Azole compounds

FIELD: chemistry.

SUBSTANCE: invention relates to compounds which are pyridin-3-yl 4-(3-phenyl-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[3-(4-fluoromethyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[5-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate, 2,6-dimethylpyridin-3-yl 4-[5-(3,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[3-(2-fluorophenyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[5-(3-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate and 6-methylpyridin-3-yl 4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate or to a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having inhibiting effect on fatty acid amide hydrolase (FAAH).

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for treating neuropathic pain.

13 cl, 38 tbl, 159 ex

The technical field

The invention relates to azole compound, which can be used as active ingredient in pharmaceutical compositions, particularly pharmaceutical compositions for the treatment of neuropathic pain.

Prior art

It is known that hydrolase fatty acid amides (FAAH) hydrolyzes endocannabinoid to its inactivation (non-patent document 1). "Endocannabinoid" is a generic term for biomolecules that act on the cannabinoid receptors for the manifestation of their physiological activity. As typical endocannabinoids known anandamide, palmitoylethanolamide, oleamide and 2-arachidonoylglycerol. In addition, it is known that Delta-9-tetrahydrocannabinol, which is the active ingredient in cannabis (marijuana), inactivates the cannabinoid receptor (non-patent document 2).

In mammals so far, it is known to have two types of cannabinoid receptors - CB1 and CB2. CB1 expressed in Central and peripheral nervous system, and when activated, it shows the psychological action, analgesic action, or the like. CB2 expressed in the immune system and when activated, it shows anti-inflammatory, analgesic (anti-inflammatory) effect or the like./p>

It is known that non-steroidal anti-inflammatory medicines and narcotic analgesic drugs such as morphine and the like, which are conventional analgesics, poorly effective for the treatment of neuropathic pain. In the field of medicine for pain relief used anti-epileptic drugs, such as pregabalin and the like, and antidepressant drugs such as DULOXETINE and the like, are used to treat pain, but their analgesic effects are insufficient, and there are problems with the Central side effects such as drowsiness, dizziness and the like.

Cannabinoid receptor is effective in patients with neuropathic pain, but its use is largely limited due to its psychological effects (non-patent document 3).

On the other hand, when the FAAH inhibitor is injected animal, it exhibits analgesic effect against neuropathic pain and inflammatory pain, but the side effects are celebrating, when the cannabinoid receptor is introduced to an animal, such as sedation, reduced body temperature, catalepsy, and the like, are not observed (non-patent documents 4 and 5), and thus, it is expected that in hibitor FAAH is an excellent pharmaceutical treatment for pain, in particular, a pharmaceutical agent for the treatment of neuropathic pain.

As compounds with inhibitory activity against FAAH known compounds that can act as analgesic drugs, anxiolytic drugs, anti-epileptic drugs, anti-emetics, means for treatment of cardiovascular diseases or medicines for glaucoma.

For example, in patent document 1 describes a compound represented by the following formula (A) as compounds with inhibitory activity against FAAH.

Formula 1

(In the formula represents a variety of ring group which may be substituted, and the like, and A represents phenyl which may be substituted, phenylalkyl, which may be substituted, dibenzofurans, dibenzothiazyl, Naftoli, indolyl, fluorenyl or carbazolyl. Details can be found in this publication).

In addition, in patent document 2 describes a compound represented by the following formula (B) as compounds with inhibitory activity against FAAH.

Formula 2

(In the formula, R represents a variety of ring group which may be substituted, Il the like, and X and Q are the same or different from each other and represent, respectively, O and S. in Addition, R₁and R₂can be combined with the N atom to which they can be connected to form a substituted or unsubstituted ring. Details can be found in this publication).

In addition, in patent document 3 describes a compound represented by the following formula (C) as compounds with inhibitory activity against FAAH.

Formula 3

(Details can be found in this publication).

All compounds disclosed in this document, have structures that are different from the compounds of formula (I) according to the present invention.

In addition, in patent documents 4 and 5 disclose the connection urea represented by the following formula (D), as an inhibitor of FAAH.

Formula 4

(In this formula, Z represents O or S, and R²is piperidine-1,4-diyl or piperazine-1,4-diyl, each of which may be substituted. Details can be found in these publications).

The list of documents

Patent documents

[Patent document 1] International application no WO2003/065989

[Patent document 2] International application no WO2004/033422

[Patent document 3] International application no WO2006/088075

[Patent document 5] International application no WO2007/020888

Non-patent documents

[Non-patent document 1] "Annual review o f biochemistry", (USA), 2005, Vol. 74, p. 411-432

[Non-patent document 2] "Current Medicinal Chemistry", (USA), 1999, Vol. 6, p. 635-664

[Non-patent document 3] "Expert opinion on p harmacotherapy", (UK), 2006, Vol. 7, p. 607-615

[Non-patent document 4] "the British Journal of Ph armacology", (UK), 2007, Vol. 152, p. 624-32

[Non-patent document 5] "Nature Medicine", (UK), 2003, Vol. 9, p. 76-81

A brief description of the invention

The problem to be solved by invention

Is the connection that can be used as an active ingredient of pharmaceutical compositions, particularly pharmaceutical compositions for the treatment of pain, and using the specified connection is missing or reduced fears of side effects and dependence, similar to those observed in the use of hashish.

Means for solving the problem

Applicants have conducted extensive studies of compounds with inhibitory activity against FAAH, and, as a result, found that the compound of formula (I) exhibits excellent inhibitory activity against FAAH, whereby it was established the present invention.

That is, the present invention regarding the seeking to the compound of formula (I) or its pharmaceutically acceptable salts and pharmaceutical compositions containing the compound of formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

Formula 5

where

ring A represents an azole ring,

R is the same or different from each other and represent H or lower alkyl,

X is identical or different from each other and represent H, halogen or halo-lower alkyl,

n and m are the same or different from each other and represent 1 or 2.

In addition, the present invention relates to pharmaceutical compositions for the treatment of neuropathic pain, containing the compound of formula (I) or its pharmaceutically acceptable salt, i.e. for the treatment of neuropathic pain, containing the compound of formula (I) or its pharmaceutically acceptable salt.

In addition, the present invention relates to the use of compounds of formula (I) or its pharmaceutically acceptable salt to obtain a pharmaceutical composition for the treatment of neuropathic pain, and to a method for treating neuropathic pain comprising the administration to a patient an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

The effects of the invention

The compound of formula (I)or its pharmaceutically acceptable salt, has an inhibitory activity with respect to the research Institute of FAAH and can be used as a tool for the prevention and/or treatment of diseases, associated with FAAH, in particular neuropathic pain.

The best option of carrying out the invention

Hereinafter the present invention will be described in detail.

"Lower alkyl" represents a linear or branched alkyl having 1-6 carbon atoms (hereinafter simply denoted as C_1-6), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-hexoloy group or the like. In another embodiment, it represents methyl or ethyl, and in another embodiment is methyl.

"Azole ring, among monocyclic conjugated, unsaturated 5-membered rings, ring means having 2-4 heteroatoms selected from O, S and N, as atoms constituting the ring, in which at least one of the heteroatoms is n, In accordance with the location of the heteroatoms in the ring, its examples include 1,2-azole, 1,3-azole, 1,2,4-azole, 1,2,3,4-azole, and the like; examples of the 1,2-azole include pyrazole, and isoxazol isothiazol; examples of 1,3-azole include imidazole, oxazole and thiazole; examples of 1,2,4-azole include 1,2,4-triazole, 1,2,4-oxadiazole and 1,2,4-oxadiazol; and examples of the 1,2,3,4-azole include tetrazole and the like compounds. When the "azole ring" represents a divalent ring group, it represents a divalent group, obrazovan the Yu removing a hydrogen atom in any position.

"Halogen" means F, Cl, Br or I.

"Halogen-lower alkyl" means a linear or branched alkyl having 1-6 carbon atoms (C_1-6alkyl), substituted by 1-5 halogen atoms.

