Novel phenylalanine derivatives

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

 

The technical field to which the invention relates

The present invention relates to new derivatives of phenylalanine and the use of derivatives of phenylalanine in the quality of medicines. The present invention also relates to compounds that can be used as therapeutic agents or preventive agents against inflammatory diseases in which the pathology is involved, the process of adhesion-dependent α-4 integrin. It is known that α-4 integrin is involved in the development of rheumatoid arthritis, inflammatory intestinal diseases (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus, multiple sclerosis, Sjogren syndrome, asthma, psoriasis, Allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, metastasis of tumors and transplant rejection. Compounds of the present invention, which has antagonistic effect on α 4 integrins can be used as therapeutic agents or preventive agents against these diseases.

In addition, it is known that α-4 integrins are able to participate in the development of pre-eclampsia, ischemic cardiovascular disorders (including cerebral infarction), scleroderma, ankylosing spondylitis, psoriatic the CSOs arthritis, sarcoidosis, giant cell arteritis diagnostics, uveitis, pneumosclerosis, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer's disease, spinal cord injury, traumatic brain injury, primary sclerosing cholangitis, cirrhosis caused by hepatitis C, chronic active hepatitis, sacroiliitis, ankylosing spondylitis, episcleritis, iritis, uveitis, nodular erythema, pyoderma gangrenosum and autoimmune hepatitis. Compounds of the present invention can also be used as therapeutic agents or preventive agents against these diseases.

In addition, the compounds of the present invention can also be used as therapeutic agents or preventive agents against these diseases, but also diseases, pathology which can participate α 4 integrins.

The present invention also relates to methods of producing the above phenylalanine derivatives and their synthesis intermediates.

Background of the invention

In General it is known that inflammatory reactions, when the microorganism is introduced into the fabric, or when tissue is damaged, leukocytes play an important role in the destruction of the microorganism or in the repair of damaged tissue is. It is also considered that in such cases, the white blood cells, normally circulating in the blood must pass through the vascular wall and re-submitted to the damaged tissue. It was found that infiltration of leukocytes from the blood vessel into the tissue is carried out by integrin molecules, which are a group of heterodimeric proteins, expressed on leukocytes. Molecule integrin divided at least into 8 subfamilies (subfamily with β1 to β8), depending on their β-chains. Known typical of the subfamily are a subfamily β1 and β3 involved in cell adhesion ingredients to the extracellular matrix, such as collagen and fibronectin; the β2 subfamily, involved in intercellular adhesion in the immune system; and subfamily β7, which is mainly involved in the infiltration of leukocytes into mucosal tissue (non-patent publication 1). With regard to the above-described α4 integrins, known 2 of their molecules. They represent a molecule VLA-4 (very late antigen-4)belonging to the subfamily β1, and including β1 α4 chain and the molecule LPAM-1 (molecule-1 adhesion HEV lymphocytic pieroway plaques)belonging to the subfamily β7 and including β7 chain α4. Usually most of leukocytes circulating in the blood have only a low affinity adhesion to the vascular endothelium cells, and they can't in order to go from the blood vessel. However, lymphocytes, mainly including T-cells and b-cells leave the blood vessels with the help of the so-called phenomenon of homing lymphocytes, in which they move from the blood into lymphoid tissue via the lymphatic vessel under physiological conditions. It is known that the molecules of LPAM-1 are involved in homing lymphocytes in the lymphoid tissue of the gastrointestinal tract, such as paeroa plaque (non-patent publication 2). On the other hand, when there is inflammation, vascular endothelial cells are activated by cytokine and chemokine released from inflamed tissue, called the expression of a group of antigens on the cell surface adhesion molecules involved in leukocyte adhesion to the vascular endothelium cells, and many leukocytes leave the blood vessel in the direction of the inflamed tissue via adhesion molecules and infiltrate it.

