Piperazine compound inhibiting prostaglandin-d-synthase

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a piperazine compound presented by formula , wherein R¹ represents C_1-6 alkyl; R² represents hydroxy, C_1-6 alkyl which can contain a substitute specified in saturated or unsaturated 5-6 member heterocycle with 1-3 heteroatoms specified in oxygen and nitrogen, -(C=O)-N(R³)(R⁴) or -(C=O)-OR⁵; R³ and R⁴ may be identical or different, and each represents hydrogen or C_1-6 alkyl which can contain a substitute specified in saturated or unsaturated 5-6 member heterocycle with 1-3 heteroatoms specified in oxygen and nitrogen, or R³ and R⁴ bound through a nitrogen atom whereto R³ and R⁴ are attached, can form a saturated heterocyclic group specified in 5-6 member heterocycle with 1-3 heteroatoms specified in oxygen and nitrogen; R⁵ represents hydrogen or C_1-6 alkyl; and n represents 1 or 2; or a salt thereof. Also, the invention refers to a pharmaceutical compositions and an agent exhibiting prostaglandin-D-synthase activity and based on the compound of formula I, as well as to a method of preventing and treating a disease wherein prostaglandin D2 is involved.

EFFECT: there are prepared and described new compounds which may be effective in treating the diseases wherein prostaglandin D2 is involved.

11 cl, 19 ex, 4 tbl

The technical field

The present invention relates to pieperazinove the compound or its salts and pharmaceutical compositions containing pieperazinove compound or its salt as an active ingredient, and, in particular, to means for the prevention and/or treatment of allergic diseases, inflammatory diseases and myodegeneration disease, due to its inhibitory action on the hematopoietic prostaglandin-D-synthase.

The level of technology

Prostaglandin D2 (PGD2) is an inflammatory mediator produced in large quantities released fat cells, which are activated by the binding of antigens with immunoglobulin E (NPL 1), and, as expected, plays an important role in the explanation of the mechanism of allergic reactions. High concentrations of PGD2 detected in bronchoalveolar lavage fluid of asthmatics (NPL 2), and reported that the bronchospasm was induced by inhalation of prostaglandin D2 in patients with asthma, in contrast to healthy subjects (NPL 3).

On the other hand, the synthases that produce PGD2, called prostaglandin-D-synthase. There are two different types: hematopoietic prostaglandin-D-synthase and prostaglandin-D-synthase lipoxinol type. PGD2 is involved in the beginning and exacerbation of various diseases, including allergies, and R is untranslated mechanisms of the body; therefore, pharmaceutical compositions that can improve the quality of excess production, are considered as very effective in the treatment of various diseases.

Human hematopoietic prostaglandin D synthase (H-PGDS) was mainly distributed in the placenta, lung, fetal liver, lymph nodes, brain, heart, thymus, bone marrow and spleen. In addition, at the cellular level, they reportedly expressed in microglia in the brain, megakaryocytes and Langerhans cells in the skin; Kupffer cells in the liver; macrophages; and many other antigen-presenting cells such as dendritic cells, mast cells and Th2 cells.

In addition, due to the fact that H-PGDS in large quantities expressed in the fat cells or inflammatory cells in the nasal mucosa in allergic rhinitis or nasal polyps chronic sinusitis, it is believed that PGD2 produced H-PGDS, plays an important role in the beginning and exacerbation of allergic diseases such as asthma, rhinosinusitis, dermatitis and chronic obstructive pulmonary disease (NPL 4). Was additionally confirmed by the expression of H-PGDS in the necrotic part of the skeletal muscles, in which the expression of H-PGDS are not usually found (NPL 5). Based on the above, it was hypothesized that PGD2 produced hematopoietic prostaglandin-D-synthase, animal involved in diseases, accompanied by tissue damage, such as muscular dystrophy, amyotrophic lateral sclerosis, multiple sclerosis, ulcerative colitis, rheumatoid arthritis and chronic obstructive arterial disease (NPL 6).

It is therefore expected that the inhibitor H-PGDS can be used as a pharmaceutical preparation, which is used as a means of preventing and/or treating diseases such as allergic disease, inflammatory disease, involving PGD2 produced hematopoietic prostaglandin-D-synthase, or its metabolite, as well as necrosis of muscles and traumatic brain damage.

In some sources relating inhibitor H-PGDS (for example, PTL 1 and 2) and the source of the Patent Literature 3, revealed the inhibitor H-PGDS, has a structure similar to the compound of the present invention. It is also widely studied pharmacological properties piperazinone compounds, addition of inhibitors of H-PGDS.

Source Patent Literature 4 discloses as a hedgehog signaling inhibitor pieperazinove connection with fuelleborni pieperazinove structure. Source Patent Literature 5 discloses a wide range piperazinone compounds as compounds that interact with potassium channels.

Source Patent The Literature 6 discloses the connection of urea with piperazinone ring as a connection useful for treatment of diseases involving hydrolase fatty acid amides.

A list of the sources cited

Patent Literature

PTL 1: WO2007-007778

PTL 2: WO2007-041634

PTL 3: WO2008-122787

PTL 4: WO2007-054623

PTL 5: WO99/007672

PTL 6: WO2008-023720

Non-patent Literature

NPL 1: J. Immunol., 129, 1627-1631 (1982)

NPL 2: N. Eng. J. Med., 315, 800-804 (1986)

NPL 3: N. Eng. J. Med., 311, 209-213 (1984)

NPL 4: Arch. Otolaryngol Head Neck Surg., 133, 693-700 (2007)

NPL 5: Acta Neuropathol., 104, 377-384 (2002)

NPL 6: Am J Pathol., 174(5), 1735-1744 (2009)

Brief description of the invention

Technical task

The main objective of the present invention is to provide a new compound which shows, in low dose, high inhibitory activity against prostaglandin-D-synthase, and, in particular, H-PGDS.

Another additional objective of the present invention is to provide a drug with few side effects and high safety, where the efficacy of the medicinal product is due to its inhibiting H-PGDS activity, in the prevention and/or treatment of diseases mediated by PGD2, which is generated by the synthase or its metabolite.

The solution of the problem

The authors of the present invention have conducted an extensive study of compounds exhibiting inhibition of H-PGDS action, and found that the new piperaz the new connection, represented by formula (I), has a very high inhibitory activity against H-PGDS. The authors conducted further research and made the present invention.

The present invention provides pieperazinove compound, pharmaceutical composition, the inhibitor of prostaglandin-D-synthase and means for the prevention and/or treatment of diseases involving prostaglandin D2 or its metabolite, as described below.

1. Pieperazinove compound represented by formula (I),

where

R¹represents a C_1-6alkyl;

R²represents hydroxy, C_1-6alkyl, which may contain one or more substituents, -(C=O)-N(R³)(R⁴or -(C=O)-OR⁵;

R³and R⁴can be the same or different and each represents hydrogen or C_1-6alkyl, which may contain one or more substituents, or

R³and R⁴connected through the nitrogen atom is attached to R³and R⁴, can form a saturated heterocyclic group;

R⁵represents hydrogen or C_1-6alkyl, which may contain one or more substituents; and

n represents 1 or 2;

or its salt.

2. Pieperazinove compound or its salt according to paragraph 1, where/p>

R¹represents methyl or ethyl;

R²represents hydroxy, C_1-6alkyl which may have one or more saturated or unsaturated heterocyclic groups as substituents, -(C=O)-N(R³)(R⁴or -(C=O)-OR⁵;

R³and R⁴can be the same or different and each represents hydrogen or C_1-6alkyl which may have one or more saturated or unsaturated heterocyclic groups as substituents, or

R³and R⁴connected through the nitrogen atom is attached to R³and R⁴can generate pyrrolidinyl, piperidinyl, piperazinil, morpholino;

R⁵represents hydrogen, methyl, ethyl, tert-butyl or benzyl; and

n represents 1 or 2.

3. Pieperazinove compound or its salt according to item 1 or 2, where

R¹represents methyl;

R²represents a C_1-3alkyl, which may contain morpholino, pyrazolyl or triazolyl as substituents, -(C=O)-N(R³)(R⁴or -(C=O)-OR⁵; and triazolyl may contain one or two substituent;

R³and R⁴connected through the nitrogen atom is attached to R³and R⁴, can form morpholino;

R⁵represents hydrogen, methyl or ethyl; and

it presents the 2.

4. Pieperazinove compound or its salt according to any one of items 1-3, where

R¹represents methyl;

R²is a linear C_1-3alkyl, which may contain any of 1,2,3-triazole, 3,5-dimethyl-1,2,4-triazolyl, morpholino as a substituent, -(C=O)-N(R³)(R⁴or -(C=O)-OR⁵;

R³and R⁴connected through the nitrogen atom is attached to R³and R⁴, can form morpholino;

R⁵represents hydrogen or ethyl; and

n represents 2.

5. Pieperazinove compound or its salt according to item 1, selected from the group consisting of the following:

N-(4-(4-hydroxypiperidine-1-yl)phenyl)-4-((1-methylpyrrole-2-yl)carbonyl)-1-piperazinecarboxamide,

4-((((1-methylpyrrole-2-yl)carbonyl)-1-piperazinil)carbonyl)amino-4-phenylpiperidine-4-carboxylic acid,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholinomethyl-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(3-(2-(1,2,4-triazole-1-yl)ethyl)pyrrolidin-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholinobutyrophenone-1-yl)phenyl)-1-piperazinecarboxamide,

4-(1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(1,2,3-triazole-1-yl)ethyl)piperidine-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(1,2,4-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(3,5-dimethyl-1,2,4-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(pyrazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(3-(1,2,4-triazole-1-yl)propyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(3-(1,2,3-triazole-1-yl)propyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-acylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-piperidine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(4-methylpiperazin-1-yl-carbonyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-morpholinoethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide and

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(pyridine-3-letiltasaval)piperidine-1-yl)phenyl)-1-piperazinecarboxamide.

6. Pharmaceutical composition comprising an effective amount of at least one of the compounds according to paragraphs 1-5 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

7. Inhibitor prostage the DIN-D-synthase, comprising an effective amount of a compound according to any one of items 1 to 5, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

8. The means for the prevention and/or treatment of diseases involving prostaglandin D2 or its metabolite, where the tool includes an effective amount of a compound according to any one of items 1 to 5, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

9. The tool in accordance with paragraph 8, wherein the disease involving prostaglandin D2 or its metabolite, an allergic disease, inflammatory disease or myodegeneration disease.

10. The method of preventing and/or treating diseases involving prostaglandin D2 or its metabolite, where the method comprises the administration to the mammal of a compound according to any one of items 1 to 5 in a quantity effective to prevent or treat disease.

11. The use of compounds according to any one of items 1 to 5 to obtain funds for the prevention and/or treatment of a disease in which prostaglandin D2 or its metabolite.

12. The compound according to any one of items 1 to 5 for use in the method of preventing and/or treating a disease in which prostaglandin D2 or its metabolite.

Useful effects of the invention

The present invented the e provides new pieperazinove connection, represented by the above formula (I)or its salt, which is an inhibitor of prostaglandin-D-synthase and, in particular, inhibitors of H-PGDS.

Pieperazinove compound or its salt according to the present invention exhibits excellent activity against inhibition of H-PGDS in vitro. In addition, because Guinea pigs with antigen-induced rhinitis was observed inhibitory H-PGDS activity on the wash fluid from the nasal cavity and inhibitory eosinophilic infiltration activity, it was shown that pieperazinove compound or its salt have excellent activity against improving conditions nasal congestion and inhibiting eosinophilic inflammation activity. In addition, studies on the effect of capturing the forelegs of mdx mice was shown to be a significant improvement on the loss of muscular strength, which demonstrates that pieperazinove compound or its salt of the present invention can be used to treat myodegeneration diseases, such as muscular dystrophy.

Thus, since pieperazinove compound or its salt according to the present invention exhibits excellent inhibitory H-PGDS activity, it can be used as a means for preventing and/or treating diseases involving PGD2 or its metabolite, is such as allergic disease, inflammatory disease and myodegeneration disease, and assumed other applications.

Description of embodiments

Pieperazinove compound represented by formula (I),

,

where

R¹represents a C_1-6alkyl;

R²represents hydroxy, C_1-6alkyl, which may contain one or more substituents, -(C=O)-N(R³)(R⁴or -(C=O)-OR⁵;

R³and R⁴can be the same or different and each represents hydrogen or C_1-6alkyl, which may contain one or more substituents, or

R³and R⁴connected through the nitrogen atom is attached to R³and R⁴, can form a saturated heterocyclic group;

R⁵represents hydrogen or C_1-6alkyl, which may contain one or more substituents; and

n represents 1 or 2;

or its salt.

Pieperazinove compound of the present invention, which is represented by formula (I)is a compound with (N-acylpyrrole-2-yl)carbonyl and phenylenecarbonyl, which is a new connection and not specifically disclosed in the above references.

For example, in the source Patent Literature 3 (WO2008/122787) revealed a wide range Pieper is Zinovich compounds, inhibiting H-PGDS; however, is completely silent about the piperazinovom connection with (N-acylpyrrole-2-yl)carbonyl, which is contained in the compound of the present invention. Additionally, as shown in the test examples described below, the compounds shown in examples (Reference examples 13-8) source Patent Literature 3, do not show inhibition of PGD2 action on the wash fluid from the nasal cavity in Guinea pigs with antigen-induced rhinitis.

Source Patent Literature 4 (WO2007/054623) discloses inhibiting the hedgehog signaling pathway pieperazinove connection with fuelleborni pieperazinove structure; however, in contrast to the source Patent Literature 4, the present invention is that (N-acylpyrrole-2-yl)carbonyl contained in the compound of the present invention, limited fullcarbon. Further, Patent Literature 4 is completely silent about the inhibition of H-PGDS activity.

Source Patent Literature 5 (WO99/007672) reveals shrinkable pieperazinove connection, benzoylpiperazine connection etc. as a compound that interacts with potassium channels. However, in the source patent literature 5 discloses a compound containing (N-acylpyrrole-2-yl)carbonyl, as in the present connection, and completely mind Civetta about inhibiting H-PGDS activity.

Source Patent Literature 6 (WO2008/023720) reveals the connection of urea containing piperidine ring, as compounds for the treatment of diseases associated with hydrolases fatty acid amides. However, the source Patent Literature 6 discloses a compound containing (N-acylpyrrole-2-yl)carbonyl, as in the present connection, and is completely silent about the inhibition of H-PGDS activity.

As shown in the test examples below, pieperazinove connection that does not contain (N-acylpyrrole-2-yl)carbonyl, practically does not show inhibition of H-PGDS actions.

Examples of "substituents" in the present description include halogen, hydroxy, cyano, nitro, alkyl, halogenated, cycloalkyl, cycloalkenyl, aralkyl, alkenyl, quinil, alkoxy, halogenoalkane, cycloalkane, cycloalkylation, aralkylated, alkylthio, cycloalkylation, amino, mono - or dialkylamino, cycloalkylation, acyl, acyloxy, oxo, carboxy, alkoxycarbonyl, Uralelectromed, carbarnoyl, saturated or unsaturated heterocyclic group, an aromatic hydrocarbon, saturated heterocyclics etc. If such substituents are present, their number usually ranges from 1 to 3.