"Neuropathic pain" means pain caused by dysfunction of the peripheral or Central nervous system, and its examples include diabetic neuropathic pain, post herpetic pain, neuropathy caused by HIV, neuropathy caused by anticancer agents, pain after spinal cord injury or pain that accompanies multiple sclerosis, and the like. The main clinical symptoms of neuropathic pain include constricting pain, burning pain, hyperalgesia, allodynia, and the like.

Below are embodiments of the compounds of formula (I).

(1) a Compound in which ring a represents a 1,2-azole, 1,3-azole 1,2,4-azole or 1,3,4-azole; in another embodiment, ring a represents a 1,2,4-oxadiazole, 1,2,4-triazole, 1,3-oxazol or pyrazole, or in another embodiment, ring And represents one of the rings represented by the following formulas (II)-(VI):

Formula 6

In another embodiment, ring And represents one of the rings represented by the formulas (IV)-(VI). In yet another embodiment, the compound contains a ring A, the cat who PoE is a ring, represented by formula (IV). In yet another embodiment, the compound contains a ring which is a ring represented by the formula (V). In yet another embodiment, the compound contains a ring which is a ring represented by the formula (VI).

(2) the Compound in which R_mrepresents H, 2-methyl, 6-methyl or 2,6-dimethyl, and in another embodiment, R_mrepresents H, 2-methyl or 6-methyl.

(3) a Compound in which X_nrepresents H, 2-fluoro-, 3-fluoro-, 4-fluoro - or 3,4-debtor-.

(4) the Compound, which is a combination of two or more of the groups as described above in paragraphs(1)-(3).

Examples of specific compounds covered by the present invention include compounds described in paragraph (5) or (6) below, or their pharmaceutically acceptable salts:

(5) pyridin-3-yl 4-[3-(4-forfinal)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate,

pyridine-3-yl 4-(3-phenyl-1H-1,2,4-triazole-5-yl)piperidine-1-carboxylate,

6-methylpyridin-3-yl 4-[3-(4-forfinal)-1H-1,2,4-triazole-5-yl]piperidine-1-carboxylate,

6-methylpyridin-3-yl 4-[5-(4-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate,

2-methylpyridin-3-yl 4-[5-(4-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate,

2,6-dimethylpyridin-3-yl 4-[5-(3,4-differenl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate,

2-methylpyridin-3-yl 4-[3-(2-what terphenyl)-1H-1,2,4-triazole-5-yl]piperidine-1-carboxylate,

6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazole-1-yl)piperidine-1-carboxylate,

2-methylpyridin-3-yl 4-[5-(3-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate, and

6-methylpyridin-3-yl 4-[4-(4-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate.

(6) pyridin-3-yl 4-(3-phenyl-1H-1,2,4-triazole-5-yl)piperidine-1-carboxylate,

6-methylpyridin-3-yl 4-[3-(4-forfinal)-1H-1,2,4-triazole-5-yl]piperidine-1-carboxylate,

6-methylpyridin-3-yl 4-[5-(4-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate,

2,6-dimethylpyridin-3-yl 4-[5-(3,4-differenl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate,

2-methylpyridin-3-yl 4-[3-(2-forfinal)-1H-1,2,4-triazole-5-yl]piperidine-1-carboxylate,

6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazole-1-yl)piperidine-1-carboxylate,

2-methylpyridin-3-yl 4-[5-(3-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate and

6-methylpyridin-3-yl 4-[4-(4-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate.

In some cases, depending on the type of substituents, the compound of formula (I) may be tautomers or geometrical isomers. In the present description, the compound of formula (I) will be described in only one form of isomers, however, the present invention includes other isomers, isolated forms of the isomers or a mixture.

In addition, in some cases, the compound of formula (I) may have asymmetric(s) atom(s) of carbon, or an axis of asymmetry and, consequently, about what about can exist in the form of optical isomers. The present invention also includes an isolated form of optical isomers of compounds of formula (I), and their mixture.

In addition, pharmaceutically acceptable prodrugs of compounds represented by formula (I)are also included in the present invention. Pharmaceutically acceptable prodrug refers to a compound having a group which can be converted into the amino group, hydroxyl group, carboxyl group or the like by solvolysis or under physiological conditions. Examples of groups for the formation of prodrugs include groups described in the publication Prog. Med., 5, 2157-2161 (1985) or "Iyakuhin no Kaihatsu (Pharmaceutical Research and DevE1opment)" (Hirokawa Publishing Company, 1990), vol. 7, Bunshi Sekkei (Drug Design), 163-198.

In addition, the compound of formula (I) can form acid additive salt or a salt with a base depending on the type of substitution, and these salts are included in the present invention, as they are pharmaceutically acceptable salts. In particular, examples include acid additive salts with inorganic acids such as hydrochloric acid, Hydrobromic, itestosterone, sulphuric, nitric, phosphoric and other, and with organic acids such as formic, acetic, propionic, oxalic, malonic, succinea, fumaric, aleinova, milk, Apple, almond, wine, cibenzoline the traveler, Detelina, lemon, methansulfonate, econsultation, benzosulfimide, p-toluensulfonate, spartanovka, glutamic and other salts of potassium, magnesium, calcium, aluminum and the like, or layers with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like, salts with various amino acids and derivatives of amino acids, such as acetylation and the like, ammonium salts, and others.

In addition, the present invention also includes various hydrates or solvate and crystalline polymorphs of compounds of formula (I) and their pharmaceutically acceptable salts. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

Ways to get

The compounds of formula (I) and their pharmaceutically acceptable salts can be obtained by applying various known synthesis methods using the characteristics based on their basic skeletons or types of substituents. At the same time, depending on the type of functional groups from the point of view of the methods of obtaining, in some cases, the effective substitution of functional groups suitable protective group (a group which can easily be transformed into the functional group), at the stage of obtaining the source material or sub is face-to-face connection. Examples of the protective group include protective groups described in “Protective Groups in Organic Synthesis (4^thedition, 2007)”written by Greene and Wuts, and the like, which may be appropriately selected and used depending on the reaction conditions. In these methods, the desired compound can be obtained by introducing a protective group to conduct the reaction, and then, if desired, removing the protective group.

In addition, prodrugs of the compounds of formula (I) can be obtained by introducing a specific group at the stage of reception of a starting material or intermediate compounds in the same manner as for the above protective groups, or by carrying out the reaction using the obtained compound of formula (I). The reaction can be carried out by applying a method known to the person skilled in the art, such as conventional etherification, amidation, dehydration, and the like.

Will be described below are representative methods for obtaining the compounds of formula (I). Each of the methods of obtaining can also be performed with reference to the links attached to the explanation. In addition, methods of obtaining of the present invention is not limited to the following examples.

The method of obtaining 1

Scheme 7

(Scheme L represents a leaving group).

Connect the s of the formula (I) can be obtained by converting compound (VII) in the derived complex ester of carboxylic acid (VIII), which then interacts with the amine compound (IX).

In the present description, examples of leaving groups include Cl, imidazolyl, phenoxy and 4 nitrophenoxy group.

The first stage is carried out by interaction of the compound (VII) with an equivalent amount or an excess Carboniferous reagent in the presence of a base under conditions of from cooling to heating, preferably at a temperature from -20°C to 80°C in an inert solvent, usually for about 0.1 hours to days. In the next stage without further processing of the reaction mixture obtained in the first stage, an equivalent amount or excessive amount of amine compound (IX) is added to the reaction mixture, and the mixture is subjected to reaction under conditions of from cooling to heating, preferably at a temperature from -20°C to 80°C in an inert solvent, usually for about 0.1 hours to days. The solvent used in this reaction is not specifically limited, but examples include halogenated hydrocarbons such as dichloromethane (DCM), 1,2-dichloroethane (DCE), chloroform and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as simple diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane (DME) and the like, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl shall zett, acetonitrile or a mixture thereof. Examples Carboniferous reagent include diphosgene, triphosgene, 1,1'-carbonyldiimidazole (CDI), 4-nitrophenyl chloroformate, phenyl chloroformate and the like. When the derived complex ester of carboxylic acid (VIII), which is an intermediate compound, steadily, it may be first selected, and then subjected to the next reaction. Further, for the reaction used in this way to obtain, you can refer to the following publication: “Organic Functional Group Preparations”, written S.R. Sandler and W. Karo, 2^ndEdition< Viol. 2, Academic Press Inc., 1991.

