pharmaceutical compositions containing these compounds, method of inhibiting PDE4 enzyme and to methods treatment using these compounds.

EFFECT: new compounds with useful biological properties.

62 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new nitroxide compounds with formula I: where one of A, B and D represents N-O and others represent CR6; R1 represents alkyl, containing 1 to 4 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; R2 represents alkyl, containing 1 to 12 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; cycloalkylalkylk, containing 3 to 10 carbon atoms, which is unsubstituted or substituted once or several times with oxo, aryl, containing 6 to 14 carbon atoms, which is unsubstituted or substituted once or several times with OCF3; or a heterocyclic group, which is saturated, partially saturated or unsaturated, with 5 to 10 atoms in the ring, where at least 1 atom in the ring is an atom of N, O, or S; R3 represents cycloalkyl, containing 3 to 10 carbon atoms, which is unsubstituted once or several times with oxo, aryl, containing from 6 to 14 carbon atoms or which is unsubstituted or substituted once or several times with OCF3; or heteroaryl, with 5 to 10 atoms in the ring, in which at least 1 atom in the ring is a heteroatom; R represents H or alkyl, containing 1 to 4 carbon atoms. The invention also relates to pharmaceutically used salts of these compounds, pharmaceutical compositions containing these compounds, method of inhibiting PDE4 enzyme and to methods treatment using these compounds.

EFFECT: new compounds with useful biological properties.

62 cl, 6 ex

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to compound of formula (I) in which m represents integer number, equal 1 or 2; R1 represents group, selected, in particular from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, naphtyl, chinolinyl, isochinolinyl, benzisoxazolyl, tienopyridinyl, said group is possibly substituted with one or several groups of R3, similar or different from each other or by group R4, R2 represents group of general formula CHR5CONHR6, R3 represents halogen atom or one of the following groups: piano, nitro, C1-6-alkyl, C1-6-alkoxy, C1-6-trifluoralkyl, C1-6-trifluoralkoxy, benzyloxy, phenyloxy, R4 represents group, selected, in particular from phenyl, benzofuranyl, naphtyl; one orseveral groups R4 can by substituted with one or several groups R3, similar or different from each other; R5 represents hydrogen atom or C1-3-akyl group; R6 represents hydrogen atom or alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl -C1-3-alkylene group; as base, salts of binding of acid, hydrate or solvate. Also invention relates to method of obtaining compound of formula I, its use as medicine and to based on it pharmacological composition.

EFFECT: novel derivatives of 1-pyperazine and 1-homopyperazincarboxilates, useful for prevention or treatment of pathology, in which endogen cannabinoids and/or any other substrates, metabolised by ferment FAAH, participate.

12 cl, 3 tbl, 11 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new azetidine compounds with general formula (I): where Het is piperadino, substituted with hydroxyl, oxo, cyano, 1,3-dioxolan-2-yl, fluorine atom; or Het is morpholino or thiomorpholino, possibly substituted on its sulphur atom with one or two oxygen atoms; or Het is piperazino, substituted on its nitrogen atom in position 4 with C1-C4alkyl, C3-C4cycloalkyl or C1-C4acyl; R1 represents hydrogen; R2 represents fluoro, bonded in position four; R3 is hydrogen; R4 is C1-C4alkyl or C3-C4cycloalkyl; Ar is phenyl, substituted in its positions 3 and 5 with groups, independently chosen from halogen and C1-C4alkyl, where one or more hydrogen atoms of the alkyl group can be substituted with a fluorine atom. The invention also relates to the new compound's enantiomer or its pharmaceutically used salt.

EFFECT: compounds I exhibit antagonistic activity towards NK1 and NK2, which allows for their use in pharmaceutical compositions for making medicine for curing respiratory, cardiovascular, neurotic, painful, oncological, inflammatory and/or gastroenteric upsets.