As antigens on the cell surface in cells of the vascular endothelium involved in leukocyte adhesion, were known E-selectin (adhesion molecule, mainly involved in the adhesion of neutrophils), ICAM-1 and VCAM-1, mainly involved in the adhesion of lymphocytes in the lymphoid tissue of the gastrointestinal tract, such as paeroa plaque (non-patent publication 1). It is known that these adhesion molecules, VCAM-1, act as a ligand and VLA-4, and LPAM-1,and that MAdCAM-1 acts as a ligand LPAM-1. As a ligand and VLA-4, and LPAM-1, also known fibronectin, which is a type of extracellular matrix (non-patent publication 1). Subfamily β1 integrin applies to VLA-4, includes at least 6 integrins (VLA-1 to VLA-6), using the extracellular matrix, such as fibronectin, collagen and laminin, as ligands. Many integrins, using the extracellular matrix as ligands, such as VLA-5, subfamily β3 and subfamily β5, recognize the sequence arginine-glycine-aspartic acid (RGD) in fibronectin, vitronectin, tenascin and osteopontin. On the other hand, when the interaction of VLA-4 and fibronectin sequence RGD is not involved, but the segment of the peptide CS-1, including leucine - aspartic acid - valine (LDV) as a core sequence that is involved in this interaction (non-patent publication 3). Cltmtnts et al. found a sequence similar to the LDV, the amino acid sequences VCAM-1 and MAdCAM-1. It was found that the variant obtained by partial modification of the CS-1-like sequence of molecules VCAM-1 and MAdCAM-1, cannot communicate with VLA-4 or LPAM-1 (non-patent publication 4-7). Thus, it was found that CS-1-like sequence are important for the interaction of VLA-4 with LPAM-1 and VCAM-1 and MAdCAM-1.

It was reported that the cyclic peptide is within CS-1-like structure, is antagonistic in relation to the interaction of VLA-4 or LPAM-1 and VCAM-1, MAdCAM-1 or Cs peptide-1 (non-patent publication 8). The above facts indicate that all of the interaction of α4 integrin and VCAM-1, MAdCAM-1 or fibronectin can be blocked by use of a suitable antagonist of α4 integrin (the term "antagonist of α4 integrin in the description indicates a substance antagonistic against α4β1 and/or α4β7 integrin).

It is also known that the expression of VCAM-1 in vascular endothelium cells caused by inflammatory factors, such as LPS, TNF-α or IL-1, and that when there is inflammation, infiltration of leukocytes from the blood vessel into the tissue is the mechanism of adhesion of VLA-4 with VCAM-1 (non-patent publication 9-11). Due to the fact that VLA-4 expressed on the surface of activated lymphocytes, monocytes, eosinophils, mast cells and neutrophils, the mechanism of adhesion of VLA-4/VCAM-1 plays an important role in the infiltration of these cells into inflamed tissue. It was reported that VLA-4 expressed on various sarcomatoid cells such as melanoma cells, and it was found that the mechanism of adhesion of VLA-4/VCAM-1 is involved in the metastasis of these tumors. The study of the expression of VCAM-1 in various pathological tissues, it became apparent that the mechanism of adhesion of VLA-4/VCAM-1 is involved in various pathological conditions. Namely, the message is elk, in addition to the activated vascular endothelium cells, the expression of VCAM-1 is increased in inflamed tissues of patients with autoimmune diseases such as rheumatoid lesions of the synovium (not patent publication 12 and 13), the lungs and the Airways in asthma (non-patent publication 14) and allergic diseases (non-patent publication 15), systemic lupus erythematosus (non-patent publication 16), Sjogren syndrome (non-patent publication 17), multiple sclerosis (non-patent publication 18) and psoriasis (non-patent publication 19); atherosclerotic plaques (non-patent publication 20), in the intestinal tissues of patients with inflammatory intestinal diseases such as Crohn's disease and ulcerative colitis (non-patent publication 21 and 22)in the inflamed tissue of the islets of Langerhans in patients with diabetes (non-patent publication 23) and implants at the time of transplant rejection of heart or kidney disease (non-patent publication 24 and 25). The mechanism of adhesion of VLA-4/VCAM-1 is involved in the development of these various diseases.

There are many reports showing that the introduction of antibodies to VLA-4 or VCAM-1 in vivo was effective in facilitating the flow of diseases in experimental models of inflammatory diseases. In particular, Yednock et al. and Baron et al. reported that the introduction of in vivo antibody FR is in α4 integrins was effective in combating illness or fight encephalomyelitis in models of experimental autoimmune encephalomyelitis, i.e. models of multiple sclerosis (non-patent publication 26 and 27). Zeidler et al. reported that the introduction of in vivo antibody against α4 integrin was effective in controlling the incidence of murine collagen arthritis model of rheumatoid arthritis) (non-patent publication 28). On therapeutic effects of antibodies against α4 integrin on models of asthma was reported by Abraham et al. and Sagara et al. (non-patent publication 29 and 30). The effect of antibodies against α4 integrin in models of inflammatory intestinal diseases reported by Podolsky et al. (non-patent publication 31). The effect of antibodies against α4 integrin and antibodies against VCAM in models of insulin-dependent diabetes mellitus was reported by Baron et al. (non-patent publication 32). On the basis of research on models of baboons became obvious that the restenosis of blood vessels after angioplasty, performed due to atherosclerosis, it is possible to inhibit the introduction of antibodies against α4 integrin (non-patent publication 33). It was also reported that the antibody against α4 integrin or against VCAM effective for inhibition of graft rejection or inhibition of metastasis of cancer (non-patent publication 34 and 35). On therapeutic effects of antibodies against VCAM-1 in models of inflammatory intestinal diseases reported by Sans et al. (non-patent publication 44).