In alternate examples of the halogen include chlorine, bromine, fluorine and iodine.

In the substituents of the alkyl or halogenated are cobiprostone linear or branched C _1-6alkyl group or a group in which one to all hydrogen atoms, alkyl groups substituted with halogen, described above. Examples include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, and halogenoalkane groups, such as trifluoromethyl.

In the substituents cycloalkyl preferably represents C_3-7cycloalkyl group, and its examples include cyclopropyl, cyclobutyl, cyclofenil, cyclohexyl and cyclofenil.

In the substituents cycloalkenyl preferably represents C_1-6alkyl group, substituted C_3-7cycloalkyl, and its examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

In the substituents aralkyl is a preferably linear or branched C_1-6alkyl group, substituted C_6-14aromatic hydrocarbon group, and its examples include benzyl, phenylethyl, phenylpropyl, naphthylmethyl and naphtalate.

The Vice alkenyl preferably represents C_2-6alkenylphenol group containing a double carbon-carbon bond, and examples include vinyl, allyl, methylvinyl, propenyl, butenyl, pentenyl and hexenyl.

In alternate quinil is predpochtitel what about C _2-6alkylamino group containing a triple carbon-carbon bond, and its examples include ethinyl and propargyl.

In the alkoxy substituents or halogenoalkane is a preferably linear or branched C_1-6alkoxy group or alkoxy group substituted with halogen, described above, and examples include methoxy, ethoxy, n-propoxy, isopropoxy, 1 methylpropoxy, n-butoxy, isobutoxy, tert-butoxy, 2-methylbutoxy, neopentylene, pentane-2-yloxy, formatosi, deformedarse, triptoreline, 1,1-diflorasone, 2,2-diflorasone, 2,2,2-triptoreline, 1,1,2,2-tetrafluoroethoxy, perforators, 3-fluoro-2-(permitil)propoxy, 1,3-ditropan-2-yloxy and 2,2,3,3,3-pendaftar-1-propoxy.

In the substituents of cycloalkane preferably represents C_3-7cycloalkane group, and its examples include cyclopropane, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy, cycloheptylamine.

In the substituents of cycloalkylation preferably represents C_1-6alkoxy group, substituted C_3-7cycloalkyl, and its examples include cyclopropylmethoxy, cyclopropylmethoxy, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethoxy.

In the substituents of alkylthio is a preferably linear or branched C_1-6alkylthio group, and its examples include methylthio, this is LTI, n-propylthio, isopropylthio, n-butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the substituents of cycloalkylation preferably represents C_1-6alkylthio group, substituted C_3-7cycloalkyl, and its examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl.

In the substituents of aralkylated is preferably a hydroxy group with the above aralkyl group, and examples include benzyloxy, penetrate, phenylpropoxy, naphthalenyloxy, naphthylethylene.

In the substituents of the mono - or dialkylamino represent a mono - or diaminopropan, substituted linear or branched C_1-6alkyl group, and its examples include methylamino, dimethylamino, ethylamino, diethylamino, methylethylamine.

In the substituents of cycloalkylation is alkylamino group substituted by the above-mentioned cycloalkyl group, and its examples include cyclopropanemethylamine, cyclobutanemethanamine, cyclopentylamine.

In the acyl substituents represents a linear or branched C_1-6acyl group or benzoyloxy group, and its examples include formyl, acetyl, propionyl, n-butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl.

In alternate ACI is hydroxy represents a linear or branched C _1-6acyloxy group or a benzoyloxy group, and its examples include formyloxy, acetoxy, propionyloxy, n-butyryloxy, isobutyryloxy, valeriote, isovalerianic, pivaloyloxy.

In the substituents alkoxycarbonyl represents a carbonyl group substituted by the above-mentioned alkoxy group, and its examples include methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, 1-methylpropanesulphonic, n-butoxycarbonyl, isobutoxide, tert-butoxycarbonyl, 2-methylbutadiene, neopentylglycol and pentane-2-jocstarbunny.

In the substituents Uralelectromed preferably represents a carbonyl group substituted by the above-mentioned aralkylated group, and its examples include benzyloxycarbonyl, ventilatsioonil, phenylpropanolamine, naphthylethylenediamine and naphthylethylenediamine.

In alternate examples of carbamoyl include-CONH₂, (mono - or dialkyl)carbarnoyl, (mono - or diaryl)carbarnoyl, (N-alkyl-N-aryl)carbarnoyl, pyrrolidinecarbonyl, piperidinylcarbonyl, piperazinylcarbonyl and morpholinomethyl.

In the substituents, saturated or unsaturated heterocyclic groups are preferably monocyclic or bicyclic saturated or unsaturated heterocyclic groups containing the ü any of the following: oxygen, the nitrogen or sulphur, preferably in an amount of from 1 to 4. Their examples include pyrrolidinyl, piperidinyl, piperazinil, hexamethylenimine, morpholine, thiomorpholine, homopiperazine, tetrahydrofuranyl, tetrahydropyranyl, imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, tetrazolyl, pyridyl, Persil, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazoles, methylenedioxyphenyl, atlanticcity, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, purinol, hinely, ethanolic, chinsali and Minoxidil.

In the substituents of the aromatic hydrocarbon is preferably a C_6-14aromatic hydrocarbon group, and examples include phenyl and naphthyl.

In alternate full heterocyclic group is a monocyclic saturated heterocyclic group containing any of the following: oxygen, nitrogen and sulfur, in the number one or two, and its examples include hydroxy-containing groups pyrrolidinyl, piperidinyl, piperazinil, hexamethylenimine, morpholine, thiomorpholine or homopiperazine, such as tetrahydropyranyloxy, tetrahydropyranyloxy.

"C_1-6alkyl"represented as R¹in the formula (I), represents a linear or branched C_1-6alkyl is to Rupp, and its examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Of them, methyl and ethyl are preferred, and methyl is more preferable.

Examples of "C_1-6of alkyl that may have one or more substituents" of the "Ci-6 alkyl"represented as R²in the formula (I)include C_1-6the alkyl represented as R¹in the formula (I). Of them C_1-3alkyl is preferred, a C_1-3alkyl, such as methyl, ethyl, n-propyl, preferred.

Examples of "substituents" "C_1-6of alkyl that may have one or more substituents"represented by R²include the above-mentioned substituents. Hydroxy and saturated or unsaturated heterocyclic groups are preferred; morpholino, pyrazolyl and triazolyl more preferable; and morpholino, 1,2,3-triazolyl and 1,2,4-triazolyl especially preferred. The unsaturated heterocyclic group may contain substituents. The preferred Deputy is methyl, and the number of substituents is 1 or 2. Preferred examples of "C_1-6of alkyl, which may contain one or more substituents"represented by R²include morpholino, 1,2,3-triazolyl and 3,5-dimethyl-1,2,4-triazolyl.

Examples "_1-6of alkyl" of the "C_1-6of alkyl, which may content the forth one or more substituents", represented as R³and R⁴in the formula (I)include C_1-6the alkyl represented as R¹in the formula (I). Of them With_1-3alkyl is preferred.

Examples of "substituents" "C_1-6of alkyl, which may contain one or more substituents"represented as R³and R⁴include the above-mentioned substituents. Of them saturated or unsaturated heterocyclic group are preferred.

Examples of the "saturated heterocyclic group", which can be formed from R³and R⁴in the formula (I) and the nitrogen atom is attached to R³and R⁴include pyrrolidinyl, piperidinyl, piperazinil, morpholino, and morpholino is preferred.

Preferred examples of "C_1-6of alkyl that may have one or more substituents"represented as R⁵in the formula (I)include methyl, ethyl, tert-butyl and benzyl.

In the formula (I), n represents 1 or 2 and is preferably 2.

Pieperazinove connection according to the present invention can be obtained in accordance with the following reaction schemes 1 to 5.

The reaction scheme 1

In the above reaction scheme 1, R¹and R²are as above, R represents a protective group aminogroup the dust or hydrogen, and n represents 1 or 2.

The method according to the present invention includes a first stage in which pieperazinove compound represented by the formula (1a)or its salt is condensed with the compound terracarbon acid represented by the formula (1b), or its active derivative usual method with the formation of the amide compounds represented by the formula (2), and the second stage, in which the amine compound obtained by removal of the protective group of amino group, or its salt is condensed with the amine compound represented by the formula (1c), or its active derivative usual method with the formation of compounds represented by formula (I).

The first stage

In the first stage pieperazinove compound represented by the formula (1a)or its salt is condensed with the compound terracarbon acid represented by the formula (1b), or its active derivative ordinary method, thereby obtaining the amide compound represented by the formula (2).

Examples of active derivatives of the compound (1b) include active esters, such as esters, such as methyl esters; galodamadruga, such as acid chlorides; and N-hydroxybenzotriazole; symmetric acid anhydrides; and mixtures of anhydrides of acids with alkylcarboxylic acids.

If the compound (1b) is reacted with the NWO is one acid or if the active ester or gelegenheid react without selection it can be used condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine chloride.

If 1 mol piperazinovogo compounds represented by formula (1a)or its salt is used from 0.5 to 10 mol, and preferably from 0.8 to 2 mol, of the compound of carboxylic acid represented by the formula (1b), or its active derivative, the amount of the condensing agent is from 0.5 to 20 mol, and preferably from 0.8 to 3 mol per 1 mol piperazinovogo compounds represented by formula (1a)or its salt.

Although depending on the active derivatives or condensing agent, the reaction is usually carried out in a solvent which is inactive to the reaction at -20 to 150°C, and preferably from 0 to 100°C. Examples of such a solvent include galogenirovannyie hydrocarbon, such as dichloromethane and chloroform; aromatic hydrocarbons such as toluene; a simple ether, such as tetrahydrofuran; esters such as ethyl acetate; an alcohol such as methanol and ethanol; water; acetonitrile; N,N-dimethylformamide; N,N-dimethylacetamide; dimethyl sulfoxide and pyridine.

The reaction can be carried safely if it is done in the presence of from about 0.5 to 20 mol, and preferably from 0.8 to 5 mol, of base such as Tr is ethylamine, diisopropylethylamine, N-methylmorpholine, N,N-diethylaniline, 4-(N,N-dimethylamino)pyridine, pyridine, 1 mol piperazinovogo compounds represented by formula (1a)or its salt.

The second stage

In the second stage protective group R amino group in the amide compound represented by the formula (2), remove the conventional known method, and the obtained compound and the amine compound represented by the formula (1c), or its active derivative are condensed in the usual method of forming a compound represented by the formula (I).

The removal of the protective group can be performed in an acidic environment, if the protective group R is a formyl or tert-butoxycarbonyl, and removing the protective group can be performed by catalytic reduction method, if the protective group R represents benzyl or benzyloxycarbonyl.

For condensation, it is preferable to use an active derivative c tseplyayuschimisya groups obtained by reaction of the amine compounds represented by the formula (1c), with triphosgene, 1,1'-carbonyl diimidazol (CDI), phenylcarbamates, 4-nitrophenylphosphate, etelcharge.com or the like, is inactive in the reaction, a solvent such as dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate or N,N-dimethylacetamide, at from -20 to 150°C, and preferably from 0 to 100°C, in the presence of organic the CSO Foundation, such as triethylamine or pyridine, or without it.

Active derivatives of the formula (1c) can contain the group off. Active derivatives can be used in the reaction after separation or can be prepared in the reaction system and used without isolation. Examples of groups include removal of chlorine, imidazolyl, phenoxy, 4-nitrophenoxy, ethoxy.

Examples of salts of amine compounds represented by the formula (2)include acid additive salts with inorganic acids such as hydrochloric acid, Hydrobromic acid and sulfuric acid, or with organic acids such as carbonic acid and methanesulfonamide acid.

If 1 mol of the amine compounds represented by the formula (1c), or its active derivative use from 0.5 to 10 mol, and preferably from 0.8 to 2 mol, of amine compounds represented by the formula (3), or its salt, the amount of the condensing agent is from 0.5 to 20 mol, and preferably from 0.8 to 3 mol, per 1 mol of the amine compounds represented by the formula (1c), or its salt.

Although depending on the active derivatives or condensing agent, the reaction is usually carried out in a solvent which is inactive to the reaction at -20 to 150°C, and preferably from 0 to 100°C. Examples of such a solvent include galogenirovannyie carbohydrate is od such as dichloromethane and chloroform; aromatic hydrocarbons such as toluene; a simple ether, such as tetrahydrofuran; esters such as ethyl acetate; an alcohol such as methanol and ethanol; water; acetonitrile; N,N-dimethylformamide; N,N-dimethylacetamide; dimethyl sulfoxide and pyridine.

The reaction can be carried safely if it is done in the presence of from about 0.5 to 20 mol, and preferably from 0.8 to 5 mol, of base such as triethylamine, diisopropylethylamine, N-methylmorpholine, N,N-diethylaniline, 4-(N,N-dimethylamino)pyridine, pyridine, 1 mol piperazinovogo compounds represented by formula (1C), or its active derivative.

The compound (I) of the present invention can be obtained by performing the first stage and second stage.

Pieperazinove compound represented by the formula (1a), or its salt, the connection terracarbon acid represented by the formula (1b), or its active derivative and the amine compound represented by the formula (1c), or its salt known in the field or can be obtained well-known in this field methods.

The reaction scheme 2

In the above reaction scheme 2, R¹and R²defined above, R represents a protective group of an amino group or hydrogen, and n represents 1 or 2.

The method according to the present image is meniu includes the first stage, where pieperazinove compound represented by the formula (3)or its salt is condensed in the usual method with the amine compound represented by the formula (1c), or its active derivative forming compound urea represented by the formula (4), and a second stage in which the amine compound obtained by removing the protective group of amino group, or its salt is condensed in the usual method of connection terracarbon acid represented by the formula (1b), or its active derivative, obtaining the compound represented by formula (I).

The first stage

In the first stage pieperazinove compound represented by the formula (3), and its salt is condensed with the amine compound represented by the formula (1c), in accordance with the usual method, as in the condensation reaction, performed in the second stage of the reaction scheme 1, thereby obtaining the compound of urea represented by the formula (4).

The second stage

In the second stage protective group R amino group in the compound of urea represented by the formula (4)is deleted, as in the reaction of removing the protective group is performed in the second stage of the reaction scheme 1, and then the connection terracarbon acid represented by the formula (1b), or its active derivative is condensed in the usual method, as in the first stage of reaction scheme 1, thereby obtaining a compound ol stavlennie formula (I).