The method of obtaining 2

Scheme 8

(In the scheme of one of the Y¹and Y²is, for example, a group selected from-CO₂H, -CONH₂, -CONH-NH₂, -N₃, -OH and the like, and thus, the other represents a group selected from-C(=N-OH)-NH₂, -C(=O)NH-NH₂, -C(=O)-CH₂-Br, etinilnoy group and the like. The same applies to the description below).

This method of obtaining is a method in which the compound (X) interacts with the compound (XI) to obtain the ring And by receiving the connection formula (I). The compound of formula (I) can be obtained by selection of the appropriate type Y¹and Y²in accordance with the desired ring And using the method for the synthesis of azole to LCA. For example, when obtaining the compounds of formula (I)in which ring a represents a 1,2,4-oxadiazol-3,5-diyl, you can use the compound (X) and the compound (XI)in which Y¹represents-CO₂H and Y²represents-C(=N-OH)-NH₂. Further, when the ring a is a 1,3,4-oxadiazol-2,5-diyl, Y¹and Y²can be used accordingly-CO₂H and-C(=N-OH)-NH₂. Further, when the ring a represents a 1,2,3-triazole-1,4-diyl, Y¹and Y²can be used accordingly-N₃and etinilnoy group. Further, when the ring a represents a 1,3-oxazol-2,4-diyl, Y¹and Y²can be used, respectively,- CONH-NH₂and-C(=O)-CH₂-Br. Further, when the ring a represents tetrazol-2,5-diyl, Y¹and Y²can be used respectively tetrazol-3-yl, and-OH. In addition, a link to the different methods of synthesis of azole rings can be found in the following publications: @Yetrocyclic Compounds, New Edition, Applications, written by Hiroshi Yamanaka, Tohru Hino, Masako Nakagawa Takao Sakamoto, published by Kodansha, Ltd., Scientific, 2004.

The method of obtaining 3

Scheme 9

(Scheme L²represents a divalent linking chain having 1-2 atoms, relevant to the length of the chain, and represents, for example, -HN-NH-, -C ₂-NH - or methylene. The same applies to the description below).

This method of obtaining represents the way in which the ring And synthesized intramolecular end ring by reaction of the compound (XII) and thus obtained the compound of the formula (I). For example, the compound of formula (I)in which ring a is a pyrazole-3,5-diyl can be obtained by the interaction of the compounds (XII), in which L²represents a methylene in the presence of hydrazine monohydrate. Further, the compound of formula (I)in which ring a is a 1,3,4-oxadiazol-2,5-diyl can be obtained by the interaction of the compounds (XII), in which L²is a-HN-NH-, in basic conditions using taillored. Further, the compound of formula (I)in which ring a represents a 1,3-oxazol-2,5-diyl can be obtained by the interaction of the compounds (XII), in which L²represents-CH₂-NH - in the presence of phosphorus oxychloride. In this regard, various methods of synthesis of azole ring, you can refer to the following publication: Heterocyclic Compounds, New Edition, Appplicastions, written by Hiroshi Yamanaka, Torhu Hino, Masako Nakagawa and Takao Sakammoto, published by Kodansha, Ltd., Scientific, 2004.

Methods of synthesis of source material

Method 1 get the source material

(Scheme 10)

(In the scheme of P presented yet protective group of amino group. And it represents, for example, tert-butoxycarbonyl group. The same applies to the description below).

Amine compound (IX) can be obtained by interaction of the compound (XI) with compound (XIII) to form ring A, and removing the protective group of amino group. As Y¹and Y²can be used the same group as in the above-described method of obtaining 2 in accordance with the type of the target ring A.

How 2 get the source material

(Scheme 11)

The compound (X) can be obtained by removing the protective group of the amino group of compound (XIII), which then interacts with the above-described compound (VIII). The reaction may be conducted in the same manner as in the above-described method of obtaining 1.

Method 3 to retrieve the source material

(Scheme 12)

The compound (XII) can be obtained by interaction of the compound (XIV) with compound (XV). As Y³suitable Deputy is chosen according to the L²compound (XII). For example, when L²compound (XII) represents a methylene, methyl may be used as the Y³; when L²is-HN-NH -,- HN-NH₂can be used as the Y³; and when L²represents-CH₂-NH -,- CH₂-NH₂can Exec Lisovets as Y ³.

The compound of formula (I) can be isolated and purified in the form of the free compounds, pharmaceutically acceptable salt, hydrate, MES or crystalline polymorphic compound. Pharmaceutically acceptable salt of the compounds of formula (I) can be obtained by conventional reactions of formation of salt.

Isolation and purification can be carried out by the use of common chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.

Various isomers can be separated by selecting the appropriate starting compound or by using difference in physicochemical properties between the isomers. For example, optical isomers can be converted into each pure stereochemical isomer by a General optical resolution (for example, by fractional crystallization, making the connection in diastereomeric salts with optically active bases or acids, chromatography using a chiral column or similar methods). Further, they can also be obtained from the appropriate optically active starting compound.

The pharmacological activity of the compounds of the present invention was confirmed by the following tests.

Example test 1

Screening for substances which tion, inhibitory activity of FAAH using cells derived from cancer of the bladder person:

(1) Screening for substances that inhibits the activity of FAAH:

Obtained from cancer of the bladder human cells cell line 5637 (HTB-9; ATCC) were sown on 48-hole culture plate in a quantity of 1×10⁵cells/well using environment RPMII640 (Invitrogen)containing 10% fetal calf serum (HyClone). After cultivation at 37°C for 12 hours or longer, the cells were washed with 400 μg/well buffer (balanced salt solution Hank, 20 mm Hepes-NaOH (pH of 7.4). The test substance dissolved in DMSO (dimethyl sulfoxide)was added to the substrate solution (the above buffer containing 3 µci/ml of radioactively labeled anandamide (Anandamide [ethanolamine 1-³H]) and 10 μm anandamide), so that the concentration ranged from 0.003 nm to 30 nm. As a control were added one DMSO. To the above cells were added 100 μl/well of substrate solution and incubated in CO₂incubator at 37°C for 30 minutes. Then, the device for cell culture were transferred to ice; the substrate solution was removed by suction; and to it was added an ice-cold solution for lysis of the cells (the above buffer containing 0.5% Triton X-100 and 100 μm of compounds with inhibiting FAAH activity, complex 3'-carb is movepanel-3-silt ether cyclohexylcarbamate acid (URB597; Cayman chemical; Kathuria et al., Nature Med., Vol. 9, pp. 76-81, 2003)). The resulting cell lysate separately transferred into vials for samples with a capacity of 1.5 ml, to which was added 150 μl of a solution of chloroform/methanol in a ratio of 1:1 (by volume), followed by stirring. After centrifugation (15,000 rpm, 2 minutes) destroyed product ethanolamine (ethanolamine 1-³H) was separated in the upper layer (the layer of water/methanol), and unreacted radioactively labeled anadamide separated in the lower layer (chloroform layer). 25 µl of the upper layer was transferred into a 96-well resistant to organic solvent microplate (PicoPlate-96; Perkin E1mer), were added 150 μl of Microscint-20 (Perkin E1mer) and a measurement was performed with a scintillation microplate counter (TopCount^TM; Beckman). Substance that, compared with control, was given a reduced value measurement, was selected as a substance that inhibits the activity of FAAH.

(2) the Measurement of IC₅₀substance that inhibits the activity of FAAH:

The compound dissolved in DMSO to a concentration of 10 mm, was added to the substrate solution so that the concentration ranged from 0.003 nm to 30 nm. In accordance with the method described above, the compound was analyzed to determine their influence on the activity of FAAH. As a negative control was used DMSO, and as a positive control to restoreultra added URB597 to a concentration of 10 μm. When the measured value of the positive control set at 0%, and the measured value of the negative control set at 100%, obtained values of the IC₅₀the tested substance.