As described above, in contrast to VCAM-1, MAdCAM-1, which was before the hat is a ligand LPAM-1, constitutively expressed in visokoindustrialny venules (HEV) in the mucous membrane of the intestine, mesenteric lymph nodes, pijarowski plaques and spleen, and it is involved in homing lymphocytes mucosa. It is also known that the mechanism of adhesion LPAM-1/MAdCAM-1 not only plays a physiological role in homing lymphocytes, but is also involved in some pathological processes. Briskin et al. reported an increase in the expression of MAdCAM-1 in inflamed areas of the intestinal tract of patients with inflammatory intestinal disease such as Crohn's disease and ulcerative colitis (non-patent publication 36). Hanninen et al. reported that induction of expression was observed in the inflamed tissue of the islets of Langerhans of NOD mice, which represent a model for insulin-dependent diabetes mellitus (non-patent publication 37). The fact that the mechanism of adhesion LPAM-1/MAdCAM-1 is involved in the progression of the disease, is evident from the fact that the state of inflammatory intestinal diseases in mouse models (non-patent publication 38) and the model described above in NOD mice, facilitated by the introduction of in vivo antibodies to MAdCAM or antibodies to β7 integrin (not patent publication 39 and 40).

The above facts point to the possibility that the use of a locking mechanism of adhesion of VLA-4/VCAM-1, LPAM-1/VCAM-1 or LPAM-1/MAdCAM-1 suitable ant what genista effective in the treatment described above chronic inflammatory diseases. With regard to therapeutic effect of a suitable antagonist (antagonist), then it is possible to verify on the experimental model described in the above literature or other publications, such as non-patent publication 45 and 46. Using antibodies against VLA-4 as an antagonist of VLA-4 are described in patent publications 1-4. Peptide compounds as antagonists of VLA-4 are described in patent publications 5-8. Amino acid derivatives that can be used as antagonists of VLA-4, described in patent publications 9-13. Low molecular weight inhibitor of α4 integrin, which can be introduced orally, are described in patent publications 14 and 15.

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[Patent publication 12] WO 99/37618.

[Patent publication 13] WO 99/43642.

[Patent publication 14] WO 02/16329.

[Patent publication 15] WO 03/070709.

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Description of the invention

The object of the present invention is to provide new compounds having an antagonistic effect against α4 integrin.

Another object of the present invention is to provide new compounds having an antagonistic effect against α4 integrin, which can be introduced orally.

Another object of the present invention is to provide pharmaceutical compositions comprising such novel compounds and their pharmaceutically acceptable carrier.

An additional object of the present invention is the provision of a medicinal product containing such new connections.

An additional object of the present invention is the provision of antagonists α4 integrin.

Another object of the present invention is the provision of therapeutic agents or prophylactic agents against diseases, the pathology of which involves a process dependent on α4 integrin adhesion, such as inflammatory diseases, rheumatoid arthritis, inflammatory intestinal diseases (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus, multiple sclerosis, Sjogren syndrome, asthma, psoriasis, Allergy, diabetes, cardiovascular is s disease, arterial sclerosis, restenosis, tumor proliferation, metastasis of tumors, and transplant rejection.

Another object of the present invention is the provision of therapeutic agents or prophylactic agents against diseases such as preeclampsia, ischemic cardiovascular disorders (including cerebral infarction), scleroderma, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, giant cell arteritis diagnostics, uveitis, pneumosclerosis, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer's disease, spinal cord injury, traumatic brain injury, primary sclerosing cholangitis, cirrhosis of the liver caused by hepatitis C, chronic active hepatitis, sacroiliitis, ankylosing spondylitis, episcleritis, iritis, uveitis, nodular erythema, pyoderma gangrenosum and autoimmune hepatitis.

Another object of the present invention is the provision of therapeutic agents or prophylactic agents against these diseases, but also diseases in which α4 integrins may be involved in the development of pathology.

Another object of the present invention are methods of obtaining the above new compounds and their synthesis intermediate soy is ineni.

