Triazolopyridine compound and action thereof as prolyl hydroxylase inhibitor and erythropoietin production inducer

FIELD: chemistry.

SUBSTANCE: invention relates to a triazolopyridine compound of general formula [I] or a pharmaceutically acceptable salt, where the partial structural formula: is a group represented by any of the following formulae: or R1 is (1) a hydrogen atom, (2) C1-6alkyl group, (3) phenyl group or (4) C3-8cycloalkyl group; R2 is (1) a hydrogen atom, (2) C1-10alkyl group, (3) phenyl group, optionally substituted with identical or different 1-3 substitutes selected from the following groupB, (4) C3-8cycloalkyl group, (5) C3-8cycloalkenyl group, (6) thienyl group, optionally substituted with 1 substitute selected from halogen or C1-6alkyl group, (7) phenyl-C1-6alkyl group (wherein phenyl is optionally substituted with different or identical 1-2 substitutes selected from halogen, C3-8cycloalkyl or halogen-C1-6alkyl group) or (8) C3-8cycloalkyl-C1-6alkyl group; R3 is (1) a hydrogen atom, (2) a halogen atom, (3) C1-6alkyl group, (4) phenyl group (6) phenyl-C1-6alkyl group; and each of R4 and R5 are both hydrogen atoms or a group B: (a) a halogen atom, (b) C1-6alkyl group, (c) C3-8cycloalkyl group, (d) cyano group and (e) halogen-C1-6alkyl group. The invention also relates to the specific compounds, a pharmaceutical composition based on the compound of formula [I] and to use of the compound with the formula [I].

EFFECT: obtaining novel triazolopyrine compounds, having inhibitory activity on prolyl hydroxylase and capable of inducing erythropoietin production.

30 cl, 34 tbl

 

The technical field to which the invention relates

The present invention relates to a new triazolopyridines the compounds having inhibitory activity against prolylhydroxylase (here and later in this document also referred to as "PHD") and the ability to induce the production of erythropoietin (hereinafter in this document also referred to as "EPO"). The present invention also relates to an inhibitor prolylhydroxylase (here and later in this document also referred to as "inhibitor PHD") and to the agent inducing the production of erythropoietin (hereinafter in this document also referred to as "agent, inducing the production of EPO").

The level of technology

EPO is a consisting of 165 amino acid hormone that promotes the growth of red blood cells. EPO is mainly produced in the kidney and partially in the liver and its production is increased in conditions of reduced oxygen content.

Anemia refers to a condition characterized by low content of red blood cells and hemoglobin in the blood. The symptoms result from oxygen starvation due to a reduced number of red blood cells or changes in the dynamics of blood flow due to increased breathing rate and heart rate to compensate for oxygen deficiency and include a "General feeling of weakness, the fatigue", "shortness of breath", "palpitations", "heavy head", "dizziness", "bad complexion, stiffness in the shoulders, difficulty awakening in the morning", etc.

The cause of anemia, usually divided into low production, increased destruction, and increased loss of red blood cells, and anemia include anemia due to disorders of hematopoiesis in the bone marrow, anemia due to iron deficiency, vitamin B12or folic acid, bleeding during an accident or surgery, anemia associated with chronic inflammation (autoimmune diseases, cancer, chronic transmissible diseases, plasmocytoma the dyscrasias, and so on), anemia associated with endocrine diseases (hypothyroidism, autoimmune polyglandular syndrome, diabetes mellitus type IA, dysfunctional uterine bleeding, and so on), anemia associated with chronic heart failure, anemia associated with ulcers, anemia associated with liver disease, senile anemia drug anemia, renal anemia (anemia associated with renal failure), anemia associated with chemotherapy, etc.

In 1989, the recombinant human EPO was approved by the Department for quality control of food and drug administration (FDA) for the application of the Oia in renal anemia, anemia associated with AZT therapy in patients with HIV, anemia associated with chemotherapy in patients with malignant tumor, or to reduce the amount of transfused blood for patients undergoing surgery. Moreover, its application was extended to anemia of prematurity, etc.,

Renal anemia treated with erythropoiesis stimulators (ESA). Renal anemia is mainly caused by decreased production of EPO in the interstitial cells at the periphery of the renal tubules of the kidney. There is an application in which recombinant human erythropoietin very often used as a Supplement to the EPO. Recombinant human erythropoietin has drastically reduced the number of patients requiring periodic blood transfusion, improved variety of symptoms associated with anemia, and has made a significant contribution to the improvement of ADL (activities of daily living) and QOL (quality of life). On the other hand, being a biological drug, it is costly and requires high medical costs. In addition, it has a short half-life of blood and requires intravenous 2-3 times per week after dialysis circuit in patients on hemodialysis. Thus, reducing the frequency of injection, it is desirable to prevent medical complications, as well as from the point of view of the volume of medical practices and medical waste the century Moreover, for patients on peritoneal dialysis and patients with renal insufficiency in predialysis period, for which was used a subcutaneous injection, providing a longer period, you still want a single injection per week or two weeks. In this case, the patient often requires a hospital visit only for the introduction of recombinant human erythropoietin, which creates a burden on patients.

Moreover, by modifying EPO adding a new circuit or sugar chain PEG was developed drug EPO prolonged effect, with a prolonged half-life from blood by intravenous injection or subcutaneous injection. However, because they were designed only injectable drugs for the prevention of medical complications and reduce the burden on patients is desirable to develop oral input ESA.

Moreover, it is assumed that oral input ESA will be applicable for a wider range of therapies not only renal anemia, but anemia due to various reasons.

As typical molecules that promote the transcription of EPO may be mentioned hypoxia-induced factor (here and later in this document also referred to as "HIF"). HIF is a protein consisting of heteroge the EPA, contains adjustable oxygen α-subunit and consistently expressed β-subunit, where the Proline in the α-subunit hydroxylases prolylhydroxylase (PHD) in the presence of oxygen, and the resulting α-subunit binds with protein von Hippel-Lindau (VHL) and ubiquitinated. However, since in conditions of reduced oxygen content of the α-subunit is not subject to hydroxylation PHD, it is not ubiquitinated, and is associated with intranuclear hypoxia-responsive element (HRE) for promotion of transcription of EPO below contains a gene HIF. Therefore, inhibition of PHD activity leads to the prevention of ubiquitinate HIF and its stabilization. Therefore, increased production of EPO.

Examples of diseases that are expected to be improved by inhibition of PHD to stabilize HIF include coronary heart disease (angina, myocardial infarction, and so on), ischemic cerebrovascular disorders (stroke, cerebral embolism, transient cerebral ischemic attacks and so on), types of chronic renal failure (ischemic nephropathy, tubulo-interstitial disorders of the kidneys, and so on), diabetic complications (diabetic ulcers and so on), cognitive impairment (dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and so on) and so on

CRATAERINA of the INVENTION

The tasks to be solved by the present invention

From the results obtained in earlier studies, it was found that the drug, which inhibits prolylhydroxylase (PHD), promotes the development of erythropoietin (EPO) and is effective for prevention or treatment of various diseases and pathologies (violations), caused by reduced secretion of EPO, in particular, for the treatment of anemia.

Accordingly, the present invention is directed to providing a drug possessing inhibitory activity against prolylhydroxylase (PHD). In addition, the present invention is directed to providing a drug with the ability to induce the production of EPO.

Means of solving problems

The authors of the present invention have found the compounds having inhibitory activity against prolylhydroxylase (PHD) and the ability to induce the production of EPO, and has issued the present invention.

More specifically the present invention relates to the next.

[1] a Compound represented by the following formula [I] (hereinafter also referred to as "compound of the present invention"), or its pharmaceutically acceptable salt, or its MES:

,

in which

partial structural formula:

represents a group represented by any of the following formulas:

;

R1represents a

(1) a hydrogen atom,

(2) C1-6alkyl group,

(3) C6-14aryl group,

(4) C3-8cycloalkyl group,

(5) C6-14aryl-C1-6alkyl group, or

(6) C3-8cycloalkyl-C1-6alkyl group;

R2represents a

(1) a hydrogen atom,

(2) C1-10alkyl group,

(3) C6-14aryl group, optionally substituted by same or different 1 to 5 substituents selected from the following group B,

(4) C3-8cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,

(5) C3-8cycloalkenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,

(6) heteroaryl group, optionally substituted by same or different 1 to 5 substituents selected from the following group B (in which heteroaryl contains, besides carbon atom, 1 to 6 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom),

(7) C6-14aryl-C1-6alkyl group (in which C6-14aryl optionally substituted by same or different 1 to 5 substituents selected from CL is blowing group B), or

(8) C3-8cycloalkyl-C1-6alkyl group (in which C3-8cycloalkyl optionally substituted by same or different 1 to 5 substituents selected from the following group B);

R3represents a

(1) a hydrogen atom,

(2) a halogen atom,

(3) C1-6alkyl group,

(4) C6-14aryl group,

(5) C3-8cycloalkyl group or

(6) C6-14aryl-C1-6alkyl group; and

each of R4and R5independently represents a

(1) a hydrogen atom, or

(2) C1-6alkyl group,

group B:

(a) a halogen atom,

(b) C1-6alkyl group,

(c) C3-8cycloalkyl group,

(d) cyano, and

(e) a halogen-C1-6alkyl group.

[2] the Compound described in the above item [1], in which the partial structural formula:

is a group represented by the following formula

,

or its pharmaceutically acceptable salt, or MES.

[3] the Compound described in the above item [1], in which the partial structural formula:

is a group represented by the following formula

,

or its pharmaceutically acceptable salt, or MES.

[4] Connect the group of described in the above item [1], in which the partial structural formula:

is a group represented by the following formula

,

or its pharmaceutically acceptable salt, or MES.

[5] the Compound described in the above item [1], in which the partial structural formula:

is a group represented by the following formula

,

or its pharmaceutically acceptable salt, or MES.

[6] the Compound described in any of the above paragraphs [1]-[5], in which R4and R5both represent hydrogen atoms, or its pharmaceutically acceptable salt, or MES.

[7] the Compound described in any of the above paragraphs [1]-[5], in which R3represents a hydrogen atom, or its pharmaceutically acceptable salt, or MES.

[8] the Compound described in any of the above paragraphs [1]-[5], in which R1represents a hydrogen atom, or its pharmaceutically acceptable salt, or MES.

[9] the Compound described in any of the above paragraphs [1]-[5], in which R2represents a

(1) C1-10alkyl group,

(2) C6-14aryl group, not necessarily for sennou the same or different 1 to 5 substituents, selected from the above group B,

(3) C6-14aryl-C1-6alkyl group (in which C6-14aryl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B), or

(4) C3-8cycloalkyl-C1-6alkyl group (in which C3-8cycloalkyl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B),

or its pharmaceutically acceptable salt, or MES.

[10] the Compound described in the above item [2], in which R4and R5both represent hydrogen atoms, or its pharmaceutically acceptable salt, or MES.

[11] the Compound described in the above item [10], in which R3represents a hydrogen atom, or its pharmaceutically acceptable salt, or MES.

[12] the Compound described in the above item [11], in which R1represents a hydrogen atom, or its pharmaceutically acceptable salt, or MES.

[13] the Compound described in the above item [12], in which R2represents a

(1) C1-10alkyl group, or

(2) C6-14aryl-C1-6alkyl group (in which C6-14aryl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B,

or its pharmaceutically acceptable salt, or MES.

[14] the Compound represented by the following formula [I-1], or its pharmaceutically acceptable salt, or its MES:

where the partial structural formula:

represents a group represented by any of the following formulas:

;

R11represents a

(1) a hydrogen atom,

(2) C1-6alkyl group,

(3) phenyl group,

(4) C3-8cycloalkyl group,

(5) phenyl-C1-6alkyl group, or

(6) C3-8cycloalkyl-C1-6alkyl group;

R21represents a

(1) a hydrogen atom,

(2) C1-10alkyl group,

(3) a phenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,

(4) C3-8cycloalkyl group,

(5) C3-8cycloalkenyl group,

(6) a thienyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,

(7) phenyl-C1-6alkyl group (in which the phenyl optionally substituted by same or different 1 to 5 substituents selected from the following group B), or

(8) C3-8cycloalkyl-C1-6alkyl group;

R31isone

(1) a hydrogen atom,

(2) a halogen atom,

(3) C1-6alkyl group,

(4) phenyl group,

(5) C3-8cycloalkyl group or

(6) phenyl-C1-6alkyl group; and

each of R41and R51independently represents a

(1) a hydrogen atom, or

(2) C1-6alkyl group;

group B:

(a) a halogen atom,

(b) C1-6alkyl group,

(c) C3-8cycloalkyl group,

(d) cyano, and

(e) a halogen-C1-6alkyl group.

[15] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[16] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[17] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[18] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[19] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[20] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[21] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[22] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[23] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[24] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[25] the Compound represented by the following formula:

,

or its pharmaceutically acceptable salt, or MES.

[26] the Pharmaceutical composition containing the compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES, and pharmaceutically acceptable carrier (hereinafter also referred to as "the pharmaceutical composition of the present invention").

[27] the Inhibitor prolylhydroxylase containing compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES.

[28] the Agent induzirovannomu erythropoietin, containing the compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES.

[29] a Therapeutic tool against anemia containing compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES.

[30] a Therapeutic agent against renal anemia containing compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES.

[31] Use of the compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES to obtain inhibitor prolylhydroxylase.

[32] Use of the compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES to obtain the agent inducing the production of erythropoietin.

[33] Use of the compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES to obtain a therapeutic agent against anemia.

[34] Use of the compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES to obtain a therapeutic agent against renal anemia.

[35] the Method of Inga the financing of prolylhydroxylase, includes introduction to the mammal an effective amount of the compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES.

[36] a Method of inducing production of erythropoietin, comprising the administration to a mammal an effective amount of the compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES.

[37] a Method of treating anemia, comprising the administration to a mammal an effective amount of the compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES.

[38] a Method of treating renal anemia, including introduction to the mammal an effective amount of the compound described in any of the above paragraphs [1]-[25], or its pharmaceutically acceptable salt, or MES.

[39] Packaging for commercial use, including pharmaceutical composition described in the above item [26], and the associated printed material, and printed material indicates that the pharmaceutical composition can or should be used for the treatment or prevention of a disease selected from anemia and renal anemia.

[40] a Kit comprising the pharmaceutical composition described in the above item [26], and is provided with it printed material, and in the printed material indicates that the pharmaceutical composition can or should be used for the treatment or prevention of a disease selected from anemia and renal anemia.

An implementation option to apply the present invention in practice

The definition of each substituent, or each slice to be used in the present description, is as follows.

"Halogen atom" is a fluorine atom, chlorine atom, bromine atom or iodine atom.

"C1-10alkyl group represents an alkyl group with unbranched or branched chain, containing the number of carbon atoms from 1 to 10, preferably an alkyl group with unbranched or branched chain, containing the number of carbon atoms from 1 to 7. For example, there can be mentioned methyl group, ethyl group, through the group, isopropyl group, bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, pencilina group, isopentyl group, tert-pencilina group, 1-ethylpropyl group, neopentylene group, exilda group, 2-ethylbutyl group, 3,3-dimethylbutyl group, 3,3-dimethylpentyl group, heptylene group, anjilina group, Danilina group decile group, etc.

"C1-6alkyl group" represents alkyl which ing group with unbranched or branched chain, contains the number of carbon atoms from 1 to 6, preferably an alkyl group with unbranched or branched chain, containing the number of carbon atoms from 1 to 3. For example, can be referred to such groups as shown in the example above, "C1-10alkyl groups and containing a number of carbon atoms from 1 to 6.

"C1-3alkyl group represents an alkyl group with unbranched or branched chain, containing the number of carbon atoms from 1 to 3. For example, can be referred to such groups as shown in the example of the above-mentioned alkyl groups and containing a number of carbon atoms from 1 to 3.

"C6-14aryl group represents an aromatic hydrocarbon group containing a number of carbon atoms from 6 to 14. For example, there may be mentioned phenyl group, naftalina group, antenna group, angenlina group, atulananda group, tortilla group, phenanthroline group, pentylaniline group and so on, and preference is given to phenyl group.

"C3-8cycloalkyl group" is a saturated cycloalkyl group containing a number of carbon atoms from 3 to 8, preferably from 3 to 5, and, for example, can be mentioned cyclopropyl group, cyclobutyl group, cyclopentenone group, cyclohex is supplemented flax group, cycloheptyl group, cyclooctyl group, etc.

"C3-5cycloalkyl group" is a saturated cycloalkyl group containing a number of carbon atoms from 3 to 5. For example, can be referred to such groups as shown in the example above, "C3-8cycloalkyl groups and containing a number of carbon atoms from 3 to 5.

"C6-14aryl-C1-6alkyl group" represents a C6-14aryl-C1-6alkyl group, a C6-14aryl fragment represents a higher "C6-14aryl group, and its C1-6the alkyl fragment represents a higher "C1-6alkyl group, and preference is given to C6-14aryl-C1-6alkyl group in which C1-6the alkyl fragment is a C1-6alkyl group with an unbranched chain. Examples of C6-14aryl-C1-6alkyl groups include phenylmethylene group, phenylethylene group, phenylpropyl group, phenylbutyl group, phenylmethylene group, phenylhexanoic group, naphthylmethyl group, naphthylethylene group, afterripening group, NativeWindow group, naphthylmethyl group, artilheiro group, antiloitering group, intermational group, isultimately group, fertility the ing group, phenantroline group, pentylaniline group, etc.

"C3-8cycloalkyl-C1-6alkyl group" represents a C3-8cycloalkyl-C1-6alkyl group, a C3-8cycloalkenyl fragment represents a higher "C3-8cycloalkyl group", and its C1-6the alkyl fragment represents a higher "C1-6alkyl group. Its examples include cyclopropylmethyl group, cyclopropylethyl group, cyclopropylamino group, cyclopropylmethyl group, cyclopropylethyl group, cyclopropylethyl group, cyclobutylmethyl group, cyclobutylmethyl group, cyclobutylmethyl group, cyclobutylmethyl group, cyclobutylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclopentylmethyl group, cyclopentylpropionyl group, cyclopentylmethyl group, cyclopentylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclohexylethyl group, cyclohexylamino group, cyclohexylmethyl group, cyclohexylethyl group, cyclohexylamino group, cycloheptylmethyl group, cycloheptylmethyl group, cycloheptylmethyl group, cycloheptylmethyl group, cycloheptylmethyl group, cycloheptyl hexoloy group, cyclooctylmethyl group, cyclooctylamino group, cyclooctylamino group, cyclooctylmethyl group, cyclooctylmethyl group, cyclooctylamino group, etc.

"C3-8cycloalkenyl group" represents cycloalkenyl group containing a number of carbon atoms from 3 to 8 and containing at least one, preferably 1 or 2, double bonds. For example, there can be mentioned cyclopropylamino group, cyclobutenyl group, cyclopentenyl group, cyclopentadienyls group, cyclohexenyl group, cyclohexadienyl group (2,4-cyclohexadiene-1-ilen group, 2,5-cyclohexadiene-1-ilen group, and so on), cycloheptenyl group, cyclooctadiene group, etc.

"Heteroaryl group" is an aromatic heterocycle containing, besides carbon atoms as ring atoms 1-6 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, where the number of ring atoms is 3-14, including monocycle and a condensed ring.

"Monocyclic heteroaryl group" is a monocyclic heteroaryl group, preferably containing 1-4 heteroatoms, and, for example, can be mentioned thienyl group (e.g., thiophene-2-yl, thiophene-3-yl), furilla group (e.g., furan-2-yl, furan-3-yl, and so on), pyrrolidine groups is (for example, 2-pyrrolin-1-ilen group, 3-pyrrolin-3-yl, and so on), oxazolidine group (for example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and so on), isoxazolidine group (e.g., isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, and so on), thiazolidine group (e.g., thiazol-2-yl, thiazol-4-yl, the thiazole-5-yl, and so on), isothiazoline group (for example, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, and so on), imidazolidine group (for example, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, and so on), pyrazolidine group (for example, pyrazole-1-yl, 1H-pyrazole-3-yl, 2H-pyrazole-3-yl, 1H-pyrazole-4-yl, and so on), oxadiazolidine group (for example, 1,3,4-oxadiazol-2-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, and so on), thiadiazolidine group (for example, 1,3,4-thiadiazole-2-yl, 1,2,3-thiadiazole-4-yl, 1,2,3-thiadiazole-5-yl, 1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl, 1,2,5-thiadiazole-3-yl, and so on), thiazolidine group (for example, 1,2,4-triazole-3-yl, 1,2,4-triazole-1-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-2-yl, 1,3,4-triazole-1-yl and so on), tetrataenia group (for example, tetrazol-1-yl, tetrazol-2-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, and so on), Peregrina group (for example, pyridine-2-yl, pyridin-3-yl, pyridine-4-yl, and so on), pyrimidinyl group (for example, the pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, and so on), pyridazinyl group (for example, pyridazin-3-yl, pyridazin-4-yl, and so on), piratininga group (the example pyrazin-2-yl, and so on), trainline group (for example, 1,3,5-triazine-2-yl, and so on), etc.

Examples of the "condensed heteroaryl group" include pinolillo group, izohinolinove group, chinazolinei group, khinoksalinona group, talinolol group, indolinyl group, naphthyridinone group, indolenine group, benzimidazolyl group, indolinyl group, benzofuranyl group, benzothiazoline group, benzoxazolyl group, benzothiazolyl group, benzodioxolyl group, benzothiazolyl group, tetrahydropyridine group, dihydrobenzofuranyl group, dihydrobenzofuranyl group, dihydroergotoxine group, intentionally group, tetrahydroaminoacridine group, 5,7-dihydropyrrolo[3,4-d]pyrimidinyl group, 6,7-dihydro-5H-cyclopentylmethyl group, imidazo[2,1-b]thiazolidine group, pteridinyl group, parinello group, etc.

"Halogen-C1-6alkyl group" represents a higher "C1-6alkyl group, which is substituted by same or different 1 to 5 halogen atoms, and, for example, can be mentioned chloromethyl, vermeil, deformity, trifluoromethyl, methyl bromide, chloroethyl, foradil, bromacil, chloropropyl, forproper, bromopropyl etc.

"Group B" includes the following substitute groups (a)-(e):

(a)the above-defined "halogen atom",

(b) defined above "C1-6alkyl group"

(c) defined above "C3-8cycloalkyl group"

(d) a cyano, and

(e) defined above "halogen-C1-6alkyl group".

"C6-14aryl group, optionally substituted by same or different 1 to 5 substituents selected from group B" is a defined above "C6-14aryl group which is optionally substituted by same or different 1 to 5 substituents, and includes unsubstituted C6-14aryl group. The substituents are the same or different and selected from defined above, the "group B".

"C3-8cycloalkyl group, optionally substituted by same or different 1 to 5 substituents selected from group B" is a defined above "C3-8cycloalkyl group, which is optionally substituted by same or different 1 to 5 substituents, and includes unsubstituted C3-8cycloalkyl group. The substituents are the same or different and selected from defined above, the "group B".

"C3-8cycloalkenyl group, optionally substituted by same or different 1 to 5 substituents selected from group B" is a defined above "C3-8cycloalkenyl group, which is optionally substituted by the same or different is scored 1-5 substituents, and includes unsubstituted C3-8cycloalkenyl group. The substituents are the same or different and selected from defined above, the "group B".

"Heteroaryl group optionally substituted by the same or different 1 to 5 substituents selected from group B" is a defined above "heteroaryl group which is optionally substituted by same or different 1 to 5 substituents, and includes unsubstituted heteroaryl group. The substituents are the same or different and selected from defined above, the "group B".

In the above formula [I] preferred groups are as described below.

Partial structural formula:

represents a group represented by any of the following formulas:

.

As a partial structural formulas are preferred groups represented

and so on

As a partial structural formula is preferred group represented by

.

R1represents a

(1) a hydrogen atom,

(2) C1-6alkyl group,

(3) C6-14aryl group,

(4) C3-8cycloalkyl group,

(5) C6-14aryl-C1-6alkyl group Il is

(6) C3-8cycloalkyl-C1-6alkyl group.

R1preferably represents

(1) a hydrogen atom,

(2) C1-3alkyl group (e.g. methyl),

(3) C6-14aryl group (e.g. phenyl),

(4) C3-5cycloalkyl group (for example, cyclopropyl),

(5) C6-14aryl (e.g. phenyl)-C1-3alkyl (preferably C1-3alkyl with an unbranched chain, for example, ethyl) group,

(6) C3-8cycloalkyl (e.g., cyclohexyl)-C1-3alkyl (e.g. ethyl) group, or etc.

R1more preferably represents a hydrogen atom.

R2represents a

(1) a hydrogen atom,

(2) C1-10alkyl group,

(3) C6-14aryl group, optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B,

(4) C3-8cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from the aforementioned group B,

(5) C3-8cycloalkenyl group optionally substituted by the same or different 1 to 5 substituents selected from the aforementioned group B,

(6) heteroaryl group, optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B (which is IMO the carbon atom of heteroaryl contains 1-6 heteroatoms, selected from nitrogen atom, oxygen atom and sulfur atom),

(7) C6-14aryl-C1-6alkyl group (in which C6-14aryl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B), or

(8) C3-8cycloalkyl-C1-6alkyl group (in which C3-8cycloalkyl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B).

R2preferably represents

(1) a hydrogen atom,

(2) C1-10alkyl group,

(3) C6-14aryl group, optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B,

(4) C3-8cycloalkyl group (for example, cyclopentyloxy, tsiklogeksilnogo, cycloheptyl),

(5) C3-8cycloalkenyl group (for example, cyclohexenyl),

(6) heteroaryl group (preferably monocyclic heteroaryl group, for example, thienyl) optionally substituted by the same or different 1 to 5 (e.g. 1) substituents selected from the aforementioned group B

(for example, (a) halogen atom (e.g. chlorine atom), and

(b) C1-6an alkyl group (e.g., methyl))

(in which in addition to carbon atom in heteroaryl contains 1-6 (e.g., 1-4) heteroatoms selected from a nitrogen atom, the volume of oxygen and sulfur atom (for example, the sulfur atom)),

(7) C6-14aryl-C1-6alkyl group (in which C6-14aryl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B), or

(8) C3-8cycloalkyl-C1-3alkyl group (in which C3-8cycloalkyl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B).

R2more preferably represents a

(1) C1-10alkyl group (for example, ethyl, sawn, ISO-propyl, boutelou, isobutylene, pentelow, isopentyl, tert-pentelow, hexeline, 1-ethylpropyl, 2-ethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpentyl),

(2) C6-14aryl group (e.g. phenyl), optionally substituted by same or different 1 to 5 (e.g., 1-3) substituents selected from the aforementioned group B

(for example, (a) halogen atom (e.g. chlorine atom, a fluorine atom),

(b) C1-3alkyl group (e.g. methyl),

(c) C3-5cycloalkyl group (for example, cyclopropyl),

(d) cyano, and

(e) a halogen-C1-3an alkyl group (for example, triptoreline)),

(3) C6-14aryl (e.g. phenyl)-C1-6alkyl (preferably C1-6alkyl with an unbranched chain, for example, methyl, ethyl, various) groups is,

(C6-14aryl optionally substituted by same or different 1 to 5 (e.g., 1-3) substituents selected from the aforementioned group B

(for example, (a) halogen atom (e.g. chlorine atom, a fluorine atom),

(b) C3-8cycloalkyl group (for example, cyclopropyl) and

(c) halogen-C1-3an alkyl group (for example, triptoreline))) or

(4) C3-8cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl)-C1-3alkyl (e.g. methyl, ethyl) group

(C3-8cycloalkyl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B).

R2even more preferably represents a

(1) C1-6alkyl group (for example, boutelou, pentelow, 1-ethylpropyl),

(2) phenyl, optionally substituted by same or different 1 to 3 substituents selected from the

(a) a halogen atom (e.g. chlorine atom, fluorine atom),

(b) C1-3alkyl groups (e.g. methyl),

(c) C3-5cycloalkyl group (for example, cyclopropane) and

(d) a halogen-C1-3alkyl groups (for example, triptoreline),

(3) phenylethyl or

(4) cyclopentolate.

R2especially preferably represents butyl, phenylethyl or 4-fluoro-3-triptoreline.

In another embodiment, the of the present invention R 2preferably represents

(1) C1-10alkyl group, or

(2) C6-14aryl-C1-6alkyl group (in which C6-14aryl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B).

R3represents a

(1) a hydrogen atom,

(2) a halogen atom,

(3) C1-6alkyl group,

(4) C6-14aryl group,

(5) C3-8cycloalkyl group or

(6) C6-14aryl-C1-6alkyl group.

R3preferably represents

(1) a hydrogen atom,

(2) a halogen atom (e.g. chlorine atom),

(3) C1-6alkyl group (for example, ethyl, pentelow),

(4) C6-14aryl group (e.g. phenyl) or

(5) C6-14aryl (e.g. phenyl)-C1-6alkyl (preferably C1-6alkyl with an unbranched chain, for example, ethyl) group.

R3more preferably represents a hydrogen atom.

Each of R4and R5independently represents a

(1) a hydrogen atom, or

(2) C1-6alkyl group.

Each of R4and R5preferably independently represents a

(1) a hydrogen atom, or

(2) C1-3alkyl group (e.g. methyl).

More preferably, R4and R5both represent atomisation.