The reaction scheme 3

In the above reaction scheme 3, each of X¹X²and X³represents a functional group removal, Z¹is a nitro-group or a protective amino group, and R⁶and R⁷is such as the "substituents" in the "C_1-6alkyl group, which may contain one or more substituents"represented by R². R⁶and R⁷in particular represents a substituted or unsubstituted heterocyclic group, m represents from 0 to 3, and n represents 1 or 2.

The method of obtaining, as shown in reaction scheme 3, is the same as for compound amine (1c) in the reaction schemes 1 and 2. The method includes the following four stages:

the first stage in which aminecontaining compound represented by formula (3b), reacts with the removal of functional groups with a compound containing X¹represented by the formula (3a), with the formation of hydroxyacetamido compounds represented by formula (3c);

the second stage in which the compound represented by the formula (3d), reacts with hydroxycobalamin compound (3c) for introducing a functional group removal of X²thus is formed the compound represented by the formula (3E);

the third stage, in which connection the imposition of the amine (3f) shall enter into a condensation reaction with the functional group removal of X ²thus is formed the compound represented by formula (3g); and

the fourth stage, in which the conventional method is carried out restoration of the nitro group or the removal of the protective group of the amino group of compound (3g)obtained in the third stage, the thus formed compound amine (3h).

The first stage

Any functional group removal can be used as X¹compounds (3a) in the first stage. Examples include halogen, such as fluorine and chlorine, methanesulfonate, p-toluensulfonate, tripterocalyx.

The reaction is carried out in a suitable solvent, using from 0.5 to 10 mol, and preferably from 0.8 to 2 mol, of amine compounds represented by the formula (3b)or its salt to 1 mol of the compound represented by (3a), in the presence of from 0.5 to 10 mol, and preferably from 0.8 to 3 mol, of base per 1 mol of compound represented by formula (3a), at from -20 to 180°C, and preferably from 0 to 150°C, thereby obtaining hydroxystearate compound represented by formula (3c).

Can be used any solvent that does not adversely influence the reaction. Examples of suitable solvents include halogenated hydrocarbons such as dichloromethane and chloroform; aromatic hydrocarbons such as toluene; a simple ether, such ka is tetrahydrofuran; ester such as ethyl acetate; an alcohol such as methanol and ethanol; water; acetonitrile; N,N-dimethylformamide; N,N-dimethylacetamide; N-organic; dimethyl sulfoxide and pyridine. Can be used as a single solvent, or a combination of them.

Examples of bases include inorganic bases such as sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, and organic bases such as pyridine, 4-(N,N-dimethylamino)pyridine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and tert-butyl potassium.

The second stage

The reaction is carried out in a suitable solvent, using from 0.5 to 10 mol, and preferably from 0.8 to 2 mol, of the compound containing the functional group removal, represented by the formula (3d), 1 mol hydroxyacetamido compounds represented by (3c), in the presence of from 0.5 to 10 mol, and preferably from 0.8 to 3 mol, of base per 1 mol of compound represented by formula (3c), at from -20 to 180°C, and preferably from 0 to 150°C, thereby obtaining a compound represented by the formula (3e).

Can be used any solvent that does not adversely influence the reaction. Examples of suitable solvents include halogenated hydrocarbons such as dichloromethane and chloroform; aromatic Ugledar is d, such as toluene; a simple ether, such as tetrahydrofuran; esters such as ethyl acetate; acetonitrile; N,N-dimethylformamide; N,N-dimethylacetamide; N-organic; dimethyl sulfoxide and pyridine. Can be used as a single solvent, or a combination of them.

Examples of the base include inorganic bases such as sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, and organic bases such as pyridine, 4-(N,N-dimethylamino)pyridine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and tert-butyl potassium.

The third stage

The reaction is carried out in a suitable solvent, using from 0.5 to 10 mol, and preferably from 0.8 to 3 mol, of amine compounds represented by the formula (3f), per 1 mol of compound represented by formula (3e), the reaction is carried out in the presence of from 0.5 to 10 mol, and preferably from 0.8 to 3 mol, of base per 1 mol of compound represented by formula (3e), at from -20 to 180°C, and preferably at from 0 to 150°C, thereby obtaining a compound represented by the formula (3g).

Can be used any solvent that does not adversely influence the reaction. Examples of suitable solvents include halogenated hydrocarbons such as dichloromethane and chloroform; aromatic hydrocarbons, such ka is toluene; a simple ether, such as tetrahydrofuran; esters such as ethyl acetate; acetonitrile; N,N-dimethylformamide; N,N-dimethylacetamide; N-organic; dimethyl sulfoxide and pyridine. Can be used as a single solvent, or a combination of them.

Examples of the base include inorganic bases such as sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, and organic bases such as pyridine, 4-(N,N-dimethylamino)pyridine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and tert-butyl potassium.

The fourth stage

If Z¹is a nitrogroup, recovery can be commanded under any conditions suitable for the recovery of nitro group to amino group. It is preferable that the reaction conditions are selected based on the properties of other functional groups nitrocompounds (3g).

The usual methods of recovery include the following:

(A) From 0.01 to 10 mol, and preferably 0.03 to 5 mol, of catalyst recovery, such as reduced iron, tin chloride or ferric chloride in water, alcohol such as methanol or ethanol, a simple ether, such as tetrahydrofuran, or a mixture of its solvent, is reacted in the presence of from 0.3 to 30 moles, and preferably from 0.5 to 20 moles, ammonium salts such as ammonium chloride, hydras is to hydrate, hydrochloric acid, etc. on 1 mol of the nitro compounds represented by formula (3g), at from 0 to 150°C, and preferably from 20 to 120°C.

(B) Gaseous hydrogen in alcohols, ethers, esters, such as ethyl acetate, organic acids such as formic acid and acetic acid, or a mixture of its solvent, is reacted under normal pressure or increased pressure in the presence of from 0.001 to 1 mol, and preferably from 0.01 to 0.3 mol, of catalyst recovery, such as a palladium catalyst on carbon, platinum oxide and rineiski Nickel catalyst, 1 mol of nitro compounds represented by formula (3g), at from 0 to 120°C, and preferably from 20 to 100°C; or from 0.5 to 20 mol, and preferably from 1 to 10 mol, formic acid, ammonium formate or cyclohexene 1 mol of nitro compounds represented by formula (3g), was used as a hydrogen source instead of gaseous hydrogen.

If Z¹is a protective amino group, its removal can be performed as in the second stage of the reaction scheme 1, to obtain compounds amine (3h).

Compounds (3a), (3b), (3d) and (3f)used in the reaction scheme 3, are known or can be obtained by known methods.

The amine compound (1c) in the reaction scheme 1 or 2, i.e. the amine compound represented by the formula (4f), can be the ü obtained by the method shown in reaction scheme 4 below.

The reaction scheme 4

In the reaction scheme 4 X¹, Z¹, R³and R⁴defined above, R⁸is the same as R⁵or a silyl protecting group such as tert-butyldimethylsilyl, l represents from 0 to 3, and n represents 1 or 2.

Receiving method shown in the reaction scheme 4, includes a first stage in which the functional group removal of compounds (4a), containing the X¹, reacts with aminecontaining compound of ester represented by the formula (4b), with the formation containing ester compound represented by the formula (4c); the second stage, which removes the ester group of compounds of ester (4c), which is then condensed with the amine compound represented by the formula (4d), the usual method with the formation of the amide compounds represented by the formula (4e); and a third stage in which the nitro-group of the compound (4e) is restored or a protective group of the amino group is removed in the usual method, thus forming amine compound (4f).

The first stage

At this stage containing ester compound represented by the formula (4c), can be obtained by the same method as in the first stage of reaction scheme 3.

The second stage

At this stage complex EF the R connection containing ester represented by the formula (4c), deleted conventional known method, and then condensed with the amine compound represented by the formula (4d), or its salt by the same method as in the first stage of reaction scheme 1, with the formation of the amide compounds represented by the formula (4e).

The third stage

At this stage, Z¹can be converted into the amino group by the same method as in the fourth stage of reaction scheme 3.

Compounds (4a), (4b) and (4d)used in the reaction scheme 4, is known or can be obtained by a known method.

Of the compounds of the present invention, compounds having a specific functional group can be converted into other compounds according to the invention by chemical modification of these groups, as shown below in reaction scheme 5.

The reaction scheme 5

In the reaction scheme 5, R¹, R³, R⁴, R⁸n and l are defined above.

In the production method, shown in reaction scheme 5, compound carboxylic acid, obtained by removing the protective group of the compound of ester represented by the formula (5a), or its active derivative is condensed by the same method as in the first stage of reaction scheme 1, with an amine compound represented by the formula (5b), with the formation of amide compounds (5c).

If the compound (I)to the / establishment, which can be used as an active ingredient of a medicinal product according to the present invention, contains one or more asymmetric carbons, due to the presence of such a symmetric carbon atoms can form optical isomers (enantiomers and diastereomers) and other isomers. The present invention encompasses isomers, which can be selected, and mixtures thereof.

The compound (I), which can be used as an active ingredient of a medicinal product according to the present invention encompasses pharmaceutically acceptable prodrugs. Pharmaceutically acceptable prodrugs are compounds with functional groups that can be transformed by chemical effects, such as solvolysis or under physiological conditions, amino, hydroxy, carboxy, carbonyl or similar functional group of the compound (I), which is the active component of the medicinal product according to the present invention. Examples of functional groups of prodrugs include the groups mentioned in "Iyakuhin no Kaihatsu Development of Pharmaceuticals), Vol. 7, pp. 163-198, Hirokawa Publishing (1990).

The compound (I), which can be used as an active ingredient of a medicinal product according to the present invention may form an acid additive salt or a salt with a base. Such salts are included in the present invention, if they are pharmaceutically acceptable. Specific examples include keys, the ratio of additive salts with inorganic acids, such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonate acid, para-toluensulfonate acid, glutamic acid etc; salts with inorganic bases, such as sodium, potassium, magnesium, calcium, aluminum, and so, organic bases such as methylamine, ethylamine, meglumin, ethanolamine, etc. or basic aminokislotami, such as lysine, arginine, ornithine, etc.; and ammonium salts.

The present invention additionally encompasses a hydrate, solvate and crystalline polymorphs of compound (I), which can be used as an active ingredient of a medicinal product according to the present invention and its pharmaceutically acceptable salts.

In the pharmaceutical composition comprising pieperazinove compound or its salt of the present invention, if necessary, may be added to pharmaceutical carrier to create a suitable dosage forms in accordance with the goals of the s treatment and prevention. Examples of dosage forms include oral formulations, injections, suppositories, ointments, plasters, etc. Of these oral formulations are preferred. Such dosage forms can be obtained by conventional methods known to experts in this field.

As a pharmaceutical carrier, as a component of the drug, can be used various organic or inorganic carriers which are added as excipient, binder, disintegrant, grease or dye in solid preparations, or as a solvent, solubilizers component suspendisse component, isotonic component, a buffer or a softening agent in liquid preparations. In addition, if necessary, can be used additives for pharmaceutical preparations, such as an antiseptic, antioxidant, colorant, sweetener and stabilizer.

Oral solid composition is prepared as follows. Excipient, optionally together with a binder, disintegrant, lubricant, colorant, sweetener/flavoring agent, etc. add to the compound of the present invention to obtain the usual ways of tablets, coated tablets, granules, powders, capsules or the like

Examples of excipients include lacto is, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid.

Examples of the binder include water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, a liquid α-starch, liquid gelatin, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone.

Examples of disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride of stearic acid and lactose.

Examples of lubricants include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol.

Examples of colorants include titanium oxide and iron oxide.

Examples of sweeteners/flavorings include sucrose, peel, wild orange, citric acid and tartaric acid.

Oral liquid preparations prepared as follows. Sweetener, buffer, stabilizer, flavoring and sweetening etc. add to the compound of the present invention to obtain with conventional methods of liquid medicines for ingestion, syrup, elixir or the like, In this case suitable sweeteners/flavorings such as described above. Examples of buffers included the t sodium citrate, and examples of stabilizers include tragakant, gum Arabic and gelatin. If you want, enteric coated or plated for longer effect can be applied by methods known in the field of oral medicine. Examples of components of coatings include hypromellose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethyleneglycol and Tween 80 (registered trade mark).

Injectable form is prepared as follows. Tool to bring the pH, buffer, stabilizer, isotonic component, a local anesthetic, etc. add to the compound of the present invention, receiving conventional methods of injecting drug for subcutaneous injection, intravenous drug for intramuscular injection or injecting intravenous drugs. Examples of suitable means for bringing the pH and buffers in this case include sodium citrate, sodium acetate and sodium phosphate. Examples of suitable stabilizers include sodium pyrosulfite, EDTA, thioglycolic acid and timelocal acid. Examples of suitable local anesthetics include procaine and lidocaine. Examples of suitable isotonic components include sodium chloride, glucose, D-mannitol, and glycerin.

Candles prepared as follows. The pharmaceutical carrier known this about the Asti, such as polyethylene glycol, lanolin, cocoa butter and triglycerides of fatty acids, added to the compound of the present invention, optionally together with Tween 80 (registered trade mark) or similar surface-active agent, followed by conventional cooking method.

The ointment is prepared as follows. Regular basis, a stabilizer, a moisturizing component, a preservative, etc. add in the necessary quantities to the compound of the present invention, mix and prepare the dosage form usual method. Examples of bases include liquid paraffin, medical vaseline, bleached beeswax, octyldodecyl alcohol and paraffin. Examples of preservatives include methyl parahydroxybenzoate, metilparagidroksibenzoat and sodium propyl parahydroxybenzoate.

The patches can be prepared by usual method by covering the main substrate of the above ointment, cream, gel, paste, etc. are Examples of substrates include woven or nonwoven fabrics made of cotton, staple fibers and chemical fibers; films and foamed sheets made of soft vinyl chloride, polyethylene and polyurethane.

A number of compounds of the present invention, contained in a single dosage form depends on the condition of the patient or dosage forms. The desirable amount in about the Noah unit dosage form is from about 0.05 to about 1000 mg for oral composition, from about 0.01 to about 500 mg injectable form, and from about 1 to about 1000 mg for candles.

Daily dose medications in such dosage form depends on the condition, body weight, age, sex, etc. of the patient. For example, the daily dose for an adult (body weight: 50 kg) can in General be from about 0.05 to about 5000 mg, and preferably from 0.1 to 1000 mg, and preferably is injected in one or in two or three divided doses a day.

Since the introduction of the medicinal product containing the compound of the present invention, inhibiting H-PGDS activity is manifested in mammals and, in particular, in humans, the compound of the present invention can be used for the treatment, prevention or improvement of diseases caused PGD2 produced by synthase, or its metabolite. The compound of the present invention can be introduced mammals, including humans, monkeys, mice, rats, rabbits, dogs, cats, cows, horses, pigs and sheep. The compound can be administered to the mammal orally or neironalna conventional methods.

Examples of diseases for treatment, prevention or improvement of a pharmaceutical agent containing the compound of the present invention, include allergic disease, nosplit the aspects of the disease and myodegeneration disease.