To resolve the above problems, the applicants have synthesized various derivatives of phenylalanine and found that certain new derivatives of phenylalanine have excellent antagonistic activity against α4 integrin in the presence of serum, and that the total excretion of low. Applicants have also discovered that certain new derivatives of phenylalanine exhibit high area under the curve of the dynamics of change in time of the concentration in plasma (AUC) and high bioavailability with oral administration. They also found that such derivatives have high antagonistic activity against α4 integrin in vivo in oral introduction. The present invention was created based on these data. The implementation of the present invention provides the possibility of reducing the dosage and number of doses of a preparation containing a derivative of phenylalanine.

Namely, the present invention is described as follows:

[1] the Derivatives of phenylalanine following formula (1) or their pharmaceutically acceptable salts:

where R11 represents a hydroxyl group, CNS group having 1-6 carbon atoms which may have a Deputy (deputies), morpholinoethoxy group or benzyloxy group, Kotor which may be substituted by a methyl group (or groups) or methoxy group (or groups), R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 represents 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholine group, 3-tetrahydrocanabinol group or 1-piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms, R14 represents a methyl group or ethyl group,

R1' represents a hydrogen atom, a fluorine atom or a chlorine atom,

X1represents-CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -CH(R1a)CH(R1b)CH(R1c)CH(R1d)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c) -, or 1,3-pyrrolidinyl, where R1a, R1b, R1c and R1d each independently represents a hydrogen atom or methyl group, and

Y11and Y12are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[20] Derivatives of phenylalanine following formula (2) or their pharmaceutically acceptable salts:

where R21 represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or a benzyloxy group which may be substituted by a methyl group (or groups) or methoxy group (groups)

R22 represents a hydrogen atom or alkyl group having 1-3 carbon atoms,

R24 is predstavljaet methyl group or ethyl group,

R2' represents a hydrogen atom, a fluorine atom or a chlorine atom,

X2represents-CH(R2a)-, -CH2CH2- or-N(R2a)CH2CH2-where R2a represents a hydrogen atom or methyl group, and

Y21and Y22are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[23] Derivatives of phenylalanine following formula (3) or their pharmaceutically acceptable salts:

where R31 represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or a benzyloxy group which may be substituted by a methyl group (or groups) or methoxy group (groups)

R34represents methyl group or ethyl group,

R3' represents a hydrogen atom or a fluorine atom,

formula (3-1) represents the 4-morpholinyl group, 4-thiomorpholine group, 3-tetrahydrocanabinol group, 1-piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms, or 1-imidazolidinyl group which may be substituted by methyl group, ethyl group or amino group,

where X3 represents an oxygen atom, a nitrogen atom which may be substituted by an alkyl group having 1-3 carbon atom, or a sulfur atom, and

Y31and Y32 are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[28] Derivative of phenylalanine following formula (4) or their pharmaceutically acceptable salts:

where R41represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or a benzyloxy group which may be substituted by a methyl group (or groups) or methoxy group (groups)

The ring represents a benzene ring, pyridine ring, thiophene ring, piperidine ring, the first position of which may be substituted by an alkyl group having 1-3 carbon atoms, pieperazinove ring, the first and/or fourth position of which may be substituted by an alkyl group having 1-3 carbon atoms, or pyrolidine ring, the first position of which may be substituted by an alkyl group having 1-3 carbon atom.

R44represents methyl group or ethyl group, and

Y41and Y42are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[30] Derivatives of phenylalanine following formula (5) or their pharmaceutically acceptable salts:

where R51represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or benzyloxy group, to which I may be substituted methyl group (or groups) or methoxy group (groups)

R54represents methyl group or ethyl group,

R5' represents a hydrogen atom or a fluorine atom,

R5a and R5b each independently represents a hydrogen atom or alkyl group having 1-3 carbon atoms, or

N(R5a)R5b represents 1-pyrrolidinyl group or 1-piperidinyloxy group, and

Y51and Y52are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[32] Derivatives of phenylalanine following formula (6) or their pharmaceutically acceptable salts:

where R61represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or a benzyloxy group which may be substituted by a methyl group (or groups) or methoxy group (groups)

And6is any of the following formulas (6-1)to(6-6):

and Y61and Y62are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[35] Derivatives of phenylalanine following formula (7) or their pharmaceutically acceptable salts:

where R71represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or a benzyloxy group which may be substituted by a methyl group (or groups) or methoxy group (groups)

74represents methyl group or ethyl group,

R7is alkylamino group having 3-5 carbon atoms, cycloalkenyl group having 4-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, or through the group, and

Y71and Y72are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[38] Derivatives of phenylalanine following formula (8) or their pharmaceutically acceptable salts:

where R81represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group, benzyloxy group which may be substituted by a methyl group (or groups) or methoxy group (or groups), or hydroxyethylene group,