20 cl, 6 dwg, 54 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutics. Production of ginkgo biloba extract with low content of 4'-O-methylpyridoxine and/or biflavones involves the stages as follows: (a) production of ginkgo biloba solution in a solvent, (b) application of the solution on an adsorbing resin chosen from styrene copolymer and divinylbenzene or bromated styrene copolymer and divinylbenzene, and elution of the purified extract from adsorbing resin by a solvent, with biflavones kept on the adsorbing resin and/or (c) application of the solution on a strong-acid ion exchanger and elution of the purified extract from the ion exchanger with a solvent with 4'-O-methylpyridoxine kept on the ion exchanger. The solvent at the stages (a), (b) and (c) is independently chosen from aqueous alkanole containing 1-3 carbon atoms, and aqueous ketone containing 3-6 carbon atoms, and (d) concentration and drying of the extract solution to prepare the dry extract with 4'-O-methylpyridoxine not exceeding 20 w.f. and/or biflavone content not exceeding 25% of content in the original extract. Ginkgo extract is applied for making a medical product for treatment of dementia and its symptoms and/or cerebral and peripheral blood circulation disturbances, or a food additive. The medical product or food additive for treatment of dementia and its symptoms and/or cerebral and peripheral blood circulation disturbances is characterised by ginkgo extract content.

EFFECT: invention allows producing extract with low content of 4'-O-methylpyridoxine and/or biflavones.

11 cl, 2 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: according to the invention pharmaceutical composition contains carbostyril derivative and serotonin reuptake inhibitor in pharmaceutically acceptable carrier. Carbostyril derivative is aripiprazole. Serotonin reuptake inhibitor can include fluoxetine, duloxetine, venlafaxine, milnaciprane, cytalopram, fluvoxamine, paroxetine, sertraline or escitalopram. According to the invention, the pharmaceutical composition can be used for treatment of phrenopathy patients, particularly suffering from depression or major depressive disorder.

EFFECT: according to the invention, the composition is characterised with synergetic action and can be applied in relatively small amounts, possesses lower by-effects and satisfactory safety characteristics.

36 cl, 8 dwg, 9 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: according to the invention pharmaceutical composition contains carbostyril derivative and serotonin reuptake inhibitor in pharmaceutically acceptable carrier. Carbostyril derivative is aripiprazole. Serotonin reuptake inhibitor can include fluoxetine, duloxetine, venlafaxine, milnaciprane, cytalopram, fluvoxamine, paroxetine, sertraline or escitalopram. According to the invention, the pharmaceutical composition can be used for treatment of phrenopathy patients, particularly suffering from depression or major depressive disorder.

EFFECT: according to the invention, the composition is characterised with synergetic action and can be applied in relatively small amounts, possesses lower by-effects and satisfactory safety characteristics.

36 cl, 8 dwg, 9 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: according to the invention pharmaceutical composition contains carbostyril derivative and serotonin reuptake inhibitor in pharmaceutically acceptable carrier. Carbostyril derivative is aripiprazole. Serotonin reuptake inhibitor can include fluoxetine, duloxetine, venlafaxine, milnaciprane, cytalopram, fluvoxamine, paroxetine, sertraline or escitalopram. According to the invention, the pharmaceutical composition can be used for treatment of phrenopathy patients, particularly suffering from depression or major depressive disorder.

EFFECT: according to the invention, the composition is characterised with synergetic action and can be applied in relatively small amounts, possesses lower by-effects and satisfactory safety characteristics.

36 cl, 8 dwg, 9 ex, 3 tbl

FIELD: medicine; oncology.

SUBSTANCE: in treatment of breast cancer in mammal introduction of rapamicine esters with aromatase inhibitor in form of combination o in pharmaceutical composition is realised. As rapamicine esters CCI-779 or 42-O-(2-hdroxy)ethylrapamicine is introduced, as aromatase inhibitor - letrozole in subtherapeutic doses.

EFFECT: enhancing anti-tumor effect due to synergetic effect resulting from combination of definite rapamicine ester with particular aromatase inhibitor.

7 cl, 2 ex

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