In the formula [I] more preferred is a compound represented by the following formula [Ia]

,

in which

partial structural formula:

represents a group represented in the form

;

R1arepresents a

(1) a hydrogen atom,

(2) C1-3alkyl group (e.g. methyl),

(3) C6-14aryl group (e.g. phenyl),

(4) C3-5cycloalkyl group (for example, cyclopropyl),

(5) C6-14aryl (e.g. phenyl)-C1-3alkyl (preferably, C1-3alkyl with an unbranched chain, for example, ethyl) group, or

(6) C3-8cycloalkyl (e.g., cyclohexyl)-C1-3alkyl (e.g. ethyl) group;

R2arepresents a

(1) a hydrogen atom,

(2) C1-10alkyl group,

(3) C6-14aryl group, optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B,

(4) C3-8cycloalkyl group (for example, cyclopentyloxy, tsiklogeksilnogo, cycloheptyl),

(5) C3-8cycloalkenyl group (for example, cyclohexenyl),

(6) heteroaryl group (preferably monocyclic heteroaryl group, for example, thienyl), neobyazatel is substituted by same or different 1 to 5 (for example, 1) substituents selected from the aforementioned group B

(for example, (a) halogen atom (e.g. chlorine atom), and

(b) C1-6an alkyl group (e.g., methyl))

(in which in addition to carbon atom in heteroaryl contains 1-6 (e.g., 1-4) heteroatoms selected from a nitrogen atom, oxygen atom and sulfur atom (for example, sulfur atom)),

(7) C6-14aryl-C1-6alkyl group (in which C6-14aryl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B), or

(8) C3-8cycloalkyl-C1-3alkyl group (in which C3-8cycloalkyl optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B);

R3arepresents a

(1) a hydrogen atom,

(2) a halogen atom (e.g. chlorine atom),

(3) C1-6alkyl group (for example, ethyl, pentelow),

(4) C6-14aryl group (e.g. phenyl) or

(5) C6-14aryl (e.g. phenyl)-C1-6alkyl (preferably C1-6alkyl with an unbranched chain, for example, ethyl) group; and

each of R4aand R5aindependently represents a

(1) a hydrogen atom, or

(2) C1-3alkyl group (e.g. methyl).

As the compounds of the present invention is preferred from the Association, represented by the above formula [Ia], in which

R1arepresents a hydrogen atom;

R2arepresents a

(1) C1-10alkyl group (for example, ethyl, sawn, ISO-propyl, butyl, isobutylene, pentelow, isopentyl, tert-pentelow, hexeline, 1-ethylpropyl, 2-ethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpentyl),

(2) C6-14aryl group (e.g. phenyl), optionally substituted by same or different 1 to 5 (e.g., 1-3) substituents selected from the aforementioned group B

(for example, (a) halogen atom (e.g. chlorine atom, a fluorine atom),

(b) C1-3alkyl group (e.g. methyl),

(c) C3-5cycloalkyl group (for example, cyclopropyl),

(d) cyano, and

(e) a halogen-C1-3an alkyl group (for example, triptoreline)),

(3) C6-14aryl (e.g. phenyl)-C1-6alkyl (preferably, C1-6alkyl with an unbranched chain, for example, methyl, ethyl, various)

(C6-14aryl, optionally substituted by same or different 1 to 5 (e.g., 1-3) substituents selected from the aforementioned group B

(for example, (a) halogen atom (e.g. chlorine atom, a fluorine atom),

(b) C3-8cycloalkyl group (for example, cyclopropyl) and

(c) halogen-C1-6alkyl g is the SCP (e.g., triptoreline))) or

(4) C3-8cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl)-C1-3alkyl (e.g. methyl, ethyl) group

(C3-8cycloalkyl, optionally substituted by same or different 1 to 5 substituents selected from the aforementioned group B);

R3arepresents a hydrogen atom; and

R4aand R5aboth represent hydrogen atoms.

In another embodiment of the present invention from the compounds represented by formula [I], preferred is a compound represented by the following formula [I-1]:

,

in which

partial structural formula:

represents a group represented by any of the following formulas:

;

R11represents a

(1) a hydrogen atom,

(2) C1-6alkyl group (e.g. methyl),

(3) phenyl group,

(4) C3-8cycloalkyl group (for example, cyclopropyl),

(5) phenyl-C1-6alkyl group, or

(6) C3-8cycloalkyl-C1-6alkyl group;

R21represents a

(1) a hydrogen atom,

(2) C1-10alkyl group (for example, ethyl, n-sawn, ISO-propyl, n-boutelou, isobutylene, n-pentylene is, n-hexoloy, 1-ethylpropyl, 3-methylbutyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, 3,3-dimethylpentyl),

(3) a phenyl group optionally substituted by the same or different 1 to 5 substituents (for example, fluorine atom, chlorine atom, stands, cyano, cyclopropyl, trifluoromethyl) selected from the above group B,

(4) C3-8cycloalkyl group (for example, cyclopentyloxy, tsiklogeksilnogo, cycloheptyl),

(5) C3-8cycloalkenyl group (for example, cyclohexenyl),

(6) a thienyl group optionally substituted by the same or different 1 to 5 substituents (for example, a chlorine atom, stands) selected from the above group B,

(7) phenyl-C1-6alkyl group (for example, phenylmethylene, phenylethylene, phenylpropionyl) (in which the phenyl optionally substituted by same or different 1 to 5 substituents (for example, fluorine atom, chlorine atom, cyclopropyl, trifluoromethyl) selected from the above group B), or

(8) C3-8cycloalkyl-C1-6alkyl group (for example, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylethyl);

R31represents a

(1) a hydrogen atom,

(2) a halogen atom (e.g. chlorine atom),

(3) 1-6alkyl group (for example, ethyl, n-pentelow),

(4) phenyl group,

(5) C3-8cycloalkyl group or

(6) phenyl-C1-6alkyl group (for example, phenylethylene); and

each of R41and R51independently represents a

(1) a hydrogen atom, or

(2) C1-6alkyl group (e.g. methyl).

Of the compounds represented by the formula [I-1], a connection that

R11represents a

(1) a hydrogen atom,

(2) C1-6alkyl group (e.g. methyl),

(3) phenyl group, or

(4) C3-8cycloalkyl group (for example, cyclopropyl);

R21represents a

(1) a hydrogen atom,

(2) C1-10alkyl group (for example, ethyl, n-sawn, ISO-propyl, n-boutelou, isobutylene, n-pentelow, n-hexoloy, 1-ethylpropyl, 3-methylbutyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, 3,3-dimethylpentyl),

(3) a phenyl group optionally substituted by the same or different 1 to 5 substituents (for example, fluorine atom, chlorine atom, stands, cyano, cyclopropyl, trifluoromethyl) selected from the above group B,

(4) C3-8cycloalkyl group (for example, cyclopentyloxy, tsiklogeksilnogo, cycloheptyl),

(5) C3-8cycloalkenyl group (for example, cyclohexenyl is),

(6) a thienyl group optionally substituted by the same or different 1 to 5 substituents (for example, a chlorine atom, stands) selected from the above group B,

(7) phenyl-C1-6alkyl group (for example, phenylmethylene, phenylethylene, phenylpropionyl) (in which the phenyl optionally substituted by same or different 1 to 5 substituents (for example, fluorine atom, chlorine atom, cyclopropyl, trifluoromethyl) selected from the above group B), or

(8) C3-8cycloalkyl-C1-6alkyl group (for example, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylethyl);

R31represents a

(1) a hydrogen atom,

(2) a halogen atom (e.g. chlorine atom),

(3) C1-6alkyl group (for example, ethyl, n-pentelow),

(4) phenyl group, or

(6) phenyl-C1-6alkyl group (for example, phenylethylene);

each of R41and R51independently represents a

(1) a hydrogen atom, or

(2) C1-6alkyl group (e.g. methyl),

is preferred

connection, where

R11represents a hydrogen atom, methyl, phenyl or cyclopropyl;

R21represents a hydrogen atom; ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-Pentti is, n-hexyl, 1-ethylpropyl, 3-methylbutyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, 3,3-dimethylpentyl; phenyl, optionally substituted by same or different 1 to 5 substituents selected from a fluorine atom, chlorine atom, methyl, cyano, cyclopropyl and trifloromethyl; cyclopentyl, cyclohexyl, cycloheptyl; cyclohexenyl; thienyl, optionally substituted by same or different 1 to 5 substituents selected from a chlorine atom and methyl; phenylmethyl, phenylethyl, phenylpropyl (phenyl, optionally substituted by same or different 1 to 5 substituents selected from a fluorine atom, chlorine atom, cyclopropyl and trifloromethyl); cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl;

R31represents a hydrogen atom, a chlorine atom, ethyl, n-pentyl, phenyl or phenylethyl; and

each R41and R51independently represents a hydrogen atom or methyl,

is more preferred.

As the compounds of the present invention, or its pharmaceutically acceptable salt, or its MES compounds described in the examples 1-122, are preferred, the compounds described in the examples 1, 2, 21, 31, 40, 44, 47, 52, 60, 74, 79, 116, 118, 119, 120, 121 and 122 are especially preferred.

Pharmaceutically acceptable salt of the compound, to depict ablanovo formula [I], can be any salt, provided that it forms a non-toxic salt with the compound of the present invention. Its examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with amino acids, etc.,

Examples of salts with inorganic acid include a salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, Hydrobromic acid, etc.,

Examples of salts with organic acid include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, triperoxonane acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzosulfimide acid, para-toluensulfonate acid, etc.,

Examples of the salt with inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, etc.,

Examples of salts with organic base include methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, Ethylenediamine, Tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenziletilendiaminom, guanidine, pyridine, picoline, choline, cinchonine, meglumin etc.

P is emery salt with amino acid include salts with lysine, arginine, aspartic acid, glutamic acid, etc.,

Each salt can be obtained by interaction of the compound represented by the formula [I], with inorganic base, organic base, inorganic acid, organic acid or amino acid in accordance with the known method.

"MES" is a compound represented by the formula [I] or its pharmaceutically acceptable salt, where the solvent molecule is coordinated, and also includes hydrates. As MES pharmaceutically acceptable MES is preferred and include, for example, hydrate, ethanolate, dimethylsulfoxide, etc., compounds represented by the formula [I] or its pharmaceutically acceptable salt. Its specific examples include hemihydrate, monohydrate, dihydrate and monoethanol compounds represented by the formula [I], monohydrate sodium salt, 2/3 ethanolate dihydrochloride, etc., compounds represented by the formula [I].

MES compounds of the present invention or its pharmaceutically acceptable salt may be obtained in accordance with the method knownper se.

In addition, the compound represented by the formula [1] or its pharmaceutically acceptable salt, or MES, has various isomers. For example, E-form and Z-form is present as geometric isomers in the presence of asymmetric carbon atom, enantiomer and the diastereoisomer present as stereoisomers based on it, and in the presence of axial chirality present stereoisomers based on it. Moreover, it can also be tautomers. Accordingly, the present invention covers all of these isomers and mixtures thereof.

In addition, the compound of the present invention, or its pharmaceutically acceptable salt, or its MES can be labeled with an isotope (for example,3H,14C,35S, and so on).

As compounds represented by the formula [I] or its pharmaceutically acceptable salt, or its MES preferred is a compound represented by the formula [I] or its pharmaceutically acceptable salt, or MES, each of which essentially cleared. More preferred is a compound represented by the formula [I] or its pharmaceutically acceptable salt, or MES, each of which is purified to a purity acceptable for a pharmaceutical product.

In the present invention, the prodrug of the compound represented by the formula [I] can also be applied as a medicinal product. "Prodrug" is a derivative of the compound of the present invention, containing a chemically or metabolically degradable group, which after the introduction into the body is restored to the similar connection means, for example, hydrolysis, solvolysis or decomposition under physiological conditions, and manifests his usual efficiency. It includes non-covalent complex, and salt. The prodrug is applicable, for example, to improve absorption when administered orally or target target fragment.

In the compound of the present invention, examples of the modified fragment include highly reactive functional group such as hydroxyl group, carboxyl group, amino group, etc.

Specific examples hydroxymorphinone group include acetyl group, propionyl group, isobutyryl group, pivaloyl group, Palmitoyl group, benzoyloxy group, 4-methylbenzoyl group, dimethylcarbamoyl group, dimethylaminomethylphenol group, alphagroup, alaninol group, fumarello group, etc. can also be mentioned the sodium salt of 3-carboxybenzoyl group, 2-carboxyethylgermanium group, etc.

Specific examples carboxymethylcelluose group include methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, tert-boutelou group, pivaloyloxymethyl group, carboxymethyl group, dimethylaminomethyl group, 1-(atomic charges)ethyl group, 1-(this is bicarbonate)ethyl group, 1-(isopropoxycarbonyl)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, benzyl group, phenyl group, ortho-taillow group, morpholinomethyl group, N,N-diethylcarbamoyl group, phthalidyl group, etc.

Specific examples aminemodified groups include tert-boutelou group, docosanol group, pivaloyloxymethyl group, alaninol group, hexylberberine group, intelceremony group, 3-methylthio-1-(acetylamino)propelleronline group, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, tetrahydrofuranyl group, pyrrolidinyloxy group, etc.

Examples of the pharmaceutical composition include oral preparations such as tablet, capsule, granule, powder, toffee, syrup, emulsion, suspension, etc. and parenteral means, such as a drug for external application, suppository, injectable medication, eye drops, nasal preparation, pulmonary preparation, etc.

The pharmaceutical composition of the present invention prepared in accordance with the method known in the field of pharmaceutical preparations by mixing, if necessary, the connection is to be placed, represented by the formula [I] or its pharmaceutically acceptable salt, or its MES with a suitable amount of at least one type of pharmaceutically acceptable carrier, etc., Although the content of the compound represented by the formula [I] or its pharmaceutically acceptable salt, or its MES in the pharmaceutical composition varies depending on the dosage form, dose, etc., it is, for example, from 0.1 to 100 wt%. from the whole composition.

Examples of "pharmaceutically acceptable carrier include various organic or inorganic substances-media, usually applied as used in the preparation of substances, for example, a filler, a powder, a binding agent, a sliding agent, a lubricant, etc. for solid preparations, and a solvent, solubilizer, contributing to suspendirovanie agent, isotonic agent, buffering agent, soothing agent, etc. for liquid preparations. Moreover, if necessary, apply additives such as preservative, antioxidant, colorant, sweetener, etc.

Examples of the filler include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboximetilkrahmal, hydroxypropylcellulose low with what epent replacement Arabian gum, etc.

Examples of the powder include carmellose, carmellose calcium, carmellose sodium, sodium carboximetilkrahmal, croscarmellose sodium, crosspovidone, hydroxypropylcellulose with a low degree of substitution, hypromellose, crystalline cellulose, etc.,

Examples of "binders" include hydroxypropylcellulose, hypromellose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, Arabian gum, etc.

Examples of substances that contribute slip" include weak anhydrous silicic acid, magnesium stearate, etc.,

Examples of the lubricant include magnesium stearate, calcium stearate, talc, etc.,

Examples of the solvent include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc.

Examples of solubilization include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.,

Examples of "contributing to suspendirovanie funds" include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerylmonostearate etc.

Examples of "isotonic means" include glucose, D-sorbitol, sodium chloride, D-mannitol, etc.,

Examples of the buffer is wow substances include sodium phosphate, sodium acetate, sodium carbonate, sodium citrate, etc.,

Examples of "sedative" include benzyl alcohol, etc.,

Examples of the preservative include metilparagidroksibenzoat, chlorbutanol, benzyl alcohol, dehydroacetic sodium, sorbic acid, etc.,

Examples of the antioxidant include sodium sulfite, ascorbic acid, etc.,

Examples of the dye include dyes (e.g., food color red No. 2 or 3, food color yellow No. 4 or 5 and so on), β-carotene, etc.,

Examples of sweetening agents include saccharin sodium, dipotassium glycyrrhizinate, aspartame, etc.

The compound of the present invention, or its pharmaceutically acceptable salt, or its MES have the ability to induce the production of EPO due to the inhibitory effect against prolylhydroxylase (PHD) and can be used for the prevention or treatment of various diseases and pathologies (violations), caused by reduced secretion of EPO.

As various diseases and pathologies (violations), caused by reduced secretion of EPO may be referred to anemia, etc.

In General, anemia include anemia due to disorders of hematopoiesis in the bone marrow, anemia due to iron deficiency, vitamin B12or folic acid, bleeding during an accident or surgery, anemia, who associirovannyy with chronic inflammation (autoimmune diseases, malignancy, chronic transmissible diseases, plasmocytoma the dyscrasias, and so on), anemia associated with endocrine diseases (hypothyroidism, autoimmune polyglandular syndrome, diabetes mellitus type IA, dysfunctional uterine bleeding, and so on), anemia associated with chronic heart failure, anemia associated with ulcers, anemia associated with liver disease, senile anemia drug anemia, renal anemia (anemia associated with renal failure), anemia associated with chemotherapy, etc.

Examples of diseases that are expected to be improved by inhibition of PHD to stabilize HIF include coronary heart disease (angina, myocardial infarction, and so on), ischemic cerebrovascular disorders (stroke, cerebral embolism, transient cerebral ischemic attacks and so on), types of chronic renal failure (ischemic nephropathy, tubulo-interstitial disorders of the kidneys, and so on), diabetic complications (diabetic ulcers and so on), cognitive impairment (dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and so on) and so on

The inhibitor prolylhydroxylase (PHD) and the agent inducing the production of EPO, according to the present invention preferably use is as a treatment for anemia, more preferably as a treatment for renal anemia.

The pharmaceutical composition of the present invention may be administered orally or parenterally (e.g., local, rectal, intravenous administration etc) human and non-human mammals (e.g. mouse, rat, hamster, Guinea pig, rabbit, cat, dog, pig, cow, horse, sheep, monkey, etc). The dose varies depending on subject of administration, disease, symptom, dosage form, route of administration, etc., for Example, the daily dose for oral administration to an adult patient (body weight about 60 kg) is generally in the range from about 1 mg to 1 g, based compounds of the present invention as an active ingredient. This number can be entered once or in several portions.

Because the connection of the present invention, or its pharmaceutically acceptable salt, or its MES inhibits PHD and induces the production of EPO, it can be used as an active ingredient of a therapeutic agent or a prophylactic agent against anemia.

"To inhibit PHD" means to specifically inhibit prolylhydroxylase and to eliminate or reduce its activity. For example, this means to specifically inhibit the work is at prolylhydroxylase in the undermentioned conditions of Test example 1. "To inhibit PHD" preferably means to inhibit PHD man. As a PHD inhibitor" is preferable to "the PHD inhibitor man."

"To induce EPO production" means production of erythropoietin in the kidneys, etc. strengthened. For example, this means that production of erythropoietin induced in the undermentioned conditions of Test example 2. "To induce the production of EPO" preferably means "to induce the production of EPO person". "Agent inducing the production of EPO preferably represents an agent inducing the production of EPO man."

The above-mentioned compound represented by the formula [I] or its pharmaceutically acceptable salt, or its MES can be used in combination with one or many other drugs (called here or later in this document concomitant medication) in accordance with the method commonly used in the medical field (called here or later in this document complex application).

The duration of the aforementioned compounds represented by the formula [I] or its pharmaceutically acceptable salt, or its MES and the concomitant drug is not limited, and they can be introduced to the subject of administration in the form of a combined preparation, or both drugs may be introduced simultaneously or che the ez-set time intervals. In addition, the pharmaceutical composition according to the present compound and the concomitant drug can be used as a medicine in the form of a set. The dose of the concomitant drug is similar to the dose used in the clinic, and can be appropriately selected in accordance with the subject of administration, disease, symptom, dosage form, by injection, time of administration, combination, etc., Form the introduction of the concomitant drug is not particularly limited, and requires only its combination with the compound of the present invention or its pharmaceutically acceptable salt, or MES.

Examples of the concomitant drug include a means for the treatment and/or prevention of anemia or similar, and can be used in combination with the compound of the present invention.

Examples of "therapeutic agent and/or prophylaxis against anaemia include ferric citrate, ferric sulfate, etc.,

As a PHD can be mentioned PHD2 and PHD3.

Further specifically explained the methods for obtaining compounds of the present invention, or its pharmaceutically acceptable salt, or MES. However, there is no need to say that the present invention is not limited to such methods of obtaining. For connection on astasia the invention, or its pharmaceutically acceptable salt, or MES order reactions can be appropriately changed. The reaction can be started from seed or fragment substitution, which seemed appropriate.

In addition, between the respective stages can be switched on stage corresponding transformation of the Deputy (conversion or further modification Deputy). In the presence of reactive functional groups accordingly can be used for protecting and removing the protective groups. Moreover, if necessary, to facilitate the reaction can be used reagent other than the reagent described as an example. In addition, the original connection method which is not described, is either commercially available or can be easily obtained by combining known reactions of synthesis.

The compound obtained at each stage, can be cleaned by conventional means such as distillation, recrystallization, column chromatography, etc. In some cases the connection can be applied in the next stage without isolation and purification.

The following method of obtaining a "room temperature" means 1-40°C.

The method of obtaining I-1

where each R11aand R11cp is ecstasy carboxylato group, such as methyl group, ethyl group, benzyl group, tert-bucilina group, etc.,, R11brepresents hydroxylamino group such as acetyl group, benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group and so on, each of X11aand X11brepresents a halogen atom such as chlorine atom, bromine atom, iodine atom, fluorine atom, etc., leaving group, such as a pair of toluensulfonate, methysulfonylmethane, triftormetilfullerenov etc.

Stage 1

The compound [I-1-2] can be obtained by metallation of compound [I-1-1] in accordance with the conventional method and the introduction of the carboxyl group with the use of carbon dioxide. The metallation is accomplished by the interaction with the ORGANOMETALLIC reagent, such as n-utility, second-utility, diisopropylamide lithium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide, potassium, lithium amide, sodium amide, etc., in conditions of low temperature in hexane, benzene, toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane, etc., separately or in a mixed solvent, for cat the eye should liaising with carbon dioxide to obtain the compound [I-1-2].

Stage 2

The compound [I-1-3] can be obtained by introducing a protective group into the carboxyl group of compound [I-1-2] in accordance with the generally accepted method. For example, if the protecting group is tert-bucilina group, compound [I-1-3] can be obtained by interaction with tert-butyl-2,2,2-trichloroacetimidate in conditions of low temperature to heating in the presence of acid, such as para-toluensulfonate acid, methanesulfonate acid, boron TRIFLUORIDE, trichloride boron, tribromide boron, trichloride aluminum chloride, bromovalerate, phosphoric acid, sulfuric acid, acetic acid, triperoxonane acid, etc. in the hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, etc., separately or in a mixed solvent.

Stage 3

The compound [I-1-4] can be obtained by introducing a hydroxyl group protected by a protective group represented by R11bin the compound [I-1-3] in accordance with the generally accepted method. For example, with the introduction of a hydroxyl group protected by benzyl group, compound [I-1-3] is subjected to interaction with benzyl alcohol under conditions of low temperature to heating in the presence of a base, such contritely, tert-piperonyl potassium, potassium carbonate, sodium hydride, n-utility, diisopropylamide lithium, etc., in hexane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, etc., separately or in a mixed solvent, whereby can be obtained compound [I-1-4].

Stage 4

The compound [I-1-5] can be obtained by interaction of the compound [I-1-4] with hydrazine monohydrate in conditions of low temperature to heating in chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, water, etc., separately or in a mixed solvent.

Stage 5

The compound [I-1-6] can be obtained by interaction of the compound [I-1-5] artaphernes connection, such as triethylorthoformate, triethylorthoformate, etc., or with formic acid under conditions of low temperature to heating in the presence of acid, such as para-toluensulfonate acid, methanesulfonate acid, boron TRIFLUORIDE, trichloride boron, tribromide boron, chloride, bromovalerate, phosphoric acid, sulfuric acid, etc., in hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, is canola, 2-propanol, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, etc., separately or in a mixed solvent or without solvent.

Stage 6

The compound [I-1-7] can be obtained by the reaction endocycles rearrangement of compound [I-1-6] conditions from room temperature to heating in the presence of a base such as sodium hydroxide, morpholine, piperidine, pyrrolidine, etc. in hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., separately or in a mixed solvent.

Stage 7

The compound [I-1-8] can be obtained by removing carboxylamide group of compound [I-1-7] in accordance with the generally accepted method. For example, if R11arepresents a tert-boutelou group, compound [I-1-8] can be obtained by interaction with an acid, such as para-toluensulfonate acid, methanesulfonate acid, boron TRIFLUORIDE, trichloride boron, tribromide boron, trichloride aluminum chloride, bromovalerate, phosphoric acid, sulfuric acid, acetic acid, triperoxonane acid, etc., in conditions of low temperature to heating in hexane, PI is reforme, the methylene chloride, ethyl acetate, toluene, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, water, etc., separately or in a mixed solvent. If R11arepresents a methyl group, ethyl group or a tert-boutelou group, compound [I-1-8] can be obtained by hydrolysis of compound [I-1-7] under the conditions of low temperature to heating in the presence of a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium hydroxide, etc., in a mixed solvent consisting of water and solvent, such as methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, acetonitrile, etc.,

Stage 8

The compound [I-1 to 9] can be obtained by introducing a protective group into the carboxyl group of compound [I-1-8] according to the conventional method. For example, if the protecting group is an ethyl group, compound [I-1 to 9] can be obtained by interaction of the compound [I-1-8] with N,N-dimethylformamidine in conditions of low temperature to heating in chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl what sulfoxide, N,N-dimethylformamide, acetonitrile, etc., separately or in a mixed solvent.

Stage 7 and stage 8 can be skipped. In this case, R11a=R11c.

Stage 9

The compound [I-1 to 10] can be obtained by introducing the leaving group in the pyridine ring compounds [I-1 to 9] in accordance with the generally accepted method. Can be obtained disubstituted compound [I-1-11]. If the leaving group is an atom of iodine, then for a metallation of compound [I-1 to 10] and the compound [I-1-11] can be obtained by interaction with the ORGANOMETALLIC reagent, such as n-utility, second-utility, diisopropylamide lithium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide, potassium, lithium amide, sodium amide, etc., in conditions of low temperature in hexane, toluene, 1,2-dimethoxyethane, diethyl ether, 1,4-dioxane, tetrahydrofuran, etc., separately or in a mixed solvent, with subsequent implementation of the interaction with iodine.

The method of obtaining I-2

,

where R12arepresents carboxylate group such as methyl group, ethyl group, benzyl group, tert-bucilina group, etc. and the values of other symbols are defined above. Even if R2in [I-2-1]-a[I-2-4] is different from that defined what's deputies, it can be used as a specific Deputy can be eventually obtained by implementing the corresponding transformation of the Deputy.

Stage 1

The compound [I-2-1] can be obtained by introducing a substituent R2or his predecessor in compound [I-1 to 10] in accordance with the generally accepted method. For example, if R2represents boutelou group, compound [I-2-1] can be obtained by interaction of the compound [I-1 to 10] butylboronic acid in conditions from room temperature to heating in the presence of a palladium catalyst, such as dichloride [1,1-bis(diphenylphosphino)ferrocene]palladium(II), tetrakis(triphenylphosphine)palladium dichloride bis(triphenylphosphine)palladium(II), acetyltryptophan palladium, etc. and the base, such as potassium acetate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, triethylamine, diisopropylethylamine, sodium phosphate, cesium carbonate, etc., by adding, if necessary, salts of silver, such as silver carbonate, silver nitrate, silver oxide(I), etc., in hexane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, water, etc., separately or in a mixed solvent.

Stage 2

The compound [I-2-2] mo is for can be obtained by removing carboxylamide group of compound [I-2-1] in the same way, as in the method of obtaining I-1, stage 7.

Stage 3

The compound [I-2-3] can be obtained by condensation of compound [I-2-2] with a derivative of glycine represented by the formula H2NC(R4)(R5)COOR12ain accordance with the generally accepted method. For example, compound [I-2-3] can be obtained by condensation of compound [I-2-2] with a derivative of glycine represented by the formula H2NC(R4)(R5)COOR12ain conditions of low temperature to heating in the presence of a condensing agent, such as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or its salt, diphenylphosphoryl, etc. and, if necessary, N-hydroxysuccinimide, 1-hydroxybenzotriazole, dimethylaminopyridine, etc. and, if necessary, adding a base such as potassium carbonate, sodium bicarbonate, cesium carbonate, triethylamine, diisopropylethylamine, morpholine, pyridine, etc. in a solvent such as N,N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene, etc.,

Stage 4

The compound [I-2-4] can be obtained by removing hydroxylamino group, R11bcompound [I-2-3] in accordance with the generally accepted method. For example, if R11brepresents a benzyl group, compound [I-2-4] can be obtained p is the hydrogenation under the conditions from room temperature to heating in a hydrogen atmosphere under conditions of normal pressure to high pressure in the presence of a catalyst, such as palladium carbon, palladium hydroxide, platinum oxide, platinum-carbon, Raney Nickel, etc., in hexane, methanol, ethanol, 2-propanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, acetic acid, water, etc., separately or in a mixed solvent.

Stage 5

The compound [I-2-5] can be obtained in the same manner as in the method of obtaining I-1, stage 7, by deleting carboxylamide group of compound [I-2-4].

The method of obtaining I-3

where even if R2and R3in [I-3-1] and [I-3-2] are non-specific substituents, they can be used, because certain substituents can be eventually obtained by the corresponding transformation of the Deputy, and the values of other symbols are defined above.

Stage 1

The compound [I-3-1] can be obtained by introducing substituents R2and R3or their predecessor in the compound [I-1-11] in the same manner as in the method of obtaining I-2, stage 1. For example, if the predecessor R2and R3enter alkenylphenol group, compound [I-3-1] can be obtained by interaction of the compound [I-1-11] with alkenylboronic acid in the same manner as in the method of obtaining I-2, stage 1.

Stage 2

Connected is e [I-3-2] can be obtained by removing the protective groups R 11bcompound [I-3-1] in the same manner as in the method of obtaining I-2, stage 4.