R82represents methyl group or ethyl group,

R84represents methyl group or ethyl group,

n8represents an integer from 0 to 2, and

Y81and Y82are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[41] the Derivatives of phenylalanine following formula (9) or their pharmaceutically acceptable salts:

where R91represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or a benzyloxy group which may be samodeyatelnoj group (or groups) or methoxy group (groups)

R92represents a hydroxyl group, CNS group having from 1 to 6 carbon atoms, amino group or a benzyloxy group which may be substituted by a methyl group (or groups) or methoxy group (groups)

R94represents methyl group or ethyl group,

X9represents an atomic bond, -CH2-, -CH2CH2-or-CH=CH-, and

Y91and Y92are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[44] the Derivatives of phenylalanine following formula (10) or their pharmaceutically acceptable salts:

where R101is CNS group having 2-6 carbon atoms, or morpholinoethoxy group,

R10represents methyl group or ethyl group,

R104represents methyl group or ethyl group, and

Y101and Y102are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[46] the Derivatives of phenylalanine following formula (11) or their pharmaceutically acceptable salts:

where R111is CNS group having 1-6 carbon atoms, or morpholinoethoxy group,

R114represents methyl group or ethyl group, and

Y111and Y112are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, M).

[47] the Derivatives of phenylalanine following formula (12) or their pharmaceutically acceptable salts:

where R121is CNS group having 1-6 carbon atoms, or morpholinoethoxy group,

R124represents methyl group or ethyl group, and

And are any of the following formulas (12-1) and (12-2):

[48] the Derivatives of phenylalanine following formula (13) or their pharmaceutically acceptable salts:

where R131represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or a benzyloxy group which may be substituted by a methyl group (or groups) or methoxy group (or groups), R13a and R13b each independently represents a hydrogen atom or alkyl group having 1-3 carbon atoms, or N(R13a)R13b represents 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholine group, 3-tetrahydrocanabinol group or 1-piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 atoms carbon, and

Y131and Y132are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[49] the Derivatives of phenylalanine following formula (14) or their pharmaceutical is acceptable salt:

where R141 represents a hydroxyl group, CNS group having 1-6 carbon atoms, or morpholinoethoxy group,

R144 represents methyl group or ethyl group,

hydroxyl group on hinazolinam the ring is in the sixth or seventh position of the ring, and

Y141and Y142are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[51] the Pharmaceutical composition comprising a derivative of phenylalanine or its pharmaceutically acceptable salt according to any one of the above claims 1 to 50 as the active ingredient and pharmaceutically acceptable carrier.

[52] the Antagonist of α4 integrin, comprising a derivative of phenylalanine or its pharmaceutically acceptable salt according to any one of the above claims 1 to 50 as the active ingredient.

[53] a Therapeutic agent or a prophylactic agent against inflammatory diseases, pathology involving the process of adhesion-dependent α4 integrin, comprising a derivative of phenylalanine or its pharmaceutically acceptable salt according to any one of the above claims 1 to 50 as the active ingredient.

[54] Therapeutic agent or a prophylactic agent against rheumatoid arthritis, inflammatory intestinal diseases (including Crohn's disease m ulcer is th colitis), systemic lupus erythematosus, multiple sclerosis, Sjogren syndrome, asthma, psoriasis, Allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, metastasis of tumors and transplant rejection, which contains a derivative of phenylalanine or its pharmaceutically acceptable salt according to any one of the above claims 1 to 50 as the active ingredient.

[55] a Therapeutic agent or a prophylactic agent against pre-eclampsia, ischemic cardiovascular disorders (including cerebral infarction), scleroderma, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, giant cell arteritis diagnostics, uveitis, pneumosclerosis, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer's disease, spinal cord injury, traumatic brain injury, primary sclerosing cholangitis, cirrhosis caused by hepatitis C, chronic active hepatitis, sacroiliitis, ankylosing spondylitis, episcleritis, iritis, uveitis, nodular erythema, pyoderma gangrenosum and autoimmune hepatitis, including derivative of phenylalanine or its pharmaceutically acceptable salt any of the above claims 1 to 50 as the active ingredient.

[56] a Therapeutic agent or p is fractionthe tool against diseases, in pathology which can participate α4 integrins, including derivative of phenylalanine or its pharmaceutically acceptable salt according to any one of the above claims 1 to 50 as the active ingredient.