Examples of allergic diseases include bronchial asthma, hay fever, allergic rhinitis, sinusitis, otitis media, allergic conjunctivitis, spring catarrhal inflammation, allergic dermatitis, contact dermatitis and allergies to foods. Of them, preferred are bronchial asthma, pollinosis, allergic rhinitis and sinusitis. Examples of inflammatory diseases include chronic obstructive pulmonary disease, interstitial pneumonia, hypersensitive pneumonitis, eosinophilic pneumonia, rheumatic arthritis, degenerative arthritis, multiple sclerosis, inflammatory bowel disease, skin diseases (psoriasis, eczema, erythema syndrome itching, pimple, etc.), post-PTCA restenosis, chronic obstructive artery disease, reperfusion injury and reaction to graft rejection.

Examples myodegeneration diseases include muscular dystrophy, such as muscular dystrophy Duchenne, which is myogenic disease, muscular dystrophy Becker muscular dystrophy pelvic girdle and congenital muscular dystrophy; various myopathy, such as congenital myopathy; amyotrophic lateral sclerosis, which is neurogenic muscle atrophy; muscle contraction; cardiomyopathy (myocardial infarction) and diabetic peripheral the ski vascular disorders (vascular disorders of smooth muscle). Preferred examples myodegeneration diseases for treatment, prevention or improvement of a drug containing the compound of the present invention, include muscular dystrophy DuChene, muscular dystrophy Becker and amyotrophic lateral sclerosis.

In addition, it is assumed that the drug containing the compound of the present invention, will improve the treatment and prevention of problems, mucus secretion, reproductive problems, disorders of blood coagulation, sleep disorders, pain, vision problems, obesity, immunopathy and autoimmune diseases; prevent exacerbation of the disease is Alzheimer's disease or brain damage and/or improve the prognosis after brain damage. In addition, it can lead to inhibition of malignancy cells and metastatic tumor growth, they can also be used for therapy of cancer.

In addition, they can be used for the treatment and/or prevention of proliferative disorders caused by PGD2 or its metabolites, such as fibroblast proliferation, diabetic retinopathy and tumor angiogenesis. In addition, because they can inhibit PGD2-induced smooth muscle contraction, they can also be used for treatment and/or prevention of infertility, dysmenorrhea, premature birth and leukocyte-eosinophil the different disorders.

EXAMPLES

The present invention is described below in detail with Reference examples, Examples and case studies, which do not limit the scope of the invention.

In the further description of the spectra of 1H-NMR was measured using TMS (tetramethylsilane was) as an internal standard, and chemical shifts are listed δ (ppm). As for the chemical shifts of the absorption spectra, the permanent binding (J) and the number of protons, they are shown in parentheses.

The following characters are used for absorption spectra: s - singlet, d - doublet, t - triplet, square - Quartet, DD : double doublet, m = multiplet, ush. - wide and USS broad singlet.

In addition, the following symbols are used in structural formulas of compounds: Me = methyl Et = ethyl.

Example 1

N-(4-(4-hydroxypiperidine-1-yl)phenyl-4-((1-methylpyrrole-2-yl)carbonyl)-1-piperazinecarboxamide

Example 1(1)

4-hydroxy-N-(4-nitrophenyl)piperidine

4-chloronitrobenzene (31,5 g, 200 mmol) was dissolved in N,N-dimethylacetamide (80 ml) was added potassium carbonate (35,9 g, 260 mmol) and 4-hydroxypiperidine (22,3 g, 220 mmol), then stirred while heating to 130°C for 3 hours. After cooling to room temperature, to the mixture was added water and collecting the precipitate by filtration. The obtained solid substance was dried under reduced pressure, thereby obtaining 4-hydroxy-N-(4-nitrophenyl)is hypericin (41,3 g, 93%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,52-of 1.74 (m, 2H), 1,92-2,04 (m, 2H), 3,14-to 3.35 (m, 2H), of 3.73-4,08 (m, 3H), PC 6.82 (d, J=9.6 Hz, 2H), 8,11 (d, J=9.6 Hz, 2H)

Example 1(2)

4-hydroxy-N-(4-AMINOPHENYL)piperidine

4-hydroxy-N-(4-nitrophenyl)piperidine (11.1 g, 50 mmol)obtained in example 1(1), was dissolved in methanol (100 ml) and tetrahydrofuran (50 ml) was added 10% palladium on coal (8.0 g), then stirred at room temperature in the environment of hydrogen gas for 7 hours. After insoluble matter was filtered through celite, the filtrate was concentrated under reduced pressure, was added diethyl simple ether to the resulting residue and the precipitate was collected by filtration, thereby obtaining 4-hydroxy-N-(4-AMINOPHENYL)piperidine (9,25 g, 94%) as a red-purple solid.

1H-NMR (CDCl3): δ (ppm) of 1.65-1.77 in (m, 2H), 1,94-2,11 (m, 2H), 2.71 to to 2.85 (m, 2H), 3,23-to 3.92 (m, 5H), only 6.64 (d, J=8,9 Hz, 2H), 6,83 (d, J=8,9 Hz, 2H)

Example 1(3)

N-(4-(4-hydroxypiperidine-1-yl)phenyl)-4-((1-methylpyrrole-2-yl)carbonyl)-1-piperazinecarboxamide

4-nitrophenyl chloroformate (242 mg, 1.2 mmol) was dissolved in tetrahydrofuran (3 ml) and tertrahydrofuran ring solution (4 ml) of 4-hydroxy-N-(4-AMINOPHENYL)piperidine (211 mg, 1.0 mmol)obtained in example 1(2), was added dropwise at -30°C. After stirring for 30 minutes at this temperature, to the mixture was added 1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperazine hydro is Lorig (252 mg, 1.1 mmol) and triethylamine (of 0.49 ml, 3.5 mmol), then stirred at room temperature for 17 hours. In the reaction mixture were added saturated aqueous sodium bicarbonate solution, and then extraction was performed with ethyl acetate. The organic layer was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered and then the residue obtained by evaporation under reduced pressure, was purified flash chromatography (medium pressure column of silica gel (NH silica gel, methanol:chloroform = 0:1 to 1:50), thereby obtaining N-(4-(4-hydroxypiperidine-1-yl)phenyl)-4-((1-methylpyrrole-2-yl)carbonyl)-1-piperazinecarboxamide (256 mg, 62%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1,60-of 1.78 (m, 2H), 1.93 and-of 2.08 (m, 2H), 2,80-2,95 (m, 2H), 3,40-3,63 (m, 6H), 3.75 to 3,90 (m, 5H), of 3.80 (s, 3H), between 6.08-x 6.15 (m, 1H), 6,25 (USS, 1H), 6,32-6,40 (m, 1H), 6,70-6,77 (m, 1H), 6.90 to (d, J=8,9 Hz, 2H), 7,21 (d, J=8,9 Hz, 2H)

Example 2

4-((((1-methylpyrrole-2-yl)carbonyl)-1-piperazinil)carbonyl)amino-4-phenylpiperidine-4-carboxylic acid

Example 2 (1)

Ethyl ester of 1-(4-nitrophenyl)piperidine-4-carboxylic acid

In accordance with the method of example 1(1), using ethyl ether isonipecotic acid instead of 4-hydroxypiperidine received ethyl ester 1-(4-nitrophenyl)piperidine-4-carboxylic acid (95%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) of 1.27 (t, J=72 Hz, 3H), 1,80-1,90 (m, 2H), 2.00 in of 2.08 (m, 2H), 2,54-2,62 (m, 1H), 3,01-3,14 (m, 2H), 3,84-to 3.92 (m, 2H), 4,17 (sq, J=7.2 Hz, 2H), 6,83 (d, J=7.2 Hz, 2H), 8,11 (d, J=7.2 Hz, 2H)

Example 2(2)

Ethyl ester of 1-(4-AMINOPHENYL)piperidine-4-carboxylic acid

In accordance with the method of example 1(2), using the ethyl ester of 1-(4-nitrophenyl)piperidine-4-carboxylic acid obtained in example 2(1), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained ethyl ester 1-(4-AMINOPHENYL)piperidine-4-carboxylic acid (Qty.) in the form of a reddish-brown oil.

1H-NMR (CDCl3): δ (ppm) of 1.27 (t, J=7,1 Hz, 3H), 1,78 and 2.13 (m, 4H), 2,30-2,47 (m, 1H), 2,55 is 2.75 (m, 2H), 3,20-to 3.64 (m, 4H), 4,15 (sq, J=7,1 Hz, 2H), only 6.64 (d, J=8,9 Hz, 2H), PC 6.82 (d, J=8,9 Hz, 2H)

Example 2(3)

Ethyl ester of 4-((((1-methylpyrrole-2-yl)carbonyl)-1-piperazinil)carbonyl)amino-4-phenylpiperidine-4-carboxylic acid

In accordance with the method of example 1(3), using the ethyl ester of 1-(4-AMINOPHENYL)piperidine-4-carboxylic acid obtained in example 2(2), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained ethyl ester 4-((((1-methylpyrrole-2-yl)carbonyl)-1-piperazinil)carbonyl)amino-4-phenylpiperidine-4-carboxylic acid (80%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) of 1.27 (t, J=7,1 Hz, 3H), 1,75-2,12 (m, 4H), 2,33-2,48 (m, 1H), 2,67-2,84 (m, 2H), 3,42-the 3.65 (m, 6H), 3,70-3,93 (m, 4H), 3,79 (s, 3H), 4,15 (sq, J=7,1 Hz, 2H), 6,06-x 6.15 (m, 1H), 6.30-in-6,40 (m, 1H), 6,41 (USS, 1H), 6,69-6,76 (m, 1H), to 6.88 (d, J=9.0 Hz, 2H), 7,22 (d, J=9.0 Hz, 2H)

Example 2(4)

4-((((1-methylpyrrole-2-yl)Carbo who yl)-1-piperazinil)carbonyl)amino-4-phenylpiperidine-4-carboxylic acid

Ethyl ester of 4-((((1-methylpyrrole-2-yl)-carbonyl)-1-piperazinil)-carbonyl)amino-4-phenylpiperidine-4-carboxylic acid (234 mg, 0.5 mmol)obtained in example 2(3), was dissolved in tetrahydrofuran (1.5 ml) and ethanol (1.5 ml), was added 2 N. aqueous sodium hydroxide solution (1.4 ml, 2.8 mmol), then stirred at room temperature for 5 hours. After cooling the reaction mixture to 0°C was added to the reaction mixture 2 N. hydrochloric acid (1.4 ml, 2.8 mmol), and then were mixed extraction solvent methanol:chloroform (1:10). The organic layer was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered and then the residue obtained by evaporation under reduced pressure, washed with diethyl simple ether thus obtained 4-((((1-methylpyrrole-2-yl)carbonyl)-1-piperazinil)carbonyl)amino-4-phenylpiperidine-4-carboxylic acid (167 mg, 75%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1,79 and 2.13 (m, 4H), 2,38-of 2.54 (m, 1H), 2,65-2,87 (m, 2H), 3.45 points-to 3.67 (m, 6H), 3,71-of 3.94 (m, 4H), of 3.80 (s, 3H), 6,05-6,14 (m, 1H), 6,28-6,46 (m, 2H), 6,68-6,77 (m, 1H), make 6.90 (d, J=8,9 Hz, 2H,), 7,21 (d, J=8,9 Hz, 2H)

Example 3

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Example 3(1)

1-(4-nitrophenyl)piperidine-4-carboxylic acid

Ethyl ester of 1-(4-nitrophenyl)piperidine-4-carbon is Oh acid (2,78 g, 10 mmol)obtained in example 2(1), was dissolved in ethanol (10 ml) was added 4 N. aqueous sodium hydroxide solution (5 ml, 20 mmol). The mixture was heated under reflux for 1 hour. After cooling to room temperature, to the mixture was added water (30 ml) and 2 N. hydrochloric acid (10 ml)and the precipitate was collected by filtration, was thus obtained 1-(4-nitrophenyl)piperidine-4-carboxylic acid (2,47 g, 97%) as a yellow solid.

1H-NMR (DMSO-d6): δ (ppm) 1,49 by 1.68 (m, 2H), 1,84 is 2.00 (m, 2H), 2,50-of 2.66 (m, 1H), 3,01-3,19 (m, 2H), 3,90-of 4.05 (m, 2H), 7,02 (d, J=9.4 Hz, 2H), 8,03 (d, J=9.4 Hz, 2H), to 12.28 (ush., 1H)

Example 3(2)

1-(4-nitrophenyl)piperidine-4-morpholinylcarbonyl

1-(4-nitrophenyl)piperidine-4-carboxylic acid (10.1 g, 40 mmol)obtained in example 3(1), was dissolved in N,N-dimethylformamide (25 ml) was added morpholine (5.2 g, 60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9,2 g, 48 mmol) and 1-hydroxybenzotriazole monohydrate (6.7 g, 44 mmol), then stirred overnight while heating to 70°C. After cooling to room temperature added water, the precipitate was collected by filtration and dried by heating under reduced pressure, thereby obtaining 1-(4-nitrophenyl)piperidine-4-morpholinylcarbonyl (12.1 g, 95%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,80-of 2.08 (m, 4H), 2,68-of 2.81 (m, 1H), 2.95 and-3,13 (m, 2H), 3.46 in-of 3.78 (m, 8H), 3,89-4,07 (m, 2H), for 6.81 (d, J=8,4 Hz, 2H), 8,11 (d, J=8,4 Hz, 2H)

Example 3(3)

1-(4-AMINOPHENYL)piperidine-4-morpholinylcarbonyl

In accordance with the method of example 1(2), using 1-(4-nitrophenyl)piperidine-4-morpholinylcarbonyl obtained in example 3(2), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained 1-(4-AMINOPHENYL)piperidine-4-morpholinylcarbonyl (90%) as a reddish-purple solid.