Stage 3

The compound [I-3-3] can be obtained by interaction of the compound [I-3-2] with a derivative of glycine represented by the formula H2NC(R4)(R5)COOH. For example, compound [I-3-3] can be obtained by interaction of the compound [I-3-2] with the sodium salt derivative of glycine in conditions from room temperature to heating in hexane, chloroform, methylene chloride, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, 2-methoxyethanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, water, etc., separately or in a mixed solvent.

The method of obtaining I-4

,

where even if R3in [I-4-2] and [I-4-3] is different from the defined substituents, it can be used, because certain substituents can be eventually obtained by the corresponding transformation of the Deputy, and the values of other symbols are defined above.

Stage 1

The compound [I-4-1] can be obtained by mixing the compounds [I-1-11] under conditions of low temperature to heating in the presence of a palladium catalyst, such as dichloride [1,1-bis(diphenylphosphino)ferrocene]palladium(II), tetrakis (reperfusion)palladium, dichloride bis(triphenylphosphine)palladium(II), acetyltryptophan palladium, etc., and a reducing agent such as a hydride tri-n-butyanova etc., hexane, chloroform, methylene chloride, ethyl acetate, benzene, toluene, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethyl ether, acetonitrile, water, etc., separately or in a mixed solvent.

Stage 2

The compound [I-4-2] can be obtained by replacing X11bcompound [I-4-1] Deputy R3or by his predecessor in the same manner as in the method of obtaining I-2, stage 1.

Stage 3

The compound [I-4-3] can be obtained by removing the protective groups R11bcompound [I-4-2] in the same manner as in the method of obtaining I-2, stage 4.

Stage 4

The compound [I-4-4] can be obtained by interaction of the compound [I-4-3] with a derivative of glycine represented by the formula H2NC(R4)(R5)COOH or its salt with the metal in the same manner as in the method of obtaining I-3, stage 3.

The method of obtaining the I-5

,

where the value of each of the symbols defined above.

Stage 1

The compound [I-5-1] can be obtained by introducing a substituent R3in the compound [I-1 to 10] in accordance with the generally accepted method. For example, if R3is a group of chlorine, the connection shall prolong [I-5-1] can be obtained by interaction of the compound [I-1 to 10] gloriouse agent, such as hexachloroethane and so on, in conditions of low temperature in the presence of an ORGANOMETALLIC reagent, such as n-utility, disiliskiler lithium bis(trimethylsilyl)amide, sodium, hexamethyldisilazide potassium, diisopropylamide lithium, tert-piperonyl etc., hexane, benzene, toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane, etc., separately or in a mixed solvent.

Stage 2

The compound [I-5-2] can be obtained by substitution of the substituent X11bcompound [I-5-1] Deputy R2or by his predecessor in the same manner as in the method of obtaining I-2, stage 1.

Stage 3

The compound [I-5-3] can be obtained by removing the protective groups R11bcompound [I-5-2] in the same manner as in the method of obtaining I-2, stage 4.

Stage 4

The compound [I-5-4] can be obtained by interaction of the compound [I-5-3] with a derivative of glycine represented by the formula H2NC(R4)(R5)COOH or its salt with the metal in the same manner as in the method of obtaining I-3, stage 3.

The method of obtaining I-6

,

where R16arepresents hydroxylamino group such as acetyl group, benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group is a, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group and so on, each of R16band R16crepresents carboxylate group such as methyl group, ethyl group, benzyl group, tert-bucilina group, etc., X16arepresents a halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc., or a leaving group, such as a pair of toluensulfonate, methysulfonylmethane, triftormetilfullerenov, etc. and the values of other symbols are defined above. Even if R2in [1-6-4]-[1-6-10] are different from the defined substituents, they can be used, because certain substituents can be eventually obtained by the corresponding transformation of the Deputy.

Stage 1

The compound [I-6-2] can be obtained by introducing a hydroxyl group protected by a protective group, R16ain the compound [I-6-1] in the same manner as in the method of obtaining I-1, stage 3.

Stage 2

The compound [I-6-3] can be obtained by introducing a carboxyl group protected by a protective group, R16bin the compound [I-6-2] in the same manner as in the method of obtaining I-1, stage 1.

Stage 3

The compound [I-6-4] can be obtained by introducing a substituent R2or the pre is restonica in compound [I-6-3] in the same way, as in the method of obtaining I-2, stage 1.

Stage 4

The compound [I-6-5] can be obtained from compound [I-6-4] in the same manner as in the method of obtaining I-1, stage 4.

Stage 5

The compound [I-6-6] can be obtained from compound [I-6-5] in the same manner as in the method of obtaining I-1, stage 5.

Stage 6

The compound [I-6-7] can be obtained from compound [I-6-6] in the same manner as in the method of obtaining I-1, stage 6.

Stage 7

The compound [I-6-8] can be obtained by removing carboxylamide group of compound [I-6-7] in the same manner as in the method of obtaining I-1, stage 7.

Stage 8

The compound [I-6-9] can be obtained by condensation of compound [I-6-8] with a derivative of glycine represented by the formula H2NC(R4)(R5)COOR16cin the same way as in the method of obtaining I-2, stage 3.

Stage 9

The compound [I-6-10] can be obtained by removing hydroxylamino group, R16acompound [I-6-9] in the same manner as in the method of obtaining I-2, stage 4.

Stage 10

The compound [I-6-11] can be obtained by removing carboxylamide group of compound [I-6-10] in the same manner as in the method of obtaining I-1, stage 7.

The method of obtaining I-7

,

where R17arepresents carboxylate group, such as methyl groups is, ethyl group, benzyl group, tert-bucilina group, etc., X17arepresents a halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc., or a leaving group, such as a pair of toluensulfonate, methysulfonylmethane, triftormetilfullerenov etc.

Stage 1

The compound [I-7-2] can be obtained by interaction of the compound [I-7-1] with cyanamide in the presence of an ORGANOMETALLIC reagent, such as acetylacetonate, Nickel(II), etc., under conditions of low temperature to heating in hexane, ethyl acetate, chloroform, methylene chloride, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethylsulfoxide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, water, etc., separately or in a mixed solvent.

Stage 2

The compound [I-7-3] can be obtained by converting the hydroxyl group of compound [I-7-2] in the stretching group in accordance with generally accepted way. For example, if the leaving group X17ais the chlorine atom, the compound [I-7-3] can be obtained by chlorination of the compound [I-7-2] thionyl chloride, oxalicacid, triphosgene, pentachloride phosphorus, phosphorus oxychloride, etc., under conditions of low temperature to heating in hexane, ethylacetate, is cetone, chloroform, methylene chloride, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethylsulfoxide, N,N-dimethylformamide, 2-pyrrolidone, acetonitrile, etc., separately, or their mixed solvent, or without solvent in the presence of, if necessary, a base such as triethylamine, pyridine, 4-(dimethylamino)pyridine, N-methylmorpholine, diisopropylethylamine, tetramethylethylenediamine, etc. and, if necessary, N,N-dimethylformamide.

Stage 3

The compound [I-7-4] can be obtained by interaction of the compound [I-7-3] with N,N-dimethylformamidine in conditions of low temperature to heating in ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, etc., separately or in a mixed solvent, and then with hydroxylamine or its hydrochloride.

Stage 4

The compound [I-7-5] can be by dehydration of compound [I-7-4] with the use of polyphosphoric acid, thionyl chloride, phosphorus oxychloride, para-toluensulfonate, acetic anhydride, acetylchloride, triperoxonane anhydride, etc., under conditions of low temperature to a high temperature in hexane, ethyl acetate, acetone, chloroform, toluene, 1,4-dioxane, is tetrahydrofurane, 1,2-dimethoxyethane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, etc., separately or in a mixed solvent.

The method of obtaining I-8

,

where R18arepresents hydroxylamino group such as acetyl group, benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group, etc.,, R18brepresents carboxylate group such as methyl group, ethyl group, benzyl group, tert-bucilina group, etc. and the values of other symbols are defined above.

Stage 1

The compound [I-8-1] can be obtained by introducing a substituent R2or his predecessor in compound [I-7-5] in accordance with the generally accepted method in the same manner as in the method of obtaining I-2, stage 1.

Stage 2

The compound [I-8-2] can be obtained by introducing a hydroxyl group protected by a protective group represented by the formula, R18ain the compound [I-8-1]. For example, if you enter a hydroxyl group protected by a methyl group, the compound [I-8-2] can be obtained by interaction of the compound [I-8-1] with sodium methoxide in y is s from low temperature to heating in hexane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, methanol, water, etc., separately or in a mixed solvent, or with a base, such as triethylamine, tert-piperonyl potassium, sodium methoxide, potassium carbonate, sodium hydride, n-utility, diisopropylamide lithium, etc., in conditions of low temperature to heating in methanol separately or in a mixed solvent of hexane, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, etc.,

Stage 3

The compound [I-8-3] can be obtained by removing carboxylamide group of compound [I-8-2] in the same manner as in the method of obtaining I-1, stage 7.

Stage 4

The compound [I-8-4] can be obtained by implementing the condensation of compound [I-8-3] with a derivative of glycine represented by the formula H2NC(R4)(R5)COOR18bin the same way as in the method of obtaining I-2, stage 3.

Stage 5

The compound [I-8-5] can be obtained by removing hydroxylamino group, R18aand carboxylamide group, R18bcompound [I-8-4] according to the conventional method. For example, if R18arepresents a methyl group, and R18brepresents a tert-boutelou group, compound [I-8-5 can be obtained by mixing the compound [I-8-4] conditions from room temperature to heating in the presence of acid, such as para-toluensulfonate acid, methanesulfonate acid, boron TRIFLUORIDE, a complex of boron TRIFLUORIDE in diethyl ether, trichloride boron, tribromide boron, chloride, bromovalerate, phosphoric acid, sulfuric acid, acetic acid, triperoxonane acid, etc., in hexane, ethyl acetate, acetone, chloroform, methylene chloride, ethyl acetate, toluene, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetic acid, water, etc., separately or in a mixed solvent.

The method of obtaining the I-9

,

where R19arepresents carboxylate group such as methyl group, ethyl group, benzyl group, tert-bucilina group, etc.,, R19bis a metal that forms a salt with a carboxylic acid or phenol, such as lithium, sodium, calcium, etc. and the values of other symbols are defined above.

Stage 1

The compound [I-9-1] can be obtained by removing carboxylamide group of compound [I-8-1] in the same manner as in the method of obtaining I-1, stage 7.

Stage 2

The compound [I-9-2] can be obtained by condensation of compound [I-9-1] with a derivative of glycine represented by the formula H2 NC(R4)(R5)COOR19ain the same way as in the method of obtaining I-2, stage 3.

Stage 3

The compound [I-9-3] can be obtained by interaction of the compound [I-9-2] to the base. For example, if R19brepresents sodium, compound [I-9-3] can be obtained by interaction of the compound [I-9-2] with sodium hydroxide in conditions from room temperature to heating in dimethyl sulfoxide, N,N-dimethylformamide, dimethylacetamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, methanol, ethanol, 2-methoxyethanol, 2-ethoxyethanol, water, etc., separately or in a mixed solvent.

Stage 4

The compound [I-9-4] can be obtained by interaction of the compound [I-9-3] with an acid, such as acetic acid, para-toluensulfonate acid, methanesulfonate acid, triperoxonane acid, hydrogen chloride, bromovalerate, phosphoric acid, sulfuric acid, etc., in conditions of low temperature to heating in dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, methanol, ethanol, 2-methoxyethanol, 2-ethoxyethanol, water, etc., separately or in a mixed solvent.

The way to obtain II-1

,

DG is R 21arepresents hydroxylamino group such as benzyl group, acetyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group, etc.,, R21brepresents carboxylate group such as methyl group, ethyl group, benzyl group, tert-bucilina group, etc. and the values of other symbols are defined above. Even if R2in [II-1-8]-[II-1-9] are different from the defined substituents, they can be used, because certain substituents can be eventually obtained by the corresponding transformation of the Deputy.

Stage 1

The compound [II-1-2] can be obtained by interaction of the compound [II-1-1] 2,5-hexandione in conditions of low temperature to heating in the presence of acid, such as para-toluensulfonate acid, methanesulfonate acid, boron TRIFLUORIDE, trichloride boron, tribromide boron, trichloride aluminum chloride, bromovalerate, phosphoric acid, sulfuric acid, Sultanova acid, acetic acid, triperoxonane acid, etc. in the hexane, chloroform, methylene chloride, ethyl acetate, methanol, ethanol, 2-propanol, tolua is e, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, water, etc., separately or in a mixed solvent.

Stage 2

The compound [II-1-3] can be obtained by introducing a hydroxyl group protected by a protective group represented by the formula, R21ain the compound [II-1-2] in the same manner as in the method of obtaining I-1, stage 3.

Stage 3

The compound [II-1-4] can be obtained by mixing the compound [II-1-3] under the conditions of low temperature to heating in the presence of a base, such as triethylamine, tert-piperonyl potassium, potassium carbonate, sodium hydride, diisopropylamide lithium, etc. and chloride of hydroxylamine in methanol, ethanol, 2-propanol, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, water, etc., separately or in a mixed solvent.

Stage 4

The compound [II-1-4] lead in the interaction with N,N-dimethylformamidine in conditions from room temperature to heating in ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, etc., separately or in a mixed solvent to obtain compound that is subjected to interaction with hydroxylamine or its salt in the presence of the basis of the project, such as triethylamine, diisopropylethylamine, morpholine, pyridine, etc. in conditions of low temperature to a high temperature in hexane, ethyl acetate, acetone, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, etc., separately or in a mixed solvent, and subjected to interaction with polyphosphoric acid or hydroxylamine-O-sulfonic acid, whereby can be obtained compound [II-1-5].

Stage 5

The compound [II-1-6] can be obtained by introducing a carboxyl group in the compound [II-1-5] in the same manner as in the method of obtaining I-1, stage 1.

Stage 6

The compound [II-1-7] can be obtained by introducing a protective group, R21bin the carboxyl group of compound [II-1-6] in accordance with the generally accepted method. For example, if R21brepresents an ethyl group, compound [II-1-7] can be obtained by interaction of the compound [II-1-6] with N,N-dimethylformamidine in conditions from room temperature to heating in hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, etc., separately or in a mixed solvent.

Stage 7

The compound [II-1-8] can be obtained by introducing a substituent R2or his predecessor in the compound [II-1-7] in accordance with the generally accepted method. For example, with the introduction of tert-butylacetophenone group of the compound [II-1-8] can be obtained by interaction of the compound [II-1-7] with tert-butylaniline in conditions from room temperature to heating in the presence of a palladium catalyst, such as dichloride [1,1-bis(diphenylphosphino)ferrocene]palladium(II), tetrakis(triphenylphosphine)palladium dichloride bis(triphenylphosphine)palladium(II), acetyltryptophan palladium, etc., bases such as potassium acetate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, triethylamine, diisopropylethylamine, sodium phosphate, cesium carbonate, etc., and copper iodide in hexane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, water, etc., separately or in a mixed solvent.

Stage 8

The compound [II-1-9] can be obtained by removing the protective groups with hydroxylamine group, R21athe compound [II-1-8] in the same manner as in the method of obtaining I-2, stage 4.

Stage 9

The compound [II-1-10] can be obtained from compound [II-1-9] in the same manner as in the method of obtaining I-3, stage 3.

In this way receive has been described a method of obtaining, when R1represents a hydrogen atom. If R1represents the above and other than a hydrogen atom Deputy, at the stage 4 and stage 5 instead of N,N-dimethylformamidine can be used N,N-dimethylformamidine, substituted desired Deputy, and further may be conducted in a manner similar to the method described in this receipt.

The method of obtaining III-1

,

where each of R31aand R31drepresents carboxylate group such as methyl group, ethyl group, benzyl group, tert-bucilina group and so on, each of R31band R31crepresents aminosidine group, such as benzyloxycarbonyl group, tert-butoxycarbonyl group, benzyl group, etc., each of X31aand X31brepresents a halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc., leaving group, such as a pair of toluensulfonate, methysulfonylmethane, triftormetilfullerenov, etc. and the values of other symbols are defined above.

Stage 1

The compound [III-1-2] can be obtained by introducing in accordance with generally accepted way of leaving groups X31b in the compound [III-1-1] obtained by removing the protective group R11bcompounds [I-1-4] in the same manner as in the method of obtaining I-2, stage 4. For example, if X31brepresents a bromine atom, the compound [III-1-2] can be obtained by interaction of the compound [III-1-1] with bromine or N-bromosuccinimide in conditions of low temperature to heating in hexane, chloroform, methylene chloride, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, water, etc., separately or in a mixed solvent.

Stage 2

The compound [III-1-3] can be obtained by introducing R31bin the compound [III-1-2] in accordance with the generally accepted method. For example, if R31brepresents a benzyl group, the compound [III-1-3] can be obtained by interaction of the compound [III-1-2] benzylchloride or benzylbromide in the presence of a base such as potassium carbonate, tert-piperonyl potassium, sodium hydride, cesium carbonate, etc., in ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, water, etc., separately or in a mixed solvent.

Stage 3 and stage 4

[III-1-6] can be obtained by removing the protective group R31athe compound [III-1-3] in the same manner as in the method of obtaining -1, stage 7, the conversion of the compound into the acid chloride in accordance with the conventional method, the interactions of the acid chloride derived from glycine represented by the formula H2NC(R4)(R5)COOR31din the presence of a base, such as triethylamine, diisopropylethylamine, pyridine, etc. in conditions of low temperature to heating in hexane, chloroform, methylene chloride, ethyl acetate, toluene, tetrahydrofuran, etc., separately or in a mixed solvent to obtain the compound [III-1-4], and the interaction of this compound with the compound [III-1-5] under the conditions of low temperature to heating in the presence of a base, such as triethylamine, diisopropylethylamine, pyridine, etc. in hexane, chloroform, methylene chloride, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, etc., separately or in a mixed solvent.

Stage 5

The compound [III-1-7] can be obtained from compound [III-1-6] in the same manner as in the method of obtaining I-2, stage 1.

Stage 6

The compound [III-1-8] can be obtained by removing the protective groups R31bthe compound [III-1-7] in the same manner as in the method of obtaining I-2, stage 4.

Stage 7

The compound [III-1-9] can be obtained by removing aminosidine group, R31cthe compound [III-1-8] in accordance with a conventional method, for Example, if R31crepresents a tert-butoxycarbonyl group, the compound [III-1-9] can be obtained by mixing under conditions of low temperature to room temperature in the presence of an acid such as hydrogen chloride, sulfuric acid, bromovalerate, phosphoric acid, acetic acid, triperoxonane acid, etc., in hexane, chloroform, methylene chloride, ethyl acetate, toluene, methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, water, etc., separately or in a mixed solvent.

Stage 8

The compound [III-1-10] can be obtained from compound [III-1-9] in the same manner as in the method of obtaining I-1, stage 5.

Stage 9

The compound [III-1-11] can be obtained by removing carboxylamide group of compound [III-1-10] in the same manner as in the method of obtaining I-1, stage 7.

The method of obtaining III-2

,

where R32arepresents carboxylate group such as methyl group, ethyl group, benzyl group, tert-bucilina group, etc. and the values of other symbols are defined above.

Stage 1

The compound [III-2-1] can be obtained from compound [I-6-5] in the same manner as in the method of obtaining I-1, stage 5.

Stage 2

The compound [III-2-2] can be obtained by removing carboxylases the Oh group of compound [III-2-1] in the same way, as in the method of obtaining I-1, stage 7.

Stage 3

The compound [III-2-3] can be obtained by condensation of compound [III-2-2] with a derivative of glycine represented by the formula H2NC(R4)(R5)COOR32ain the same way as in the method of obtaining I-2, stage 3.

Stage 4

The compound [III-2-4] can be obtained by removing the protective groups R16athe compound [III-2-3] in the same manner as in the method of obtaining I-2, stage 4.

Stage 5

The compound [III-2-5] can be obtained by removing carboxylamide group of compound [III-2-4] in the same manner as in the method of obtaining I-1, stage 7.

The method of obtaining IV-1

,

where R41arepresents hydroxylamino group such as acetyl group, benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group, etc.,, R41brepresents carboxylate group such as methyl group, ethyl group, benzyl group, tert-bucilina group and so on, each of X41aand X41brepresents a halogen atom such as chlorine atom, bromine atom, iodine atom, etc., leaving group, such as para-toluensulfonyl the group, methysulfonylmethane, triftormetilfullerenov, para-toluensulfonyl group, methanesulfonyl group, etc. and the values of other symbols are defined above.

Stage 1

The compound [IV-1-2] can be obtained by converting the leaving group X41athe compound [IV-1-1] formyl group in accordance with generally accepted way. The compound [IV-1-2] can be obtained by interaction of the compound [IV-1-1] with an ORGANOMETALLIC reagent, such as n-utility, second-utility, diisopropylamide lithium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide, potassium, lithium amide, sodium amide, etc., under conditions of low temperature in hexane, benzene, toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane, etc., separately or in a mixed solvent, and then with N,N-dimethylformamide.

Stage 2 and stage 3

The compound [IV-1-4] can be obtained by interaction of the compound [IV-1-2] with hydrazine containing a leaving group X41bin conditions from room temperature to heating in ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, etc., separately or in a mixed solvent, and then by the adding the base, such as morpholine, piperidine, pyrrolidine, etc., and stirring the mixture.

Stage 4

The compound [IV-1-5] can be obtained from compound [IV-1-4] in the same manner as in the method of obtaining I-1, stage 1.

Stage 5

The compound [IV-1-6] can be obtained by condensation of compound [IV-1-5] with a derivative of glycine in the same manner as in the method of obtaining I-2, stage 3.

Stage 6

The compound [IV-1-7] can be obtained by removing the protective groups R41athe compound [IV-1-6] in the same manner as in the method of obtaining I-2, stage 4.

Stage 7

The compound [IV-1-8] can be obtained by removing carboxylamide group of compound [IV-1-7] in the same manner as in the method of obtaining I-1, stage 7.

In this way receive has been described a method of obtaining, when R1represents a hydrogen atom. If R1represents the above and other than a hydrogen atom Deputy, at the stage 1 and stage 2 instead of N,N-dimethylformamide can be used N,N-dimethylformamide, substituted desired Deputy, and later can be carried out in a manner similar to the method described in this receipt.

Examples

The following Examples specifically explains the method for obtaining compounds of the present invention, or its pharmaceutically acceptable salt, or its Solvay is and. However, the present invention is not limited to the Examples.

Example 1

Getting hydrochloride {[5-(4-fluoro-3-triptoreline)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid

Stage 1-1

In a stream of nitrogen mixed Diisopropylamine (198 ml) and tetrahydrofuran (1000 ml) and cooled in a bath with a mixture of dry ice/hexane was added dropwise n-utility (was 2.76 M, 500 ml). After stirring in a bath with a mixture of dry ice/hexane for 1 h was added dropwise 2,4-dichloropyridine. After stirring under cooling in a bath with a mixture of dry ice/hexane for 1 h was blown with carbon dioxide until the termination of rising temperatures, preventing the decrease of the temperature below -60°C. was Blown with carbon dioxide for 30 minutes under cooling in a bath with a mixture of dry ice/hexane, was added dropwise 4 N. hydrochloric acid (1000 ml). The aqueous layer was twice extracted with ethyl acetate (1000 ml, 500 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained solid is suspended in hexane to obtain compound (243 g, 96%) described in the above schema.

1H-NMR (DMSO-D6) δ: 7,74 (1H, d, J=5.6 Hz), of 8.47 (1H, d, J=5.6 Hz), 14,53 (1H, user. c).

Stage 1-2

Mixed connection (234 g) obtained in stage 1-1, and tetrahydrofuran (1200 ml), and added a complex of boron TRIFLUORIDE/diethyl ether (8 ml). Then when cooled on ice was added dropwise tert-butyl-2,2,2-trichloroacetimidate (361 ml). To this reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (1200 ml) and water (1200 ml) and the aqueous layer was extracted with ethyl acetate (1200 ml). The organic layer was washed with saturated saline solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. To the obtained residue was added hexane (1800 ml). Insoluble material was filtered, and the filtrate was concentrated under reduced pressure to obtain compound (326 g), described in the above scheme, in the form of a crude product.

1H-NMR (CDCl3) δ: 1,63 (9H, s), 7,31 (1H, d, J=5,2 Hz), 8,31 (1H, d, J=5,2 Hz).

Stage 1-3

Under a stream of nitrogen while cooling on ice, mixed sodium hydride (60% suspension in oil, 58 g) and N,N-dimethylformamide (1000 ml). To the mixture was added the compound (326 g) obtained in stage 1-2, was dissolved in N,N-dimethylformamide (300 ml) was added thereto. To this mixture was added a mixture of benzyl alcohol (136 ml) and N,N-dimethylformamide (200 ml). After stirring under cooling on ice for 15 min was added hydride NAT the Oia (60% suspension in oil, to 5.2 g). After stirring under cooling in ice for 20 min was added water (3000 ml), precipitated precipitated solid was filtered and the filtrate was dried under reduced pressure at 50°C during the night. The solid was purified by the method of column chromatography (eluent: hexane/ethyl acetate = 10/1 - only ethyl acetate). The obtained solid is then suspended in hexane to obtain the target product. At the same time, the filtrate was concentrated, purified column chromatography and suspended in hexane to obtain the target product. The target products were combined with obtaining compound (334 g, yield 83%) described in the above schema.

1H-NMR (CDCl3) δ: of 1.55 (9H, s) to 5.17 (2H, s), 6,83 (1H, d, J=6.0 Hz), 7,32-7,42 (5H, m), 8,24 (1H, d, J=6.0 Hz).

Stage 1-4

Mixed connection (167 g) obtained in stage 1-3, hydrazine monohydrate (127 ml) and 1,4-dioxane (1200 ml) and stirred the reaction mixture at 94°C for 17 hours After cooling to room temperature, was added ethyl acetate (1700 ml) and sequentially washed with a mixture of saturated aqueous sodium bicarbonate (500 ml)/water (500 ml), saturated aqueous sodium hydrogen carbonate (250 ml)/water (250 ml) and saturated aqueous sodium hydrogen carbonate (200 ml)water (200 ml). The organic layer was dried over self the volume of sodium was filtered and concentrated under reduced pressure. By twice repeating the operation received connection (266 g), described in the above scheme, in the form of a crude product.

1H-NMR (CDCl3) δ: of 1.42 (9H, s), 3,98 (2H, user. c) 5,09 (2H, s), 6,32 (1H, d, J=5.6 Hz), 7,28 was 7.45 (5H, m), of 7.96 (1H, user. c) 8,08 (1H, d, J=5.6 Hz).

Stage 1-5

Mixed connection (266 g) obtained by the method similar to that described for stages 1-4, and triethylorthoformate (1000 ml), was added monohydrate para-toluensulfonate acid (80 g) and stirred the mixture at 56°C for 1 h, the Reaction mixture was concentrated under reduced pressure and suspended the obtained residue in hexane/ethyl acetate (2/1). Then the residue is suspended in a saturated aqueous solution of sodium bicarbonate/water (1/1) to obtain compound (209 g, 76%) described in the above schema.

1H-NMR (DMSO-D6) δ: for 1.49 (9H, s), are 5.36 (2H, s), 7,22 (1H, d, J=7,6 Hz), 7,32 is 7.50 (5H, m), to 8.62 (1H, d, J=7,6 Hz), 9,13 (1H, s).

Stage 1-6

Mixed connection (200 g) obtained in stage 1-5, and ethyl acetate (600 ml) was added morpholine (160 ml) and stirred the mixture at 74°C for 3 hours the Mixture was left to cool to room temperature and added to water (600 ml). The aqueous layer was extracted with ethyl acetate (400 ml), the organic with the AOI were combined and sequentially washed with 5% aqueous solution of potassium hydrosulfate (600 ml) and saturated salt solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain compound (194 g, 97%) described in the above schema.

1H-NMR (CDCl3) δ: equal to 1.59 (9H, s), 5,28 (2H, s), 6,85 (1H, d, J=7,6 Hz), 7,33-7,46 (5H, m), 8,29 (1H, s), and 8.50 (1H, d, J=7,6 Hz).

Stage 1-7

Under a stream of nitrogen and cooled in a bath with a mixture of dry ice/hexane mixed connection (194 g), obtained at the stage 1-6, and tetrahydrofuran (600 ml) and was added dropwise a solution of iodine (151 g) in tetrahydrofuran (500 ml). To this mixture was added dropwise a 1.6 M bis(trimethylsilyl)amide lithium (788 ml), without lowering the temperature below -60°C. After stirring under cooling in a bath with a mixture of dry ice/hexane for 2 h was added dropwise 4 N. hydrochloric acid in ethyl acetate (315 ml), without lowering the temperature below -60°C. To this reaction mixture was added sodium sulfite (76 g), a saturated aqueous solution of ammonium chloride (1000 ml), water (800 ml) and hexane/ethyl acetate (1/1, 1000 ml). The organic layer was sequentially washed with a saturated aqueous solution of sodium bicarbonate (500 ml) and saturated brine (800 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product is suspended in hexane is obtaining compound (188 g, 70%) described in the above schema.

1H-NMR (DMSO-D6) δ: of 1.46 (9H, s), of 5.39 (2H, s), 7,33-7,51 (5H, m), 7,87 (1H, s), 8,43 (1H, s).