Sample test 2

Screening for substance that inhibits the activity of FAAH using homogenate of tissue of rats that were administered the test substance:

(1) the Introduction of rats and obtaining of tissue homogenate:

The test substance suspended in 0.5% solution of methylcellulose (MC), oral was administered to 6-week old male SD rats (Japan SLC) at a dose of 1 mg/kg as a control, two rats orally was administered 0.5% MC solution. After 60 minutes the rats were killed by decapitation under ether anesthesia, and then they took the right hemisphere.

To the brain tissue of rats was added 2 ml of ice-cold buffer (50 mm Tris-HCl (pH 8.0), 1 mm EDTA (ethylenediaminetetraacetic acid)), and brain tissue is homogenized by the homogenizer on ice to obtain a homogeneous solution. Next, using a generator of ultrasonic waves (UR-20P (power control 4), Tommy Seiko) solution homogenate was subjected to ultrasonic fragmentation within 5 seconds. The protein concentration in the resulting homogenates were measured in accordance with the method of binding dye (CBB solution (Kumasi brilliant blue for protein analysis; Nacalai Te3sque Inc.)). Using buffet is a (50 mm Hepes (pH 7,4), 1 mm EDTA) homogenates of brain tissue of rats was diluted so that the concentration of protein in them was 60 μg/ml, through getting this enzyme solutions.

(2) Measurement of activity of FAAH

To 200 μl of enzyme solution was added 50 μl of substrate solution (2 μm anandamide with fluorescent label (Arachidonyl-AMC (7-amino-4-methyl Coumarin)) (BIOMOL), Hepes (pH of 7.4) 1 mm EDTA and 0.5 mg/ml BSA (bovine serum albumin)), followed by reaction at room temperature for 90 minutes. The measurement was performed with a scintillation microplate counter (TopCount^TM; Beckman).

When installing FAAH activity control rats not treated with the test substance, set on 100% and the activity of FAAH, not containing tissue homogenate buffer (50 MSM Hepes (pH of 7.4), 1 mm EDTA), set to 0%, was determined by the relative value (%)activity of FAAH tissue homogenate of rats that were administered the test substance.

The presence of therapeutic effect in neuropathic pain can be confirmed by methods known to experts in this field, or modified in specified ways. For example, using the model ligation of spinal nerves L5/L6 in rats, which is in accordance with a partial modification of the method of Kim and Chung (Pain, Vol. 50, pp. 355-363, 1992), we can estimate the improving effect connection for a significant reduction in the CAA response to tactile stimulation (allodynia), and on this basis it is possible to confirm the effect of the treatment of neuropathic pain.

Example test 3

Effect against allodynia compounds in rats by ligation of the L5/L6 spinal nerves (model of neuropathic pain)

5-6-week-old male SD rats were subjected to surgery ligation silk threads left their spinal nerves L5 and L6 under pentobarbital anesthesia. For the evaluation of analgesic effect used test with hairs von Frey. That is, the register indexed hind legs of the animal during stimulation of the hairs, where minimal impact hairs, which caused the reaction straightening, considered as a threshold response to mechanical stimulation (log grams). In the preliminary test, it was confirmed that the reaction threshold of the paws of an animal on the operated side was significantly reduced (when allodynia) within from 7 days to 14 days after surgery, the effect against allodynia test compounds were evaluated at any day within from 7 days to 14 days after surgery. On the day before the day when it was supposed to test test the connection, measured the threshold of the reaction before the introduction of the test compounds. The test animals were grouped so that was a slight difference of mean values of threshold reactions between groups and their variations within groups before rst is the group of the tested compounds. When evaluating test compounds was measured threshold reactions after administration of test compounds. 3 mg/kg of the test compounds orally was administered 60 minutes prior to measurement of the reaction threshold. When installing the reaction threshold of the paw with the operated and not operated side in the group with the introduction of the solvent, respectively, at 0% and 100% of the expected activity of the test compound for its effect against allodynia (frequency recovery).

For several representative compounds of the present invention the test results of the sample test 1 (the value of the IC₅₀and the test results of the sample test 3 (frequency recovery) is shown below. In this regard, in the table “-“ indicates that the measurement was not conducted.

Comparative compound a: Compound of example 126 in patent document 3

In the above test, it was shown that the compound of formula (I) has an inhibitory activity against FAAH and is effective in models of neuropathic pain. Therefore, the compound of formula (I) can be used as a tool for the prevention and/or treatment of various diseases associated with FAAH. In addition, it can be used, along with other indications, as a treatment for neuropathic pain.

Pharmaceutical composition containing one or more kinds of the compounds of formula (I) or its pharmaceutically acceptable salt as an active ingredient, can be obtained in accordance with the conventional method using a pharmaceutical carrier, pharmaceuticalstreatment or the like, what is usually used in this field.

The introduction can be carried out by any kind of oral administration via tablets, pills, capsules, granules, powders, liquid preparations and the like, or parenteral administration via injections such as intraarticular, intravenous, intramuscular or other, suppository, eye drops, eye ointments, percutaneous liquid preparations, ointments, transdermal systems, liquid preparations for administration through mucous membranes, linings for insertion through the mucous membranes, inhalation drugs, and the like.

As solid compositions for oral administration are used tablets, powders, pellets or similar forms. In such solid compositions one or two or more active ingredients are mixed with at least one inactive excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate and/or the like. In accordance with the conventional method, the composition may contain inactive additives such as lubricating agents such as magnesium stearate and the like, leavening agents, such as sodium carboximetilkrahmal and the like, stabilizers and solubilizing agents. Tablets or pills may be p is covered sugar coating or, if necessary, the film gastro - or Intercollege substances.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs or the like and contains a conventional inert diluent such as purified water or ethanol. In addition to the inert diluent, the liquid composition may contain adjuvants, such as solubilizing agents, wetting agents and suspendresume agents, sweetening agents, flavors, fragrances and preservatives.

Injectable preparations for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. As the aqueous solvent can be used distilled water for injection or physiological saline. Examples of non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and the like, alcohols such as ethanol and the like, Polysorbate 80 (Pharmacopoeia), etc. This composition can also contain agents toychest, antiseptics, wetting agents, emulsifying agents, dispersing agents, stabilizers and / or solubilizing agents. They are sterilized, for example, by filtration through inhibiting bacteria filter, mixing with bactericidal agents or irradiation. In addition, they can also be used recip is of sterile solid compositions and dissolving or suspendirovanie them in sterile water or a sterile solvent for injection before use.

The agent for external use include ointments, plasters, creams, jellies, cataplasma, aerosols, lotions, eye drops, eye ointments, and the like. These tools contain conventional ointment bases, lasonya bases, aqueous or non-aqueous preparations, suspensions, emulsions and the like. Examples of ointment bases or lasonic bases include polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene, gidrirovannoe castor oil, glyceryl the monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate and the like.

As a means for insertion through mucous membranes, such as inhalation means, means for intranasal and the like, used tools in solid, liquid or semi-liquid state, and they can be obtained in accordance with well-known methods. For example, they may as appropriate be added known excipients, as well as agents that regulate pH, antiseptics, surfactants, lubricating agents, stabilizers, thickeners or similar ingredients. For their introduction can be used appropriate devices for inhalation or insufflation. For example, the compound may be administered separately or in the form of powders made up of a mixture, or in the form of a solution or suspension of Association it is farmatsevticheskii acceptable carriers using well-known devices or aerosol dispensers, such as inhalation device for the introduction of high doses, and the like. The dry powder inhalers, or similar devices may be designed for single or multiple applications, and can be applied dry powder or containing powder capsules. Alternatively, they can be in the form of an aerosol spray in sealed cans, which uses an appropriate propellant, such as chlorphenesin or hydrofluroalkane, or a suitable gas, such as carbon dioxide or the like.