The present invention also provides the following compounds, which are intermediate compounds in the synthesis of phenylalanine derivatives of the formula (1): isopropyl(S)-2-(2,6-dichloraniline)-3-(4-nitrophenyl)propionate, isopropyl(S)-2-(2,6-dichloraniline)-3-(4-AMINOPHENYL)propionate, isopropyl(S)-3-[4-(2-amino-5-identitymine)phenyl]-2-(2,6-dichloraniline)propionate, isopropyl(S)-2-(2,6-dichloraniline)-3-[4-(6-iodine-2,4-dioxo-1,2,3,4-tetrahydro-2H-hinzelin-3-yl)phenyl]propionate, isopropyl(S)-2-(2,6-dichloraniline)-3-[4-(6-iodine-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2H-hinzelin-3-yl)phenyl]propionate, (S)-3-{4-[2-(2,6-dichloraniline)-2-isopropoxycarbonyl]phenyl}-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-carboxylic acid, isopropyl(S)-2-(2,6-dichloraniline)-3-[4-(6-hydroxymethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2H-hinzelin-3-yl)phenyl]propionate, isopropyl(S)-3-[4-(6-chloromethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2H-hinzelin-3-yl)phenyl]-2-(2,6-dichloraniline)propionate and isopropyl(S)-2-(2,6-dichloraniline)-3-[4-(6-hydroxy-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2H-hinzelin-3-yl)phenyl]propionate.

Best mode for carrying out image is etenia

"An alkyl group having 1-6 carbon atoms" is either straight, or branched, or cyclic. Her examples are methyl, ethyl, sawn and ISO-propyl group, bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, cyclopropylmethyl group, cyclobutyl group, pencilina group, isopentyl group, exilda group, 1-methylbutoxy group, 1,1-dimethylpropylene group, cyclopropyl group, cyclopentenone group and tsiklogeksilnogo group. Additionally, the "alkyl group having 1-3 carbon atom is either straight or branched, and refers to methyl, ethyl, sawn and ISO-propyl group.

"CNS group having 1-6 carbon atoms" refers to those groups, the alkyl portion of which is straight or branched, or cyclic. Her examples are methoxy, ethoxy, propyloxy, isopropoxy, bucalossi, isobutoxy, sec-Butylochka, tert-Butylochka, pentyloxy, isopentylamine, 1 methylbutoxy, 1,1-dimethylpropylene, 2-methylbutoxy, neopentylene, hexyloxy, isohexane, 1 methylpentane, 1,1-dimethylbutylamino, cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy group.

"CNS group having 2-6 carbon atoms" refers to those groups, the alkyl portion of which t is aetsa straight or branched, or cyclic. Her examples are ethoxy, propyloxy, isopropoxy, bucalossi, isobutoxy, sec-Butylochka, tert-Butylochka, pentyloxy, isopentylamine, 1 methylbutoxy, 1,1-dimethylpropylene, 2-methylbutoxy, neopentylene, hexyloxy, isohexane, 1 methylpentane, 1,1-dimethylbutylamino, cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy group.

"Extensive CNS group having 3-6 carbon atoms" refers to those groups, the alkyl portion which is branched or cyclic. They can be replaced by a methoxy group or a hydroxyl group. Her examples are isopropoxy, sec-Butylochka, tert-bucalossi, 1 methylbutoxy, 1,1-dimethylpropylene, 2-methylbutoxy, neopentylene, 1 methylpentane, 1,1-dimethylbutylamino, cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy group. Among them, preferred are isopropoxy group, sec-Butylochka group, 1-methylbutoxy group, cyclopentyloxy group, cyclohexyloxy group is preferred, and particularly preferred is isopropoxy group.

In "alkenylphenol group having 3-5 carbon atoms, atom (atoms) of carbon having a free radical (radicals) is not limited to the atom (atoms) SP. Her examples are 2-proponila, 3-Butyrina, 2-Buti is strong, 4-penicilina, 3-penicilina and 2-penicilina group.

"Cycloalkylation group having 4-6 carbon atoms" refers to cyclopropylmethanol, cyclobutylmethyl and cyclopentylmethyl group.

"Cycloalkyl group having 3-6 carbon atoms" refers to cyclopropyl, cyclobutyl, cyclopentyl and tsiklogeksilnogo group.

"Piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms", indicates piperazinilnom, N-methylpiperidino, N-ethylpiperazine, N-propylpiperazine and N-isopropylpiperazine group.

In "piperazinovom ring, the first and/or fourth position of which may be substituted by an alkyl group having 1-3 carbon atoms, Deputy (deputies) on the nitrogen of the first and/or fourth position may be the same or different from each other. Examples of combinations of substituents are (H, H), (H, Me), (H, Et), (H, Pr), (H, isoPr), (Me, Me), (Me, Et), (Me, Pr), (Me, isoPr), (Et, Et), Et, Pr), (Et, isoPr), (Pr, Pr), (Pr, isoPr) and (isoPr, isoPr).