Stage 1-8

Mixed connection (60 g), obtained at the stage 1-7, 4-fluoro-3-(trifluoromethyl)phenylboronic acid (29 g), complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) and dichloromethane (1/1, 5,4 g), potassium phosphate (113 g) and 1,2-dimethoxyethan (600 ml) and the mixture was stirred at 80°C for 1 h To the reaction mixture was added water and was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid was purified by the method of column chromatography (eluent: chloroform/ethyl acetate = 10/1) to obtain the crude product as described in the above wiring diagram. This product is suspended in diisopropyl ether/hexane (1/1, 500 ml) to obtain compound (45 g, 70%) described in the above schema.

1H-NMR (CDCl3) δ: of 1.61 (9H, s) 5,33 (2H, s), to 6.88 (1H, s), 7,35-of 7.48 (6H, m), of 8.04 (1H, DD, J=6,7, and 2.1 Hz), 8,11-of 8.15 (1H, m), 8,31 (1H, s).

Stage 1-9

Mixed connection (45 g) obtained in stage 1-8, and 1,4-dioxane (450 ml) and at room temperature was added 4 N. aqueous solution is hydroxide sodium (116 ml). After stirring at 100°C for 17 h, the reaction mixture was concentrated under reduced pressure. To the mixture was added water (450 ml) while cooling on ice, neutralized mixture by adding 6 N. hydrochloric acid (77 ml) and was collected in the precipitated solid by filtration to obtain compound (43 g), described in the above schema.

1H-NMR (DMSO-D6) δ: the 5.51 (2H, s), 7,34-7,38 (1H, m), 7,41 was 7.45 (2H, m), 7,50-7,52 (2H, m), 7,63 (1H, s), 7,80 (1H, DD, J=10.5V, the 8.9 Hz), 8,40-8,48 (2H, m), 8,48 (1H, s).

Stage 1-10

Mixed compound (43 g), obtained at the stage 1-9, hydrochloride complex ethyl ester of glycine (15 g), hydrate of 1-hydroxybenzotriazole (17 g) and N,N-dimethylformamide (430 ml) and at room temperature was added triethylamine (15 ml) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (21 g). After stirring at room temperature for 1 h was added water (860 ml) and saturated aqueous solution of sodium bicarbonate (215 ml) and was collected in the precipitated solid by filtration to obtain compound (43 g, 84%) described in the above schema.

1H-NMR (CDCl3) δ: of 1.33 (3H, t, J=7,1 Hz), 4,28 (2H, square, J=7,1 Hz), 4,35 (2H, d, J=4,8 Hz), vs. 5.47 (2H, s), to 6.95 (1H, s), 7,32-the 7.43 (4H, m), 7,54 (2H, d, J=7,3 Hz), 8,01 (1H, DD, J=6,4, 2.0 Hz), 8,10-to 8.14 (1H, m), 8,31 (1H, s), 9,72 (1H, t, J=4,8 Hz).

Stage 1-11

Mixed compound (43 g), obtained at the stage of 1-10, and triperoxonane acid (430 ml) and after stirring at 80°C for 6 h and the reaction mixture was concentrated under reduced pressure. To the residue was added methanol (86 ml) and water (430 ml), the mixture was stirred at room temperature for 30 min and was collected in the precipitated solid by filtration. The solid was purified by the method of column chromatography (eluent: chloroform/ethyl acetate = 10/1) to obtain compound (28 g, 79%) described in the above schema.

1H-NMR (CDCl3) δ: of 1.34 (3H, t, J=7,3 Hz), 4,30 (2H, square, J=7,3 Hz) to 4.33 (2H, d, J=5,2 Hz), 6.87 in (1H, s), 7,41 (1H, DD, J=9,7, a 8.9 Hz), 8,16-to 8.20 (1H, m), 8,24 (1H, DD, J=6,9, 2.4 Hz), compared to 8.26 (1H, s), 10,15 (1H, t, J=5,2 Hz), 14,13 (1H, s).

Stage 1-12

Mixed compound (27 g), obtained at the stage 1-11, and 2-propanol (540 ml) at room temperature was added 4 N. aqueous solution of lithium hydroxide (64 ml). After stirring at 70°C for 1 h was added 6 N. hydrochloric acid (43 ml). The mixture was left to slowly cool with stirring, and at 37°C in the sediment precipitated crystalline substance. Was added water (270 ml) and collected crystalline substances by filtration to obtain compound (22 g, 87%) as described in the above schema.

1H-NMR (DMSO-D6) δ: 4,24 (2H, d, J=5.6 Hz), 7,30 (1H, is), to 7.77 (1H, DD, J=10,5, and 9.3 Hz), at 8.36-to 8.40 (1H, m), of 8.47 (1H, d, J=6.9 Hz), at 8.60 (1H, s), becomes 9.97 (1H, user. c), 14,38 (1H, user. c).

The compound obtained was converted to the hydrochloride in accordance with the generally accepted method of obtaining compounds of Example 1.

1H-NMR (DMSO-D6) δ: 4.25 in (d, 2H, J=5.6 Hz), 7,31 (c, 1H), 7,73-of 7.82 (m, 1H), 8.34 per-8,43 (m, 1H), 8,43-8,51 (m, 1H), 8,61 (c, 1H), 9,99 (t, 1H, J=5.6 Hz).

Example 2

Getting hydrochloride [(7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid

Stage 2-1

Mixed connection of 5.00 g) obtained in stage 1-7, toluene (35 ml) and phenylacetylene (1,34 ml) and cooled on ice was sequentially added bis(triphenylphosphine)palladium dichloride (0,233 g), copper iodide (0,063 g) and triethylamine (1,85 ml). After stirring at room temperature for 2 h to the reaction mixture was added 5% aqueous ammonia (35 ml). The organic layer is then washed with 5% aqueous ammonia, saturated aqueous ammonium chloride and saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purify the resulting residue by the method of column chromatography (eluent: hexane/ethyl acetate = 3/1-1/1). The compound obtained suspended in hexane to obtain compound (a-3.84 g, 82%) as described in representation the military above.

1H-NMR (DMSO-D6) δ: to 1.48 (9H, s), 5,42 (2H, s), of 7.36 (1H, TT, J=7,1, 1.8 Hz),7,40-7,45 (2H, m), of 7.48 (2H, dt, J=7,0, 1.9 Hz), 7,51-7,58 (3H, m), 7,72 (2H, DD, J=7,7, 1,6 Hz), 7,78 (1H, s), 8,49 (1H, s).

Stage 2-2

Mixed connection (3,84 g) obtained in stage 2-1, toluene (29 ml) and ethyl acetate (9.5 ml), and under stirring at room temperature dropwise over 10 min was added to the mixture methanesulfonic acid (2,34 ml) and ethyl acetate (2,34 ml). After stirring at room temperature for 3 h to the reaction mixture were added ethyl acetate (9.5 ml) and collect the solid by filtration to obtain compound (4.94 g, 98%) described in the above schema.

1H-NMR (DMSO-D6) δ: of 2.38 (6H, s), of 5.48 (2H, s), 7,37 (1H, TT, J=7,2, 1.7 Hz), 7,41 was 7.45 (2H, m), of 7.48-7,52 (2H, m), 7,53 to 7.62 (3H, m), 7,71 to 7.75 (2H, m), 7,86 (1H, s), 8,67 (1H, s).

Stage 2-3

At room temperature was mixed compound (4.94 g) obtained in stage 2-2, and N,N-dimethylformamide (30 ml) and at 0°C dropwise within 10 min was added water (50 ml). Precipitated precipitated solid substance was collected by filtration to obtain compound (3,20 g, 98%) described in the above schema.

1H-NMR (DMSO-D6) δ: the 5.45 (2H, s), of 7.36 (1H, TT, J=7,4, and 2.1 Hz), the 7.43 (2H, t, J=7,3 Hz), 7,49 (2H, d, J=7.5 Hz), 7,52-of 7.60 (3H, m), 7,72 (2H, DD, J=6,7, 1.9 Hz), 7,78 (1H, s), 8,51 (1H, s) 13,59 (1H, s).

Stage 2-4

Cooperated connection (3,20 g) obtained in stage 2-3, hydrochloride complex ethyl ester of glycine (1,33 g) by the method similar to that described in Example 1, stage 1-10, to obtain the compounds (3,38 g, 81%) described in the above schema.

1H-NMR (DMSO-D6) δ: to 1.21 (3H, t, J=7,1 Hz), 4,10 (2H, d, J=5.7 Hz), 4,13 (2H, square, J=7.5 Hz), 5,44 (2H, s), 7,34 (1H, TT, J=7,2, 1.7 Hz), 7,38-the 7.43 (2H, m), 7,52-7,58 (5H, m), 7,71-7,74 (2H, m), of 7.75 (1H, s), charged 8.52 (1H, s), 9,18 (1H, t, J=5.8 Hz).

Stage 2-5

To a solution of compound (3,38 g) obtained in stage 2-4, in tetrahydrofuran (34 ml) and methanol (17 ml) was added 5% palladium carbon (0.34 g) and the mixture was stirred in an atmosphere of hydrogen at normal pressure for 4 hours, the Reaction mixture was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by the method of column chromatography (eluent: chloroform/methanol = 20/0-20/1) and suspended in hexane/diisopropyl ether (1/1) to obtain compound (to 2.29 g, 83%) described in the above schema.

1H-NMR (DMSO-D6) δ: of 1.23 (3H, t, J=7.2 Hz), of 3.12 (2H, t, J=7.8 Hz), to 3.41 (2H, t, J=7.9 Hz), 4,17 (2H, square, J=7,1 Hz), the 4.29 (2H, d, J=5.7 Hz), PC 6.82 (1H, s), 7.18 in-to 7.32 (5H, m), 8,58 (1H, s), 9,87 (1H, t, J=5.6 Hz), 14,12 (1H, s).

Stage 2-6

The compound (2.28 g), obtained at the stage 2-5, hydrolyzed pic is BOM, similar to that described in stage 1-12, and converting the compound obtained to a hydrochloride in accordance with generally accepted way of obtaining specified in the title compound (2.16 g).

1H-NMR (DMSO-D6) δ: 3,12 (t, 2H, J=7.8 Hz), to 3.41 (t, 2H, J=7.8 Hz), is 4.21 (d, 2H, J=5.6 Hz), for 6.81 (c, 1H), 7,14-7,33 (m, 5H), at 8.60 (c, 1H), 9,85 (t, 1H, J=5.6 Hz).

Example 3

Getting hydrochloride [(5-butyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid

Stage 3-1

Mixed compound (0.2 g) obtained in stage 1-7, complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) and dichloromethane (1/1, to 0.011 g), butylboronic acid (0,050 g), silver oxide(I) (0.12 g), potassium carbonate (0.15 g) and tetrahydrofuran (1.6 ml), and the mixture was stirred at 80°C for 40 h, the Insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by the method of column chromatography (eluent: hexane/ethyl acetate = 8/2-6/4) to obtain the compound (0,13 g, 77%) described in the above schema.

1H-NMR (DMSO-D6) δ: of 0.91 (t, 3H, J=7,7 Hz), 1,28-of 1.39 (m, 2H), 1,48 (c, 9H), 1,71-of 1.81 (m, 2H), 3,11 (t, 2H, J=7,7 Hz), 5,38 (c, 2H), 7.23 percent (c, 1H), 7,32-7,51 (m, 5H), 8,39 (c, 1H).

Stage 3-2

Carboxylterminal connection group (of 53.7 g) obtained in stage 3-1, was removed in a manner analogous about isonomy on stage 2-2, obtaining carboxylic acid in the form of a mixture (69,8 g, 80%) with methanesulfonic acid (290% mol.). The mixture was treated in a manner similar to that described in stage 2-3, to obtain the compounds described in the above scheme, in the form of a mixture (42.8 g, 99%) with methanesulfonic acid (50 mol%).

1H-NMR (DMSO-D6) δ: of 0.91 (t, 3H, J=7,7 Hz), 1,29-of 1.40 (m, 2H), 1,71 and 1.80 (m, 2H), 2,34 (c 1,5 H), 3,14 (t, 2H, J=7,7 Hz), 5,47 (c, 2H), 7,32 was 7.45 (m, 4H), of 7.48-7,53 (m, 2H), 8,73 (c, 1H).

Stage 3-3

By the way, is similar to that described in stage 1-10, cooperated connection (42.8 g), obtained in stage 3-2, hydrochloride complex ethyl ester of glycine (19.3 g) to obtain the compound (43,5 g, 92%) described in the above schema.

1H-NMR (CDCl3) δ: of 0.94 (t, 3H, J=7.5 Hz), is 1.31 (t, 3H, J=7,1 Hz), 1,34 was 1.43 (m, 2H), 1.70 to to 1.79 (m, 2H), 3,11 (t, 2H, J=7.5 Hz), 4.26 deaths (square, 2H, J=7,1 Hz) to 4.33 (d, 2H, J=5,2 Hz), 5,41 (c, 2H), 6,69 (c, 1H), 7,29-of 7.55 (m, 5H), 8,28 (c, 1H), 9,77 (t, 1H, J=5,2 Hz).

Stage 3-4

By the way, is similar to that described in stage 2 to 5, from compound (7.2 g), obtained in stage 3-3, received the compound (5.0 g, 90%) as described in the above schema.

1H-NMR (DMSO-D6) δ: of 0.93 (t, 3H, J=7.5 Hz), 1,22 (t, 3H, J=7,3 Hz), 1,33-1,44 (m, 2H), 1,71-of 1.81 (m, 2H), to 3.09 (t, 2H, J=7.5 Hz), 4,16 (square, 2H, J=7,3 Hz), the 4.29 (d, 2H, J=5.6 Hz), 6,85 (c, 1H), 8,54 (c, 1H), 9,88 (user. s, 1H), 14,14 (c, 1H).

Stage 3-5

By the way, is similar to that described in stage 1-12, from the compound (4.94 g) obtained in stage 3-4, received the connection (4,56 g), described in the above schema.

1H-NMR (DMSO-D6) δ: of 0.93 (t, 3H, J=7.5 Hz), 1,33-1,44 (m, 2H), 1,71 and 1.80 (m, 2H), 3,10 (t, 2H, J=7.5 Hz), 4,20 (d, 2H, J=5,2 Hz), 6,85 (c, 1H), 8,55 (c, 1H), 9,84 (user. s, 1H), 14,26 (user. s, 1H).

Stage 3-6

Mixed connection (4,56 g) obtained in stage 3-5, and 4 n hydrochloric acid in ethyl acetate (91 ml), and the mixture was stirred at room temperature for 1.5 hours the Reaction suspension was concentrated under reduced pressure, was added to the residue with hexane (100 ml), and twice concentrating the mixture under reduced pressure. To the residue was added a mixed solution of diethyl ether/hexane (1/2, 100 ml), and stirred the mixture for 30 minutes, the Solid was collected by filtration to obtain specified in the connection header (4,88 g, 96%).

1H-NMR (DMSO-D6) δ: of 0.93 (t, 3H, J=7.5 Hz), 1,34-of 1.44 (m, 2H), 1,71 and 1.80 (m, 2H), 3,10 (t, 2H, J=7.5 Hz), is 4.21 (d, 2H, J=5.6 Hz), 6,86 (c, 1H), 8,57 (c, 1H), 9,83 (t, 1H, J=5.6 Hz).

Example 4

Getting hydrochloride [(5,6-diethyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid

Stage 4-1

Under a stream of nitrogen was mixed compound (3.98 g), obtained in a manner analogous to described the on stage 1-6, and tetrahydrofuran (40 ml), and cooled in a dry ice/denatured ethanol was added dropwise a solution of iodine (3.4 g) in tetrahydrofuran (16 ml). To this mixture dropwise over 10 min was added 1M bis(trimethylsilyl)amide lithium (26,8 ml). After stirring as it is for 2.5 h, the reaction mixture was poured while cooling on ice in a mixture of a saturated aqueous solution of ammonium chloride (40 ml) and water (40 ml). To this mixture was added sodium sulfite (1.7 g), and was separated from the mixture of the organic layer. The organic layer was concentrated under reduced pressure, the obtained residue was combined with the aqueous layer was twice extracted with a mixture of ethyl acetate. The organic layer was washed with saturated brine (70 ml), dried over sodium sulfate, was filtered sodium sulfate, and concentrated the filtrate under reduced pressure. The obtained residue was purified by metol column chromatography. The resulting cleaning product was recrystallized from heptane/chloroform to obtain compounds (0,295 g, 4%) described in the above schema.

1H-NMR (CDCl3) δ: to 1.38 (t, 3H, J=7,1 Hz), 4,50 (square, 2H, J=7,1 Hz), 5,22 (c, 2H), was 7.36-7,56 (m, 5H), 8,33 (c, 1H).

Stage 4-2

By the way, is similar to that described in Example 1, stage 1-8, from compound (0.1 g) obtained in stage 4-1, received the connection is 0.019 g, 30%, described in the above schema.

1H-NMR (CDCl3) δ: to 1.38 (t, 3H, J=7,1 Hz), 4,50 (square, 2H, J=7,1 Hz), 5,09 (c, 2H), 5,73 (DD, 1H, J=17.7 and, of 1.4 Hz), USD 5.76 (DD, 1H, J=11,5, 1,4 Hz), equal to 6.05 (DD, 1H, J=11,5, 1,4 Hz), 6,77 (DD, 1H, J=17.7 and, to 11.7 Hz), 6.87 in (DD, 1H, J=17,7, 1.2 Hz), 7,14 (DD, 1H, J=17,7, and 11.5 Hz), 7,35-7,44 (m, 5H), of 8.37 (c, 1H).

Stage 4-3

By the way, is similar to that described in Example 2, stage 2 to 5, from compound (0.036 g), obtained in stage 4-2, received the connection (0,020 g, 75%) described in the above schema.

1H-NMR (CDCl3) δ: of 1.23 (t, 3H, J=7.5 Hz), of 1.36 (t, 3H, J=7.5 Hz), of 1.52 (t, 3H, J=7,3 Hz), 2,78 (square, 2H, J=7.5 Hz), 3,25 (square, 2H, J=7.5 Hz), with 4.64 (square, 2H, J=7,3 Hz), compared to 8.26 (c, 1H), 13,10 (c, 1H).

Stage 4-4

Mixed connection (0,020 g) obtained in stage 4-3, 2-methoxyethanol (2 ml), was added sodium salt of glycine (0,030 g). After stirring at 130°C for 1.5 h the mixture was cooled to room temperature. To the reaction mixture were added 1 N. hydrochloric acid (0,34 ml) and water (10 ml), and stirred the mixture. The precipitate was collected by filtration and dried under reduced pressure. To the obtained solid substance was added ethyl acetate (1 ml), and 4 N. hydrochloric acid in ethyl acetate (0.1 ml) and the mixture was stirred at room temperature for 20 minutes, the Solid was collected by filtration to obtain specified in the connection header (0,052 mg, 67%).

1H-NMR (DMSO-D6) δ: 1,15 (t, 3H, J=7.5 Hz), of 1.29 (t, 3H, J=7.5 Hz), 2,72 (square, 2H, J=7.5 Hz), 3,20 (square, 2H, J=7,6 Hz), is 4.21 (d, 2H, J=5.6 Hz), charged 8.52 (c, 1H), 9,95 (t, 1H, J=5.6 Hz).

Example 5

Getting hydrochloride [(7-hydroxy-6-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid

Stage 5-1

Mixed compound (1.31 g) obtained by the method similar to that described in Example 4, stage 4-1, tetrakis(triphenylphosphine)palladium(0) (0,137 g) and tetrahydrofuran (15 ml), and cooled on ice was added hydride tri-n-butyanova (0.7 ml). After stirring under cooling in ice for 20 min and the mixture was stirred at room temperature for 20 min and then concentrated under reduced pressure. The obtained residue was purified by the method of column chromatography (eluent: hexane/ethyl acetate = 10/0-1/1) to obtain compound (0,44 g, 44%) described in the above schema.

1H-NMR (CDCl3) δ: 1.39 in (t, 3H, J=7.2 Hz), 4,51 (square, 2H, J=7,2 Hz), 5,23 (c, 2H), was 7.36-7,56 (m, 5H), 8,31 (c, 1H), 8,99 (c, 1H).

Stage 5-2

By the way, is similar to that described in Example 1, stage 1-8, from compound (0,070 g) obtained in stage 5-1, received the connection (0,078 g, 109%) described in the above schema.

1H-NMR (CDCl3) δ: USD 1.43 (t, 3H, J=7,1 Hz), 4,54 (square, 2H, J=7,1 Hz), 5,17 (c, 2H), 7,13 (d, 1H, J=9.3 Hz), 7.29 trend was 7.45 (m, 11H), 8.34 per (c, 1H), 8,80 (c, 1H).

<> Stage 5-3

By the way, is similar to that described in Example 2, stage 2 to 5, from compound (0,070 g) obtained in stage 5-2, obtained compound (0.037 g, 72%) described in the above schema.

1H-NMR (CDCl3) δ: 1,54 (t, 3H, J=7.2 Hz), 3.00 and (c, 4H), 4,66 (square, 2H, J=7,2 Hz), 7,16-7,31 (m, 5H), 8,20 (c, 1H), 8,23 (c, 1H), 13,17 (c, 1H).

The compound obtained at this stage was converted to a hydrochloride by a method similar to that described in Example 4, stage 4-4, and in accordance with generally accepted way of obtaining specified in the connection header.

1H-NMR (DMSO-D6) δ: 2,93 (c, 4H), 4,22 (d, 2H, J=5.7 Hz), 7,19 (TT, 1H, J=7,1, 1.8 Hz), 7.23 percent-7,31 (m, 4H), 8,50 (c, 1H), 8,78 (c, 1H), becomes 9.97 (c, 1H).

Example 6

Getting hydrochloride [(5-butyl-6-chloro-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid

Stage 6-1

Mixed compound (200 mg) obtained by the method similar to that described in Example 4, stage 4-1, hexachlorethane (224 mg) and tetrahydrofuran (4.0 ml) at -78°C was added bis(trimethylsilyl)amide lithium (0,473 ml). After stirring at -78°C for 2 h the mixture was slowly warmed to -40°C. After this mixture was added dropwise to saturated aqueous sodium hydrogen carbonate solution was added ethyl acetate. The organic layer was separated from the mixture and was twice extracted aqueous layer etelaat the om. The organic layers were combined, washed twice with saturated saline solution, dried over sodium sulfate and concentrated under reduced pressure. The concentrated residue was purified by the method of column chromatography (eluent: hexane/ethyl acetate = 3/1-2/1) to give the crude product (180 mg) containing described in the above scheme, the compound as the main component.

Stage 6-2

By the way, is similar to that described in Example 3, stage 3-1, from compound (180 mg) obtained in stage 6-1, obtained compound (71 mg), described in the above schema.

1H-NMR (DMSO-D6) δ: of 0.94 (3H, t, J=7.5 Hz), of 1.28 (3H, t, J=7,1 Hz), of 1.37 to 1.47 (2H, m), 1,68 is 1.75 (2H, m), 3,32-3,37 (2H, m), 4,37 (2H, square, J=7,1 Hz), 5,19 (2H, s), 7,37-7,52 (5H, m), to 8.57 (1H, s).

Stage 6-3

Mixed compound (70 mg) obtained in stage 6-2, and triperoxonane acid (1 ml) and the mixture was stirred at room temperature for 3 hours To this reaction mixture was added chloroform and concentrated mixture under reduced pressure. To the concentrated residue was added 4 N. hydrochloric acid in ethyl acetate (1 ml) and stirred the mixture. Added hexane (3 ml) and stirred the mixture. The solid substance was collected by filtration to obtain compound (50 mg, 83%) as described in the sight of the purposes of the above scheme.

1H-NMR (DMSO-D6) δ: to 0.92 (3H, t, J=7,3 Hz) is 1.31 (3H, t, J=7,1 Hz), 1,37-to 1.45 (2H, m), 1,62 was 1.69 (2H, m), 3,17 (2H, t, J=7,7 Hz), 4,35 (2H, square, J=7,1 Hz), 8,69 (1H, s).

Stage 6-4

By the way, is similar to that described in Example 4, stage 4-4, from the compound (50 mg) obtained in stage 6-3, obtained compound (48 mg, 88%) as described in the above schema.

1H-NMR (DMSO-D6) δ: of 0.93 (t, 3H, J=7,3 Hz), of 1.36 to 1.47 (m, 2H), 1,64-1,72 (m, 2H), 3.15 and of 3.28 (m, 2H), 4,15 (d, 2H, J=2,8 Hz), a total of 8.74 (user. s, 1H), 10,20 (user. s, 1H).

Example 7

Getting hydrochloride [(7-hydroxy-2-methyl-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid

Stage 7-1

Mixed 2,4,6-trichloropyridin (50 g) and N,N-dimethylformamide (400 ml) and cooled on ice portions was added sodium hydride (60% suspension in oil, 11.5g). To this mixture while cooling on ice dropwise over 40 min was added benzyl alcohol (28 ml) and the mixture was stirred at the same temperature for 3 hours While cooling on ice, was added dropwise water (550 ml) and collected the obtained solid by filtration to obtain compound (50 g, 72%) described in the above schema.

1H-NMR (CDCl3) δ: 5,11 (c, 2H), 6,86 (c, 2H), was 7.36-7,46 (m, 5H).

Stage 7-2

When cooled in a bath of dry ice/acetone sexualityrelated (250 ml) and n-utility (1,65 M, 119 ml) and added dropwise within 30 min was added to a solution of the compound (50 g) obtained in stage 7-1 in tetrahydrofuran (110 ml). To this mixture is added dropwise within 1 h solution was added di-tert-BUTYLCARBAMATE (45 ml) in tetrahydrofuran (100 ml) and the mixture was stirred at the same temperature for 30 minutes To extinguish the reaction was added water (450 ml) to separate the organic layer was added ethyl acetate (200 ml) and washed organic layer with water (200 ml) and saturated saline (200 ml). The organic layer was concentrated under reduced pressure, the residue was purified by the method of column chromatography (eluent: hexane/ethyl acetate = 50/0-11/1), and then suspended obtained solid in hexane (100 ml) to obtain compound (15.7 g, 31%) described in the above schema.

1H-NMR (CDCl3) δ: 1,53 (c, 9H), 5,11 (c, 2H), 6,86 (c, 1H), 7,32-7,46 (m, 5H).

Stage 7-3

Mixed connection (15 g) obtained in stage 7-2, and 1,4-dioxane (150 ml), was added potassium carbonate (18 g), phenylenecarbonyl acid (7,1 g), complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) and dichloromethane (1/1, 1.8 g) and water (45 ml) and the mixture was stirred at 80°C for 1.5 h under heating. Added phenylenecarbonyl acid (0.64 g) and the mixture was stirred for 1.5 hours the Mixture was cooled to room temperature, and DL is the separation of the organic layer was added water, the ethyl acetate and saturated salt solution. The organic layer was concentrated under reduced pressure and purify the resulting residue by the method of column chromatography (eluent: chloroform). To the obtained solid substance was added isopropyl alcohol (100 ml) and suspended the mixture at 70°C for 0.5 h under cooling on ice with obtaining compound (11.5 g, 62%) described in the above schema.

1H-NMR (CDCl3) δ: 1.55V (c, 9H), to 5.21 (c, 2H), 6.87 in (c, 1H), 7,01 (d, 1H, J=15,9 Hz), 7,30-7,44 (m, 8H), 7,56 (d, 2H, J=7,1 Hz), the 7.65 (d, 1H, J=16.1 Hz).

Stage 7-4

Mixed connection (11.5g), obtained at the stage 7-3, ethyl acetate (120 ml) and 2% platinized carbon (2.5 g) and the mixture was stirred in hydrogen atmosphere (to 3.8 kgf/cm2) at room temperature for 23 hours, the Reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain compound (11.5 g, 100%) as described in the above schema.

1H-NMR (CDCl3) δ: 1.55V (c, 9H), to 3.02 (user. s, 4H), of 5.05 (c, 2H), 6,55 (c, 1H), 7,16-7,41 (m, 10H).

Stage 7-5

By the way, is similar to that described in Example 1, stage 1-4, from compound (11.5g), obtained at the stage 7-4, obtained compound (11.9 g, 104%) as described in the above schema.

1H-NMR (CDCl3) δ: 1.39 in (c, 9H), of 2.92 (t, 2H, J=8,2 Hz), 3,03 (who, 2H, J=8,2 Hz), 4,05 (user. s, 2H), 5,00 (c, 2H), 6,10 (c, 1H), 7,16-the 7.43 (m, 10H), 8,10 (c, 1H).

Stage 7-6

Mixed compound (126 mg) obtained in stage 7-5, monohydrate para-toluensulfonate acid (50 mg) and triethylorthoformate (1 ml), was added toluene (1 ml) and the mixture was heated at 60°C for 1 h the Reaction mixture at room temperature was added dropwise to saturated aqueous sodium hydrogen carbonate solution was added ethyl acetate to separate an organic layer. The organic layer was concentrated under reduced pressure and was purified concentrated residue according to the method of thin-layer chromatography (eluent: chloroform/methanol = 9/1) to obtain compound (32 mg, 24%) described in the above schema.

1H-NMR (CD3OD) δ: rate of 1.51 (9H, s), with 2.93 (3H, s), 3,06 (2H, t, J=7,6 Hz), 3,52 (2H, t, J=7,6 Hz), 5,16 (2H, s), 6,72 (1H, s), 7,14-of 7.48 (10H, m).

Stage 7-7

By the way, is similar to that described in Example 1, stage 1-6, from compound (55 mg) obtained in stage 7-6, received the compound (29 mg, 53%) described in the above schema.

1H-NMR (CD3OD) δ: for 1.49 (9H, s), 2,52 (3H, s), of 3.13 (2H, t, J=7,6 Hz), 3,42 (2H, t, J=7,7 Hz), 5,16 (2H, s), 6,83 (1H, s), 7,15-7,19 (3H, m), 7.24 to 7,28 (2H, m), 7,32-7,44 (5H, m).