In the case of oral administration is preferable that the daily dose is usually approximately from 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and preferably from 0.1 to 10 mg/kg of body weight, and this dose is injected in one piece or fractional 2-4 portions. Also, in the case of intravenous administration, suitable daily dose is from about 0.0001 to 10 mg/kg of body weight, and the introduction is carried out once a day, or two or more times per day. Additionally, the tool for insertion through the mucous membranes is introduced in a dose of from about 0.001 to 100 mg/kg of body weight once a day, or two or more times per day. The dose is appropriately determined in each specific case, taking into account symptoms, age and gender, and the like factors.

The compound of formula (I) can be applied to the binachi with a variety of therapies or prophylactic methods used to treat diseases in which the compound of formula (I) is effective, as described above. Combination drug may be administered simultaneously or separately and continuously or after the desired time interval. Drugs subject to joint introduction, can be a mixture or obtained separately.

Examples

Following methods to obtain the compounds of formula (I) will be described in more detail with reference to examples. In this regard, the present invention is not limited to the compounds described in the examples below. Also, methods of making the compounds which are the source material, as shown in the examples of the preparation. In addition, methods for obtaining the compounds of formula (I) are not limited to methods of obtaining the specific examples below, and the compound of formula (I) can be obtained in accordance with a combination of such methods of obtaining or ways that are obvious to experts in this field.

Example obtain 1

Under ice cooling to a mixture of tert-butyl 4-(4-phenyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (5,79 g) and DCM (30 ml) was added a 4 M hydrochloride/dioxane (30 ml) followed by stirring for 3 hours. The obtained solid substance was collected by filtration, washed simple diisopropyl ether and then dried under reduced pressure to obtain 4-(4-phenyl-1,3-is eazol-2-yl)piperidine hydroxychloride (4,51 g).

Example of getting 2

To a mixture of tert-butyl 4-(aminocarbonyl)piperidine-1-carboxylate (500 mg) and DMF (5 ml) was added 2-bromo-1-(4-chlorophenyl)alanon (573 mg), followed by stirring at room temperature for 2 hours, and the solvent evaporated under reduced pressure. To the residue were added water and ethyl acetate, and the organic phase was separated. The organic phase is washed with water and saturated brine and then dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue was dried under reduced pressure. To the residue was added DCM (6 ml) and, under ice cooling 4 M hydrochloride/dioxane (6 ml) followed by warming to room temperature and then stirring for 4 hours. The solvent is evaporated under reduced pressure, to the residue was added a simple diisopropyl ether and a small amount of methanol, and the obtained solid substance was collected by filtration. The solid is washed simple diisopropyl ether and then dried under reduced pressure to obtain 4-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]piperidine hydrochloride (437 mg).

Example for the preparation of 3

A mixture of Diisopropylamine (3,23gr) and THF (20 ml) was cooled to 0°C. and to it was slowly added 1,57M n-utility/hexane (20.4 ml) followed by stirring at the same temperature for 1 hour. Then the mixture was cooled to -70°C. and what about the drops was added acetophenone (3,84 g) followed by stirring at the same temperature for 1 hour, the reaction liquid 1). Meanwhile, to a suspension of 1-[(pyridine-3-yloxy)carbonyl]piperidine-4-carboxylic acid (2.0 g) in THF (30 ml) was added CDI (1.56 g), followed by stirring at room temperature for 1 hour, the reaction liquid 2). The reaction liquid 2 was cooled to -70°C. and to it was added dropwise to the reaction liquid 1, followed by stirring at the same temperature for 1 hour. Then, the mixture was warmed to 0°C and then warmed to room temperature. To the reaction liquid were added 0,1M hydrochloric acid (50 ml), then thereto were added water and ethyl acetate, and the organic phase was separated. The organic phase is washed with water and saturated brine and then dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (chloroform/methanol = 100/0 to 90/10) to give the pyridine-3-yl 4-(3-oxo-3-phenylpropanol)piperidine-1-carboxylate (0,93 g).

Example 4

To a mixture of 1-[(pyridine-3-yloxy)carbonyl]piperidine-4-carboxylic acid (1.5 g) and DCM (15 ml) was added 1-hydroxybenzotriazole (HOBt) (0.85 grams), benzhydrazide (0,86 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride (1,21 g), followed by stirring at room temperature for about 14 hours. To the reaction liquid were added chloroform and water, and the organic phase was separated. Organization the practical phase was washed with water and saturated brine and was dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (chloroform/methanol = 100/0 to 90/10). To the purified product was added simple diisopropyl ether and methanol, and the obtained solid substance was collected by filtration and dried under reduced pressure to obtain pyridine-3-yl 4-[(2-benzoylhydrazone)carbonyl]piperidine-1-carboxylic acid (1.22 g).

Example of getting 5

Under ice cooling to a mixture of activeselectionset hydrochloride (4,58 g) and ethanol (50 ml) was added sodium ethoxide (1.68 g), followed by stirring at the same temperature for about 20 minutes. Then at the same temperature it was added tert-butyl 4-(geringerer)piperidine-1-carboxylate (5.0 g) followed by warming to room temperature, followed by stirring for 1 hour and heated at the boiling vessel under reflux for 1 day. After cooling, the solvent is evaporated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (chloroform/methanol = 100/0 to 90/10). To the purified product was added methanol and simple diisopropyl ether and the resulting solid was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-(3-phenyl-1H-1,2,4-triazole-5-yl)piperidine-1-carboxylate (2,53 g).

Example recip is of 6

To a mixture of pyridine-3-yl 4-hydroxypiperidine-1-carboxylate (330 mg), triethylamine (0.25 ml) and DCM (7 ml) slowly dropwise added chloride methanesulfonic acid (0,13 ml) at room temperature. After stirring overnight, the reaction liquid was purified directly by chromatography on a column of silica gel (hexane/ethyl acetate = 50/50 to 0/100) to give the pyridine-3-yl 4-[(methylsulphonyl)oxy]piperidine-1-carboxylate (390 mg) as a colorless solid.

Example of getting 7

To a solution of tert-butyl 4-[amino(hydroxyimino)methyl]piperidine-1-carboxylate (3.0 g) in THF (30 ml) was added 3,5-deparmental chloride (2.4 g) and triethylamine (3,44 ml) under ice cooling, followed by stirring at room temperature for 2 hours. To the reaction liquid were added ethyl acetate and water and the organic phase was separated. The organic phase is washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To the residue was added THF (25 ml) and 1M solution of tetrabutylammonium fluoride/THF (12,4 ml) followed by stirring at 50°C for 30 minutes. The reaction liquid was concentrated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (chloroform). To the purified product was added simple diisopropyl ether and the resulting solid fuel is the substance was collected by filtration and dried to obtain tert-butyl 4-[5-(3,5-differenl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate (4,22 g) as an orange solid.

Example obtain 8

A mixture of tert-butyl 4-(geringerer)piperidine-1-carboxylate (1.0 g), 4-chlorobenzonitrile (1.7 g), potassium carbonate (0.28 g)t and butanol (8.0 ml) was heated at C for 2 h using a microwave device. After cooling, the solvent is evaporated under reduced pressure, and the residue azeotropic distillation with toluene. The residue was purified by chromatography on a column of silica gel (chloroform/methanol = 100/0 to 90/10). To the purified product was added simple diisopropyl ether and the resulting solid was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-[3-(4-chlorophenyl)-1H-1,2,4-triazole-5-yl]piperidine-1-carboxylate (0,62 g).

Example of getting 9

To a solution of 3-phenyl-1H-pyrazole (300 mg) in toluene (15 ml) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (838 mg) and (tributylphosphine)acetonitrile (1.0 g), followed by stirring at 100°C for 4 hours. The reaction liquid was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate = 100/0 to 50/50) and again purified by chromatography on a column of silica gel (hexane/ethyl acetate = 100/0 to 70/30) to obtain tert-butyl 4-(3-phenyl-1H-pyrazole-1-yl)piperidine-1-carboxylate (475 mg) as a colorless oily substance.