1H-NMR (CDCl3): δ (ppm) 1,72-1,89 (m, 2H), 1,92-of 2.15 (m, 2H), 2,45-to 2.74 (m, 3H), 3,28-of 3.80 (m, N), of 6.65 (d, J=8,9 Hz, 2H), PC 6.82 (d, J=8,9 Hz, 2H)

Example 3(4)

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 1(3)using 1-(4-AMINOPHENYL)piperidine-4-morpholinylcarbonyl obtained in example 3(3), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide (82%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1,72-2,12 (m, 4H), 2,47-2,78 (m, 3H), 3,43-3,90 (m, N), of 3.80 (s, 3H), 6,07-6,16 (m, 1H), 6,33-to 6.39 (m, 1H), 6,44 (USS, 1H), 6,69-of 6.78 (m, 1H), to 6.88 (d, J=8,9 Hz, 2H), 7,22 (d, J=8,9 Hz, 2H)

Example 4

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholinomethyl-1-yl)phenyl)-1-piperazinecarboxamide

Example 4(1)

4-hydroxymethyl-N-(4-nitrophenyl)piperidine

In accordance with the method of example 1(1), using 4-hydroxyethylpiperazine instead of 4-hydroxypiperidine, received 4-hydroxymethyl-N-(4-NITR is phenyl)piperidine (97%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) of 1.23 is 1.48 (m, 3H), 1.70 to of 1.97 (m, 3H), 2,90-of 3.07 (m, 2H), of 3.56 (t, J=5.7 Hz, 2H), 3,93-4,07 (m, 2H), for 6.81 (d, J=9.4 Hz, 2H), 8,11 (d, J=9.4 Hz, 2H)

Example 4(2)

4-tosyloxy-N-(4-nitrophenyl)piperidine

4-hydroxymethyl-N-(4-nitrophenyl)piperidine (47,3 g, 200 mmol)obtained in example 4(1), was dissolved in pyridine (300 ml), was added p-toluensulfonate (45,8 g, 240 mmol) while cooling on ice, followed by stirring for 4 hours. In the reaction mixture was added water and the precipitate was collected by filtration. The obtained solid substance was dried under reduced pressure, the thus obtained 4-tosyloxy-N-(4-nitrophenyl)piperidine (72,7 g, 93%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,20-1,40 (m, 2H), 1,75-1,90 (m, 2H), 1,90-2,12 (m, 1H), 2,46 (s, 3H), 2,87-3,03 (m, 2H), 3,90 (d, J=6,4 Hz, 2H), 3,90-was 4.02 (m, 2H), 6,78 (d, J=9.4 Hz, 2H), was 7.36 (d, J=8,4 Hz, 2H), 7,79 (d, J=8,4 Hz, 2H), of 8.09 (d, J=9.4 Hz, 2H)

Example 4(3)

4-morpholinomethyl-N-(4-nitrophenyl)piperidine

4-tosyloxy-N-(4-nitrophenyl)piperidine (39,0 g, 100 mmol)obtained in example 4(2), was dissolved in methyl ethyl ketone (150 ml) was added sodium iodide (45,0 g, 300 mmol), then stirred at room temperature for 4 days. In the reaction mixture was added ethyl acetate, and the insoluble substance was filtered through celite. Then the organic layer was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. After the desiccant hotfil triviali and added diisopropyl simple ether to the residue, obtained by evaporation under reduced pressure, and the precipitate was collected by filtration, thereby obtaining the crude iodide. The crude iodide was dissolved in acetonitrile (150 ml) and potassium carbonate (19.7 g, 143 mmol) was added morpholine (12,4 ml, 143 mmol), then stirred at room temperature for 2 days. Added water in the reaction mixture, and then extraction was performed with ethyl acetate. Then the organic layer was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered and then the residue obtained by evaporation under reduced pressure, was purified flash chromatography (medium pressure column with silica gel (methanol:chloroform = 0:1 to 1:30), thus obtained 4-morpholinomethyl-N-(4-nitrophenyl)piperidine (16.2 g, 53% over 2 stages) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,17-to 1.38 (m, 2H), 1.70 to 2,00 (m, 3H), of 2.21 (d, J=7,1 Hz, 2H), 2,32 of $ 2.53 (m, 4H), 2,86 was 3.05 (m, 2H), 3,62-of 3.78 (m, 4H), 3,86-of 4.05 (m, 2H), 6,80 (d, J=9.6 Hz, 2H), 8,10 (d, J=9.6 Hz, 2H)

Example 4(4)

4-morpholinomethyl-N-(4-AMINOPHENYL)piperidine

In accordance with the method of example 1(2), using 4-morpholinomethyl-N-(4-nitrophenyl)piperidine obtained in example 4(3), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained 4-morpholinomethyl-N-(4-AMINOPHENYL)piperidine (97%) as a reddish-purple solid.

1H-NMR (CDCl3): δ (ppm) 1,2-at 1.73 (m, 3H), 1,80-of 1.95 (m, 2H), 2,16-2,70 (m, 8H), 3.27 to of 3.85 (m, 8H), only 6.64 (d, J=8.6 Hz, 2H), at 6.84 (d, J=8.6 Hz, 2H)

Example 4(5)

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholinomethyl-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 1(3), using 4-morpholinomethyl-N-(4-AMINOPHENYL)piperidine obtained in example 4(4), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholinomethyl-1-yl)phenyl)-1-piperazinecarboxamide (72%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1,22 of 1.46 (m, 2H), 1,53 is 1.75 (m, 1H), 1,81-to 1.98 (m, 2H), 2,22 (d, J=7,1 Hz, 2H), 2,33 is 2.51 (m, 4H), 2.57 m-to 2.74 (m, 2H), 3,45-3,93 (m, 14N), of 3.80 (s, 3H), between 6.08-6,14 (m, 1H), 6,32 (USS, 1H), 6,30-6,41 (m, 1H), 6,70 to 6.75 (m, 1H), 6.89 in (d, J=9.1 Hz, 2H), 7,20 (d, J=9.1 Hz, 2H)

Example 5

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(3-(2-(1,2,4-triazole-1-yl)ethyl)pyrrolidin-1-yl)phenyl)-1-piperazinecarboxamide

Example 5 (1)

3-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-nitrophenyl)pyrrolidin

4-tosyloxy-N-(4-nitrophenyl)piperidine (39,0 g, 100 mmol)obtained in example 4(2), was dissolved in methyl ethyl ketone (150 ml) was added sodium iodide (45,0 g, 300 mmol), then stirred at room temperature for 5 days. In the reaction mixture was added ethyl acetate, and insoluble matter was filtered through celite. Then the organic layer was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant tfilter ivali and then diisopropyl simple ether was added to the residue, obtained by evaporation under reduced pressure, and the precipitate was collected by filtration, thus was obtained the crude iodide. The crude iodide was dissolved in acetonitrile (160 ml) and water (40 ml) was added potassium carbonate (24,9 g, 180 mmol) and 1,2,4-triazole (to 9.32 g, 134 mmol), then stirred at 80°C for 6 hours. After cooling the reaction mixture to room temperature it was added water and the precipitate was collected by filtration and dried. The obtained solid was purified flash chromatography (medium pressure column with silica gel (methanol:chloroform = 0:1 to 1:30), thereby obtaining 3-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-nitrophenyl)pyrrolidin (16.4 g, 63% over 2 stages) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) of 1.55 and 1.80 (m, 1H), from 2.00 to 2.35 (m, 4H), 2,97-3,14 (m, 1H), 3,31-to 3.64 (m, 3H), 4,30 (t, J=7,0 Hz, 2H), 6,44 (d, J=9.4 Hz, 2H), of 7.97 (s, 1H), 8,11 (d, J=9.4 Hz, 2H), 8,12 (s, 1H)

Example 5(2)

3-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)pyrrolidin

In accordance with the method of example 1(2), using 3-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-nitrophenyl)pyrrolidine obtained in example 5(1), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained 3-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)pyrrolidin (96%) as a reddish-purple solid.

1H-NMR (CDCl3): δ (ppm) 1,65-to 1.87 (m, 1H), 2,00 is 2.43 (m, 4H), 2,75-3,70 (m, 6H), 4,25 (t, J=7,1 Hz, 2H), 6,44 (d, J=8,4 Hz, 2H), of 6.68 (d, J=8,4 Hz, 2H), 8,00 (s, 1H), 8,08 (s, 1H)

Example 5(3)

4-((1-meth is pyrrol-2-yl)carbonyl)-N-(4-(3-(2-(1,2,4-triazole-1-yl)ethyl)pyrrolidin-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 1(3), used 3-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)pyrrolidine obtained in example 5(2), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(3-(2-(1,2,4-triazole-1-yl)ethyl)pyrrolidin-1-yl)phenyl)-1-piperazinecarboxamide (62%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1,62-of 1.78 (m, 1H), 2,02-of 2.38 (m, 4H), 2,89-3,03 (m, 1H), 3,22-to 3.67 (m, 7H), of 3.77-of 3.94 (m, 4H), of 3.80 (s, 3H), 4.26 deaths (t, J=7,1 Hz, 2H), 6,07-x 6.15 (m, 1H), to 6.19 (USS, 1H), 6,33-6,41 (m, 1H), 6,48 (d, J=8,9 Hz, 2H), 6,70-of 6.78 (m, 1H), 7,16 (d, J=8,9 Hz, 2H), of 7.96 (s, 1H), of 8.09 (s, 1H)

Example 6

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholinobutyrophenone-1-yl)phenyl)-1-piperazinecarboxamide

Example 6(1)

4-hydroxyethyl-N-(4-nitrophenyl)piperidine

In accordance with the method of example 1(1), using 4-hydroxyethylpiperazine instead of 4-hydroxypiperidine, received 4-hydroxyethyl-N-(4-nitrophenyl)piperidine (100%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1.18 to of 1.40 (m, 3H), 1,47-of 1.92 (m, 5H), 2,85-3,03 (m, 2H), 3,63-of 3.78 (m, 2H), 3,85-was 4.02 (m, 2H), 6,77 (d, J=9.4 Hz, 2H), 8,07 (d, J=9.4 Hz, 2H)

Example 6(2)

4-Casinocity-N-(4-nitrophenyl)piperidine

In accordance with the method of example 4(2) used 4-hydroxyethyl-N-(4-nitrophenyl)piperidine obtained in example 6(1), instead of 4-hydroxymethyl-N-(4-nitrophenyl)piperidine was obtained 4-Casinocity-N-(4-nitrophenyl)piperidine (93%) as a yellow solid.

1H-NMR (CDCl3: δ (ppm) 1,13-of 1.35 (m, 2H), 1,55-of 1.84 (m, 5H), to 2.46 (s, 3H), 2,82-a 3.01 (m, 2H), 3,84-4,00 (m, 2H), 4,10 (t, J=6,1 Hz, 2H), 6,78 (d, J=9.4 Hz, 2H), was 7.36 (d, J=8,4 Hz, 2H), 7,80 (d, J=8,4 Hz, 2H), 8,10 (d, J=9.4 Hz, 2H)

Example 6(3)

4-morpholinoethyl-N-(4-nitrophenyl)piperidine

4-Casinocity-N-(4-nitrophenyl)piperidine (2,02 g, 5.0 mmol)obtained in example 6(2), was dissolved in acetonitrile (20 ml) was added potassium carbonate (1,38 g, 10 mmol) and morpholine (0,65 ml, 7.5 mmol), then stirred at 80°C for 15 hours. After cooling the reaction mixture to room temperature, the reaction mixture was added ethyl acetate and the organic layer was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered and then the residue obtained by evaporation under reduced pressure, was purified flash chromatography (medium pressure column with silica gel (methanol:chloroform = 1:50 to 1:20), thus obtained 4-morpholinoethyl-N-(4-nitrophenyl)piperidine (1,23 g, 77%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,17 is 1.70 (m, 5H), 1,73-of 1.88 (m, 2H), 2,29-2,52 (m, 6H), 2,84-3,03 (m, 2H), 3,60-of 3.78 (m, 4H), 3,85-a 4.03 (m, 2H), 6,77 (d, J=9.4 Hz, 2H), 8,08 (d, J=9.4 Hz, 2H)

Example 6(4)

4-morpholinoethyl-N-(4-AMINOPHENYL)piperidine

In accordance with the method of example 1(2), using 4-morpholinoethyl-N-(4-nitrophenyl)piperidine obtained in example 6(3), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained 4-morpholinoethyl-N-(4-AMINOPHENYL)piperidin whom (83%) as a reddish-purple solid.

1H-NMR (CDCl3): δ (ppm) 1,28-to 1.98 (m, 7H), 2,32-by 2.73 (m, 8H), 3,20-3,90 (m, 8H), 6,62 (d, J=8,8 Hz, 2H), 6,80 (d, J=8,8 Hz, 2H)

Example 6(5)

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholinobutyrophenone-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 1(3), using 4-morpholinoethyl-N-(4-AMINOPHENYL)piperidine obtained in example 6(4), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholinobutyrophenone-1-yl)phenyl)-1-piperazinecarboxamide (88%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1.30 and of 1.55 (m, 5H), 1.70 to 1,89 (m, 2H), 2,34 is 2.75 (m, 8H), 3,47-3,90 (m, 14N), of 3.80 (s, 3H), 6,05-6,13 (m, 1H), 6,27 (USS, 1H), 6,32-6,40 (m, 1H), 6,68 to 6.75 (m, 1H), 6.89 in (d, J=8,9 Hz, 2H), then 7.20 (d, J=8,9 Hz, 2H)

Example 7

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(1,2,3-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

Example 7(1)

4-[2-(1,2,3-triazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine

In accordance with the method of example 6(3), using 1,2,3-triazole instead of the research was obtained 4-[2-(1,2,3-triazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine (39%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,25-1,72 (m, 3H), 1.77 in-2,05 (m, 4H), 2,84 was 3.05 (m, 2H), a 3.87-Android 4.04 (m, 2H), 4,49 (t, J=7,1 Hz, 2H), 6,80 (d, J=9.5 Hz, 2H), 7,56 (d, J=0.8 Hz, 1H), 7,73 (d, J=0.8 Hz, 1H), 8,10 (d, J=9.5 Hz, 2H)

Example 7(2)

4-[2-(1,2,3-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine

In accordance with the method of example 1(2), using 4-[2-(1,2,3-triazole-1-yl)ethyl]-N-(4-nitrophenyl)PIP is ridin, obtained in example 7(1), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained 4-[2-(1,2,3-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine (91%) as a reddish-purple solid.

1H-NMR (CDCl3): δ (ppm) 1,23-to 1.60 (m, 3H), 1,65 is 2.10 (m, 4H), 2,44-by 2.73 (m, 2H), 3,10-of 3.75 (m, 4H), to 4.46 (t, J=7.4 Hz, 2H), 6,63 (d, J=8.7 Hz, 2H), for 6.81 (d, J=8.7 Hz, 2H), 7,55 (s, 1H), 7,71 (s, 1H)

Example 7(3)

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(1,2,3-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 1(3)using 4-[2-(1,2,3-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine obtained in example 7(2), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(1,2,3-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide (50%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1,31-of 1.53 (m, 3H), 1,72 is 2.00 (m, 4H), 2,55-2,78 (m, 2H), 3.46 in-3,66 (m, 6H), to 3.73-to 3.92 (m, 4H), of 3.80 (s, 3H), 4,47 (t, J=7.4 Hz, 2H), 6,05-6,14 (m, 1H), 6,32 (USS, 1H), 6,28-to 6.43 (m, 1H), 6,69-6,76 (m, 1H), to 6.88 (d, J=9.0 Hz, 2H), 7,21 (d, J=9.0 Hz, 2H), 7,56 (d, J=0.7 Hz, 1H), 7,72 (d, J=0.7 Hz, 1H)

Example 8

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(1,2,4-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

Example 8(1)

4-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine

In accordance with the method of example 6(3)using 1,2,4-triazole instead of the research was obtained 4-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine (78%) as a yellow solid

1H-NMR (CDCl3): δ (ppm) 1,23-of 1.65 (m, 3H), 1,74-2,03 (m, 4H), 2,82-to 3.09 (m, 2H), 3,85-4,08 (m, 2H), 4.26 deaths (t, J=7,1 Hz, 2H), 6,80 (d, J=9.4 Hz, 2H), 7,95 (s, 1H), 8,08 (s, 1H), 8,10 (d, J=9.4 Hz, 2H)

Example 8(2)

4-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine

In accordance with the method of example 1(2), using 4-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine obtained in example 8 (1), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained 4-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine (99%) as a reddish-purple solid.