Stage 7-8

Mixed compound (54 mg) obtained in stage 7-7, and chloroform (0.5 ml) was added triperoxonane acid (0,22 ml) and the mixture was stirred at room temperature for 2 hours The reaction mixture was concentrated under reduced pressure and the residue was subjected to azeotropic distillation with toluene to obtain the crude product (69 mg) containing compound described in the above scheme, as the main component.

The compound obtained at this stage were processed by the method similar to that described in Example 1, stage 1-10-1-12, and converting the compound obtained to a hydrochloride by a common way of obtaining specified in the connection header.

1H-NMR (DMSO-D6) δ: 2,52 (c, 3H), 3,10 (t, 2H, J=7.8 Hz), the 3.35 (t, 2H, J=7.8 Hz), 4,19 (d, 2H, J=5.7 Hz), 6,69 (c, 1H), 7.18 in-7,31 (m, 5H), 9,81 (t, 1H, J=5,5 Hz).

Example 8

Getting hydrochloride {[8-(3,3-dimethylbutyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid

Stage 8-1

2-Amino-3,5-dibromopyridine (of 50.4 g), 2,5-hexandione (23,5 g) and monohydrate para-toluensulfonate acid (2.7 g) was dissolved in toluene (300 ml) and the mixture was heated under reflux for 5 hours, removing the water. The mixture was left to cool to room temperature, was added ethyl acetate and sequentially washed with a mixture of saturated aqueous sodium bicarbonate, water and saturated salt solution (each once). The organic layer was dried over sodium sulfate, filtered and conc is piss off under reduced pressure to obtain the crude product (66.6 g), described in the above wiring diagram.

1H-NMR (CDCl3) δ: 2,00 (6H, s), of 5.92 (2H, s), by 8.22 (1H, d, J=2.4 Hz), 8,63 (1H, d, J=2,4 Hz).

Stage 8-2

By the way, is similar to that described in Example 1, stage 1-3, from compound (66.6 g) obtained in stage 8-1 received connection (58,4 g, 82%) described in the above schema.

1H-NMR (CDCl3) δ: 1,99 (6H, s), of 5.15 (2H, s), of 5.89 (2H, s), 7,37-of 7.48 (5H, m), of 7.64 (1H, d, J=2,8 Hz), 8,31 (1H, d, J=2,8 Hz).

Stage 8-3

Mixed connection (58,4 g) obtained in stage 8-2, chloride of hydroxylamine (233 g), ethanol (600 ml) and water (350 ml). To this mixture at room temperature was dropwise added triethylamine (46 ml) and ethanol (100 ml) and the mixture was heated under reflux at a bath temperature of 95°C for 89 hours, the Reaction mixture was cooled on ice and consistently added 50% aqueous sodium hydroxide solution (96 ml), 8 N. aqueous sodium hydroxide solution (134 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml). At room temperature was added water (1800 ml), the mixture was stirred for 1 h and was collected in the precipitated solid by filtration. Precipitated precipitated solid substance was dried under reduced pressure overnight and the crude product is suspended (49 g) in 2-propanol (120 ml) to obtain from the unity (34.3 g, 75%) described in the above schema.

1H-NMR (CDCl3) δ: 4,60 (2H, user. c) to 5.00 (2H, s), 7,31-7,40 (5H, m), 7,41 (1H, d, J=2,8 Hz), 7,83 (1H, d, J=2,8 Hz).

Stage 8-4

Mixed connection (7,25 g) obtained in stage 8-3, N,N-dimethylformamide (11 ml) and dimethylacetal N,N-dimethylformamide (11 ml) and the mixture was stirred under heating at 130°C for 15 minutes After stirring at room temperature for 20 min the mixture was concentrated under reduced pressure. To the obtained residue were added methanol (58 ml) and pyridine (4,2 ml), and cooled on ice was added to a mixture of hydroxylamine-O-sulfonic acid (4.1 g). After stirring at room temperature overnight under cooling on ice, was added water (29 ml) and saturated aqueous sodium hydrogen carbonate solution (58 ml) and the mixture was stirred at room temperature for 1 h resulting solid substance was collected by filtration to obtain compound (6,13 g, 78%) described in the above schema.

1H-NMR (CDCl3) δ: 5,09 (c, 2H), of 7.36 was 7.45 (m, 5H), 7,66 (d, 1H, J=2.0 Hz), 8,19 (d, 1H, J=2.0 Hz), 8,29 (c, 1H).

Stage 8-5

By the way, is similar to that described in Example 1, stage 1-1, from the compound (10 g) obtained in stage 8-4, received the connection (5,67 g, 49%) described in the above schema.

H-NMR (DMSO-D6) δ: 5,33 (c, 2H), 7,31-7,49 (m, 5H), of 8.37 (c, 1H), 8,56 (c, 1H).

Stage 8-6

To the compound (of 5.68 g), obtained at the stage 8-5, was added toluene (57 ml) and at 80°C with three portions were added diethylacetal N,N-dimethylformamide (4.5 ml). After completion of the reaction the mixture was concentrated under reduced pressure and purify the resulting residue by the method of column chromatography (eluent: chloroform/ethyl acetate = 10/1-4/1). To the obtained compound was added hexane and suspended precipitated precipitated solid substance with obtaining compound (4.68 g, 69%) described in the above schema.

1H-NMR (CDCl3) δ: 1.39 in (t, 3H, J=7,1 Hz), 4.53-in (sq., 2H, J=7,1 Hz), to 5.21 (c, 2H), 7,35-the 7.43 (m, 5H), 7,72 (c, 1H), scored 8.38 (c, 1H).

Stage 8-7

In bottle with screw cap was added the compound (100 mg) obtained in stage 8-6, tert-butylacetyl (0.1 ml), dichloride, bis(triphenylphosphine)palladium(II) (18 mg) and copper iodide(I) (5 mg). To this mixture was added tetrahydrofuran (0.4 ml) and triethylamine (0.8 ml) and tightly closed bottle. The mixture was stirred at room temperature for 1 h, was passed through a small amount of silica gel and concentrated under reduced pressure. The residue was twice purified by the method of thin-layer chromatography (eluent: hexane/ethyl acetate = 2/1) to obtain compound (85 mg, 85%) described in the above schema.

Stage 8-8

By the way, is similar to that described in Example 2, stage 2 to 5, from compound (85 mg) obtained in stage 8-7, obtained compound (62 mg, 94%) described in the above schema.

By the way, is similar to that described in Example 4, stage 4-4 indicated in the title compound was obtained from the compound obtained at this stage.

1H-NMR δ: 0,98 (c, 9H), 1,57-of 1.66 (m, 2H), 2,89-to 2.99 (m, 2H), 4.25 in (d, 2H, J=5.4 Hz), 7,42 (c, 1H), 8,64 (c, 1H), 10,42 (t, 1H, J=5.4 Hz), 13,28 (c, 1H).

Example 9

Getting [(7-hydroxy-6-phenyl[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl)amino]acetic acid

Stage 9-1

Hydroxylamino group of the compounds obtained in Example 1, stage 1-3 were removed by the method similar to that described in Example 2, stage 2-5. To a solution of the obtained compound (3,30 g) in chloroform (30 ml) cooled on ice was added N-bromosuccinimide (2,82 g). After stirring at room temperature for 5 h, the reaction mixture was separated by adding a saturated aqueous solution of sodium bicarbonate (20 ml). The organic layer is then washed with an aqueous solution of sodium sulfite and saturated saline and dried over anhydrous magnesium sulfate. After filtration the mixture was concentrated under reduced pressure to obtain compound (lower than the 5.37 g), described in the above scheme, in the form of a crude product.

1H-NMR (CDCl3) δ: of 1.66 (9H, s), 8,39 (1H, s), 12,77 (1H, s).

Stage 9-2

To a solution of compound (lower than the 5.37 g) obtained in stage 9-1, N,N-dimethylformamide while cooling on ice, was added potassium carbonate (2,19 g) and benzylbromide (1,88 ml) and the mixture was stirred at room temperature for 20 hours the Reaction mixture was separated by adding water (50 ml) and ethyl acetate (50 ml). The organic layer is then washed with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by the method of column chromatography (eluent: hexane/ethyl acetate = 3/1-1/2) to obtain compound (of 3.73 g, 65% in 2 steps) described in the above schema.

1H-NMR (CDCl3) δ: was 1.58 (9H, s), a total of 5.21 (2H, s), 7,19-7,21 (2H, m), 7,37-7,46 (3H, m), 7,76 (1H, s).

Stage 9-3

To the compound (610 mg), obtained in stage 9-2, when cooled on ice was added triperoxonane acid (180 ml) and the mixture was stirred at room temperature for 2 hours, the Reaction mixture was diluted with chloroform (6 ml) and concentrated under reduced pressure. To the residue was again added chloroform (6 ml), was added thionyl chloride (0,18 ml) and N,N-dimethylformamide (one drop) and the mixture was heated at 70°C for 30 minutes Recip the config solution was concentrated under reduced pressure to obtain compound (540 mg, 98%) described in the above schema.

Stage 9-4

To a solution of compound (540 mg) obtained in stage 9-3, in tetrahydrofuran (6 ml) cooled on ice was added diisopropylethylamine (0,29 ml) and compound tert-butyl ester of glycine (of 0.21 ml) and the mixture was stirred for 2 hours To the reaction mixture was added diisopropylethylamine (0,29 ml) and tert-BUTYLCARBAMATE and the mixture was heated at 70°C for 3 hours the Reaction mixture was concentrated under reduced pressure and the residue was purified by the method of column chromatography (eluent: hexane/ethyl acetate = 3/1-3/2) obtaining compound (790 mg, 92%) described in the above schema.

1H-NMR (CDCl3) δ: of 1.30 (9H, s) to 1.48 (9H, s), of 4.05 (2H, d, J=5.5 Hz), of 5.24 (2H, s), 6,27 (1H, s), 7,14 (2H, t, J=4,1 Hz), 7,34-7,41 (3H, m), 7,47 (1H, s), 11,50 (1H, t, J=5.4 Hz), 11,83 (1H, s).

Stage 9-5

By the way, is similar to that described in Example 1, stage 1-8, from the compound (330 mg) obtained in stage 9-4, obtained compound (280 g, 84%) described in the above schema.

1H-NMR (CDCl3) δ: 1,31 (9H, s) to 1.48 (9H, s) 4,06 (2H, d, J=5.5 Hz), and 5.30 (2H, s), 6,16 (1H, s), 7,17 (2H, d, J=7,4 Hz), 7,18 (1H, s), 7,28-7,40 (6H, m), 7,43-7,46 (2H, m), to 11.79 (1H, s), 11,85 (1H, t, J=5.4 Hz).

Stage 9-6

By the way, is similar to that described in Example 2, stage 2 to 5, from compound (120 mg), receive the TES on stage 9-5, received compound (86 mg, 87%) as described in the above schema.

1H-NMR (CDCl3) δ: of 1.45 (9H, s), for 1.49 (9H, s) to 4.15 (2H, s), 7,06-7,29 (8H, m), the 10.40 (1H, s), 10,95 (1H, s).

Stage 9-7

To a solution of compound (110 mg) obtained in stage 9-6, in chloroform (0.3 ml) was added 4 n hydrochloric acid in dioxane (1 ml) and the mixture was stirred while cooling on ice for 2 h, the Reaction mixture was concentrated under reduced pressure to obtain compound (84 mg, 87%) as described in the above schema.

1H-NMR (CD3OD) δ: for 1.49 (9H, s), Android 4.04 (2H, s), of 7.36-7,47 (5H, m), EUR 7.57 (1H, s).

Stage 9-8

To the compound (41 mg) obtained in stage 9-7, added triethylorthoformate (0,41 ml) and the mixture was heated at 100°C for 30 minutes the Reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform (1 ml). Added triperoxonane acid (2 ml) and the mixture was stirred at room temperature for 3 hours the Reaction mixture was concentrated under reduced pressure, was added 4 n hydrochloric acid in dioxane (1 ml) and the mixture was stirred at room temperature for 30 minutes the Reaction mixture was concentrated under reduced pressure and suspended residue in water to obtain the specified reception in the e compound (29 mg, 89%).

1H-NMR (DMSO-D6) δ: 4,06 (2H, d, J=5.5 Hz), 7,39-7,46 (3H, m), 7,60 (2H, DD, J=8,3, 1,4 Hz), 8,39 (1H, s), 8,86 (1H, s), 10,50 (1H, t, J=5.7 Hz), 12,59 (1H, s), of 13.75 (1H, s).

Example 10

Getting hydrochloride [(7-hydroxy[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl)amino]acetic acid

Stage 10-1

In a manner analogous to the reaction of removing carboxylamide group in Example 9, step 9-8, from compound (0,050 g) obtained in Example 1, stage 1-5, obtained crude product containing described in the above scheme, the compound as the main component.

1H-NMR (DMSO-D6) δ: ceiling of 5.60 (c, 2H), 7,35-of 7.55 (m, 5H), of 7.69 (d, 1H, J=7,7 Hz), 9,03 (d, 1H, J=7,7 Hz), 9,48 (c, 1H).

Stage 10-2

By the way, is similar to that described in Example 1, stage 1-10, from the compound obtained in stage 10-1, received the connection (0,024 g, 41%) described in the above schema.

1H-NMR (CDCl3) δ: 1,51 (c, 9H), to 4.23 (d, 2H, J=5.6 Hz), 5,35 (c, 2H), for 6.81 (d, 1H, J=7,7 Hz), 7,26-7,51 (m, 5H), 8,10 (d, 1H, J=7,7 Hz), 8,67 (c, 1H), 9,66 (user. s, 1H).

The compound obtained at this stage were subjected to removal hydroxylamino group and carboxylamide group by methods similar to those described above, and converting the compound obtained to a hydrochloride by a common way of obtaining specified in the connection header.

1H-NMR (DMSO-D ) δ: 4,07 (c, 2H), of 6.65 (d, 1H, J=7,7 Hz), 8,32 (d, 1H, J=7,7 Hz), 8,99 (c, 1H), to 10.09 (c, 1H).

Example 11

Getting [(6-hydroxy[1,2,3]triazolo[1,5-a]pyridine-7-carbonyl)amino]acetic acid

Stage 11-1

Mixed 2-bromo-5-hydroxypyridine (5.8 g), N,N-dimethylformamide (58 ml) and potassium carbonate (5.1 g) while cooling on ice was added benzylbromide (4,4 ml) and the mixture was stirred at room temperature for 13 hours To the reaction mixture were added ethyl acetate (58 ml) and water (87 ml), the organic layer was separated from the mixture and then washed twice with water (60 ml, 30 ml) and saturated saline (30 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by the method of column chromatography (eluent: hexane/ethyl acetate = 10/1-7/1) to obtain the compound (7.4 g, 83%) described in the above schema.

1H-NMR (CDCl3) δ: 5,09 (c, 2H), 7,15 (DD, 1H, J=8,1, 3.2 Hz), 7,33-7,38 (m, 1H), was 7.36 (d, 1H, J=8.1 Hz), 7,40-7,41 (m, 4H), 8,13 (d, 1H, J=3.2 Hz).

Stage 11-2

To n-butyllithium (1,54 mol./l solution in hexane, 25 ml) at -78°C is added dropwise over 7 min was added to the solution of compound (1 g) obtained in stage 11-1 in toluene (4 ml). The reaction mixture was stirred at -78°C for 50 min and was added dropwise a solution of N,N (0,352 ml) in toluene (4 ml). The reaction mixture was additionally stirred at -78°C for 1 h at -10°C was added water (6 ml) and the mixture was stirred at room temperature for 2 hours the Organic layer and aqueous layer were separated, the aqueous layer was extracted twice with toluene (5 ml). The organic layers were combined and washed with saturated saline (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and the mixture was filtered. The filtrate was concentrated under reduced pressure and purify the resulting residue by the method of column chromatography (eluent: hexane/ethyl acetate = 10/1-7/1) to obtain the compound (641 mg, 79%) described in the above schema.

1H-NMR (CDCl3) δ: to 5.21 (c, 2H), 7,35-7,45 (m, 6H), to 7.95 (d, 1H, J=8,9 Hz), 8,51 (d, 1H, J=2,8 Hz), 9,99 (c, 1H).

Stage 11-3

Mixed compound (637 mg) obtained in stage 11-2, methanol (6.4 ml) and tazelgettaze (574 mg) and the mixture was heated under reflux for 10 minutes, the Reaction mixture was concentrated under reduced pressure, was added morpholine (6.4 ml) and the mixture was heated under reflux for 30 minutes, the Reaction mixture was concentrated under reduced pressure and added ethyl acetate (12 ml), 2M aqueous sodium carbonate solution (6 ml) and water (5 ml). Then was added tetrahydrofuran (6 ml) and the separated organic layer. Water is Loy was twice extracted with ethyl acetate (5 ml), the organic layers were combined and washed with saturated saline (10 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting solid suspended matter in diisopropyl ether to obtain compound (566 mg, 84%) described in the above schema.

1H-NMR (CDCl3) δ: 5,12 (c, 2H), 7,11 (DD, 1H, J=9,7, 2.0 Hz), of 7.36-7,47 (m, 5H), to 7.61 (DD, 1H, J=9,7, 0.8 Hz), to 7.99 (d, 1H, J=0.8 Hz), a 8.34 (d, 1H, J=2.0 Hz).

Stage 11-4

Mixed compound (200 mg) obtained in stage 11-3, and tetrahydrofuran (2 ml) and at -40°C was added diisopropylamide lithium (2M solution in tetrahydrofuran, heptane, ethylbenzene, 0.45 ml). After stirring at -40°C for 1 h was added dry ice and leave the mixture to warm to room temperature while stirring for 1 h then was added methanol (2 ml) and the reaction mixture was concentrated under reduced pressure to obtain the compound described in the above scheme, in the form of a crude product. This product was used directly in the next stage.

Stage 11-5

By the way, is similar to that described in Example 1, stage 1-10, from the crude product obtained in stage 11-4, obtained compound (85 mg, 28% (the 2nd step)), described in the above schema.

1H-NMR (CDCl3) δ: 3,80 (c, 3H), of 4.38 (d, 2H, J=5,2 Hz), 5,32 (c, 2H), 7,24 (d, 1H, J=9.7 Hz), 7,31-7,41 (m, 3H), 7,46-7,49 (m, 2H), of 7.75 (d, 1H, J=9.7 Hz), 8,11 (c, 1H), 8,79 (user. s, 1H).

Stage 11-6

By the way, is similar to that described in Example 2, stage 2 to 5, from compound (72 mg) obtained in stage 11-5, obtained compound (40 mg, 76%) described in the above schema.

1H-NMR (CDCl3) δ: 3,83 (c, 3H), 4,37 (d, 2H, J=6.0 Hz), 7,17 (d, 1H, J=9.7 Hz), 7,80 (d, 1H, J=9.7 Hz), 8,12 (c, 1H), 10,57 (user. s, 1H), 13.56MHz (c, 1H).

The compound obtained at this stage were subjected to removal of carboxyl groups in a manner analogous to that described above, with the receipt specified in the connection header.

1H-NMR (DMSO-D6) δ: 4,28 (d, 2H, J=5,2 Hz), 7,31 (d, 1H, J=9.7 Hz), to 8.20 (d, 1H, J=9.7 Hz), 8,39 (c, 1H), 10,36 (t, 1H, J=5,2 Hz) 13,82 (c, 1H).

Example 116

Getting [(7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid

Stage 116-1

Mixed cyanamide (1.4 g) and 1,4-dioxane (20 ml) was added dimethyl-1,3-aceondeckmusic (2.0 g) and Nickel acetylacetonate(II) (0,30 g). The mixture was heated under reflux for 16 hours the Mixture was cooled to room temperature, was stirred for 1 h and collected the obtained solid by filtration. To the obtained solid substance we use and methanol (6.0 ml) and the mixture was stirred at room temperature for 1.5 hours The solid substance was collected by filtration to obtain compound (1.4 g, 64%) described in the above schema.

1H-NMR (DMSO-D6) δ: 3,80 (c, 3H), 4.92 in (c, 1H), 7,20 (c, 2H), 10,29 (c, 1H), 11,51 (c, 1H).

Stage 116-2

Mixed connection (30 g) obtained in stage 116-1, phosphorus oxychloride (150 ml) and N,N-diisopropylethylamine (30 ml) and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated three times and subjected to azeotropic distillation with toluene. When cooled on ice was added methanol (30 ml) and water (150 ml) and the mixture was stirred at room temperature for 1 h resulting solid substance was collected by filtration and combined with the solid obtained from the filtrate. Was added methanol (50 ml) and the mixture was stirred at room temperature for 1 h, the Solid was collected by filtration to obtain the initial crystalline substances. The filtrate was concentrated, was added to the residue methanol (10 ml) and collected the obtained solid by filtration to obtain secondary crystalline substances. Primary crystalline substance and a secondary crystalline substance was combined with obtaining the compound (21 g, 59%) described in the above schema.

1H-NMR (DMSO-D6) δ: 3,84 (c, 3H), 6,84 (c, 1H) 7,16 (user. s, 2H).

Stage 116-3

Mixed compound (2.2 g) obtained in stage 116-2, and 2-propanol (31 ml) was added dimethylacetal N,N-dimethylformamide (2.9 ml). The mixture was heated under reflux for 30 minutes, the Reaction mixture was cooled to room temperature, was added hydroxylamine hydrochloride (1.4 g) and the mixture was stirred at room temperature for 30 minutes the Reaction mixture was concentrated to approximately half volume and added water (40 ml) and 2-propanol (6,6 ml). The mixture was stirred at room temperature for 30 min and collected the obtained solid by filtration to obtain compound (2.2 g, 84%) described in the above schema.

1H-NMR (DMSO-D6) δ: 3,92 (c, 3H), 7,37 (c, 1H), a 7.85 (d, 1H,J=9.5 Hz), 10,12 (d, 1H,J=9.5 Hz), 10,83 (c, 1H).

Stage 116-4

Mixed compound (0.66 g) obtained in stage 116-3, and tetrahydrofuran (6.6 ml) was added triperoxonane anhydride (0,37 ml). The mixture was heated under reflux for 22 hours, the Reaction mixture was cooled to room temperature, was added ethyl acetate and a saturated aqueous solution of sodium bicarbonate and separated the organic layer. The organic layer was washed with saturated saline solution and dried over sodium sulfate. After filtrowanie the filtrate was concentrated under reduced pressure and purify the resulting residue by the method of column chromatography (eluent: chloroform/ethyl acetate = 4/1) to obtain compound (0.32 g, 51%) described in the above schema.

1H-NMR (DMSO-D6) δ: 3,99 (c, 3H), 7,92 (c, 1H), 8,71 (c, 1H).

Stage 116-5

Mixed compound (1.0 g) obtained in stage 116-4, penlivanova acid (1.2 g), potassium carbonate (1.7 g), complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) and dichloromethane (1:1) (0.083 g), cyclopentylmethyl ether (6.0 ml) and water (0.15 ml) and the mixture was stirred under heating at 50°C for 6 hours, the Reaction mixture was cooled to room temperature and twice washed organic layer is 3% aqueous solution of Diethylenetriamine (10 ml) and saturated saline (5 ml). Was added sodium sulfate and catching metal silica gel (1 g), the mixture was stirred at room temperature for 1 h and filtered through the funnel Kiriyama filled with silica gel (1 g). The filtrate was concentrated under reduced pressure to obtain compound (1,87 g), described in the above scheme, in the form of a crudely purified product.

1H-NMR (CDCl3) δ: 3,17 (t, 2H, J=7.8 Hz), of 3.48 (t, 2H, J=7.8 Hz), 4,08 (c, 3H), 6,84 (c, 1H), 7.18 in-7,28 (m, 5H), 8,42 (c, 1H).

Stage 116-6

Mixed connection (1,87 g) obtained in stage 116-5, and tetrahydrofuran and cooled on ice was added 4 N. aqueous sodium hydroxide solution (4.0 ml). After stirring at room the Oh temperature for 2 h, the reaction mixture was neutralized by adding concentrated hydrochloric acid (1.4 ml) under cooling on ice. To the suspension was added ethanol (5 ml) and water (1.3 ml) and the mixture was stirred for 1 h, the Solid was collected by filtration to obtain compound (0,847 g, 69%) described in the above schema.

1H-NMR (DMSO-D6) δ: 3,13 (t, 2H,J=7,8 Hz), of 3.45 (t, 2H,J=7.8 Hz), 7.23 percent-7,31 (m, 5H), 8,65 (c, 1H), 14,19 (c, 1H).

Stage 116-7

Mixed connection (0,200 g) obtained in stage 116-6, acetonitrile (1.0 ml), monohydrate, 1-hydroxybenzotriazole (0,122 g) and hydrochloride difficult methyl ester of glycine (0,100 g) and cooled on ice was added triethylamine (0,111 ml) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0,153 g). The mixture was stirred at room temperature for 2 hours To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (2 ml) and was collected in the precipitated solid by filtration to obtain compound (0,194 g, 78%) described in the above schema.

1H-NMR (CDCl3) δ: 3,18 (t, 2H, J=7.8 Hz), of 3.48 (t, 2H, J=7.8 Hz), 3,81 (c, 3H), 4,34 (d, 2H, J=5,2 Hz), 6,92 (c, 1H), 7,15-7,33 (m, 5H), 8,42 (c, 1H), 9,90 (c, 1H).

Stage 116-8

Mixed connection (0,150 g) obtained in stage 116-7, 2-ethoxyethanol (0.75 ml) and 8 N. aqueous sodium hydroxide solution (0,23 ml) and stirred the mixture at 90°C for 18 h To this mixture was added ethanol (0.75 ml) and water (0.2 ml) and the mixture was stirred at room temperature for 1 h The solid substance was collected by filtration to obtain crudely purified product described in the above wiring diagram (0,19 g).

1H-NMR (DMSO-D6) δ: 2,99-3,11 (m, 4H), to 3.58 (d, 2H, J=4.4 Hz), 6,01 (c, 1H), 7,20-7,27 (m, 5H), 7,86 (c, 1H), 11,23 (t, 1H, J=4.4 Hz).

Stage 116-9

Mixed connection (0,19 g) obtained in stage 116-8, and water (0.63 ml), and the mixture was heated to 50°C. acetone was Added (0,78 ml) and 6 N. hydrochloric acid (0.2 ml) and the mixture was stirred at the same temperature for 1 h After mixing while cooling on ice for 1 h were collecting the solid by filtration to obtain compound (0.11 g, 80%) described in the above schema.

1H-NMR (DMSO-D6) δ: 3,12 (t, 2H, J=7.9 Hz), 3,40 (t, 3H, J=7.9 Hz), 4,22 (d, 2H, J=5,2 Hz), 6,79 (c, 1H), 7,21-7,29 (m, 5H), 8,58 (c, 1H), 9,84 (t, 1H, J=5,2 Hz), 12,97 (c, 1H), 14,22 (c, 1H).

Stage 116-10

Mixed connection (0,050 g) obtained in stage 116-9, and methanol (3 ml) and the mixture was heated to 60°C. the Solution was cooled to room temperature and was stirred overnight. The solid substance was collected by filtration to obtain specified in the connection header (0,031 g, 61%).

1H-NMR (DMSO-D6) δ: 3,12 (t, 2H, J=7.9 Hz), 3,40 (t, 3H, J=7.9 Hz), 4,22 (d, 2H, J=5,2 Hz), 6,79 (c, 1H), 7,21-7,29 (m, 5H), 8,58 (c, 1H), 9,84 (t, 1H, J=5,2 Hz), 12,97 (c, 1H), 14,22 (c, 1H).

Example 117

Receipt is [(5-butyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid

Stage 117-1

Mixed connection (0,050 g) obtained in stage 116-4, butylboronic acid (0,042 g), silver oxide(I) (0,071 g), potassium carbonate (0,084 g), complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) and dichloromethane (1/1, 0.008 g) and tetrahydrofuran (1.0 ml) and the mixture was heated under reflux for 10 hours, the Insoluble material was filtered through celite and added a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was separated from the mixture. The organic layer was twice washed with a saturated aqueous solution of sodium bicarbonate and saturated saline solution, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purify the resulting residue by the method of thin-layer chromatography (eluent: hexane/ethyl acetate = 1/1) to obtain compound (0,046 g, 77%) described in the above schema.

1H-NMR (CDCl3) δ: 1.00 m (t, 3H, J=7.4 Hz), 1,45-of 1.53 (m, 2H), 1,79-to 1.87 (m, 2H), 3,18 (t, 2H, J=7.9 Hz), 4,08 (c, 3H), 6,92 (c, 1H), scored 8.38 (c, 1H).

Stage 117-2

Mixed connection (0,043 g) obtained in stage 117-1, and methanol (0,22 ml), was added a 28% solution of sodium methoxide in methanol (0,014 ml). The mixture was stirred at room temperature for 4 h was Added water (0,22 ml) and stirred the mixture at to matnog temperature for 1 h To the reaction mixture were added 1 N. hydrochloric acid (0.16 ml) and collected the obtained solid by filtration to obtain compound (0,026 g, 66%) described in the above schema.

1H-NMR (CDCl3) δ: 1,01 (t, 3H, J=7,3 Hz), 1,46-of 1.57 (m, 2H), 1,82-1,90 (m, 2H), 3,21 (t, 2H, J=7.9 Hz), 4,15 (c, 3H), 6,77 (c, 1H), 8,28 (c, 1H).