Example 10

To dissolve the 3-(dimethylamino)-2-(4-forfinal)acrylaldehyde (3.0 g) in ethanol (30 ml) was added hydrazine monohydrate (0,90 ml) followed by heating and boiling in the vessel under reflux for 3 hours. After cooling, the solvent is evaporated under reduced pressure until such time as the amount of the reaction liquid was reduced to about half. Thereto was added water (20 ml)and the resulting solid was collected by filtration and dried under reduced pressure to obtain 4-(4-forfinal)-1H-pyrazole (2,44 g) as a yellow solid.

Example of getting 11

To a mixture of 6-methylpyridin-3-ol (1.8 g), CDI (2.64 g) and DMSO (18 ml) was added dropwise isonipecotic acid (4,2 g) and a mixture of DMSO (18 ml) and triperoxonane acid (2.5 ml), followed by stirring at room temperature for 1 day. To the reaction liquid was added a saturated brine and chloroform, and the organic phase was separated. The organic phase was washed with saturated brine twice, and then dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. To the residue was added a simple diisopropyl ether/methanol, and the obtained solid substance was collected by filtration and dried to obtain 1-{[(6-methylpyridin-3-yl)oxy]carbonyl}piperidine-4-carboxylic acid (3.51 g) as a colourless solid.

Example 12

To a mixture of 1-[(pyridine-3-yloxy)carbonyl]piperidine-4-carboxylic acid (500 mg) and DCM (10 ml) was added HOBt (297 mg) and WSC hydrochloride (498 mg), followed by stirring at room temperature within 30 minutes. Then thereto was added 2-amino-1-(2-forfinal)Etalon hydrochloride (417 mg) and triethylamine (0.31 in ml) followed by stirring at room temperature over night. The reaction liquid was purified directly by chromatography on a column of silica gel (chloroform/methanol = 99/1 to 95/5) to give the pyridine-3-yl 4-{[2-(2-forfinal)-2-oxoethyl]carbarnoyl}piperidine-1-carboxylate (423 mg) as colorless solids.

Example of getting 13

A mixture of 1-tert-butyl 4-ethylpiperidine-1,4-in primary forms (21 g), hydrazine monohydrate (40 ml) and ethanol (200 ml) was heated by boiling in a vessel under reflux for 22 hours. After cooling, the solvent is evaporated under reduced pressure, to the residue was added a saturated brine and ethyl acetate, and the organic phase was separated. The organic phase was dried over magnesium sulfate, and the solvent evaporated under reduced pressure. To the residue was added a simple diisopropyl ether, followed by stirring for 1 hour, and the obtained solid substance was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-(geringerer)piperidine-1-carboxylate (17.8 g).

Example of getting 14

To a mixture of 6-methylpyridin-3-ol (5,00 g) and acetonitrile (44 ml) was added CDI (7,43 g), followed by stirring at room temperature for 1 hour. Then, thereto was added the piperidine-4-ol (to 4.41 g) and 4 m hydrochloride/dioxane (23 ml), followed by stirring at 50°C during the night. After cooling, to the reaction liquid were added water and chloroform, and the organic phase was separated. The organic phase was washed with saturated brine and was dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (chloroform/methanol= 99/1 to 90/10) to obtain 6-methylpyridin-3-yl 4-hydroxypiperidine-1-carboxylate (8.65 g) as a colourless solid.

Example get 15

To benzyl 4-{[[2-(4-forfinal)-2-oxoethyl]carbarnoyl}piperidine-1-carboxylate (5.5 g) was added phosphorus oxychloride (20 ml) followed by stirring at 80°C for 3 hours. After cooling, the reaction liquid was concentrated under reduced pressure, and the residue azeotropic distillation with toluene three times. To the residue was added ethyl acetate and water and the organic phase was separated. The organic phase is washed with saturated aqueous sodium bicarbonate and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate = 70/30 to 30/70) to give 4-[5(4-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate (1,84) as a colorless oily substance.

Example 16

To a solution of benzyl 4-[5-4-Fortini is)-1,3-oxazol-2-yl]piperidine-1-carboxylate (1.84 g) in ethanol (40 ml) was added 10% palladium/carbon (humidity 54%, 200 mg) followed by stirring for 6 hours in an atmosphere of hydrogen. The catalyst was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. To the residue was added ethanol and 4 M hydrochloride/dioxane (1,45 ml) and concentrated under reduced pressure. To the residue was added ethanol and ethyl acetate, followed by stirring, and the obtained solid substance was collected by filtration and dried to obtain 4-[5-4-forfinal)-1,3-oxazol-2-yl]piperidine hydrochloride (1,32 g) as a colourless solid.

Example of getting 17

A suspension of tert-butyl 4-aminopiperidine-1-carboxylate (3.88 g), octoxynol acid (1.48 g) and potassium carbonate (4,46 g) in DMF (60 ml) was stirred at room temperature for 3 hours. Then thereto was added 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzo (3.5 g), followed by stirring at room temperature for 14 hours. The solvent is evaporated under reduced pressure, to the residue was added ethyl acetate and water and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with water and saturated brine and was dried over magnesium sulfate, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (chloroform/methanol = 100/0 to 90/10) to obtain tert-butyl 4-(4-phenyl-1H-they shall Gasol-1-yl)piperidine-1-carboxylate (3.1 g).

Example of getting 18

To a mixture of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g), benzylideneaniline (16.7 g), DCM (150 ml) and acetic acid (5,75 ml) was added triacetoxyborohydride sodium (31,9 g), followed by stirring at room temperature for 2.5 days. To the reaction liquid was added water, and the organic phase was separated. The aqueous phase was extracted with chloroform, and the combined organic phase was washed with water, saturated aqueous sodium bicarbonate and saturated brine in that order and dried over magnesium sulfate, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (chloroform/methanol = 100/0 to 90/10) to obtain tert-butyl 4-{2-[(benzyloxy)carbonyl]hydrazine}piperidine-1-carboxylate (10.0 g).

Example of getting 19

To a mixture of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g) and ethanol (100 ml) was added 5% palladium/carbon (2.0 g), followed by stirring in a hydrogen atmosphere for about 2 hours. The catalyst was removed by filtration, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (chloroform/methanol = 100/0 to 90/10) to obtain tert-butyl-4-hydrazinopyridazine-1-carboxylate (4.1 g).

Example of getting 20

To a mixture of 2-methylpyridin-3-yl 4-{[2-(tert-butoxycarbonyl)g is Drazin]carboxyl}piperidine-1-carboxylate (11,98 g) and DCM (100 ml) was added a 4 M hydrochloride/dioxane (100 ml) followed by stirring at room temperature for about 15 hours. The solvent is evaporated under reduced pressure, and the residue was dissolved in methanol/water (10/1). Thereto was added potassium carbonate (8,75 g), followed by stirring for about 3 hours. The solvent is evaporated under reduced pressure and to the residue was added chloroform, followed by drying over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue was dried under reduced pressure to obtain 2-methylpyridin-3-yl 4-(geringerer)piperidine-1-carboxylate (7,49 g).

Example of getting 21

To a mixture of 2,3-difterential (5,00 g) and ethanol (55 ml) was added dropwise acetyl chloride (35 ml) under ice cooling, followed by stirring at room temperature for 7 days. The reaction liquid was concentrated under reduced pressure and to the residue was added a simple diisopropyl ether, followed by stirring for 1 hour. The obtained solid substance was collected by filtration and dried to obtain ethyl 2,3-differentcharacteristics hydrochloride (4.68 g) in the form of a white solid.

Example of getting 22

To a mixture of tert-butyl 4-[(2-benzoylhydrazone)carbonyl]piperidine-1-carboxylate (3.00 g) and THF (60 ml) was added triethylamine (7.2 ml) and toluensulfonyl chloride (4.94 g), followed by stirring at 50°C during the night. The reaction liquid was concentrated under reduced giving the situation, and the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate = 95/5 to 80/20) to obtain tert-butyl 4-(5-phenyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (2,84 g) as a colorless oily substance.