1H-NMR (CDCl3): δ (ppm) 1,20-of 1.55 (m, 3H), 1,66-1,90 (m, 4H), 2,43-of 2.64 (m, 2H), 3.27 to 3,44 (m, 2H), 3.45 points-of 4.05 (ush., 2H), 4,16 (t, J=7,3 Hz, 2H), 6,55 (d, J=8.6 Hz, 2H), 6,77 (d, J=8.6 Hz, 2H), a 7.85 (s, 1H), 8,01 (s, 1H)

Example 8(3)

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(1,2,4-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 1(3)using 4-[2-(1,2,4-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine obtained in example 8(2), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(1,2,4-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide (45%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1.30 and to 1.98 (m, 7H), 2,53 is 2.75 (m, 2H), 3.43 points-to 3.67 (m, 6H), 3,71-to 3.92 (m, 4H), of 3.80 (s, 3H), 4,25 (t, J=7,3 Hz, 2H), 6,07-x 6.15 (m, 1H), 6,27 (USS, 1H), 6,29-6.42 per (m, 1H), 6,67-6,74 (m, 1H), to 6.88 (d, J=9.0 Hz, 2H), 7,21 (d, J=9.0 Hz, 2H), 7,95 (s, 1H), 8,07 (s, 1H)

Example 9

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(3,5-dimethyl-1,2,4-triazole-1-yl)what Teal)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

Example 9(1)

4-[2-(3,5-dimethyl-1,2,4-triazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine

In accordance with the method of example 6(3), using 3,5-dimethyl-1,2,4-triazole instead of the research was obtained 4-[2-(3,5-dimethyl-1,2,4-triazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine (84%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,25-1,90 (m, 7H), of 2.33 (s, 3H), 2,41 (s, 3H), 2,86 was 3.05 (m, 2H), 3,88-4,10 (m, 4H), to 6.80 (d, J=9.4 Hz, 2H), 8,10 (d, J=9.4 Hz, 2H)

Example 9(2)

4-[2-(3,5-dimethyl-1,2,4-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine

In accordance with the method of example 1(2), using 4-[2-(3,5-dimethyl-1,2,4-triazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine obtained in example 9(1), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained 4-[2-(3,5-dimethyl-1,2,4-triazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine (97%) as a reddish purple solid.

1H-NMR (CDCl3): δ (ppm) 1,28-of 1.55 (m, 3H), 1,62-1,89 (m, 4H), of 2.33 (s, 3H), 2.40 a (s, 3H), 2,47-of 2.66 (m, 2H), 3,10-of 3.60 (m, 4H), 3,98-4,10 (m, 2H), only 6.64 (d, J=8.7 Hz, 2H), for 6.81 (d, J=8.7 Hz, 2H)

Example 9(3)

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(3,5-dimethyl-1,2,4-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 1(3)using 4-[2-(3,5-dimethyl-1,2,4-triazole-1-yl)-ethyl]-N-(4-AMINOPHENYL)piperidine obtained in example 9(2), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(3,5-dimethyl-1,2,4-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide (76%) is the form of a white solid.

1H-NMR (CDCl3): δ (ppm) 1.30 and of 1.55 (m, 3H), 1,72-of 1.95 (m, 4H), of 2.33 (s, 3H), 2.40 a (s, 3H), 2.57 m is 2.75 (m, 2H), 3,48-the 3.65 (m, 6H), to 3.73-3,90 (m, 4H), of 3.80 (s, 3H), a 4.03 (t, J=7.5 Hz, 2H), 6,06-6,13 (m, 1H), of 6.31-6,38 (m, 1H), 6,40 (USS, 1H), 6,68-6,74 (m, 1H), to 6.88 (d, J=9.1 Hz, 2H), 7,21 (d, J=9.1 Hz, 2H)

Example 10

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(pyrazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

Example 10 (1)

4-[2-(pyrazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine

In accordance with the method of example 6(3), using the pyrazole instead of the research was obtained 4-[2-(pyrazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine (72%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,23-to 1.67 (m, 3H), 1,76-to 1.98 (m, 4H), 2,84 was 3.05 (m, 2H), 3,85-a 4.03 (m, 2H), 4,21 (t, J=7,1 Hz, 2H), 6,21-6,34 (m, 1H), 6,79 (d, J=9.4 Hz, 2H), of 7.36 was 7.45 (m, 1H), of 7.48-EUR 7.57 (m, 1H), 8,10 (d, J=9.4 Hz, 2H)

Example 10(2)

4-[2-(pyrazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine

In accordance with the method of example 1(2), using 4-[2-(pyrazole-1-yl)ethyl]-N-(4-nitrophenyl)piperidine obtained in example 10(1), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained 4-[2-(pyrazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine (83%) as a reddish-purple solid.

1H-NMR (CDCl3): δ (ppm) 1,25-of 1.64 (m, 3H), 1,73 is 1.96 (m, 4H), of 2.51-2,70 (m, 2H), 3,38-of 3.53 (m, 2H), 4,10-2,70 (ush., 2H), 4,20 (t, J=7,3 Hz, 2H), and 6.25 (t, J=1.8 Hz, 1H), only 6.64 (d, J=8.7 Hz, 2H), 6,86 (d, J=8.7 Hz, 2H), 7,39 (d, J=1.8 Hz, 1H), 7,50 (d, J=1.8 Hz, 1H)

Example 10(3)

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(pyrazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

In soo is according to the method of example 1(3), using 4-[2-(pyrazole-1-yl)ethyl]-N-(4-AMINOPHENYL)piperidine obtained in example 10(2), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(pyrazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide (56%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1.30 and of 1.52 (m, 3H), 1.70 to of 1.97 (m, 4H), 2,53-to 2.74 (m, 2H), 3.45 points-to 3.67 (m, 6H), 3,71-3,93 (m, 4H), of 3.80 (s, 3H), 4,20 (t, J=7,3 Hz, 2H), 6,06-6,18 (m, 1H), 6.22 per 6,40 (m, 3H), 6,67-of 6.78 (m, 1H), to 6.88 (d, J=9.0 Hz, 2H), 7,20 (d, J=9.0 Hz, 2H), 7,39 (d, J=2.3 Hz, 1H), 7,51 (d, J=1.6 Hz, 1H)

Example 11

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(3-(1,2,4-triazole-1-yl)propyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

Example 11(1)

4-hydroxypropyl-N-(4-nitrophenyl)piperidine

In accordance with the method of example 1(1), using 4-hydroxypropiophenone instead of 4-hydroxypiperidine, received 4-hydroxypropyl-N-(4-nitrophenyl)piperidine (46%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,19-of 1.97 (m, 10H), 2,85-is 3.08 (m, 2H), 3,57 is 3.76 (m, 2H), 3,88-of 4.05 (m, 2H), 6,79 (d, J=9.6 Hz, 2H), 8,10 (d, J=9.6 Hz, 2H)

Example 11(2)

4-tiloxapol-N-(4-nitrophenyl)piperidine

In accordance with the method of example 4(2), using 4-hydroxypropyl-N-(4-nitrophenyl)piperidine obtained in example 11(1), instead of 4-hydroxymethyl-N-(4-nitrophenyl)piperidine was obtained 4-tiloxapol-N-(4-nitrophenyl)piperidine (97%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,15-of 1.84 (m, 9H), of 2.45 (s, 3H), 2,82-3,03 (m, 2H), ,84-4,00 (m, 2H), Android 4.04 (t, J=6.3 Hz, 2H), 6,78 (d, J=9.6 Hz, 2H), 7,35 (d, J=7.9 Hz, 2H), 7,79 (d, J=7.9 Hz, 2H), 8,10 (d, J=9.6 Hz, 2H)

Example 11(3)

4-[3-(1,2,4-triazole-1-yl)propyl]-N-(4-nitrophenyl)piperidine

4-tiloxapol-N-(4-nitrophenyl)piperidine (4,19 g, 10.0 mmol)obtained in example 11(2), was dissolved in acetonitrile (40 ml) was added potassium carbonate (2.76 g, 20 mmol) and 1,2,4-triazole (1.04 g, 15.0 mmol), then stirred at 80°C for 18 hours. After cooling the reaction mixture to room temperature, was added ethyl acetate in the reaction mixture, and the organic layer was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered and then the residue obtained by evaporation under reduced pressure, was purified flash chromatography (medium pressure column with silica gel (methanol:chloroform = 1:100 to 1:30), was obtained 4-[3-(1,2,4-triazole-1-yl)propyl]-N-(4-nitrophenyl)piperidine (2,47 g, 78%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,17-of 1.39 (m, 4H), 1,45-of 1.65 (m, 1H), 1.70 to 2.05 is (m, 4H), 2,83 was 3.05 (m, 2H), 3,84-was 4.02 (m, 2H), 4,18 (t, J=7,1 Hz, 2H), 6,79 (d, J=9.6 Hz, 2H), 7,95 (s, 1H), with 8.05 (s, 1H), 8,10 (d, J=9.6 Hz, 2H)

Example 11(4)

4-[3-(1,2,4-triazole-1-yl)propyl]-N-(4-AMINOPHENYL)piperidine

In accordance with the method of example 1(2), using 4-[3-(1,2,4-triazole-1-yl)propyl]-N-(4-nitrophenyl)piperidine obtained in example 11(3), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained 4-[3-(1,2,4-triazole-1-yl)impregnated is]-N-(4-AMINOPHENYL)piperidine (95%) as a reddish-purple solid.

1H-NMR (CDCl3): δ (ppm) of 1.20 to 1.48 (m, 5H), 1,65-2,07 (m, 4H), 2,43 of 2.68 (m, 2H), 3,06-of 3.77 (m, 4H), 4,17 (t, J=7,1 Hz, 2H), 6,63 (d, J=8,9 Hz, 2H), PC 6.82 (d, J=8,9 Hz, 2H), 7,94 (s, 1H), with 8.05 (s, 1H)

Example 11(5)

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(3-(1,2,4-triazole-1-yl)propyl)piperidine-1-yl)phenyl)piperazinecarboxamide

In accordance with the method of example 1(3), used 4-[3-(1,2,4-triazole-1-yl)propyl]-N-(4-AMINOPHENYL)piperidine obtained in example 11(4), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(3-(1,2,4-triazole-1-yl)propyl)piperidine-1-yl)phenyl)piperazinecarboxamide (67%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) of 1.20 to 1.48 (m, 5H), 1,66-2,05 (m, 4H), 2,52-to 2.74 (m, 2H), 3,44-the 3.65 (m, 6H), of 3.80 (s, 3H), 3.75 to to 3.92 (m, 4H), 4,17 (t, J=7,1 Hz, 2H), 6,05-6,14 (m, 1H), of 6.31 (USS, 1H), 6.30-in-6,44 (m, 1H), 6,67-6,79 (m, 1H), to 6.88 (d, J=9.1 Hz, 2H), 7,20 (d, J=9.1 Hz, 2H), 7,95 (s, 1H), with 8.05 (s, 1H)

Example 12

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(3-(1,2,3-triazole-1-yl)propyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

Example 12 (1)

4-[3-(1,2,3-triazole-1-yl)propyl]-N-(4-nitrophenyl)piperidine

In accordance with the method of example 7(1), using 4-tiloxapol-N-(4-nitrophenyl)piperidine obtained in example 11(2), instead of 4-Casinocity-N-(4-nitrophenyl)piperidine was obtained 4-[2-(1,2,3-triazole-1-yl)propyl]-N-(4-AMINOPHENYL)piperidine (69%) as a yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,16-of 1.40 (m, 4H), 1,48-to 1.67 (m, 1H), 1.70 to of 2.09 (m, 4H), 2,83 was 3.05 (m, 2H), 3,85-a 4.03 (m, 2H), and 4.40 (t, J=7,1 Hz, 2H, 6,79 (d, J=9.6 Hz, 2H), 7,54 (d, J=0.9 Hz, 1H), 7,71 (d, J=0.9 Hz, 1H), 8,10 (d, J=9.6 Hz, 2H)

Example 12(2)

4-[2-(1,2,3-triazole-1-yl)propyl]-N-(4-AMINOPHENYL)piperidine

In accordance with the method of example 1(2), using 4-[2-(1,2,3-triazole-1-yl)propyl]-N-(4-nitrophenyl)piperidine obtained in example 12(1), instead of 4-hydroxy-N-(4-nitrophenyl)piperidine was obtained 4-[2-(1,2,3-triazole-1-yl)propyl]-N-(4-AMINOPHENYL)piperidine (94%) as a reddish-purple solid.