Stage 117-3

Mixed compound (0.025 g), obtained at the stage 117-2, and N,N-dimethylformamide (0,50 ml) was added monohydrate, 1-hydroxybenzotriazole (0,016 g), complex tert-butyl ester of glycine (0,015 ml) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0,020 g). The mixture was stirred at room temperature for 1.5 hours While cooling on ice to the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution and water and collecting the obtained solid by filtration to obtain compound (0,033 g, 94%) described in the above schema.

1H-NMR (CDCl3) δ: 1.00 m (t, 4H, J=7,3 Hz) and 1.51 (c, 9H), 1,80-1,90 (m, 2H), 3,18 (t, 2H, J=7.9 Hz), is 4.21 (d, 2H, J=5,2 Hz), 6,72 (c, 1H), 8,29 (c, 1H), 9,72 (t, 1H, J=4, 2 Hz).

Stage 117-4

Mixed connection (0,030 g) obtained in stage 117-3, and 25% solution of bromovalerate in acetic acid (0,60 ml) and the mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated under reduced pressure. To polucen the mu residue while cooling on ice, was added water (0,60 ml), and 4 N. an aqueous solution of sodium hydroxide (0,23 ml). Then when cooled on ice was added 2 N. hydrochloric acid (0,23 ml) and collected the obtained solid by filtration to obtain compound (0,010 g, 42%) described in the above schema.

1H-NMR (DMSO-D6) δ: of 0.93 (t, 3H, J=7.5 Hz), 1,33-1,44 (m, 2H), 1,71 and 1.80 (m, 2H), 3,10 (t, 2H, J=7.5 Hz), 4,20 (d, 2H, J=5,2 Hz), 6,85 (c, 1H), 8,55 (c, 1H), 9,84 (user. s, 1H), 14,26 (user. s, 1H).

Stage 117-5

Mixed connection (0,100 g) obtained in stage 117-4, and methyl ethyl ketone (1.0 ml) and heated to 80°C. To the solution was added heptane (1.0 ml) and stirred the mixture at room temperature over night. The solid substance was collected by filtration to obtain specified in the connection header (0,089 g, 89%).

1H-NMR (DMSO-D6) δ: of 0.93 (t, 3H, J=7.5 Hz), 1,33-1,44 (m, 2H), 1,71 and 1.80 (m, 2H), 3,10 (t, 2H, J=7.5 Hz), 4,20 (d, 2H, J=5,2 Hz), 6,85 (c, 1H), 8,55 (c, 1H), 9,84 (user. s, 1H), 14,26 (user. s, 1H).

Connection Examples 12-115 and Examples 118-122 presented in the following Tables 3-24, was obtained in the same manner as in the above Examples 1-11, Example 116 or 117, or, if necessary, by other conventional methods.

Structural formulas and properties of the compounds of Examples 1-122 are presented in the following tables 1-24.

Table 1
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS
(M-H)
1Hydrochloride {[5-(4-fluoro-3-triptoreline)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.6 Hz), 7,31 (c, 1H), 7,73-of 7.82 (m, 1H), 8.34 per-8,43 (m, 1H), 8,43-8,51 (m, 1H), 8,61 (c, 1H), 9,99 (t, 1H, J=5.6 Hz).399397
2Hydrochloride [(7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz)) δ: 3,12 (t, 2H, J=7.8 Hz), to 3.41 (t, 2H, J=7.8 Hz), is 4.21 (d, 2H, J=5.6 Hz), for 6.81 (c, 1H), 7,14-7,33 (m, 5H), at 8.60 (c, 1H), 9,85 (t, 1H, J=5.6 Hz).341339
3Hydrochloride [(5-butyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: of 0.93 (t, 3H, J=7.4 Hz), 1.39 in (TD, 2H, J=14,8, 7,4 Hz), 1,72-to 1.79 (m, 2H), 3,10 (t, 2H, J=7,7 Hz), is 4.21 (d, 2H, J=5.5 Hz), 6,85 (c, 1H), 8,56 (c, 1H), 9,84 (t, 1H, J=5.6 Hz).293291
4Hydrochloride [(5,6-diethyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,15 (t, 3H, J=7.5 Hz), of 1.29 (t, 3H, J=7.5 Hz), 2,72 (square, 2H, J=7.5 Hz), 3,20 (square, 2H, J=7,6 Hz), is 4.21 (d, 2H, J=5.6 Hz), charged 8.52 (c, 1H), 9,95 (t, 1H, J=5.6 Hz).293291
5Hydrochloride [(7-hydroxy-6-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 2,93 (c, 4H), 4,22 (d, 2H, J=5.7 Hz), 7,19 (TT, 1H, J=7,1, 1.8 Hz), 7.23 percent-7,31 (m, 4H), 8,50 (c, 1H), 8,78 (c, 1H), becomes 9.97 (c, 1H).341339

Table 2
Approx. No.Connection nameThe structural formula1H-I IS R, δ M. D.MS (M+H)MS
(M-H)
6Hydrochloride [(5-butyl-6-chloro-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 0.93 (t, 3H, J=7,3 Hz), of 1.36 to 1.47 (m, 2H), 1,64-1,72 (m, 2H), 3.15 and of 3.28 (m, 2H), 4,15 (d, 2H, J=2,8 Hz), a total of 8.74 (user. s, 1H), 10,20 (user. s, 1H).327325
7Hydrochloride [(7-hydroxy-2-methyl-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 2,52 (c, 3H), 3,10 (t, 2H, J=7.8 Hz), the 3.35 (t, 2H, J=7.8 Hz), 4,19 (d, 2H, J=5.7 Hz), 6,69 (c, 1H), 7.18 in-7,31 (m, 5H), 9,81 (t, 1H, J=5,5 Hz).355353
8Hydrochloride {[8-(3,3-dimethylbutyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,98 (c, 9H), 1,57-of 1.66 (m, 2H), 2,89-to 2.99 (m, 2H), 4.25 in (d, 2H, J=5.4 Hz), 7,42 (c, 1H), 8,64 (c, 1H), 10,42 (t, 1H, J=5.4 Hz), 13,28 (c, 1H).321 319
9[(7-hydroxy-6-phenyl[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,06 (d, 2H, J=5.5 Hz), 7,39-7,46 (m, 3H), 7,60 (DD, 2H, J=8,3, 1,4 Hz), 8,39 (c, 1H), 8,86 (c, 1H), 10,50 (t, 1H, J=5.7 Hz), 12,59 (c, 1H), of 13.75 (c, 1H).313311
10Hydrochloride [(7-hydroxy[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,07 (c, 2H), of 6.65 (d, 1H, J=7,7 Hz), 8,32 (d, 1H, J=7,7 Hz), 8,99 (c, 1H), to 10.09 (c, 1H).237235
11[(6-hydroxy[1,2,3]triazolo[1,5-a]pyridine-7-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,28 (d, 2H, J=5,2 Hz), 7,31 (d, 1H, J=9.7 Hz), to 8.20 (d, 1H, J=9.7 Hz), 8,39 (c, 1H), 10,36 (t, 1H, J=5,2 Hz) 13,82 (c, 1H).237235

Table 3
Approx. No. Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS
(M-H)
12Hydrochloride [(7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,22 (d, 2H, J=5.6 Hz), 6,93 (d, 1H, J=7,7 Hz), 8,56 (c, 1H), 8,96 (d, 1H, J=7,7 Hz), 9,81-to 9.91 (m, 1H).237235
13Hydrochloride [(7-hydroxy-2-phenyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,27 (d, 2H, J=5.6 Hz), 6,94 (d, 1H, J=7,7 Hz), 7,55-7,58 (m, 3H), 8,31-of 8.33 (m, 2H), 9,00 (d, 1H, J=7,3 Hz), 10,11 (t, 1H, J=5,2 Hz).313311
14Hydrochloride({5-[2-(4-chlorophenyl)ethyl]-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl}amino)acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 3,12 (2H, t, J=7.9 Hz), 3,40 (2H, t, J=7,7 Hz), is 4.21 (2H, d, J=5.6 Hz), to 6.80 (1H, s), 7,27 (2H, d, J=8.5 Hz), 7,35 (2H, d, J=8.5 Hz), 8,59 (1H, s), 9,85 (1H, t, J=5.6 Hz).375373
15Hydrochloride [(2-cyclopropyl-7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,04-1,12 (m, 4H), 2,17-of 2.23 (m, 1H), 3,10 (t, 2H, J=7.9 Hz), 3,29-3,37 (m, 2H), 4,18 (d, 2H, J=5.3 Hz), 6,66 (c, 1H), 7.18 in-7,32 (m, 5H), 9,84 (t, 1H, J=4.9 Hz), 14,10 (c, 1H).381379
16Hydrochloride ({7-hydroxy-5-[2-(4-triptoreline)ethyl][1,2,4]triazolo[1,5-a]pyridine-8-carbonyl}amino)acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: is 3.21 (2H, t, J=7.8 Hz), 3,44 (2H, t, J=7.8 Hz), 4,20 (2H, d, J=5.8 Hz), 6,83 (1H, s) of 7.48 (2H, d, J=8.1 Hz), 7,66 (2H, d, J=8.1 Hz), 8,59 (1H, s), 9,81-9,88 (1H, m).409407
17Hydrochloride({5-[2-(4-forfinal)ethyl]-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl}amino)acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 3,11 (2H, t, J=7.9 Hz), 3,39 (H, t, J=7,7 Hz), is 4.21 (2H, d, J=5,2 Hz), to 6.80 (1H, s), 7,07-7,16 (2H, m), 7.23 percent-7,30 (2H, m), at 8.60 (1H, s), 9,85 (1H, t, J=5.4 Hz).359357

375
Table 4
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS
(M-H)
18Hydrochloride {[7-hydroxy-5-(3-methylbutyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 0.95 (6H, d, J=6.5 Hz), 1,58 is 1.70 (3H, m), 3,07-3,13 (2H, m), is 4.21 (2H, d, J=5.6 Hz), 6.87 in (1H, s), to 8.57 (1H, s), 9,85 (1H, t, J=5.6 Hz).307305
19Hydrochloride({5-[2-(3,5-differenl)ethyl]-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl}amino)acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 3.15 in (2H, t, J=7.8 Hz), 3,42 (2H, t, J=7.8 Hz), 4,20 (2H, d, J=5.6 Hz), 6,83 (1H, s), 6,97-7,11 (3H, m), 8,58-8,61 (1H, m), 9,79-of 9.89 (1H, m).377
20Hydrochloride [(5-cyclopentylmethyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,21-1,32 (2H, m), 1,45-1,55 (2H, m), 1,59-of 1.74 (4H, m), 2.40 a-2,49 (1H, m) to 3.09 (2H, d, J=7,3 Hz), is 4.21 (2H, d, J=5.6 Hz), to 6.88 (1H, s), 8,55 (1H, s), 9,85 (1H, t, J=5.6 Hz).319317
21Hydrochloride {[5-(3,5-differenl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.8 Hz), 7,29 (c, 1H), 7,56 (TT, 1H, J=9,3, 2.3 Hz), 7,78-7,86 (m, 2H), 8,62 (c, 1H), 9,99 (t, 1H, J=5.8 Hz).349347
22Hydrochloride [(7-hydroxy-5-phenyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.6 Hz), 7,12 (c, 1H), to 7.59 to 7.62 (m, 3H), 7,99-8,02 (m, 2H), 8,58 (c, 1H), 9,98 (t, 1H, J=5.6 Hz).313311
23Guide klorid {[5-(3-chloro-4-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.6 Hz), 7.23 percent (c, 1H), to 7.67 (DD, 1H, J=8,9, and 8.9 Hz), with 8.05 (DDD, 1H, J=8,9, of 2.4, 4.8 Hz), 8.30 to (DD, 1H, J=7,3, 2.4 Hz), 8,60 (c, 1H), 9,98 (t, 1H, J=5.4 Hz).365363

Table 5
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS
(M-H)
24Hydrochloride {[5-(3,3-dimethylbutyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,98 (c, 9H), 1,59 is 1.70 (m, 2H), 3,01-3,13 (m, 2H), 4,21 (d, 2H, J=5.6 Hz), 6.89 in (c, 1H), 8,57 (c, 1H), 9,84 (t, 1H, J=5.6 Hz).321319
25Hydrochloride {[5-(3,4-differenl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D , 400 MHz) δ: 4.25 in (d, 2H, J=5.5 Hz), 7,22 (c, 1H), 7,69 (dt, 1H, J=15,0, a 5.3 Hz), 7,92-7,94 (m, 1H), 8,17 (DDD, 1H, J=11,9, and 7.7 and 2.2 Hz), 8,60 (c, 1H), 9,98 (t, 1H, J=5,5 Hz).349347
26Hydrochloride {[7-hydroxy-5-(para-tolyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 2,42 (c, 3H), 4,24 (d, 2H, J=5.5 Hz), 7,09 (c, 1H), 7,40 (d, 2H, J=8,2 Hz), to 7.93 (d, 2H, J=8,2 Hz), 8,58 (c, 1H), becomes 9.97 (t, 1H, J=5,5 Hz).327325
27Hydrochloride [(5-cyclohexyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,21-of 1.62 (5H, m), 1,69-to 1.79 (1H, m), 1,80-of 1.88 (2H, m), 1,98-of 2.09 (2H, m), 3,31-of 3.43 (1H, m), 4,20 (2H, d, J=5.8 Hz), 6,76 (1H, s), 8,56 (1H, s), 9,80-9,87 (1H, m).319317
28Hydrochloride [(5-cyclohexylmethyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,98-1,23 (5H, m), 1.56 to to 1.70 (5H, m), 1,9-1,99 (1H, m) of 3.00 (2H, d, J=7,2 Hz), is 4.21 (2H, d, J=5.6 Hz), at 6.84 (1H, s), 8,55 (1H, s), 9,85 (1H, t, J=5.6 Hz).333331

Table 6
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
29{[7-hydroxy-5-(3-phenylpropyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 2,07-of 2.15 (m, 2H), 2,71 (t, 2H, J=7,7 Hz), of 3.12 (t, 2H, J=7,6 Hz), is 4.21 (d, 2H, J=5.5 Hz), 6,85 (c, 1H), 7,15-7,31 (m, 5H), 8,55 (c, 1H), 9,84 (t, 1H, J=5,5 Hz).355353
30Hydrochloride [(5-cyclopentyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,68-of 1.84 (m, 6H), 2,14-of 2.21 (m, 2H), 3,69 is 3.76 (m, 1H), 4,21 (d, 2H, J=5.7 Hz), 6,83 (c, 1H), 8,56 (c, 1H), 9,85 (t, 1H, J=5.6 Hz).305303
31Hydrochloride {[5-(3-fluoro-5-triptoreline)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.6 Hz), 7,37 (c, 1H), to 7.99 (d, 1H, J=9.3 Hz), 8,23 (d, 1H, J=9.3 Hz), 8.30 to (c, 1H), 8,63 (c, 1H), 10,00 (t, 1H, J=5.6 Hz).399397
32Hydrochloride {[5-(4-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,24 (d, 2H, J=5.7 Hz), 7,14 (c, 1H), 7,41-of 7.48 (m, 2H), 8.07-a 8,13 (m, 2H), 8,59 (c, 1H), becomes 9.97 (t, 1H, J=5.7 Hz).331329
33Hydrochloride {[7-hydroxy-5-(3-triptoreline)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.5 Hz), 7,28 (c, 1H), to 7.84 (t, 1H, J=7.9 Hz), 7,98 (d, 1H, J=7.9 Hz), of 8.28 (d, 1H, J=7.9 Hz), to 8.41 (c, 1H), 8,61 (c, 1H), 10,00 (t, 1H, J=5.7 Hz).381379

Table 7
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
34Hydrochloride {[5-(2-fluoro-5-triptoreline)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.6 Hz), 7,28 (c, 1H), 7,73 (DD, 1H, J=9,1, 9.1 Hz), 8,10 (DDD, 1H, J=9,1, 4,5, 2.0 Hz), 8,24 (DD, 1H, J=6,4, 2.0 Hz), to 8.57 (c, 1H), 9,95 (t, 1H, J=5.6 Hz).399397
35Hydrochloride [(7-hydroxy-5-isopropyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 1.37 (d, 6H, J=7,3 Hz), 3,67 (Sept, 1H, J=7,3 Hz), is 4.21 (d, 2H, J=5.6 Hz), 6,82 (c, 1H), 8,59 (c, 1H), 9,84 (t, 1H, J=5.6 Hz).279277
36Hydrochloride {[5-(3-chloro-5-triptoreline)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]AMI is about}acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.6 Hz), 7,37 (c, 1H), 8,14 (c, 1H), of 8.37 (c, 1H), to 8.41 (c, 1H), 8,62 (c, 1H), 9,99 (t, 1H, J=5.6 Hz).415413
37Hydrochloride {[5-(3-cyanophenyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.7 Hz), 7,28 (c, 1H), 7,81 (t, 1H, J=7.9 Hz), 8,08 (dt, 1H, J=7,9, 1.0 Hz), a 8.34 (d, 1H, J=8,4 Hz), 8,48 (t, 1H, J=1.3 Hz), 8,61 (c, 1H), 9,99 (t, 1H, J=5.7 Hz).338336
38Hydrochloride({5-[2-(4-cyclopropylmethyl)ethyl]-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl}amino)acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,59-of 0.64 (m, 2H), 0.88 to 0,93 (m, 2H), 1,83-1,90 (m, 1H), 3,06 (t, 2H, J=7.9 Hz), 3,37 (t, 2H, J=7.9 Hz), is 4.21 (d, 2H, J=5.6 Hz), for 6.81 (c, 1H), 6,99 (d, 2H, J=8.1 Hz), 7,11 (d, 2H, J=8.1 Hz), at 8.60 (c, 1H), 9,84 (t, 1H, J=5.6 Hz).381379

Table 8
PR is m No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
39Hydrochloride {[5-(2,2-dimethylpropyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,97 (c, 9H), 3,12 (c, 2H), 4,21 (d, 2H, J=5.6 Hz), 6,78 (c, 1H), 8,53 (c, 1H), 9,88 (t, 1H, J=5.6 Hz).307305
40Hydrochloride {[5-(1-ethylpropyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,78 (t, 6H, J=7,3 Hz), 1,72-of 1.94 (m, 4H), 3,37-of 3.48 (m, 1H), 4,21 (d, 2H, J=5.6 Hz), 6,85 (c, 1H), 8,55 (c, 1H), 9,88 (t, 1H, J=5.6 Hz).307305
41Hydrochloride {[5-(3-chloro-5-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,24 (d, 2H, J=5.8 Hz), 7,28 (c, 1H), 7,73 (dt, 1H, J=8,7, and 2.1 Hz), 7,88-to $ 7.91 (m, 1H), 7,98-of 8.00 (m, 1H), 8,60 (c, 1H), becomes 9.97 (t, 1H, J=5.6 Hz).365363
42Hydrochloride {[5-(3-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.5 Hz), 7,21 (c, 1H), 7,47 (TDD, 1H, J=8,6, 2,6, 0.7 Hz), to 7.64 (TD, 1H, J=8,1, 6,0 Hz), 7,87 (dt, 1H, J=7,8, 1.0 Hz), of 7.90 (dt, 1H, J=10,1, 2,1 Hz), 8,60 (c, 1H), 9,99 (t, 1H, J=5.4 Hz).331329
43[(7-hydroxy-5-isobutyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 0.94 (d, 6H, J=6.9 Hz), 2,28 (Sept, 1H, J=6,9, and 7.3 Hz), 2,98 (d, 2H, J=7,3 Hz), is 4.21 (d, 2H, J=5.6 Hz), 6,85 (c, 1H), 8,55 (c, 1H), 9,85 (t, 1H, J=5.6 Hz).293291
44{[5-(3-chlorophenyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.6 Hz), 7,22 (c, 1H), to 7.59-7,71 (m, 2H), of 7.96 (d, 1H, J=7,7 Hz), 8,11 (c, H), 8,59 (c, 1H), 9,98 (user. s, 1H), 12,99 (user. s, 1H), 14,38 (user. s, 1H).347, 349345, 347

Table 9
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
45Hydrochloride {[5-(2-ethylbutyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 0.85 (t, 6H, J=7.4 Hz), 1,25-of 1.39 (m, 4H), 1,94-2,02 (m, 1H), 3,03 (d, 2H, J=7,3 Hz), is 4.21 (d, 2H, J=5.5 Hz), 6.87 in (c, 1H), 8,56 (c, 1H), 9,85 (t, 1H, J=5,5 Hz).321319
46Hydrochloride {[5-(3,5-dichlorophenyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 3H, J=5.6 Hz), 7,30 (c, 1H), 7,89 (t, 1H, J=3.5 Hz), 8,08 (c, 1H), 8,09 (c, 1H), 8,61 (c, 1H), 9,99 (t, 1H, J=5.6 Hz).381, 38337, 381
47Hydrochloride {[5-(2-cyclopropylethyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,00-0,05 (2H, m), 0,35-0,42 (2H, m), 0,72 is 0.81 (1H, m), 1,64-of 1.73 (2H, m), 3.15 and 3.21-in (2H, m), 4,20 (2H, d, J=5.6 Hz), 6,86 (1H, s), 8,55 (1H, s), 9,79-9,87 (1H, m).305303
48Hydrochloride {[5-(3,3-dimethylpentyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (CD3OD, 400 MHz) δ: of 0.91 (t, 3H, J=7,6 Hz), and 0.98 (c, 6H), 1.39 in (square, 2H, J=7.5 Hz), 1,70 (DDD, 2H, J=8,7, 4,7, 3.8 Hz), is 3.08-3,14 (m, 2H), 4,24 (c, 2H), 6,82 (c, 1H), 8,54 (c, 1H).335333
49Hydrochloride {[7-hydroxy-5-(3,4,5-tryptophanyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.5 Hz), 7,28 (c, 1H), 8,09 (DD, 2H, J=9,0, 6,8 Hz), 8,62 (c, 1H), 9,98 (t, 1H, J=5,1 Hz).367365
50 Hydrochloride {[5-(4-chlorophenyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.6 Hz), 7,17 (c, 1H), to 7.67 (d, 2H, J=8.6 Hz), with 8.05 (d, 2H, J=8.6 Hz), 8,59 (c, 1H), 9,98 (t, 1H, J=5.6 Hz).347345

Table 10
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
51Hydrochloride [(7-hydroxy-5-(meta-tolyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 2,42 (3H, s), 4,24 (2H, d, J=5.6 Hz), to 7.09 (1H, s), 7,41-7,51 (2H, m), 7,78-to 7.84 (2H, m), 8,58 (1H, s), 9,98 (1H, t, J=5.6 Hz).327325
52Hydrochloride {[5-(3-cyclopropyl-5-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 0,82 is 0.86 (m, 2H), 1,01 was 1.06 (m, 2H), 2,03 is 2.10 (m, 1H), 4,24 (d, 2H, J=5.6 Hz), 7,15-to 7.18 (m, 1H), 7,20 (c, 1H), 7,56 (DD, 1H, J=1,4, 1,4 Hz), 7,62-the 7.65 (m, 1H), 8,59 (c, 1H), 9,98 (t, 1H, J=5.6 Hz).371369
53Hydrochloride [(5-cyclobutylmethyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,72-1,90 (m, 4H), 1,98 is 2.10 (m, 2H), 2,80 of 2.92 (m, 1H), 3,20 (d, 2H, J=7.4 Hz), 4,20 (d, 2H, J=5.6 Hz), 6,79 (c, 1H), 8,55 (c, 1H), 9,83 (t, 1H, J=5.6 Hz).305303
54Hydrochloride {[5-(2-cyclobutylmethyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,54-to 1.67 (m, 2H), 1,72-of 1.92 (m, 4H), 1,95-to 2.06 (m, 2H), 2.26 and-is 2.37 (m, 1H), 3.00 for (t, 2H, J=7,7 Hz), is 4.21 (d, 2H, J=5.6 Hz), 6,85 (c, 1H), 8,56 (c, 1H), 9,85 (t, 1H, J=5.6 Hz).319317
55Hydrochloride {[5-(2-fluoro-3-triptoreline)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 4,24 (2H, d, J=5.6 Hz), 7,25 (1H, s), to 7.61-to 7.68 (1H, m), 8,03-8,13 (2H, m), to 8.57 (1H, s), 9,87-of 10.01 (1H, m).399397

Table 11
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
56Hydrochloride {[5-(3-chloro-2-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (2H, d, J=5.6 Hz), 7,21 (1H, s), 7,47 (1H, DD, J=7,9, 3,9 Hz), 7,73 (1H, DD, J=7,1, 3.5 Hz), 7,88 (1H, DD, J=7,7, 3.8 Hz), 8,56 (1H, s), for 9.95 (1H, t, J=5.0 Hz).365363
57Hydrochloride {[7-hydroxy-5-(4-triptoreline)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,24 (2H, d, J=5.6 Hz), 7.23 percent (1H, s), of 7.96 (2H, d, J=8.1 Hz), 8,21 (2H, d J=8.1 Hz), 8,59 (1H, s), 9,99 (1H, t, J=5.3 Hz).381379
58Hydrochloride [(5-cycloheptyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,52 is 1.86 (m, 10H), 1,96-2,04 (m, 2H), 3,50-3,59 (m, 1H), 4,21 (d, 2H, J=5.5 Hz), 6,78 (c, 1H), 8,56 (c, 1H), 9,86 (t, 1H, J=5,5 Hz).333331
59Hydrochloride {[5-(2,3-differenl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.7 Hz), 7,20 (c, 1H), 7,45 (TDD, 1H, J=8,2, a 4.9, 1.4 Hz), to 7.59 (DDT, 1H, J=8,3, to 5.4, 1.2 Hz), 7,70-to 7.77 (m, 1H), 8,56 (c, 1H), 9,95 (t, 1H, J=5.6 Hz).349347
60Hydrochloride {[5-(2-cyclopentylmethyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,11-1,19 (m, 2H), 1,47-to 1.61 (m, 4H), 1,74-to 1.87 (m, 5H), 3,10 (t, 2H, J=7.5 Hz), is 4.21 (d, 2H, J=5.6 Hz), 6.87 in (c, 1H), 8,56 (c, 1H), 9,84 (t, 1H, J=5.6 Hz). 333331

Table 12
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
61Hydrochloride {[5-(2-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.6 Hz), 7,13 (c, 1H), 7,41-of 7.48 (m, 2H), 7,66-7,72 (m, 1H), 7,74 for 7.78 (m, 1H), 8,55 (c, 1H), 9,95 (t, 1H, J=5.6 Hz).331329
62Hydrochloride {[5-(4-chloro-2-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5,2 Hz), 7,16 (c, 1H), 7,55 (DD, 1H, J=8,1, 1,4 Hz), 7,74 (DD, 1H, J=10,0, 1,4 Hz), 7,81 (DD, 1H, J=8,1, 8.1 Hz), 8,56 (c, 1H), 9,94 (t, 1H, J=5,2 Hz).365363
63Hydrochlori is {[5-(4-terbisil)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 4,20 (2H, d, J=5.5 Hz), to 4.46 (2H, s), 6,74 (1H, s), 7,16 (2H, DD, J=8,9, and 4.5 Hz), was 7.45 (2H, DD, J=8,6, and 5.5 Hz), to 8.57 (1H, s), 9,83 (1H, t, J=5.4 Hz).345343
64Hydrochloride (R)-2-{[5-(3,5-differenl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}propionic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 1.52 (d, 3H, J=7,1 Hz), 4,58-of 4.67 (m, 1H), 7,28 (user. s, 1H), 7,51-to 7.59 (m, 1H), 7,81 (d, 2H, J=6.4 Hz), 8,62 (c, 1H), 10,08-10,15 (user. m, 1H).363361
65Hydrochloride [(7-hydroxy-5-propyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,97 (t, 3H, J=7.4 Hz), 1,80 (TCEs., 2H, J=7,4, 7,4 Hz), of 3.07 (t, 2H, J=7.4 Hz), is 4.21 (d, 1H, J=5.7 Hz), 6,85 (c, 1H), 8,56 (c, 1H), 9,84 (t, 1H, J=5.7 Hz).279277

Table 13
Approx. No.The name of the connection is the link The structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
66Hydrochloride of 2-{[5-(3,5-differenl)-7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}propionic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 1.52 (d, 3H, J=7,1 Hz), 4,58-of 4.67 (m, 1H), 7,28 (user. s, 1H), 7,51-to 7.59 (m, 1H), 7,81 (d, 2H, J=6.4 Hz), 8,62 (c, 1H), 10,08-10,15 (user. m, 1H).363361
67Hydrochloride (S)-2-{[5-(3,5-differenl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}propionic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 1.52 (d, 3H, J=7,1 Hz), 4,60-of 4.67 (m, 1H), 7,31 (c, 1H), 7,56 (t, 1H, J=9.3 Hz), 7,82 (d, 2H, J=6.6 Hz), 8,61 (c, 1H), 10,10 (d, 1H, J=6.6 Hz), 13,16 (user. s, 1H), 14,32 (c, 1H).363361
68Hydrochloride of 2-{[5-(3,5-differenl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}-2-methylpropionic acid1H-NMR (DMSO-D6 , 400 MHz) δ: 1,63 (c, 6H), 7,27 (c, 1H), 7,51-of 7.60 (m, 1H), 7,76-7,83 (m, 2H), 8,61 (c, 1H), 10,15 (c, 1H).377375
69Hydrochloride (S)-2-[(7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]propionic acid1H-NMR (DMSO-D6, 400 MHz) δ: for 1.49 (d, 3H, J=7,3 Hz), of 3.12 (t, 2H, J=7.8 Hz), to 3.41 (t, 2H, J=7.8 Hz), 4,56-4,63 (m, 1H), for 6.81 (c, 1H), 7.18 in-7,33 (m, 5H), 8,61 (c, 1H), becomes 9.97 (d, 1H, J=7,1 Hz).355353
70Hydrochloride (R)-2-[(7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]propionic acid1H-NMR (DMSO-D6, 400 MHz) δ: for 1.49 (d, 3H, J=7,3 Hz), of 3.12 (t, 2H, J=7.8 Hz), to 3.41 (t, 2H, J=7.8 Hz), 4,56-4,63 (m, 1H), 6,80 (c, 1H), 7.18 in-7,33 (m, 5H), 8,61 (c, 1H), becomes 9.97 (d, 1H, J=7,1 Hz).355353