An example of retrieving 23

To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g) and toluene (50 ml) was added CDI (3,9 g), followed by stirring at room temperature for 3 hours. Then thereto was added N'-hydroxybenzomorpholine (3.3 grams), followed by stirring for 1.5 hours and then heating and boiling in the vessel under reflux for 2 hours. After cooling, to the reaction liquid were added ethyl acetate and water and the organic phase was separated. The organic phase is washed with water and saturated brine and was dried over magnesium sulfate, and the solvent evaporated under reduced pressure. To the residue was added hexane and ethyl acetate, and the obtained solid substance was collected by filtration to obtain tert-butyl 4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (5,46 g).

Example of getting 24

A mixture of tert-butyl 4-(3-oxo-phenylpropanol)piperidine-1-carboxylate (3.1 g), hydrazine monohydrate (0.5 ml), ethanol (30 ml) and THF (30 ml) was stirred at room temperature for about 15 hours and at 60°C for 1 hour. Thereto was further added hydrazine monohydrate (5 ml), followed by stirring again at 60°C for 3 hours. It again was added hydrazine monohydrate (4.0 ml) followed by stirring at 60°C for 8 hours. After cooling, the solvent is evaporated under reduced pressure and to the residue was added a simple diisopropyl ether and methanol, followed by stirring. The obtained solid substance was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-(3-phenyl-1H-pyrazole-5-yl)piperidine-1-carboxylate (2,46 g).

Example get 25

To a solution of tert-butyl 4-hydrazinopyridazine-1-carboxylate (646 mg) and ethanol (15 ml) was added phenylmalonamide (444 mg), followed by stirring at 75°C for about 1.5 days. The reaction liquid was concentrated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (hexane/chloroform = 50/50 to 0/100) to obtain tert-butyl 4-(4-phenyl-1H-pyrazole-1-yl)piperidine-1-carboxylate (226 mg).

Example of getting 26

A mixture of tert-butyl 4-[(2-oxo-2-phenylethyl)carbarnoyl]piperidine-1-carboxylate (5.0 g) and trifenatate ammonium (18,9 g) was stirred at an ambient temperature of 170°C for 30 minutes. After cooling, thereto was added water and chloroform, and the aqueous phase was separated. the pH of the aqueous phase was brought to approximately 10 24% aqueous sodium hydroxide solution and was extracted with chloroform. The combined organic phase was washed with water and saturated Russolo and dried over magnesium sulfate, and the solvent evaporated under reduced pressure. The residue was dried under reduced pressure and was dissolved in DCM (20 ml) and methanol (10 ml), and thereto was added a 4 M hydrochloride/dioxane (5.3 ml). The solvent was concentrated under reduced pressure, to the residue was added a simple diisopropyl ether/methanol, and the obtained solid substance was collected by filtration and dried under reduced pressure to obtain 4-(4-phenyl-1H-imidazol-2-yl)piperidine dihydrochloride (3,29 g).

Example of getting 27

To a solution of 2,5-diferential acid (1,95 g) in THF (40 ml) was added oxalicacid (1.5 ml) and catalytic amount of DMF, followed by stirring at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure and to the residue was added THF (40 ml). Under ice cooling, it was added tert-butyl 4-[amino(hydroxyimino)methyl]piperidine-1-carboxylate ((2.5 g) and triethylamine (3.0 ml), followed by stirring at room temperature for 2 hours. To the reaction liquid were added ethyl acetate and water and the organic phase was separated. The organic phase is washed with water and saturated brine and was dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. To a solution of the residue in THF (20 ml) was added 1M solution of tetrabutylammonium fluoride/THF (10.3 ml), followed by stirring pri°C for 30 minutes. The reaction liquid was concentrated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (chloroform). To the purified product was added a 4 M hydrochloride/dioxan (40 ml) followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, then the residue was added THF, and the obtained solid substance was collected by filtration. The solid is washed with THF and ethyl acetate in this order and dried under reduced pressure to obtain 4-[5-(2,5-differenl)-1,2,4-oxadiazol-3-yl]piperidine hydrochloride (2.58 g).

Example of getting 28

To a suspension of 3-(4-forfinal)-1H-1,2,4-triazole (700 mg) in toluene (15 ml) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (1.3 g) and (tributylphosphine)acetonitrile (2.0 g), followed by stirring at 110°C for 15 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (chloroform/methanol = 100/0 to 97/3). To the purified product was added a 4 M hydrochloride/dioxane (15 ml), followed by stirring at room temperature for 16 hours. To the reaction liquid was added ethyl acetate, and the obtained solid substance was collected by filtration and dried under reduced pressure to obtain 4-[3-(4-forfinal)-1H-1,2,4-triazole-1-yl]the of piperidine of hydrochloride (422 mg).

An example of obtaining 29

To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g) and DCM (50 ml) was added HOBt (3,09 g), 4-vorbisgain (3,53 g) and WSC hydrochloride (5,02 g), followed by stirring at room temperature over night. To the reaction liquid was added ethyl acetate, followed by washing with water/saturated brine (1:1), saturated aqueous sodium bicarbonate and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. To the residue was added THF (160 ml), chloride p-toluensulfonyl (8,32 g) and triethylamine (12 ml), followed by stirring at 60°C over night. The reaction liquid was concentrated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate = 90/10 to 50/50) to obtain tert-butyl 4-[5-(4-forfinal)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (of 5.83 g) as a pale brown solid.

In much the same way as for the compounds of the above examples get from 1 to 29 were obtained compounds of examples as shown in the table, to be described below, using each of the corresponding starting materials. Structure, methods of preparation and physicochemical data of the compounds of examples of the preparation is shown in a small town in Alannah following tables 2-11.

Example 1

The same procedure as in the example described above, the receiving 14, pyridin-3-yl 4-(4-phenyl-1,3-thiazol-2-yl)piperidine-1-carboxylate hydrochloride was obtained from 4-(4-phenyl-1,3-thiazol-2-yl)piperidine hydrochloride.

Example 2

The same procedure as in the example described above, the receiving 24, pyridine-3-yl 4-(3-phenyl-1H-pyrazole-5-yl)piperidine-1-carboxylate was obtained from pyridine-3-yl 4-(3-oxo-3-phenylpropanol)piperidine-1-carboxylate.

Example 3

The same procedure as in the example described above, the receiving 22, pyridine-3-yl 4-[3-(4-forfinal)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate was obtained from 1-[(pyridine-3-yloxy)carbonyl]piperidine-4-carboxylic acid.

Example 4

To a mixture of 1-[(pyridine-3-yloxy)carbonitriding-4-carboxylic acid (300 mg), 4-ftorangidridy (222 mg), HOBt (170 mg) and DCM (6 ml) was added WSC hydrochloride (299 mg), followed by stirring at room temperature over night. The reaction liquid was purified directly by chromatography on a column of silica gel (chloroform/methanol = 99/1 to 90/10). The residue was dissolved in THF (6 ml) and to it was added toluensulfonyl chloride (686 mg) and triethylamine (1.0 ml) followed by stirring at 50°C for 8 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate = 70/30 to 0/100). It cleaned up the th product was added isopropanol/water, and the obtained solid substance was collected by filtration and dried to obtain pyridine-3-yl 4-[5-(4-forfinal)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (224 mg) as a colorless solid.

Example 5

The same procedure as in the example described above, the receiving 22, pyridine-3-yl 4-(5-phenyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate was obtained from pyridine-3-yl 4-[(2-benzoylhydrazone)carbonyl]piperidine-1-carboxylate.

Example 6

To a mixture of pyridine-3-yl 4-[(methylsulphonyl)oxy]piperidine-1-carboxylate (221 mg) and DMSO (4 ml) was added sodium azide (96 mg), followed by stirring at 60°C for 8 hours. The reaction liquid was diluted with ethyl acetate and washed with water and saturated brine in that order. The organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate = 70/30 to 0/100). To the purified product (149 mg) and the solution ethynylbenzene (of 0.066 ml) in tert-butanol (10 ml) was added water (2 ml), sodium ascorbate (12 mg) and copper sulfate (II) (1.5 mg), followed by stirring overnight. The reaction liquid was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue behaviour is whether chromatography on a column of silica gel (chloroform/methanol = 99/1 to 90/10). To the purified product was added simple diisopropyl ether/ethyl acetate, followed by stirring, and the obtained solid substance was collected by filtration and dried to obtain pyridine-3-yl 4-(4-phenyl)-1H-1,2,3-triazole-1-yl)piperidine-1-carboxylate (165 mg) as a colorless solid.