1H-NMR (CDCl3): δ (ppm) 1,23 of 1.46 (m, 5H), 1,59-to 1.87 (m, 2H), 1,90-2,05 (m, 2H), 2,45 2.63 in (m, 2H), 3,30-to 3.52 (m, 4H), and 4.40 (t, J=7.2 Hz, 2H), only 6.64 (d, J=8,8 Hz, 2H), for 6.81 (d, J=8,8 Hz, 2H), 7,53 (d, J=0.7 Hz, 1H), 7,71 (d, J=0.7 Hz, 1H)

Example 12(3)

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(3-(1,2,3-triazole-1-yl)propyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 1(3)using 4-[2-(1,2,3-triazole-1-yl)propyl]-N-(4-AMINOPHENYL)piperidine obtained in example 12(2), instead of 4-hydroxy-N-(4-AMINOPHENYL)piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(3-(1,2,3-triazole-1-yl)propyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide (57%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) to 1.22 to 1.48 (m, 5H), 1,68-of 2.08 (m, 4H), 2,50-of 2.72 (m, 2H), 3,45-3,66 (m, 6H), of 3.80 (s, 3H), of 3.73-3,90 (m, 4H), 4,39 (t, J=7,1 Hz, 2H), 6,07-6,14 (m, 1H), 6.30-in-6,45 (m, 2H), 6,68-6,77 (m, 1H), 6,87 (d, J=8,9 Hz, 2H), 7,21 (d, J=8,9 Hz, 2H), 7,55 (d, J=0.8 Hz, 1H), 7,71 (d, J=0.8 Hz, 1H)

Example 13

4-((1-acylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazin Roxane

Example 13(1)

4-(benzyloxycarbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

4-nitrophenylphosphate (7,26 g, 36,0 mmol) was dissolved in tetrahydrofuran (100 ml), and tertrahydrofuran ring solution (50 ml) of 1-(4-AMINOPHENYL)piperidine-4-morpholinylcarbonyl (8,68 g, 30.0 mmol)obtained in example 3(3), was added dropwise at -30°C. After stirring for 30 minutes at this temperature was added to a mixture of tertrahydrofuran ring solution (30 ml) N-benzyloxycarbonylglycine (7,27 g, 33.0 mmol) and triethylamine (of 14.0 ml, 100 mmol), then stirred at room temperature for 13 hours and then at 60°C for 4 hours. After cooling the reaction mixture to room temperature, was added a dilute aqueous solution of sodium hydroxide, and then extraction was performed with ethyl acetate. The organic layer was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered and then the residue obtained by evaporation under reduced pressure, was purified flash chromatography (medium pressure column of silica gel (silica gel, methanol:chloroform = 0:1 to 1:30), thereby obtaining 4-(benzyloxycarbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide (9,02 g, 56%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1,72-1.87 m, 2H), 1,90-2,12 (m, 2H), 2,47-2,78 (m, 3H), 3,38-of 3.77 (m, N), 5,16 (s, 2H), 6,24 (s, 1H), to 6.88 (d, J=8,9 Hz, 2H), 7,20 (d, J=8,9 Hz, 2H), 7,29-7,44 (m, 5H)

Example 13 (2)

N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

4-(benzyloxycarbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide (of 5.89 g, 11.0 mmol)obtained in example 13(1), suspended in tetrahydrofuran (80 ml) and methanol (80 ml) was added 10% palladium on carbon (1.5 g), then stirred at room temperature in the environment of hydrogen gas for 18 hours. After filtering through celite to remove insoluble materials, the filtrate was concentrated under reduced pressure, and the obtained residue was purified flash chromatography (medium pressure column of silica gel (NH silica gel, methanol:chloroform = 1:50 to 1:15), thereby obtaining N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide (3,62 g, 82%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1,73 is 1.86 (m, 2H), 1,90-2,10 (m, 2H), 2,48 was 2.76 (m, 3H), 2,83-3,00 (m, 4H), 3,35-of 3.78 (m, 15H), to 6.22 (s, 1H), to 6.88 (d, J=9.1 Hz, 2H), 7,22 (d, J=9.1 Hz, 2H)

Example 13(3)

4-((1-acylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

1-acylpyrrole-2-carboxylic acid (153 mg, 1.1 mmol) was dissolved in N,N-dimethylformamide (3.0 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (253 mg, 1.3 mmol), 1-hydroxy is benzotriazole monohydrate (185 mg, 1.2 mmol) and N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide (201 mg, 0.5 mmol)obtained in example 13(2), then stirred under heating at 60°C for 15 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and then extraction was performed with chloroform. The extract was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered and then the residue obtained by evaporation under reduced pressure, was purified flash chromatography (medium pressure column with silica gel (methanol:chloroform = 1:50 to 1:30), thereby obtaining 4-((1-acylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide (228 mg, 44%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) to 1.38 (t, J=7,3 Hz, 3H), 1,72 is 2.10 (m, 4H), 2,48 is 2.80 (m, 3H), 3,40-to 3.92 (m, N), 4,18 (kV, J=7,3 Hz, 2H), between 6.08 and of 6.17 (m, 1H), 6,28-6,40 (m, 1H), 6,37 (USS, 1H), 6.75 in-6,83 (m, 1H), 6.89 in (d, J=8,9 Hz, 2H), 7,22 (d, J=8,9 Hz, 2H)

Example 14

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-piperidine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

4-((((1-methylpyrrole-2-yl)carbonyl)-1-piperazinil)carbonyl)amino-4-phenylpiperidine-4-carboxylic acid (440 mg, 1.0 mmol)obtained in example 2(4), was dissolved in N,N-dimethylformamide (3 ml) was added 1-ethyl-3-(3-what dimetilaminometil)carbodiimide hydrochloride (230 mg, 1.2 mmol), 1-hydroxybenzotriazole monohydrate (168 mg, 1.1 mmol) and piperidine (of 0.12 ml, 1.2 mmol), then stirred under heating at 60°C for 6 hours. After cooling the reaction mixture to room temperature, was added a saturated aqueous solution of sodium bicarbonate, then extraction was performed with ethyl acetate. The organic layer was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered and then the residue obtained by evaporation under reduced pressure, was purified flash chromatography (medium pressure column with silica gel (methanol:chloroform = 1:50 to 1:20), thereby obtaining 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-piperidine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide (226 mg, 45%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1,58-to 1.67 (m, 6H), 1.77 in is 2.00 (m, 4H), 2,54-to 2.74 (m, 3H), 3,34-3,93 (m, 17H), 6,05-x 6.15 (m, 1H), 6,32-6,50 (m, 2H), 6,68-6,77 (m, 1H), 6.89 in (d, J=8,9 Hz, 2H), 7,21 (d, J=8,9 Hz, 2H)

Example 15

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(4-methylpiperazin-1-yl-carbonyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 14, using 1-methylpiperazine instead of piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(4-methylpiperazin-1-yl-carbonyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide (14%) as a milky white solid.

1H-NMR (CDCl3): δ (m is.) 1,63-of 2.15 (m, 4H), 2,30-2,77 (m, 10H), 3,52-3,93 (m, 17H), between 6.08-x 6.15 (m, 1H), 6.30-in-6,45 (m, 2H), 6,68 to 6.75 (m, 1H), to 6.88 (d, J=8.7 Hz, 2H), 7,22 (d, J=8.7 Hz, 2H)

Example 16

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-morpholinoethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 14 using 2-aminoethylphosphonic instead of piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-morpholinoethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide (38%) as a pale yellow solid.

1H-NMR (CDCl3): δ (ppm) 1,75-2,03 (m, 4H), 2,14-to 2.29 (m, 1H), 2,34 is 2.55 (m, 6H), 2,62-2,78 (m, 2H), 3,28-to 3.41 (m, 2H), 3,49-a 3.87 (m, 17H), 6,02-6,18 (m, 2H), of 6.31-6,40 (m, 1H), gold 6.43 (s, 1H), 6,67 to 6.75 (m, 1H), 6,88 (d, J=8,8 Hz, 2H), 7,22 (d, J=8,8 Hz, 2H)

Example 17

4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(pyridine-3-letiltasaval)piperidine-1-yl)phenyl)-1-piperazinecarboxamide

In accordance with the method of example 14 using 3-aminomethylpyridine instead of piperidine was obtained 4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(pyridine-3-letiltasaval)piperidine-1-yl)phenyl)-1-piperazinecarboxamide (33%) as a milky white solid.

1H-NMR (CDCl3): δ (ppm) 1,76 of 1.99 (m, 4H), 2,13-of 2.34 (m, 1H), 2,55-to 2.74 (m, 2H), 3,44-3,88 (m, 13H), of 4.44 (d, J=5,9 Hz, 2H), 6,10 (DD, J=2.7, and 3.8 Hz, 1H), 6,25-6,40 (m, 2H), 6,56 (s, 1H), 6,69-6,76 (m, 1H), 6,84 (d, J=8,9 Hz, 2H), 7,13-7,34 (m, 3H), 7,55-to 7.67 (m, 1H), 8,45 at 8.60 (m, 2H)

Reference examples

The way A

In accordance with the method of example 13(3), using the corresponding carboxylic acid instead of 1-atile the rol-2-carboxylic acid, received the specified connection.

Method B

N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide obtained in example 13(2), suspended in tetrahydrofuran and chloroform was added triethylamine and the corresponding acid chloride, then stirred at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and then perform the extraction with chloroform. The extract was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered and then the residue obtained by evaporation under reduced pressure, was purified flash chromatography (medium pressure column of silica gel, receiving the specified connection.

Reference example 1

4-((pyrrol-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method A, yield: 53%

1H-NMR (CDCl3): δ (ppm) 1,72 and 2.13 (m, 4H), 2.49 USD is 2.80 (m, 3H), 3.46 in-4,08 (m, N), 6,23-6,32 (m, 1H), 6,33 (USS, 1H), 6,50-6,63 (m, 1H), 6.89 in (d, J=8,9 Hz, 2H), 6.90 to-7,05 (m, 1H), 7.23 percent (d, J=8,9 Hz, 2H), 9,50 (USS, 1H)

Reference example 2

4-((3,5-dimethylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method A, yield: 25%

1H-NMR (CDCl3): δ (ppm) 1,60-of 2.15 (m, 4H), 2,11 (s, 3H), of 2.23 (s, 3H), 2,47-and 2.79 (m, 3H), 3,40-3,82 (m, N), 5,74 (d, J=2.6 Hz, 1H), 6,37-is 6.54 (m, 1H), to 6.88 (d, J=8,9 Hz, 2H), 7,21 (d, J=8,9 Hz, 2H), 8,63 (USS, 1H)

Reference example

4-((1-methylpyrrole-3-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method A, yield: 42%

1H-NMR (CDCl3): δ (ppm) 1,65-2,12 (m, 4H), 2,47 is 2.80 (m, 3H), 3.45 points-a 3.87 (m, N), to 3.67 (s, 3H), 6,24-6,32 (m, 1H), 6,47 (USS, 1H), 6,53-6,62 (m, 1H), to 6.88 (d, J=8,9 Hz, 2H), 6,98-7,05 (m, 1H), 7,22 (d, J=8,9 Hz, 2H)

Reference example 4

4-(thiophene-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method A, yield: 54%

1H-NMR (CDCl3): δ (ppm) 1.70 to 2,10 (m, 4H), 2,45 is 2.80 (m, 3H), 3,43-3,91 (m, N), 6,37 (USS, 1H), 6.89 in (d, J=8,9 Hz, 2H), 7,02-7,13 (m, 1H), 7,22 (d, J=8,9 Hz, 2H), 7,25-7,37 (m, 1H), 7,40-rate of 7.54 (m, 1H)

Reference example 5

4-(thiophene-3-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method B, yield: 70%

1H-NMR (CDCl3): δ (ppm) 1,72 is 2.10 (m, 4H), 2,48 is 2.80 (m, 3H), 3,38-to 3.89 (m, N), 6,44 (USS, 1H), to 6.88 (d, J=8,9 Hz, 2H), 7,15-7,27 (m, 3H), 7,37 (DD, J=4,9, 3.0 Hz, 1H), 7,55 (DD, J=3,0, 1.3 Hz, 1H)

Reference example 6

4-((furan-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method B, yield: 76%

1H-NMR (CDCl3): δ (ppm) 1,71 is 2.10 (m, 4H), 2,48-of 2.81 (m, 3H), 3.45 points-of 4.00 (m, N), 6,34-6,46 (m, 1H), 6,51 (DD, J=3,5, 1.8 Hz, 1H), 6.89 in (d, J=8,9 Hz, 2H), 7,06 (DD, J=3,5, 0.8 Hz, 1H), 7,22 (d, J=8,9 Hz, 2H), 7,51 (DD, J=1,8, 0.8 Hz, 1H)

Reference example 7

4-((furan-3-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method A, yield: 58%

1H-NMR (CDCl3): δ (ppm) 1,73-2,07 (m, 4H), 2,50-2,84 (m, 3H), 3,47-of 3.85 (m, N), 6,53-6,62 (m, 1H), 6.87 in (d,J=8,9 Hz, 2H), 7,29 (d, J=8,9 Hz, 2H), 7,45-7,53 (m, 1H), 7,70 for 7.78 (m, 1H), 7,85 (USS, 1H)

Reference example 8

4-(isoxazol-5-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method B, yield: 56%

1H-NMR (CDCl3): δ (ppm) 1,72-of 2.09 (m, 4H), 2,49-2,78 (m, 3H), 3,48-3,90 (m, N), 6,37 (USS, 1H), at 6.84 (d, J=1.8 Hz, 1H), 6.89 in (d, J=9.1 Hz, 2H), 7,21 (d, J=9.1 Hz, 2H), 8.34 per (d, J=1.8 Hz, 1H)

Reference example 9

4-((1-Mei-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method A, yield: 27%

1H-NMR (CDCl3): δ (ppm) 1,73 is 2.10 (m, 4H), 2,47 is 2.80 (m, 3H), 3,47-3,88 (m, N), 3,91 (s, 3H), 4,14-4,34 (m, 2H), 6,27 (USS, 1H), 6.89 in (d, J=8,9 Hz, 2H), of 6.96 (d, J=1.2 Hz, 1H), 7,05 (d, J=1.2 Hz, 1H), 7,22 (d, J=8,9 Hz, 2H)

Reference example 10

4-(cyclopentanecarbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method B, yield: 84%

1H-NMR (CDCl3): δ (ppm) 1,50-2,11 (m, N), 2,47 are 2.98 (m, 4H), 3,34-of 3.80 (m, N), 6,44 (USS, 1H), to 6.88 (d, J=8,9 Hz, 2H), 7,21 (d, J=8,9 Hz, 2H)

Reference example 11

4-(benzoyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method B, yield: 69%

1H-NMR (CDCl3): δ (ppm) 1.70 to 2,10 (m, 4H), 2,47-2,77 (m, 3H), 3,30-3,95 (m, N), of 6.49 (USS, 1H), 6.87 in (d, J=9.1 Hz, 2H), 7,20 (d, J=9.1 Hz, 2H), 7,32-to 7.50 (m, 5H)

Reference example 12

4-((1-methylindol-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide

Method A, yield: 59%

1H-NMR (CDCl3): δ (ppm) 1,72 is 2.10 (m, 4H), 2,47-and 2.79 (m, 3H), 3,47-3,95 (m, 21H), 6,30 (s, 1H), 6,63 d, J=0.5 Hz, 1H), 6.89 in (d, J=8,9 Hz, 2H), 7,11-the 7.43 (m, 5H), to 7.64 (d, J=7.9 Hz, 1H)

Reference example 13

4-(3-perbenzoic)piperazine-1-carboxylic acid-(6-bromobenzimidazole-2-yl)amide

Reference example 14

4-(3-perbenzoic)piperazine-1-carboxylic acid-(5,6-dimethylbenzothiazole-2-yl)amide

Reference example 15

4-(3-perbenzoic)piperazine-1-carboxylic acid-(6-methylbenzothiazol-2-yl)amide

Reference example 16

4-(3-perbenzoic)piperazine-1-carboxylic acid-(6-methoxybenzothiazole-2-yl)amide

Reference example 17

4-(3-perbenzoic)piperazine-1-carboxylic acid-(6-chlorobenzothiazole-2-yl)amide

Reference example 18

4-(6-herperidin-2-carbonyl)piperazine-1-carboxylic acid-(4-triptoreline)amide

Reference examples 13 to 18 was synthesized according to the methods of the methods disclosed in international publication WO2008-122787.

Reference example 19

N-methoxy-N-methyl-4-(5-benzylbenzimidazole-2-yl) - for 3,5-dimethylpyrrole-2-carboxamide

The synthesis was performed by the method disclosed in international publication WO2007-007778.