MS (M-H)
Table 14
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)
71Hydrochloride [(7-hydroxy-6-pentyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 0.87 (t, 3H, J=6.9 Hz), 1,28-of 1.36 (m, 4H), 1.61 of (t, 2H, J=7,6 Hz), 2,62 (t, 2H, J=7,6 Hz), is 4.21 (d, 2H, J=5.3 Hz), and 8.50 (c, 1H), 8,88 (c, 1H), to 9.93 (c, 1H), 14,81 (c, 1H).307305
72Hydrochloride {[7-hydroxy-5-(5-methylthiophene-2-yl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 2,58 (c, 3H), 4,23 (d, 2H, J=5.5 Hz), 7,07 (d, 1H, J=3,7 Hz), 7,50 (c, 1H), 8,27 (d, 1H, J=4.0 Hz), 8,67 (c, 1H), 9,85-9,90 (user. m, 1H).333331
73Hydrochloride [(5-hexyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 0.85 (3H, t, J=7.0 Hz), 1,23-of 1.41 (6H, m), 1,71-of 1.81 (2H, m), is 3.08 (2H, t, J=7,7 Hz), 4,20 (2H, d, J=5.6 Hz), 6,85 (1H, s), 8,56 (1H, s), 9,79-9,86 (1H, m).321319
74 Hydrochloride [(7-hydroxy-5-pentyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,84-of 0.91 (m, 3H), 1,29-of 1.40 (m, 4H), 1,72 of-1.83 (m, 2H), to 3.09 (t, 2H, J=7.5 Hz), is 4.21 (d, 2H, J=5.4 Hz), 6,86 (c, 1H), 8,56 (c, 1H), 9,83 (t, 1H, J=5.4 Hz).307305
75Hydrochloride {[5-(2,5-differenl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.6 Hz), 7,19 (c, 1H), 7,49-of 7.60 (m, 2H), to 7.67-7,73 (m, 1H), 8,56 (c, 1H), 9,95 (t, 1H, J=5.6 Hz).349347

Table 15
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
76Hydrochloride {[7-hydroxy-5-(2,3,5-tryptophanyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5.5 Hz), 7,25 (c, 1H), 7,58-to 7.64 (m, 1H), 7,86-to 7.93 (m, 1H), 8,59 (c, 1H), 9,95 (t, 1H, J=5,5 Hz).367365
77Hydrochloride {[5-(2,4-differenl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5,2 Hz), 7,14 (c, 1H), 7,30-7,39 (m, 1H), 7,50-of 7.60 (m, 1H), 7,81-7,89 (m, 1H), 8,55 (c, 1H), 9,94 (t, 1H, J=5.4 Hz).349347
78Hydrochloride {[5-(4-chloro-3-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,24 (d, 2H, J=5.6 Hz), 7,26 (c, 1H), 7,82-7,86 (m, 1H), to 7.93 (DD, 1H, J=8,5, and 1.6 Hz), 8,13 (DD, 1H, J=10,5, 2.0 Hz), 8,61 (c, 1H), 9,98 (t, 1H, J=5.4 Hz).365363
79Hydrochloride {[5-(3-fluoro-5-were)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1 H-NMR (DMSO-D6, 400 MHz) δ: 2,43 (c, 3H), 4.25 in (d, 2H, J=5.3 Hz), 7,18 (c, 1H), 7,32 (d, 1H, J=9.3 Hz), of 7.70 (d, 2H, J=10.4 Hz), at 8.60 (d, 1H, J=0.7 Hz), 9,99 (t, 1H, J=5.3 Hz).345343
80Hydrochloride [(6-chloro-7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 3,05 (t, 2H, J=7.8 Hz), of 3.56 (t, 2H, J=7.8 Hz), 4,17 (d, 2H, J=5,1 Hz), 7,16-7,22 (m, 3H), 7.23 percent-7,29 (m, 2H), 8,60 (c, 1H).375373
81Hydrochloride [(6-chloro-7-hydroxy-5-propyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 3,09 (t, 2H, J=7.8 Hz), or 3.28 (t, 2H, J=7.8 Hz), 4,25 (d, 2H, J=5.6 Hz), 7,16-to 7.32 (m, 5H), was 7.36 (c, 1H), 8,68 (c, 1H), 10,42 (t, 1H, J=5.6 Hz), 13,26 (c, 1H).313311

Table 16
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D. MS (M+H)MS (M-H)
82Hydrochloride {[5-(4-cyclopropyl-2-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,82 is 0.86 (m, 2H), 1,05-1,10 (m, 2H), 2,04-2,11 (m, 1H), 4,24 (d, 2H, J=5.6 Hz), 7,06 (c, 1H), 7,14 (d, 1H, J=8.1 Hz), to 7.15 (d, 1H, J=7,7 Hz), a 7.62 (DD, 1H, J=7,7, 7,7 Hz), 8,53 (c, 1H), 9,94 (t, 1H, J=5.6 Hz).371369
83Hydrochloride [(6-hydroxy-8-phenyl[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,28 (d, 2H, J=5.5 Hz), 7,50-7,63 (m, 3H), 7,80 (c, 1H), 8,21 (d, 2H, J=7,3 Hz), a total of 8.74 (c, 1H), 10,53 (t, 1H, J=5.5 Hz), made 13.36 (c, 1H).313311
84{[8-(3-chlorophenyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,28 (d, 2H, J=5.6 Hz), 7,58-to 7.64 (m, 2H), 7,92 (c, 1H), 8,15-8,21 (m, 1H), of 8.37-8,39 (m, 1H), 8,76 (c, 1H), 10,54 (t, 1H, J=5.4 Hz), 13,06 (c, 1H), made 13.36 (c, 1H).347 345
85Hydrochloride {[8-(3,5-differenl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,28 (d, 2H, J=5.6 Hz), 7,47 (TT, 1H, J=9,3, 2.3 Hz), 8,03 (c, 1H), 8,06-to 8.14 (m, 2H), 8,78 (c, 1H), 10,54 (t, 1H, J=5.4 Hz), 13,35 (c, 1H).349347
86Hydrochloride [(8-benzyl-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,24 (d, 2H, J=5.6 Hz), 4,33 (c, 2H), 7,20-7,25 (m, 1H), 7,28-7,33 (m, 2H), 7,35 (c, 1H), 7,38-7,41 (m, 2H), 8,66 (c, 1H), the 10.40 (t, 1H, J=5.6 Hz), of 13.27 (c, 1H).327325

Table 17
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
87Hydrochloride [(6-hydroxy-8-phenethyl[1,2,4]triazolo[1,5-a]p is ridin-5-carbonyl)amino]acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 3,09 (t, 2H, J=7.8 Hz), or 3.28 (t, 2H, J=7.8 Hz), 4,25 (d, 2H, J=5.6 Hz), 7,16-to 7.32 (m, 5H), was 7.36 (c, 1H), 8,68 (c, 1H), 10,42 (t, 1H, J=5.6 Hz), 13,26 (c, 1H).341339
88{[8-(2-chlorophenyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,28 (d, 2H, J=5.6 Hz), 7,49-to 7.59 (m, 2H), 7,60-7,63 (m, 2H), to 7.67 (DD, 1H, J=7,9, and 1.4 Hz), 8,66 (c, 1H), 10,50 (t, 1H, J=5.6 Hz), 13,06 (c, 1H), 13,37 (c, 1H).347345
89Hydrochloride {[8-(3,5-dichlorophenyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,28 (d, 2H, J=5.3 Hz), 7,80 (t, 1H, J=1.9 Hz), 8,03 (c, 1H), at 8.36 (d, 2H, J=1,8 Hz), 8,77 (c, 1H), 10,53 (t, 1H, J=5.3 Hz), 13,34 (c, 1H).381379
90Hydrochloride({8-[2-(4-forfinal)ethyl]-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl}amino)acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 3,09 (t, 2H, J=7.9 Hz), with 3.27 (t, 2H, J=7,7 Hz), 4,25 (d, 2H, J=5.5 Hz), 7,10 (t, 2H, J=8,9 Hz), 7,26 (DD, 2H, J=8,7, 5.8 Hz), 7,35 (c, 1H), 8,66 (c, 1H), 10,42 (t, 1H, J=5.3 Hz), 13,26 (c, 1H).359357
91Hydrochloride [(8-cyclohexylmethyl-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,94-of 1.23 (m, 5H), 1,53 is 1.70 (m, 5H), 1,80-of 1.94 (m, 1H), 2,86 (d, 2H, J=7,2 Hz), 4,25 (d, 2H, J=5.6 Hz), was 7.36 (c, 1H), 8,62 (c, 1H), 10,42 (t, 1H, J=5.6 Hz), 13,28 (c, 1H).333331

Table 18
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
92Hydrochloride [(8-cyclohexyl-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,231,34 (m, 1H), 1,38-1,49 (m, 2H), 1,57-to 1.67 (m, 2H), 1,73-to 1.77 (m, 1H), 1,82 is 1.86 (m, 2H), 1,91 is 1.96 (m, 2H), 3,15-up 3.22 (m, 1H), 4,25 (d, 2H, J=5.6 Hz), 7,33 (c, 1H), 8,63 (c, 1H), 10,42 (t, 1H, J=5.6 Hz), to 13.29 (c, 1H).319317
93Hydrochloride [(8-cyclohex-1-enyl-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,62 by 1.68 (m, 2H), 1,74 and 1.80 (m, 2H), 2,31 to 2.35 (m, 2H), 2,49-of 2.54 (m, 2H), 4.25 in (d, 2H, J=5.6 Hz), 7,33 (c, 1H), 7,58-to 7.61 (m, 1H), 8,66 (c, 1H), 10,48 (t, 1H, J=5.6 Hz), 13,28 (c, 1H).317315
94Hydrochloride {[8-(3-chloro-4-forfinal)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,28 (d, 2H, J=5.5 Hz), to 7.64 (t, 1H, J=8,9 Hz), 7,94 (c, 1H), 8,29 (DQC., 1H, J=8,7, and 2.3 Hz), to 8.57 (DD, 1H, J=7,2, 2.3 Hz), 8,77 (c, 1H), 10,52 (t, 1H, J=5.5 Hz), made 13.36 (c, 1H).365363
95Hydrochloride {[8-(3,4-dichlorophenyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 4,28 (d, 2H, J=5.5 Hz), to 7.84 (d, 1H, J=8,4 Hz), 7,97 (c, 1H), 8,25 (DD, 1H, J=a 8.4 and 2.2 Hz), at 8.60 (d, 1H, J=2.2 Hz), 8,77 (c, 1H), 10,52 (t, 1H, J=5.5 Hz), 13,35 (c, 1H).381379

Table 19
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
96Hydrochloride {[8-(5-chlorothiophene-2-yl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.26 deaths (d, 2H, J=5.5 Hz), 7,35 (d, 1H, J=4, 2 Hz), 8,06 (c, 1H), they were 8.22 (d, 1H, J=4, 2 Hz), 8,78 (c, 1H), 10,41 (t, 1H, J=5.5 Hz), 13,35 (c, 1H).353351
97Hydrochloride {[8-(3,5-bis-triptoreline)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,29 (d, 2H, J=5.5 Hz), 8,24 (c, 1H), 8,29 (c, 1H), 8,82 (c, 1H), 8,98 (c, 2H), 10,55 (t, 1H, J=5.5 Hz), made 13.36 (c, 1H).449447
98Hydrochloride {[8-(2-cyclohexylethyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 0.85 to 1.34 (m, 6H), 1,53-to 1.82 (m, 7H), 2,94-to 3.02 (m, 2H), 4.25 in (d, 2H, J=5.6 Hz), 7,40 (c, 1H), 8,63 (c, 1H), 10,41 (t, 1H, J=5.6 Hz), 13,28 (c, 1H).347345
99Hydrochloride {[8-(2-cyclopentylmethyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 1,07-1,22 (m, 2H), 1.41 to of 1.65 (m, 4H), 1.70 to to 1.86 (m, 5H), 2,93-to 3.02 (m, 2H), 4.25 in (d, 2H, J=5.6 Hz), 7,40 (c, 1H), 8,64 (c, 1H), 10,41 (t, 1H, J=5.6 Hz), 13,28 (c, 1H).333331
100Hydrochloride ({6-hydroxy-8-[2-(2-triptoreline)ethyl][1,2,4]triazolo[1,5-a]pyridine-5-carbonyl}amino)acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 3,21-to 3.35 (m, 4H), 4,25 (d, 2H, J=5.6 Hz), 7,38 (c, 1H), 7,44 (t, 1H, J=7.5 Hz), 7,56 (d, 1H, J=7,7 Hz), 7,63 (t, 1H, J=7,7 Hz), of 7.70 (d, 1H, J=7.5 Hz), or 8.6 (c, 1H), 10,43 (t, 1H, J=5.6 Hz), 13,28 (c, 1H).409407

Table 20
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
101Hydrochloride ({6-hydroxy-8-[2-(3-triptoreline)ethyl][1,2,4]triazolo[1,5-a]pyridine-5-carbonyl}amino)acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 3,20 (DD, 2H, J=9,4, 6.5 Hz), 3,32 (DD, 2H, J=9,4, 6.5 Hz), 4,25 (d, 2H, J=5.6 Hz), 7,40 (c, 1H), 7,49-to 7.59 (m, 3H), 7,63 (c, 1H), 8,68 (c, 1H), 10,42 (t, 1H, J=5.6 Hz), of 13.27 (c, 1H).409407
102Hydrochloride ({6-hydroxy-8-[2-(4-triptoreline)ethyl][1,2,4]triazolo[1,5-a]pyridine-5-carbonyl}amino)acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 3,17-3,24 (m, 2H), 3,28-to 3.36 (m, 2H), 4.25 in (d, 2H, J=5.6 Hz), 7,40 (c, 1H), of 7.48 (d, 2H, J=7.9 Hz), the 7.65 (d, 2H, J=7.9 Hz), 8,68 (c, 1H), 10,42 (t, 1H, J=5.6 Hz), of 13.27 (c, 1H). 409407
103Hydrochloride {[8-(3-chloro-5-cyclopropylmethyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,84-of 0.90 (m, 2H), 1,01 was 1.06 (m, 2H), 2,03 is 2.10 (m, 1H), 4,28 (d, 2H, J=5.4 Hz), 7,31 (DD, 1H, J=1,8, 1.8 Hz), 7,83 (DD, 1H, J=1,8, 1.8 Hz), 7,93 (c, 1H), 8,13 (DD, 1H, J=1,8, 1.8 Hz), 8,75 (c, 1H), 10,53 (t, 1H, J=5.4 Hz), 13,35 (c, 1H).387385
104Hydrochloride {[8-(3-fluoro-5-triptoreline)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,29 (d, 2H, J=5.5 Hz), 7,89 (d, 1H, J=8.6 Hz), 8,12 (c, 1H), 8,46 (d, 1H, J=8.6 Hz), 8,63 (c, 1H), 8,80 (c, 1H), 10,54 (t, 1H, J=5.5 Hz), made 13.36 (c, 1H).399397
105Hydrochloride {[8-(3-chloro-5-forfinal)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,28 (d, 2H, J=5.3 Hz), 7,62-to 7.67 (m, 1H), 8,03 (c, 1H), 8,13-8,19 (m, 1H), 8,31 (c, 1H), 8,78 (c, 1H), 10,54 (t, 1H, J=5.3g is), 13,35 (c, 1H).365363

Table 21
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
106Hydrochloride {[8-(4-fluoro-3-triptoreline)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,29 (d, 2H, J=5.6 Hz), 7,71-7,80 (m, 1H), 8,03 (c, 1H), 8,56-8,63 (m, 1H), 8,73-8,82 (m, 2H), 10,53 (t, 1H, J=5.6 Hz), 13,37 (c, 1H).399397
107Hydrochloride [(6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,27 (d, 2H, J=5.3 Hz), 7,56 (d, 1H, J=9.7 Hz), of 8.09 (d, 1H, J=9.7 Hz), 8,68 (c, 1H), 10,49 (t, 1H, J=5.3 Hz), to 13.29 (user. s, 1H).237235
1081H-NMR (DMSO-D6, 400 MHz) δ: 4,24 (d, 2H, J=5,2 Hz), 7,62-to 7.67 (m, 2H), 7,86 (c, 1H), compared to 8.26-8,31 (m, 2H), total of 8.74 (c, 1H), 10,53 (t, 1H, J=5,2 Hz), 13,31 (user. s, 1H).347345
109Hydrochloride({8-[2-(3,5-differenl)ethyl]-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl}amino)acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 3,13 (t, 2H, J=7.9 Hz), 3,30 (t, 2H, J=7.9 Hz), 4,25 (d, 2H, J=5,2 Hz), 6,98-was 7.08 (m, 3H), 7,40 (c, 1H), 8,67 (c, 1H), 10,42 (t, 1H, J=5,2 Hz), of 13.27 (user. s, 1H).377375
110Hydrochloride {[6-hydroxy-8-(3-triptoreline)[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,29 (d, 2H, J=5.5 Hz), 7,82 (t, 1H, J=7.9 Hz), to $ 7.91 (d, 1H, J=7.9 Hz), 8,00 (c, 1H), 8,48 (d, 1H, J=7.9 Hz), 8,70 (c, 1H), 8,78 (c, 1H), 10,54 (t, 1H, J=5.5 Hz), made 13.36 (user. s, 1H).381379

Table 22
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
111Hydrochloride [(7-hydroxy-3,6-diphenyl[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.09 to (d, 2H, J=5.5 Hz), of 7.36-7,44 (m, 3H), EUR 7.57-7,66 (m, 5H), of 7.90 (d, 2H, J=7,3 Hz), 8,00 (c, 1H), 10,56 (t, 1H, J=5.3 Hz), 12,61 (c, 1H), 13,95 (c, 1H).389387
112Hydrochloride [(7-hydroxy-3-methyl-6-phenyl[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 2,62 (c, 3H), of 4.05 (d, 2H, J=5.5 Hz), 7,39-7,46 (m, 3H), 7,63 (d, 2H, J=6.8 Hz), 8,21 (c, 1H), 10,54 (t, 1H, J=5.3 Hz), 12,58 (c, 1H), 13,44 (c, 1H).327325
113[(7-hydroxy-3-phenyl[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl)amino]acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 4,06-4,24 (m, 2H), 6,47-6,74 (m, 1H), 7,58-7,71 (m, 3H), 7,78-7,89 (m, 2H), 7,99-8,42 (m, 1H), 9,99-10,43 (m, 1H).313311
114Hydrochloride [(7-hydroxy-3-phenethyl[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: is 3.08 (t, 2H, J=7,7 Hz), or 3.28 (t, 2H, J=7,7 Hz), of 4.05 (d, 2H, J=5,2 Hz), 6,46 (d, 1H, J=7,3 Hz), 7,16-7,25 (m, 1H), 7,26-to 7.32 (m, 4H), 8,19 (d, 1H, J=7,3 Hz), 10,33 (user. s, 1H), 13,52 (user. s, 1H).341339
115Hydrochloride {[3-(2-cyclohexylethyl)-7-hydroxy[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,90-0,98 (m, 2H), 1,17-1,22 (m, 3H), 1,28-of 1.40 (m, 1H), 1,62-to 1.67 (m, 5H), 1,75-of 1.78 (m, 2H), 2,96 (t, 2H, J=7.9 Hz), Android 4.04 (d, 2H, J=5,2 Hz), of 6.52 (d, 1H, J=7,7 Hz), 8,21 (d, 1H, J=7,7 Hz), 10,28 (user. s, 1H).347345

Table 23
Approx. No.Connection nameStructure the structural formula 1H-NMR, δ, M. D.MS (M+H)MS (M-H)
116[(7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 3,12 (t, 2H, J=7.9 Hz), 3,40 (t, 3H, J=7.9 Hz), 4,22 (d, 2H, J=5,2 Hz), 6,79 (c, 1H), 7,21-7,29 (m, 5H), 8,58 (c, 1H), 9,84 (t, 1H, J=5,2 Hz), 12,97 (c, 1H), 14,22 (c, 1H).341339
117[(5-butyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: of 0.93 (t, 3H, J=7.5 Hz), 1,33-1,44 (m, 2H), 1,71 and 1.80 (m, 2H), 3,10 (t, 2H, J=7.5 Hz), 4,20 (d, 2H, J=5,2 Hz), 6,85 (c, 1H), 8,55 (c, 1H), 9,84 (user. s, 1H), 14,26 (user. s, 1H).293291
118{[5-(3-fluoro-5-triptoreline)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4.25 in (d, 2H, J=5,1 Hz), 7,39 (c, 1H), to 7.99 (d, 1H, J=8.6 Hz), 8,23 (d, 1H, J=9.5 Hz), 8,31 (c, 1H), 8,62 (c, 1H), 9,98 (c, 1H), 13,01 (c, 1H), 14.4V (c, 1H).399397
119[(7-hydroxy-5-pentyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: from 0.88 (t, 3H, J=7,6 Hz), 1,28-of 1.40 (m, 4H), 1,73 of-1.83 (m, 2H), to 3.09 (t, 2H, J=7,6 Hz), is 4.21 (d, 2H, J=5.5 Hz), 6,85 (c, 1H), 8,54 (c, 1H), 9,84 (t, 1H, J=5.5 Hz), 12,94 (c, 1H), 14,25 (c, 1H).307305

Table 24
Approx. No.Connection nameThe structural formula1H-NMR, δ, M. D.MS (M+H)MS (M-H)
120{[5-(3-chlorophenyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 4,24 (d, 2H, J=5.3 Hz), 7,22 (c, 1H), 7,58-of 7.70 (m, 2H), of 7.96 (d, 1H, J=7,7 Hz), 8,11 (c, 1H), 8,59 (c, 1H), becomes 9.97 (c, 1H), 14,38 (c, 1H).347345
121{[5-(4-the tor-3-triptoreline)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid 1H-NMR (DMSO-D6, 400 MHz) δ: 4,24 (2H, d, J=5.6 Hz), 7,30 (1H, s), to 7.77 (1H, DD, J=10,5, and 9.3 Hz), at 8.36-to 8.40 (1H, m), of 8.47 (1H, d, J=6.9 Hz), at 8.60 (1H, s), becomes 9.97 (1H, user. c), 14,38 (1H, user. c).399397
122{[5-(3-cyclopropyl-5-forfinal)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino}acetic acid1H-NMR (DMSO-D6, 400 MHz) δ: 0,81-0.87 (m, 2H), 1,00-of 1.07 (m, 2H), 2,03 is 2.10 (m, 1H), 4,22 (d, 2H, J=5.6 Hz), 7,13-of 7.23 (m, 2H), 7,56 (c, 1H), 7,63 (d, 1H, J=9.3 Hz), 8,58 (c, 1H), 9,99 (c, 1H), 14,36 (c, 1H).371369

Examples of preparation of the composition according to the present invention include the following preparation of the composition. However, the present invention is not limited by such examples of preparation of the composition.

The sample preparation part 1 (getting capsules)
1) connection Example 130 mg
2) microcrystalline cellulose10 mg
3) lactose 19 mg
4) magnesium stearate1 mg

Components 1), 2), 3) and 4) are mixed and put into a gelatin capsule.

Example preparation of part 2 (getting the pill)
1) connection Example 110 g
2) lactose50 g
3) corn starch15 g
4) carmellose calcium44 g
5) magnesium stearate1 g

The total number of components 1), 2), 3) and 30 g of component 4) are kneaded with water, dried under vacuum and sieved. The sifted powder is mixed with 14 g of component 4) and 1 g of the component 5) and tabletirujut mixture using teletrauma machine. So, get 1000 tablets containing 10 mg of the compound of Example 1 on the pill.

The following describes the valuation techniques inhibitory activity against human PHD and induction of EPO production of the compounds of the present invention, or its pharmaceutically acceptable salt, or MES.

Test example 1

Measured the e inhibitory activity towards PHD man

i) Expression and purification PHD2 person

PHD2 of human expressed in insect cells (Sf9 cells). Was carried out by the insertion of a FLAG sequence at the N-terminal part of PA site registered sequence PHD2 person (NM_022051), the sequence was inserted in the vector pVL1393 and confirmed the sequence. Vector and baculovirus was cotranslationally in Sf9 and insulated in Sf9 baculovirus expressing PHD2 person. Using virus received cells expressing PHD2 person. After growing the cells at 27°C for 72 h was added to lyse solution with different content of protease inhibitors and destroy cells by ultrasound. The cell lysate was applied to a column Packed with affinity gel ANTI-FLAG M2 Affinity Gel Freezer Safe (SIGMA), washed, suirable and collected PHD2 person with an added N-terminal FLAG sequence. By the method of Western blotting using anti-FLAG antibodies and anti-PHD2 antibody was confirmed that the cleaning product is a PHD2 person.

ii) Expression and purification of complex VBC

The VBC complex (VHL/alongin B/alongin C) expressed inEscherichia coli(BL21(DE3)). Was carried out by the insertion of a GST-fusion N-terminal part of PA site registered sequence VHL person (NM_000551). Was carried out by the insertion of a FLAG sequence at the N-terminal part of Tran the air parcel registered sequence longina B person (NM_207013), the sequence was inserted in the vector pETDuet-1 and confirmed the sequence. Was carried out by inserting His sequence in the N-terminal part of PA site registered sequence longina C person (NM_005648), the sequence was inserted in the vector pETDuet-1 and confirmed the sequence. After transfection of the indicated expression vectors inEscherichia coli(BL21(DE3)),Escherichia coliwere grown at 37°C in a medium containing IPTG. Collected byEscherichia colidestroyed by ultrasound and were applied to a column Packed with Ni-NTA superflow (QIAGEN), washed, suirable and assembled product. Eluate was applied on a column Packed with glutathione Sepharose 4B was washed, was suirable and assembled product. By the method of Western blotting using anti-GST antibodies·anti-FLAG antibody and anti-His antibody confirmed that the cleaning product is a VHL/elogin/alongin C man.

iii) Binding activity of the complex VBC

On streptavidin coated tablet was measured binding activity of the VBC complex obtained in the above item (ii), in relation to 19 residues labeled with Biotin incomplete peptide (HIF-1α-C19) based on a sequence of HIF-1α or labeled with Biotin incomplete peptide (HIF-1α-C19 (Hyp)), where polynomy the balance in the above-mentioned sequence gidroksilirovanii. For detection ELISA was performed using the m anti-GST antibodies and confirmed the binding of the complex VBC only gidroksilirovanii incomplete peptide HIF-1α.

iv) Measurement of inhibitory activity against PHD person

With regard to the enzymatic activity of PHD2 person, hydroxylation prolinnova residue contained in the 19 residues of incomplete peptide based on the sequence of HIF-1α, as a substrate was measured by the method of TR-FRET (fluorescent resonance energy transfer with a time resolution).

The enzyme and substrate, each was diluted in 50 mm Tris-cleaners containing hydrochloride buffer (pH 7.5) containing 50 μm of ferric sulfate, 120 mm NaCl, 0.1% BSA, 0.1 mm ascorbic acid, 10 μm 2-oxoglutaric acid, 0.2 mm CHAPS and diluted test the connection, dimethylsulfoxide (DMSO).

Test the connection, and the substrate solution was added to the 96-well plate. The reaction was initiated by adding to the reaction system of an enzyme solution PHD2 person (final concentration 1 nm). After incubation at 25°C for 30 min was added a stop solution containing EDTA and the solution was added VBC complex containing europium (Eu) and Xlent, and determined the content of gidrauxilirovannogo prolinnova residue by the method of fluorescence spectroscopy with time resolution. Fluorescence with a time resolution was measured in each well and, based on the values in the wells without added enzyme and without addition of the test compounds was calculated inhibitory activity (%) of the tested compounds the Oia in relation to the PHD person. Inhibitory activity of each compound against PHD person presents as values IC50(μm) or values inhibitory activity (%) in relation to the PHD person under 30 microns in subsequent Tables 25-29. In these Tables of values consisting solely of numbers that represent the values of the IC50(μm), and the values containing %, represent the values of the inhibitory activity (%) in relation to the PHD person at 30 ám.

Table 25
Approx. No.IC50(μm) or inhibitory activity (%)in vitroat 30 µm
10,42
20,22
30,45
47,15
51,17
60,87
71,59
80,49
9of 1.57
101,33
110,29
120,82
131,31
140,23
151,80
160,32
170,29
180,48
190,26
200,59
210,25
220,21
230,19
240,57
250,25
260,33
270,74
281,38
290,92

Table 26
Approx. No.IC50(μm) or inhibitory activity (%)in vitroat 30 µm
300,98
310,80
320,38
330,46
340,43
350,88
360,72
370,20
380,59
391,25
400,87
410,26
420,24
430,93
440,20
450,92
460,29
470,56
48059
490,24
500,18
510,26
520,89
530,50
540,44
550,23
560,19
570,20
580,55

Table 27
Approx. No.IC50(μm) or inhibitory activity (%)in vitroat 30 µm
590,26
600,74
610,22
620,28
630,36
64to 6.88
65 0,72
661,50
670,90
685,94
691,62
7038%
712,47
720,40
737,09
740,85
750,21
760,22
770,24
780,15
790,23
800,71
816,09
820,15
830,19
840,11
850,16
860,83
870,37

Table 28
Approx. No.IC50(μm) or inhibitory activity (%)in vitroat 30 µm
880,16
890,12
900,29
911,53
920,69
930,51
940,11
950,12
960,29
970,13
981,13
990,87
1000,82
1010,37
1020,51
1030,18
1040,19
1050,10
1060,23
1070,65
1080,16
1090,17
1100,15
1111,10
1123,09
1130,56
1141,20
1151,80

Table 29
Approx. No.IC50(μm) or inhibitory activity (%)in vitroat 30 µm
1160,18
1170,39
1180,64
1190,64
1200,12
1210,33
1220,96

Test example 2

Activity against production of EPO man

The activity of test compounds against developing human EPO was measured using Hep3B (ATCC), created from a cell line derived from human liver.