Fifth, sixth, seventh and eighth position chineselanguage rings indicate the following formula:

-CO-R11, -CO-R21, -CO-R31, -CO-R41, -CO-R51, -CO-R61, -CO-R71, -CO-R81, -CO-R91, -CO-R101, -CO-R111, -CO-R121, -CO-R131 and-CO-R141 in formulas (1)to(14) of the present invention indicate carboxyl group or CT is auxillou group proletarienne modifications which turns into a carboxyl group in vivo. Namely, R11, R21, R31, R41, R51, R61, R71, R81, R91, R101, R111, R121, R131 and R141 (hereinafter referred to as R11-R141) indicate a hydroxyl group or a group which is substituted by a carboxyl group in vivo. Specific examples of the carboxyl group in proletarienne modifications described, for example, non-patent publications 41-43.

R11-R141 includes, for example, CNS group having 1-8 carbon atoms, which may have a Deputy (deputies), aryloxyalkyl group which may have a Deputy (deputies), arylalkyl group which may have a Deputy (deputies), heteroaromatic group which may have a Deputy (deputies), and heteroaromatic group which may have a Deputy (deputies).

CNS group having 1-8 carbon atoms, indicates here on the group, the alkyl part of which is straight or branched, or cyclic. Her examples are methoxy, ethoxy, propyloxy, isopropoxy, bucalossi, isobutoxy, sec-Butylochka, tert-Butylochka, pentyloxy, isopentylamine, 1 methylbutoxy, 1,1-dimethylpropylene, 2-methylbutoxy, neopentylene, hexyloxy, isohexane, 1 methylpentane, 1,1-dimethylbutylamino, heptyloxy, octyloxy, cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy, College is talocci, cyclooctylamine group.

CNS group having 1-8 carbon atoms, preferably represents CNS group having 1-6 carbon atoms. Specifically, they include methoxy group, ethoxy group, isopropoxy group, bucalossi group, isobutoxy group, sec-Butylochka group, pentyloxy group, cyclopentyloxy group. Especially preferably, they include a methoxy group, ethoxy group, isopropoxy group, bucalossi group.

CNS group having 1-6 carbon atoms, which has a Deputy (deputies), preferably includes morpholinoethoxy group, 2-methoxyethoxy group and 1-methyl-2-methoxyethoxy group; arylalkyl group which may have a Deputy (deputies), preferably includes a benzyloxy group; aryloxy group which may have a Deputy (deputies), preferably includes phenyloxy group and 2-methoxyphenoxy group; and heteroaromatic group which may have a Deputy (deputies), preferably includes furanose group.

The term "aryl" in "aryloxy group" refers to phenyl and naphthyl.

The term "heteroaryl" heteroaromatic group" indicates a 5-8-membered mono-, bi - or tricyclic heteroaromatic ring group containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxygen atoms, sulfur and azo is as a ring atom. For example, they include pyridyl, pyridazinyl, pyrimidyl (= pyrimidinyl), pyrazinyl, furyl, thienyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolin, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothiazol, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzofurazanyl, benzothiadiazoles, purinol, chinolin (= chinoline), ethanolic, cinnoline, phthalazine, hintline, honokalani, pyridinyl, imidazolyl, imidazothiazoles, imidazolidinyl, dibenzofurans, dibenzothiazyl, carbazolyl and acridines.

Deputy (deputies) of the CNS group, which may have a Deputy (deputies)" includes, for example, morpholinyl group, piperidinyl group, pyrrolidinyl group, dimethylamino group, diethylamino group, methoxy group, pivaloyloxy group, ethoxycarbonyl group, cyclohexyloxycarbonyloxy group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a 2-benzyloxyphenol group and hydroxy group. Methoxy group having About 2-benzyloxyphenol group as a Deputy (deputies), indicates 3-oxo-1,3-dihydro-2-benzofuran-1 iloxi group.

Deputy (deputies) in aryloxy group which may have a Deputy (deputies)includes IU is a hydroxy group and a methyl group.

Deputy (deputies) in heteroaromatic group which may have a Deputy (deputies)" includes methoxy group and a methyl group.

We can assume that the derivatives of phenylalanine of formula (1)to(14) are optical isomers and compounds specified in the present invention include all of these optical isomers. Moreover, both compounds formed by one optical isomer, and a mixture of the optical isomers are included in the compounds of the present invention. Further, in regard to the stereochemistry phenylalanine part, accurately indicated in the formulas (1)to(14), preferred L-form.