Examples of research

Example study 1: Inhibitory activity against hematopoietic prostaglandin D synthase (H-PGDS)

The tests were performed in accordance with the method Urade, Y. et al. (J. Biol. Chem., 262, 3820-3825, (1987)). More specifically, the reaction mixture (49 μl)containing 100 mm Tris-HCl (pH 8.0), 1 mm restored glutathione, 0.1 mg/ml γ-Glo is Alina and human H-PGDS (q.s), the compound (final concentration: 0.01 to 100 μm), pre-incubated at 25°C for 5 minutes. A solution of DMSO (final concentration: 1%) was added to the solvent control group. Then added 1 μl of [14C] prostaglandin-H2 (final concentration: 10 μm) to start the reaction. After one minute after start of the reaction, was added 250 μl of stopping the reaction solution (diethyl ether/methanol/1M citric acid (30/4/1)) at a temperature of -20°C to terminate the reaction. After stopping the reaction with 50 μl of the upper part of the layer (phase organic solvent) was applied on the plate for thin-layer chromatography and dispersed at -20°C for 45 min (mobile phase: diethyl ether/methanol/acetic acid (90/2/1)). After drying, the TLC plates TLC plates showed within 1-24 hours and analyzed radioactivity corresponding to prostaglandin D2 (PGD2), using the image analyzer (Fujifilm Corporation manufacturer). Area (%)corresponding to the binding of PGD2 to pass, was calculated to determine the degree of inhibition (%) 0.1 ám connections for each sample relative to the control group in each experiment, as well as inhibitory concentration at 50% (IC50 value (nm) in respect of H-PGDS. The results are shown in table 1.

Connection reference examples 1-12 are compounds in which (N-acylpyrrole-2-yl)carbonyl group, which is distinctive for the compounds of the present invention, replaced by another substitute, such as a heterocyclic ring. As shown in table 1, pieperazinove connection with (N-acylpyrrole-2-yl)carbonyl group, as in the compounds of the present invention, showed a strong inhibitory H-PGDS activity, while compounds in reference examples 1-12 showed little inhibitory activity.

Further compounds according to reference examples 13-17 are compounds with a structure similar to that of compounds of the present invention may have a structure including fermentology group and aminocarbonyl group, and show high inhibitory GST2 (Range A) activity. Connection reference example 18 is a connection involving ftorpirimidinu group and aminocarbonyl group, and is effective against metabolic syndrome in mice. All these compounds are disclosed in the source Patent Literature 3.

It is seen that the compounds of the present invention exhibit a stronger inhibitory H-PGDS activity is, than by reference to the examples 13-18.

Example research 2

Activity against inhibition of PGD2 production in the nasal cavity of Guinea pigs with antigen-induced rhinitis

Physiological saline solution containing 1 mg/ml ovalbumin, was subcutaneously injected into the back of 5-week old male Guinea pigs Std:Hartley in the amount of 1 ml/body for active sensitization (initial sensitization). After one and two weeks after the initial sensitization 20 μl of physiological saline containing 10 mg/ml ovalbumin, was injected into each nasal cavity by using the pipettor (sensitization nazalnam the introduction). Three weeks after the initial sensitization, 20 μl of physiological saline containing 10 mg/ml ovalbumin, was injected into each nasal cavity by using the pipettor to cause reaction rhinitis.

The analyzed compound (30 mg/kg) orally was administered 1 hour before induction reaction rhinitis. Animals in the control group received only the oral environment.

30 minutes after induction of response rhinitis nasal cavity was washed under anesthesia by pentobarbital sodium. The wash fluid from the nasal cavity (phosphate-saline buffer containing 3 mm EDTA and 10 μm indomethacin) was applied using a peristaltic pump (Gilson, Inc.), in the direction from the trachea to the top of respi atomnogo tract a flow rate of 1 ml/min, and the fluid from the nasal cavities was collected for 1 minute. The collected fluid was centrifuged to separate the supernatant as the wash fluid from the nasal cavity. The concentration of PGD2 in the wash fluid from the nasal cavity was determined using an EIA kit (set of prostaglandin D2-MOX EIA, Cayman Chemical).

The rate of decrease in PGD2 in the wash fluid from the nasal cavity was calculated by the following formula. The results are shown in table 2.

The rate of decrease in PGD2 in the wash fluid from the nasal cavity (%) =

{(Concentration of PGD2 in the control group, the concentration of PGD2 in the group, which has introduced the connection) ÷ (concentration of PGD2 in the control group, the concentration of PGD2 in the normal group)} × 100

8 or more samples were taken from each group to determine whether the expression of activity against inhibition of PGD2 activity, and compared the concentrations of PGD2 in the wash fluid from the nasal cavity of the control group and each value in the group, which was administered connection. It should be noted that cases in which the significance level was below 0.05 were considered as having activity, and they are marked in the table by the symbol (*). Reference example 19, known as a inhibitor H-PGDS was used as a positive control.

In accordance with the results presented in table 2, the compound of the present invention showing the rate of decrease in the concentration of PGD2, similar to that of reference example 19 (these connections are active). On the contrary, reference examples 13-18, open source Patent Literature 3, showed a significant reduction in the concentration of PGD2.

Example research 3

The activity in relation to inhibition of eosinophil infiltration in Guinea pigs with antigen-induced rhinitis

Phi is biologicheskii saline, containing 1 mg/ml ovalbumin, were injected subcutaneously in the back of male 5-week-old Guinea pigs Std:Hartley in the amount of 1 ml/body for active sensitization (initial sensitization). After one and two weeks after the initial sensitization, 20 μl of physiological saline containing 10 mg/ml ovalbumin, was injected into each nasal cavity by using the pipettor (sensitization nazalnam the introduction). Three weeks after the initial sensitization, 20 μl of physiological saline containing 10 mg/ml ovalbumin, was injected into each nasal cavity by using the pipettor to induce the reaction rhinitis.

The analyzed compound (30 mg/kg) was administered to a total of orally 3 times (2 times in sensitization nazalnam introduction and 1 time at the induction reaction rhinitis) for 1 hour prior sensitization or induction. Animals in the control group received only the oral environment.

6 hours after induction of the reaction rhinitis, nasal cavity was washed under anesthesia by pentobarbital sodium. The wash fluid from the nasal cavity (phosphate-saline buffer containing 3 mm EDTA and 10 μm indomethacin) was filed by a peristaltic pump (Gilson, Inc.) in the direction from the trachea to the upper respiratory tract at a flow rate of 1 ml/min and the liquid from the cavities of the nose was collected for 3 minutes. Collected was incostitutional through the cell filter (40 μm) and centrifuged at 4°C, 300×g for 10 minutes. Then the supernatant was removed by suction. 250 ál of wash liquid from the nasal cavity was added to the cell pellets, forming a suspension. The total number of cells (×10⁵cells) of cell suspension was determined using an automated Hematology counter (F-820, Sysmex Corporation).

Cell smear was prepared on a centrifuge device for collecting cells (Cytospin-3, Shandon). After staining of cells staining solution were counting the number of monocytes, the number of eosinophils and the number of neutrophils, so that the total number of cells was 300 cells observed under the microscope (200x magnification). Calculate the ratio of the components of each cell and the number of eosinophils in the wash fluid from the nasal cavity was determined by the following formula.

The number of eosinophils (×10⁵cells) =

(The number of eosinophils ÷ total estimated quantity (300)) × total number of cells

The fall in the number of eosinophils in the wash liquid in the nasal cavity was calculated as an indicator of inhibition eosinophiles infiltration was determined by the following formula. The results are shown in table 3.

The rate of inhibition (%) =

{(The number of eosinophils in the control group the number of eosinophils in the group which was administered compounds) ÷ (the number of eosinophils in the control is the group - the number of eosinophils in the normal group)} × 100

16 samples were selected from each group, and compared the number of eosinophils in the wash fluid from the nasal cavity from the control group with each value of the group in which he introduced the connection. It should be noted that cases in which the significance level was below 0.05 were considered as having activity, and they are marked in the table (*)characters.

As can be seen from the results shown in table 3, the compounds of the present invention show significant activity in relation to inhibition of eosinophil is infiltratio. On the contrary, reference examples 13-17, open source Patent Literature 3, as compounds with high inhibitory GST2 (Range A) activity or increased eosinophilic infiltration, showed no significant activity in relation to inhibition of eosinophil infiltration.

Example research 4

Research on the strength of grip of the front limbs of mice

The studies used a 4-week-old male mice C57BL/10-mdx (mdx) as the group with the disease, and 4-week-old male mice C57BL/10Sn (wild-type) as the normal group. After transportation mice kept for a period of acclimatization. The original settings of each subject was measured at 5 weeks of age and were selected 10 mice from each group. The next day the analyzed compound (30 mg/kg) was administered to mice orally once a day consecutively for 4 weeks. Animals in the control group received only the carrier for oral administration. Force capture of the forelimb were measured at 4 weeks after the beginning of the introduction. The value obtained by dividing the average of 5 measured values (kg) grip force of the forelimb, obtained using a small device measuring grip force of the animal (GPM-100M, Melquest), body weight (kg), used as an indicator for evaluation (reference literature: Muscle Nerve., 35, 43-48 (2007)).

9 or more who Bristow were selected from each group to determine whether the expression of activity in relation to increasing the grip force of the forelimb. First, it was confirmed by a significant decrease in the values of the control group compared with those in the normal group, and then compares the value of the control group with the group that was administered the compound. Cases in which the significance level was below 0.05 were considered as having activity, and they are marked in the table of symbols (#) and (*). The results are shown in table 4.

In accordance with the results presented in table 4 observed a significant decrease in muscle strength in the control group compared with normal group. Clearly shows that the compound of the present invention exhibits activity towards strengthening the grip force of the forelimb compared with the control group. Then as in reference examples 13-17 any significant activity was absent.

1. Pieperazinove compound represented by formula (I),

where R¹represents a C_1-6alkyl;
R²represents hydroxy, C_1-6alkyl, which may contain a Deputy chosen from saturated or unsaturated 5-6 membered heterocycle with 1 to 3 heteroatoms selected from oxygen and nitrogen,
-(C=O)-N(R³)(R⁴or -(C=O)-OR⁵;
R³and R⁴can be the same or different and each represents hydrogen or C_1-6alkyl, which may contain a Deputy chosen from saturated or unsaturated 5-6 membered heterocycle with 1 to 3 heteroatoms selected from oxygen and nitrogen, or
R³and R⁴connected through the nitrogen atom is attached to R³and R⁴,
may form a saturated heterocyclic group selected from 5-6 membered heterocycle is 1 to 3 heteroatoms, selected from oxygen and nitrogen;
R⁵represents hydrogen or C_1-6alkyl; and
n represents 1 or 2; or its salt.

2. Pieperazinove compound or its salt according to claim 1, where
R¹represents methyl or ethyl;
R²represents hydroxy, C_1-6alkyl which may have one or more saturated or unsaturated 5-6 membered heterocyclic group with 1-3 heteroatoms, selected from oxygen and nitrogen as substituents, -(C=O)-N(R³)(R⁴or -(C=O)-OR⁵; R³and R⁴can be the same or different and each represents hydrogen or C_1-6alkyl which may have one or more saturated or unsaturated 5-6 membered heterocyclic group with 1-3 heteroatoms, selected from oxygen and nitrogen, as substituents, or
R³and R⁴connected through the nitrogen atom is attached to R³and R⁴can generate pyrrolidinyl, piperidinyl, piperazinil, morpholino;
R⁵represents hydrogen, methyl, ethyl, tert-butyl; and n represents 1 or 2.

3. Pieperazinove compound or its salt according to claim 1, where R¹represents methyl;
R²represents a C_1-3alkyl, which may contain morpholino,
pyrazolyl or triazolyl as to cover the oil, -(C=O)-N(R³)(R⁴or -(C=O)-OR⁵; and triazolyl may contain one or two substituent;
R³and R⁴connected through the nitrogen atom is attached to R³and R⁴,
can form morpholino;
R⁵represents hydrogen, methyl or ethyl; and
n represents 2.

4. Pieperazinove compound or its salt according to claim 1, where
R¹represents methyl;
R²is a linear C_1-3alkyl, which may contain any of 1,2,3-triazole, 3,5-dimethyl-1,2,4-triazolyl, morpholino as a substituent, -(C=O)-N(R³)(R⁴or -(C=O)-OR⁵;
R³and R⁴connected through the nitrogen atom is attached to R³and R⁴,
can form morpholino;
R⁵represents hydrogen or ethyl; and
n represents 2.

5. Pieperazinove compound or its salt according to claim 1, selected from the group consisting of the following:
N-(4-(4-hydroxypiperidine-1-yl)phenyl)-4-((1-methylpyrrole-2-yl)carbonyl)-1-piperazinecarboxamide,
4-((((1-methylpyrrole-2-yl)carbonyl)-1-piperazinil)carbonyl)amino-4-phenylpiperidine-4-carboxylic acid,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholinomethyl-1-yl)phenyl)-1-piperazinecarboxamide,
4((1-methylpyrrole-2-yl)carbonyl)-N-(4-(3-(2-(1,2,4-triazole-1-yl)ethyl)pyrrolidin-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholinobutyrophenone-1-yl)phenyl)-1-piperazinecarboxamide,
4-(1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(1,2,3-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(1,2,4-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(3,5-dimethyl-1,2,4-triazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-(pyrazole-1-yl)ethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(3-(1,2,4-triazole-1-yl)propyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(3-(1,2,3-triazole-1-yl)propyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-acylpyrrole-2-yl)carbonyl)-N-(4-(4-morpholine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-piperidine-1-yl-carbonitriding-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(4-methylpiperazin-1-yl-carbonyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide,
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(2-morpholinoethyl)piperidine-1-yl)phenyl)-1-piperazinecarboxamide and
4-((1-methylpyrrole-2-yl)carbonyl)-N-(4-(4-(pyridine-3-letiltasaval)piperidine-1-yl)phenyl)-1-piperazinecarboxamide.

6. Pharmaceutical composition, proyavlyaya the inhibitory activity against prostaglandin-D-synthase, comprising an effective amount of at least one of the compounds according to claims 1 to 5, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

7. The means for the prevention and/or treatment of diseases involving prostaglandin D2 or its metabolite, comprising an effective amount of a compound according to any one of claims 1 to 5, or its pharmaceutically acceptable salt.

8. The tool in accordance with claim 7, where the disease involving prostaglandin D2 or its metabolite, an allergic disease, inflammatory disease or myodegeneration disease.

9. The method of preventing and/or treating diseases involving prostaglandin D2 or its metabolite, comprising the administration to a mammal of a compound according to any one of claims 1 to 5 in a quantity effective to prevent or treat disease.

10. The use of compounds according to any one of claims 1 to 5 to obtain funds for the prevention and/or treatment of a disease in which prostaglandin D2 or its metabolite.

11. The use of compounds according to any one of claims 1 to 5 for the prevention and/or treatment of a disease in which prostaglandin D2 or its metabolite.