The Hep3B cells were grown in a modified environment, the Needle containing 10% fetal bovine serum, and were diluted test the connection, dimethylsulfoxide (DMSO).

The Hep3B cells were grown in 96-well tablet and after 24 h were added to the test compound at each concentration. After incubation at 37°C for 24 h were collected culture supernatant. The concentration of human EPO produced in the culture supernatant was measured using a kit for EPO-ELISA man (produced by StemCell Technologies, 01630) in accordance with the description of the manufacturer, and expected activity of the tested compounds against developing human EPO (%) based on the maximum output under these conditions, and the production values without the addition of test compounds. The activity of each test compound against vyrabotki the EPO person presented in the following Tables 30-34 values IC 50(μm) or activity values of the tested compounds against developing human EPO (%) at 30 μm. In these Tables of values consisting solely of numbers that represent the values of the IC50(μm), and those containing %, represent the values of the activity of the tested compounds against developing human EPO (%) at 30 μm.

Table 30
Approx. No.EC50(μm) or the activity of production (%)in vitroat 30 µm
19,9
210,9
312,4
438%
511,5
620,8
718,4
8the 13.4
91%
100%
111%
12 5%
131%
145,1
1529,1
167,0
178,8
186,1
196,6
206,6
21to 12.0
2213,7
237,8
24of 5.4
2514,1
267,5
277,7
2813,9
2911,3

5,6
Table 31
Approx. No.EC50(μm) or the activity of production (%)in vitro
3015,4
3112,1
32the 15.6
33the 10.1
3415,0
3543%
3610,5
3711%
388,7
3922,3
4017,7
419,1
4214,2
4323,6
4410,4
459,9
464,8
47to 12.0
484,5
4911,7
50
519,1
5210,4
538,9
544,5
558,9
568,4
57the 4.7
58the 4.7

Table 32
Approx. No.EC50(μm) or the activity of production (%)in vitroat 30 µm
5949%
608,4
6128,8
62the 10.1
6319,7
640%
6549%
6621,1
67 14,3
680%
69to 12.0
701%
7115,8
724,0
7334%
748,3
7523,7
7618,0
7718,7
786,6
797,8
8023,3
8133%
82of 5.4
8320,7
8411,0
8520,6
866%
8718,5

Table 33
Approx. No.EC50(μm) or the activity of production (%)in vitroat 30 µm
8814%
894,2
9016,6
9143%
9218,5
9316,0
94the 9.7
954,3
965,9
973,5
9825,6
9920,2
10018,0
1016%
10216,0
1036,9
1046,3
105 5,9
1066,0
1074%
1088,9
10913,7
1106,5
1110%
1120%
1130%
1140%
1150%

Table 34
Approx. No.EC50(μm) or the activity of production (%)in vitroat 30 µm
1165,6
1177,7

As can be seen from the above results, the compound of the present invention, or its pharmaceutically acceptable salt, or its MES possess inhibitory activity against PHD person and the ability to produce human EPO.

Industrial applicability

Soedinenie the present invention, or its pharmaceutically acceptable salt, or its MES inhibit the binding of HIF and PHD on the basis of its inhibitory activity towards a PHD, and stabilize HIF, which allows you to contribute to the development of EPO.

Thus, the connection of the present invention, or its pharmaceutically acceptable salt, or its MES can be a drug that is effective for prophylaxis or treatment of various diseases and pathologies (violations), caused by reduced secretion of EPO, and can be effectively used to treat anemia.

1. The compound represented by the following formula [I] or its pharmaceutically acceptable salt:

in which
partial structural formula:

represents a group represented by any of the following formulas:

R1represents a
(1) a hydrogen atom,
(2) C1-6alkyl group,
(3) phenyl group, or
(4)3-8cycloalkyl group;
R2represents a
(1) a hydrogen atom,
(2) C1-10alkyl group,
(3) a phenyl group optionally substituted by the same or different 1 to 3 substituents selected from the following group
In,
(4)3-8cycloalkyl group,
(5)3-8cycloalkenyl group,
(6) thienyl the ing group, optionally substituted by 1 Deputy selected from halogen or C1-6alkyl group,
(7) phenyl-C1-6alkyl group (in which the phenyl optionally substituted by same or different 1 to 2 substituents selected from halogen, C3-8cycloalkyl or halogen-C1-6alkyl group) or
(8)3-8cycloalkyl-C1-6akilou group;
R3represents a
(1) a hydrogen atom,
(2) a halogen atom,
(3) (C1-6alkyl group,
(4) phenyl group, or
(6) phenyl-C1-6alkyl group; and
each of R4and R5are both hydrogen atoms or
group:
(a) a halogen atom,
(b) (C1-6alkyl group,
(c)3-8cycloalkyl group,
(d) cyano, and
(e) a halogen-C1-6alkyl group.

2. Connection on p. 1, in which the partial structural formula:

is a group represented by the following formula

or its pharmaceutically acceptable salt.

3. Connection on p. 1, in which the partial structural formula:

is a group represented by the following formula

or its pharmaceutically acceptable salt.

4. Connection on p. 1, in which the partial structural formula:
img src="https://img.russianpatents.com/1191/11915280-s.jpg" height="31" width="22" />
is a group represented by the following formula

or its pharmaceutically acceptable salt.

5. The compound according to any one of paragraphs.1-4, in which R3represents a hydrogen atom, or its pharmaceutically acceptable salt.

6. The compound according to any one of paragraphs.1-5, in which R1represents a hydrogen atom, or its pharmaceutically acceptable salt.

7. The compound according to any one of paragraphs.1-5, in which R2represents a
(1) C1-10alkyl group,
(2) a phenyl group optionally substituted by the same or different 1 to 3 substituents selected from the aforementioned group b,
(3) phenyl-C1-6alkyl group (in which the phenyl optionally substituted by same or different 1 to 2 substituents selected from halogen, C3-8cycloalkyl or halogen-C1-6alkyl group) or
(4)3-8cycloalkyl-C1-6alkyl group,
or its pharmaceutically acceptable salt.

8. Connection on p. 2, in which R3represents a hydrogen atom, or its pharmaceutically acceptable salt.

9. Connection on p. 8, in which R1represents a hydrogen atom, or its pharmaceutically acceptable salt.

10. Connection on p. 9, in which R2represents a
(1) C1-10alkyl group, or
(2) phenyl-C1-6and kilou group (in which the phenyl optionally substituted by same or different 1 to 2 substituents, selected from halogen, C3-8cycloalkyl or halogen-C1-6alkyl group),
or its pharmaceutically acceptable salt.

11. The compound represented by the following formula:

or its pharmaceutically acceptable salt.

12. The compound represented by the following formula:

or its pharmaceutically acceptable salt.

13. The compound represented by the following formula:

or its pharmaceutically acceptable salt.

14. The compound represented by the following formula:

or its pharmaceutically acceptable salt.

15. The compound represented by the following formula:

or its pharmaceutically acceptable salt.

16. The compound represented by the following formula:

or its pharmaceutically acceptable salt.

17. The compound represented by the following formula:

or its pharmaceutically acceptable salt.

18. The compound represented by the following formula:

or its pharmaceutically acceptable salt.

19. The compound represented by the following formula:

or its pharmaceutically acceptable salt.

20. Connect the out, represented by the following formula:

or its pharmaceutically acceptable salt.

21. The compound represented by the following formula:

or its pharmaceutically acceptable salt.

22. Pharmaceutical composition for treating anemia or renal anemia containing compound according to any one of paragraphs.1-21 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

23. The use of compounds represented by formula (I) according to any one of paragraphs.1-10, or its pharmaceutically acceptable salt as an inhibitor of prolylhydroxylase.

24. The use of compounds according to any one of paragraphs.11-21 or its pharmaceutically acceptable salt as an inhibitor of prolylhydroxylase.

25. The use of compounds represented by formula (I) according to any one of paragraphs.1-10, or its pharmaceutically acceptable salt as an agent inducing the production of erythropoietin.

26. The use of compounds according to any one of paragraphs.11-21 or its pharmaceutically acceptable salt as an agent inducing the production of erythropoietin.

27. The use of compounds represented by formula (I) according to any one of paragraphs.1-10, or its pharmaceutically acceptable salts for the treatment of anemia.

28. The use of compounds according to any one of paragraphs.11-21 or its pharmaceutically acceptable salts for the treatment of anemia.

29. P is the physical alteration of the connection, represented by formula (I) according to any one of paragraphs.1-10, or its pharmaceutically acceptable salts for the treatment of renal anemia.

30. The use of compounds according to any one of paragraphs.11-21 or its pharmaceutically acceptable salts for the treatment of renal anemia.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein pyridine rings A, B and C are independently unsubstituted or substituted by one or more substitutes independently specified in a group consisting of: C1-6-alkyl, halogen alkyl having 1-6 carbon atoms, Hal or OR13; L1 and L2 are independently specified in residues having formula or , wherein at least one of L1 or L2 has formula (b); R1 and R2 are independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; R3 is specified in hydrogen and C1-6-alkyl; R4, R5, R6 and R7 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R8, R9, R10 and R11 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R12 is specified in a group consisting of hydrogen and C1-6-alkyl; R13 is independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; p is equal to 1 or 2; q is equal to 0, 1 or 2, and Hal is specified in a group consisting of F, Cl, Br, and I, which can be used in treating a group of amyloid protein related disturbances and disorders.

EFFECT: preparing the compounds which can be used in treating a group of amyloid protein related disturbances and disorders.

17 cl, 1 dwg, 6 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrazolopyridine derivatives of formula (I) , a based pharmaceutical composition, and using them for treating and/or preventing disorders or conditions related to nictonamide adenine dinucleotide phosphatoxidase (NADPH-oxidase), as well as to a method for preparing them and an intermediate of formula (VIII) . In general formula (I), G1 is specified in H; and optionally substituted heteroaryl-C1-C6-alkyl; G2 is specified in H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-heterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G3 is specified in H; optionally substituted amino; optionally substituted aminoalkyl; optionally substituted aminocarbonyl; optionally substituted alkoxy, optionally substituted alkoxy-C1-C6-alkyl; optionally substituted carbonyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted C1-C6-alkylaryl: optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-hterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G4 is specified in -NR2-C(O)-R1 and -(CHR3)m-(CH2)n-R4, G5 represents H.

EFFECT: preparing the pharmaceutical composition for treating and/or preventing the disorders and conditions related to nictonamide adenine dinucleotide phosphatoxidase.

16 cl, 3 tbl, 87 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein A1 represents N or C (A2); A2 represents H, F, Cl or CN; B1 represents H, OR1, SO2R1, NHR1, NHC(O)R1, F or Cl; D1 and E1 represents H or Cl; Y1 represents H, CN, NO2, F, Cl, Br, CF3, R17, OR17, SO2R17 or C(O)NH2; or Y1 and B1 together with atoms to which they are attached, represent 5- or 6-merous heteroarene having 2-3 nitrogen atoms, wherein heteroarene rings are unsubstituted or substituted by (O); G1 represents H; Z1 represents uncondensed phenylene substituted by OR41; R41 represents 6-merous heteroaryl having 1 N atom, wherein heteroaryl is condensed with R43A, R43A represents 5-merous heteroarene having 1 N atom; Z2 represents monocyclic 6-merous heterocycloalkylene having 1-2 N atoms and 0 double bonds; Z1A and Z2A are both absent; L1 represents -CH2-; Z3 represents R38 or R40; R38 represents uncondensed phenyl; R40 represents cycloalkyl, wherein cycloalkyl represents a monocyclic ring system having 3 to10 C atoms and 0 double bonds, cycloalkenyl, wherein cycloalkenyl represents monocyclic 6-merous ring having 1 heteroatom specified in a group consisting of O and N, and 1 double bond, wherein cycloalkenyl is uncondensed or condensed with R40A; R40A represents cycloalkane, wherein cycloalkane represents a monocyclic ring having 3-10 C atoms and 0 double bonds, or heterocycloalkane, wherein heterocycloalkane represents monocyclic 6-merous ring having 1 N atom and 0 double bonds (the rest substitutes are those as specified in cl. 1 of the patent claim). The invention also refers to compounds of formula

and a pharmaceutical composition containing an effective amount of the compound of formula (I) or (II) or its pharmaceutically acceptable salt.

EFFECT: compounds of formula (I) or (II) inhibiting the activity of anti-apoptotic Bcl-2 proteins.

6 cl, 5 tbl, 378 ex

FIELD: chemistry.

SUBSTANCE: in general formula

A represents optionally substituted aminocarbonyl group -N-C(O)-, in which amino group can be substituted and substituents can be selected from hydrogen, C1-C5alkyl, possibly substituted with C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which heteroatoms are selected from oxygen or nitrogen; aryl, selected from phenyl, possibly substituted with hydroxy, C1-C5alkyl, C1-C5alkoxy, halogen, C1-C5acylamino group, or naphthyl; or amino group is selected from C3-C7heterocyclyl, containing 1-2 heteroatoms in cycle, selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-C3alkyl, benzyl, phenyl, which can be substituted with halogen, and said heterocyclyl can be condensed with benzene ring; acylamino group, in which acyl is selected from C1-C6alkylcarbonyl, where alkyl can be substituted with phenyl, substituted with phenyl, in which substituents are selected from C1-C5alkoxy; 5-membered heteroaryl with heteroatom, selected from atom of oxygen or sulphur; benzoyl, possibly substituted with C1-C5alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heterocyclylcarbonyl, in which heterocyclyl is selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulphur, possibly condensed with benzene ring and possibly substituted with C1-C5alkyl, halogen; or ureido group, in which one of substituents of terminal amido group represents hydrogen, and the second substituent is selected from: C1-C3alkyl, substituted with phenyl, 5-membered saturated or aromatic heterocyclyl, in which heteroatoms are selected from oxygen or sulphur; C2-C6alkenyl; aryl, selected from phenyl, substituted with C1-C5alkyl, C1-C5alkoxy, ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarbonyl; 5-membered heterocyclyl, in which heteroatoms are selected from sulphur or oxygen atom, and possibly substituted with alkyloxycarbonyl group; B represents non-aromatic cyclic substituent, selected from C4-C6cycloalkyl; and has other values, given in the invention formula. Values R1a R1b R1c are given in the invention formula.

EFFECT: increased efficiency of application of compounds.

12 cl, 8 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new phenylamide or pyridylamide derivatives of formula

or their acceptable salts, wherein A1 is CR12 or N; A2 is CR13 or N; R1 and R2 are independently specified in hydrogen, C1-7-alkyl, halogen and C1-7-alkoxygroup; R12 and R13 are independently specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, amino group and C1-7-alkylsulphanyl; R3 is specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, cyano group, C3-7-cycloalkyl, five-merous heteroaryl and phenyl; R4 is specified in methyl and ethyl; or R3 and R4 together represent -X-(CR14R15)n- and form a part of the ring, wherein X is specified in -CR16R17-, O, S, C=O; R14 and R15 are independently specified in hydrogen or C1-7-alkyl; R16 and R17 are independently specified in hydrogen, C1-7-alkoxycarbonyl, heterocyclyl substituted by two groups specified in a halogen, or R16 and R17 together with an atom C, which they are attached to, form =CH2 group; or X is specified in a group NR18; R14 and R15 are hydrogen; R18 is specified in hydrogen, C1-7-alkyl, halogen-C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarbonyloxy-C1-7-alkyl, phenyl, wherein phenyl is unsubstituted, phenylcarbonyl, wherein phenyl is substituted by C1-7-alkoxycarbonyl, and phenylsulphonyl, wherein phenyl is substituted by carboxyl-C1-7-alkyl, or R18 and R14 together represent -(CH2)3- and form a part of the ring, or R18 together with R14 and R15 represent -CH=CH-CH= and form a part of the ring; and n has the value of 1, 2 or 3; B1 represents N or CR19 and B2 represents N or CR20, provided no more than one of B1 and B2 represents N; and R19 and R20 are independently specified in a group consisting of hydrogen and halogen-C1-7-alkyl; R5 and R6 are independently specified in a group consisting of hydrogen, halogen and cyano group; and one-three, provided R4 represents methyl or ethyl, two of the residues R7, R8, R9, R10 and R11 are specified in C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-C1-7-alkoxygroup, cyano group, C1-7-alkoxycarbonyl, hydroxy-C3-7-alkynyl, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkynyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, phenyl-carbonyl, wherein phenyl is unsubstituted, phenyl-C1-7-alkyl, wherein phenyl is substituted by 1-2 groups specified in a halogen, C1-7-alkoxygroup, carboxyl, phenyl-C2-7-alkynyl, wherein phenyl is substituted by 2 groups specified in halogen, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidine carbonyl-C1-7-alkyl, wherein pyrrolidinyl is substituted by carboxyl, and the other R7, R8, R9, R10 and R11 represent hydrogen; the term 'heteroaryl' means an aromatic 5-merous ring containing one or two atoms specified in nitrogen or oxygen; the term 'heterocyclyl' means a saturated 4-merous ring, which can contain one atom specified in nitrogen or oxygen. Besides, the invention refers to a pharmaceutical composition based on the compound of formula I.

EFFECT: there are prepared new compounds possessing the GPBAR1 agonist activity.

21 cl, 1 tbl, 190 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrazolopyridine derivatives of formula (I), a pharmaceutical composition based thereon, use for treating and/or preventing disorders or conditions associated with nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and an intermediate of formula (VIII). In general formula (I) G1 denotes H; G2 is selected from H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted phenyl; optionally substituted C1-C6-alkylaryl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted-C1-C6-alkylheterocycloalkyl and optionally substituted heterocycloalkyl-C1-C6-alkyl; G3 is selected from -(CH2)n-R1 and -(CH2)p-R5; G4 is selected from H; optionally substituted acyl; optionally substituted acylamino; optionally substituted acyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkylheterocycloalkyl and optionally substituted heterocycloalkyl-C1-C6-alkyl; G5 dentes H.

EFFECT: high effectiveness of compounds.

15 cl, 2 tbl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention refers to new phenoxymethyl compounds of formula (I) or its pharmaceutically acceptable salts, wherein: HET represents a heterocyclic ring having formula A29 or A31, wherein the far left part is connected to the group X of formula (I); X represents substituted phenyl or optionally substituted pyridinyl, wherein the substitutes are specified in C1-C4alkoxy and cyano; Z represents imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl or imidazo[1,2-b]pyridazin-6-yl each of which can be substituted, wherein the substitutes are specified in C1-C4alkyl and a halogen atom; and each R2 are independently specified in C1-C4 alkyl inhibiting at least one phosphodiesterase 10, as well as to pharmaceutical compositions containing these compounds, and methods of treating various CNS disorders.

EFFECT: preparing the new compounds.

23 cl, 2 tbl, 732 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,2,3,4-tetrahydropyrido[4,3-b]indole-containing phenothiazines of general formula 1 as inhibitors of cholinestrerases and blockers of serotonin receptors 5-HT6, a pharmaceutical preparation on their base, in particular for treatment of neurodegenerative diseases. In general formula 1, in which R1=H, (C1-C6) alkyl; R2, R3, R4, R5=H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy, R6, R7=H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy, NH2, NHAlkyl, NAlkyl2; A=CH2CH2, CH=CHCH2, CH2CH2CH2, CH2CH[(C1-C6)alkyl]C(O), CH2CH2C(O)NHCH2CH2; CH2CH[(C1-C6)alkyl]C(O)N[(C1-C6)alkyl]CH2CH2, CH2CH(OH)CH2, CH2CH(OH)CH2NHCH2CH2, CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2, CH2CHFCH2NHCH2CH2, CH2CHFCH2N[(C1-C6)alkyl]CH2CH2.

EFFECT: increased efficiency of the application of compounds.

6 cl, 1 dwg, 1 tbl, 38 ex

FIELD: veterinary medicine.

SUBSTANCE: method of normalisation of the thrombin time duration in newborn calves with iron deficiency anemia consists in the fact that ferroglukin 150 mg (2 ml) intramuscularly is prescribed to newborn calves with iron deficiency anemia, twice with the interval of 4 days, cresacyne 5 mg/kg per day, including it in the scheme of watering for 4 days, starting simultaneously with the first injection of ferroglukin and gamavit intramuscularly once a day in the morning of 0.05 ml/kg for 4 days, starting simultaneously with ferroglukin and cresacyne.

EFFECT: acceleration of normalisation of thrombin time duration, enables to reduce the risk of vascular complications in newborn calves with iron deficiency anemia, to revitalise the herd, to reduce mortality, to maintain the volume and quality of the meat and dairy products obtained from animals.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science, namely to clinical pharmacology and veterinary therapy. The method consists in administering the complex iron-dextran preparation Ferranimal-75M intramuscularly on the 5th day of calf's life in a dose of 3 ml in a combination with an intramuscular injection of the preparation Hydropeptone in a dose of 10 ml. Ferranimal-75M is injected 10 days later in a dose of 2 ml in a combination with an injection of Hyropeptone 5 ml intramuscularly in different points.

EFFECT: method provides higher antioxidative activity of calf's blood serum, reduced pro-oxidant action of iron and incorporated radionuclides, as well as higher iron accessibility in treating and preventing iron-deficiency anaemia in calves exposed to the chronic incorporated radiation.

FIELD: veterinary medicine.

SUBSTANCE: ferroglyukin is administered to new-born calves with iron deficiency anaemia at a dose of 150 mg (2 ml) intramuscularly, twice with an interval of 4 days. Crezacyne 5 mg/kg per day is included in the watering scheme for 4 days, starting simultaneously with the first injection of ferroglyukin. Gamavit is administered intramuscularly once a day in the morning at a dose of 0.05 ml/kg for 4 days, starting simultaneously with ferroglyukin and crezacyne.

EFFECT: method enables to normalise consistently the platelet activity in new-born calves with iron deficiency anaemia during a short period of exposure, transferring it to the level typical of healthy calves, after 4 days of treatment, and to provide long-term maintenance of platelet haemostasis in the optimal mode of operation, eliminating the risk of thrombotic complications in animals and contributing to their normal growth and development.

1 ex

FIELD: metallurgy.

SUBSTANCE: invention relates to casein succinylate of iron (III) wherein iron content varies from 4.5 wt % to 7 wt %, water solubility exceeds 92% while phosphorus-to-nitrogen ratio exceeds 5 wt %.

EFFECT: additionally, invention relates to production of iron (III) and to pharmaceutical composition containing casein succinylate of iron (III).

17 cl, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to benzoimidazole derivatives of formula (I), as well as to their enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts, where n equals from 2 to 4, each of R1 substituents is independently selected from H, halogen, -C1-4alkyl, -C1-4pergaloalkyl, trifluoro-C1-4alkoxy, -NO2, -CN, CO2H, -OC1-4alkyl, -SC1-4alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4alkyl, -SO2-C1-4alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rc, -O-Rc, -CH2-O-Rc, -C(O)NH-Rc, -NRaRb, benzyloxy, phenyl, optionally substituted with one-two Rd, cyanobiphenyl-4-ylmethylsulpfanyl, cyanobiphenyl-4-ylmethanesulphonyl, or -S-(CH2)2-morpholine and two adjacent groups R1 can bind with formation of an aromatic 5-6-membered ring, optionally substituted with one methyl group or two atoms of halogen, optionally containing one or two S or N; Ra and Rb each independently represents C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-Re, C1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, phenyl, benzyl; or Ra and Rb together with a nitrogen atom, which they are bound with, form a monocyclic 5-6- membered heterocycloalkyl ring, optionally containing one heteroatom, selected from O; Rc represents -C3-8cycloalkyl, phenyl, optionally substituted with one-two Rd, benzyl, optionally substituted with one-three Rd; morpholine; Rd independently represents halogen, -OH, -C1-4alkyl or -C1-4perhalogenalkyl, trifluorine C1-4alcoxy, -OC1-4alkyl, or -O-benzyl optionally substituted with halogen, Re represents -C6heterocycloalkyl, optionally containing one or two of O or N atoms, optionally substituted with a methyl group; R2 and R3 both represent H, -CF3 or C1-3alkyl; each of Z represents a C or N atom, on condition that simultaneously not more than two Z represent N. The invention also relates to particular compounds, a pharmaceutical composition, based on formula (I) compound or a particular said compound, a method of treating diseases, mediated by propyl hydroxylase activity.

EFFECT: novel derivatives of benzimidazole, possessing an inhibiting activity with respect to PHD are obtained.

11 cl, 1 tbl, 186 ex

FIELD: biotechnologies.

SUBSTANCE: in a compound of formula ,

X means N or CH, R1 means hydrogen or cyano, R2 means saturated 4-7-membered residue of heterocyclyl, which is bound through a nitrogen atom that contains 1 to 2 heteroatoms chosen from N and O. Besides, heterocyclyl residue can be replaced with one substituent chosen from a group consisting of C3-C6-cycloalkyl, or with 1-4 fluorine atoms. The invention also refers to a method for obtaining compounds and to a medicine on their basis.

EFFECT: compounds can be used for production of a medicine suitable for being used in a method of treatment or prophylaxis of cardiovascular diseases, cardiac insufficiency, anemia, chronic diseases of kidneys and kidney failure.

16 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and aims at the simultaneous control of coccidiosis and iron deficiency. The compound comprises triazinones of formulas (I) or (II) wherein R1 means CF3-SO2- or CF3-S-, R2 means CH3, each R4, R5 and R6 means Cl (chlorine) or pharmaceutically acceptable salts thereof, and iron compounds (3+) specified in a group consisting of: multinucleated complex iron (III) and polysaccharide compounds and ammonium-iron (III) citrate. What is also declared is using the above compounds for producing drug preparations.

EFFECT: using the declared group of inventions is effective for the simultaneous control of coccidiosis and iron deficiency; it is accompanied by no adverse phenomena; the compound ingredients have no negative effects on each other; and their biological activity preserves.

17 cl, 15 tbl, 7 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to production of peptide derivative mimetic of EPO, with the formula: R1-R2-(CH2)n1-R3-(CH2)n2-R4-R5 (I) and its pharmaceutical salts, where R1, R5 are selected from cyclic peptides with sequences SEQ ID NO:5, 6, 7 and 8; n1, n2 represent integer numbers independently selected from 0-10; R2, R4 are selected from -CO or -CH2; R3 is selected from O, S, CH2, N(CH2)n3NHR6, NCO(CH2)n4NHR6, CHOCONH(CH2)n5NHR6, CHSCON(CH2)n5NHR6 or CHNHCON(CH2)n5NHR6; where n3 represents an integer number selected from 1-10, n4 is an integer number selected from 2-10, n5 represents an integer number selected from 2-10, R6 is selected from H or derivatives of metoxyethylene glycol. The produced peptide or its pharmaceutically acceptable salt is used within a pharmaceutical composition for treatment of disorders characterised with EPO deficit, low or defective population of erythrocytes.

EFFECT: invention makes it possible to produce an agonist of EPO receptor having higher biological activity compared to existing EPO mimetics.

15 cl, 2 dwg, 5 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, and namely to composition for prevention of iron deficiency anemia. Composition for prevention of iron deficiency anemia, which contains source of iron, source of copper, vitamins B1, B3, B6, B9, B12, ascorbic acid, extract from nettle leaves, extract from strawberry leaves, pantohematogen and auxiliary substances, with specified component ratio.

EFFECT: composition makes it possible to extend arsenal of methods for prevention of iron deficiency anemia and is effective.

4 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to iron-enriched food product, which contains iron source in form of solid particles, where particles include core, containing iron alginate, and external layer, which contains calcium alginate, where particles are obtained by method which includes the following stages: (i) formation of core, which contains iron alginate, by contact of bioavailable water-soluble salt of iron and one water-soluble alginate salt, (ii) contact of core with water solution of calcium salt, in concentration, which constitutes from 0.025 M to concentration of lower than solution saturation point, and (iii) separation of obtained solid product. Iron-enriched food product is applied for prevention and treatment of iron deficiency conditions of people.

EFFECT: solid particles are applicable for enrichment of food products with iron and is characterised by improved load ability, as well as possesses good stability under standard storage and application conditions.

11 cl, 9 dwg, 13 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein pyridine rings A, B and C are independently unsubstituted or substituted by one or more substitutes independently specified in a group consisting of: C1-6-alkyl, halogen alkyl having 1-6 carbon atoms, Hal or OR13; L1 and L2 are independently specified in residues having formula or , wherein at least one of L1 or L2 has formula (b); R1 and R2 are independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; R3 is specified in hydrogen and C1-6-alkyl; R4, R5, R6 and R7 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R8, R9, R10 and R11 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R12 is specified in a group consisting of hydrogen and C1-6-alkyl; R13 is independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; p is equal to 1 or 2; q is equal to 0, 1 or 2, and Hal is specified in a group consisting of F, Cl, Br, and I, which can be used in treating a group of amyloid protein related disturbances and disorders.

EFFECT: preparing the compounds which can be used in treating a group of amyloid protein related disturbances and disorders.

17 cl, 1 dwg, 6 tbl, 13 ex

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