Example 7

A mixture of 6-methylpyridin-3-yl 4-carbamoylbiphenyl-1-carboxylate (500 mg), 2-bromo-1-phenylethanone (453 mg) and N,N-dimethylacetamide (5 ml) was stirred at 130°C for 3 days. After cooling, thereto was added ethyl acetate and water/saturated aqueous sodium bicarbonate solution (1:1), followed by stirring for 1 hour, and the reaction liquid was filtered. The organic phase of the filtrate was separated, washed with water/saturated brine (1:1) and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (chloroform/methanol = 99/1 to 95/5). The purified product was dissolved in ethanol, and thereto was added an excess amount of 4 M hydrochloride/dioxane. The reaction liquid was concentrated under reduced pressure and dried to obtain 6-methylpyridin-3-yl 4-(4-phenyl-1,3-oxazol-2-yl)piperidine-1-carboxylate hydrochloride (134 mg) as a pale brown amorphous substance.

Example 8

The same procedure as in the example described above, the receiving 15, pyridine-3-yl 4-[5-(2-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate the dihydrochloride was obtained from pyridine-3-yl 4-{[(2-(2-forfinal)-2-oxoethyl]carbarnoyl}piperidine-1-carboxylate.

Example 9

To a mixture of pyridine-3-yl 4-hydroxypiperidine-1-carboxylate (300 mg), 5-phenyl-1H-tetrazole (217 mg), triphenylphosphine (460 mg) and THF (3 ml) was added dropwise 2.2 M solution of diethylazodicarboxylate in toluene (0.8 ml), followed by stirring at room temperature over night. The reaction liquid was concentrated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (chloroform/methanol = 99/1 to 90/10) and again purified by chromatography on a column of silica gel (hexane/ethyl acetate = 70/30 to 0/100). To the purified product was added hexane/ethyl acetate, followed by stirring, and then the obtained solid substance was collected by filtration and dried to obtain pyridine-3-yl 4-(5-phenyl-2H-tetrazol-2-yl)piperidine-1-carboxylate (250 mg) as a colorless solid.

Example 10

To a solution of ethyl 2-chlorobenzalmalononitrile hydrochloride (435 mg) in ethanol (10 ml) was added sodium methoxide (107 g), followed by stirring at room temperature for 30 minutes. Then thereto was added 2-methylpyridin-3-yl 4-(geringerer)piperidine-1-carboxylate (500 mg), followed by stirring at 90°C for 2 days. Reacts the traditional liquid was concentrated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (chloroform/methanol = 99/1 to 90/10). The purified product was dissolved in ethanol, and thereto was added an excess amount of 4 M hydrochloride/dioxane, followed by stirring. The reaction liquid was concentrated under reduced pressure and dried to obtain 2-methylpyridin-3-yl 4-[3-(2-chlorophenyl)-1H-1,2,4-triazole-5-yl]piperidine-1-carboxylate dihydrochloride (289 mg) as a pale yellow solid.

In much the same way as for the compounds of the above examples 1-10, the compounds of the examples shown in the table below, were obtained using each of the corresponding starting materials. The structure of the compounds of examples 1-159 shown in table 12-31, and methods for their preparation and physico-chemical data are shown in tables 32-38.

In addition, the following abbreviations are used in the following tables. Pre: Number of sample receipt; Ex: Number of experiments; Str: Structural formula; Syn: Method get (Among the above examples of the/Examples of the preparation, the Number of sample receipt and the number of the example described is the same method that was used to obtain the connection. In the description of P is an Example of retrieving and E is an Example. For example, submitted that the compound of Example 30 was obtained in the same way, ka is the connection Example of getting 1, and the compound of example 11 was obtained in the same manner as the compound of example 1); Dat: physicochemical data (NMR: δ (ppm) in 1H NMR in DMSO-d₆, FAB (fast atom bombardment): FAB-MS (mass spectrometry with fast atom bombardment) (cation), FAB (without fast atom bombardment): FAB-MS (anion), ESI+ (electrospindles ionization): ESI-MS (mass spectrometry with electrospindles ionization) (cation), ESI- (without electrospindles ionization): ESI-MS (anion), EI (electron ionization):EI-MS (electron ionization-mass spectrometry) (cation); CI (chemical ionization): CI-MS (chemical ionization-mass spectrometry) (cation); APCI+ (with chemical ionization at atmospheric pressure): APCI-MS (chemical ionization at atmospheric pressure mass spectrometry) (cation)); Me: methyl; Et: ethyl; Bn: benzyl; Boc: tert-butoxycarbonyl; Ms: methanesulfonyl; TsOH: p-toluensulfonate acid; Z: benzyloxycarbonyl.

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

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Table 29

Table 30

Table 31

Industrial applicability

The compound of formula (I) or its pharmaceutically acceptable salt has inhibitory activity against FAAH and can be used as a tool for the prevention and/or treatment of diseases associated with FAAH. In particular neuropathic pain.

1. Compound which is selected from the group consisting of:
pyridine-3-yl 4-(3-phenyl-1H-1,2,4-triazole-5-yl)piperidine-1-carboxylate,
6-methylpyridin-3-yl 4-[3-(4-forfinal)-1H-1,2,4-triazole-5-yl]piperidine-1-carboxylate,
6-methylpyridin-3-yl 4-[5-(4-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate,
2,6-dimethylpyridin-3-yl 4-[5-(3,4-differenl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate,
2-methylpyridin-3-yl 4-[3-(2-forfinal)-1H-1,2,4-triazole-5-yl]piperidine-1-to the of roxelana,
6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazole-1-yl)piperidine-1-carboxylate,
2-methylpyridin-3-yl 4-[5-(3-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate and
6-methylpyridin-3-yl 4-[4-(4-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate
or their pharmaceutically acceptable salts.

2. Pharmaceutical composition having inhibitory activity against hydrolases fatty acid amides (FAAH), which contains the compound according to claim 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

3. The use of compounds according to claim 1 or its pharmaceutically acceptable salt to obtain a pharmaceutical composition for the treatment of neuropathic pain.

4. The use of compounds according to claim 1 or its pharmaceutically acceptable salts for the treatment of neuropathic pain.

5. A method of treating neuropathic pain comprising the administration to a patient an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt.

6. The compound or its pharmaceutically acceptable salt according to claim 1, which represents a pyridin-3-yl 4-(3-phenyl-1H-1,2,4-triazole-5-yl)piperidine-1-carboxylate or its pharmaceutically acceptable salt.

7. The compound or its pharmaceutically acceptable salt according to claim 1, which represents a 6-methylpyridin-3-yl 4-[3-(4-forfinal)-1H-1,2,4-triazole-5-yl]piperidine-1-carboxylate or its pharmaceutically acceptable salt.

9. The compound or its pharmaceutically acceptable salt according to claim 1, which represents a 2,6-dimethylpyridin-3-yl 4-[5-(3,4-differenl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate or its pharmaceutically acceptable salt.

10. The compound or its pharmaceutically acceptable salt according to claim 1, which represents a 2-methylpyridin-3-yl 4-[3-(2-forfinal)-1H-1,2,4-triazole-5-yl]piperidine-1-carboxylate or its pharmaceutically acceptable salt.

11. The compound or its pharmaceutically acceptable salt according to claim 1, which represents a 6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazole-1-yl)piperidine-1-carboxylate or its pharmaceutically acceptable salt.

12. The compound or its pharmaceutically acceptable salt according to claim 1, which represents a 2-methylpyridin-3-yl 4-[5-(3-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate or its pharmaceutically acceptable salt.

13. The compound or its pharmaceutically acceptable salt according to claim 1, which represents a 6-methylpyridin-3-yl 4-[4-(4-forfinal)-1,3-oxazol-2-yl]piperidine-1-carboxylate or its pharmaceutically acceptable salt.