We can assume that the derivatives of phenylalanine of formula (1)to(14), representing the diastereomers and the diastereoisomer and the mixture of diastereomers are included in the compounds of the present invention. When derivatives of phenylalanine of formula (1)to(14) of the present invention include a mobile hydrogen atom, we can assume that the derivatives of phenylalanine of formula (1)to(14) of the present invention include a variety of tautomeric forms and compounds specified in the present invention include the tautomeric forms.

Preferred examples of each of the symbols in the formula (1)

R11 preferably represents a hydroxyl group, CNS group having 1-6 carbon atoms or Ben is yloxy group, and preferably, a hydroxyl group, isopropoxy group, bucalossi group, phenyloxy group, benzyloxy group, sec-boutelou group, tert-boutelou group, 1-methylbutoxy group, 1,1-dimethylpropyl group, 1-methylpentylamino group, 1,1-dimethylbutylamino group, cyclopropyl group, cyclobutyl group, cyclopentyl group or tsiklogeksilnogo group. Among them, particularly preferred are a hydroxyl group, isopropoxy group.

An alkyl group in R12 and R13 preferably represents an alkyl group having 1-3 carbon atom.

R12 preferably represents a hydrogen atom, methyl group or ethyl group, and particularly preferably methyl group or ethyl group.

R13 preferably represents a hydrogen atom or methyl group, and particularly preferably a hydrogen atom.

Among the above, N(R12)R13 is preferably a dimethylamino group, ethylamino group or methylamino group, or N(R12)R13 represents a preferably 1-pyrrolidinyl group, 1-piperidinyl group or 4-morpholinyl group.

R14 is preferably a methyl group.

R1' preferably represents a hydrogen atom or a fluorine atom, and particularly preferably a hydrogen atom.

alsaudia position R 1' is preferably the sixth or seventh position chineselanguage rings.

X1represents preferably-CH(R1a)-, -CH(R1a)CH(R1b)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b) -, or 1,3-pyrrolidinyl, and particularly preferably-CH2-.

Replacement position X1represents preferably the sixth, seventh or eighth position chineselanguage ring, and preferable, his sixth or seventh position, and particularly preferably, its sixth position.

R1a, R1b, R1c and R1d are preferably a hydrogen atom.

And Y11and Y12represent preferably a chlorine atom.

[2] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[1], in which in the formula (1), R11 represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or a benzyloxy group which may be substituted by a methyl group (or groups) or methoxy group (or groups), the alkyl group of R12 and R13 represents an alkyl group having 1-3 carbon atoms, and X1represents-CH(R1a)-, -CH(R1a)CH(R1b)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b) -, or 1,3-pyrrolidinyl.

[3] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[2], in which in the formula (1) X1represents-CH(R1a)-, -CH2CH2-, -N(R1a)CH2CH2- or 1,3-pyrrolidinyl, where R1a represents a hydrogen atom or methyl group.

[4] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[3], in which in the formula (1), R12 and R13 each represents a hydrogen atom or alkyl group having 1-3 carbon atoms, or N(R12)R13 represents 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholine group, 3-tetrahydrocanabinol group or 1-piperazinilnom group, the fourth position may be substituted alkylenes group having 1-3 carbon atom.

[5] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[3], in which in the formula (1), R12 represents a methyl group or ethyl group,

R13 represents a hydrogen atom, methyl group or ethyl group, or

N(R12)R13 represents 1-pyrrolidinyl group, 1-piperidinyl group or 4-morpholinyl group,

R14 represents a methyl group,

R1' represents a hydrogen atom,

X1represents-CH2-located in the sixth, seventh or eighth position chineselanguage rings, and

Y11and Y12are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

Further, CR is pactically derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[5], in which in the formula (1) and Y11and Y12represent a chlorine atom.

[6] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[3], in which in the formula (1) R13 represents a hydrogen atom, methyl group or ethyl group,

X1represents-CH2-located in the sixth, seventh or eighth position chineselanguage rings, and

Y11and Y12represent the combination of (Cl, Cl).

[7] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[6], in which in the formula (1)

R13 represents a hydrogen atom, methyl group or ethyl group, and

X1represents-CH2-who is in the sixth position chineselanguage rings.

[8] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[6], in which in the formula (1)

R13 represents a hydrogen atom, methyl group or ethyl group, and

X1represents-CH2-who is in the seventh position chineselanguage rings.

[9] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[3], in which in the formula (1)

R12 and R13 each independently represents methyl group or ethyl group,

R14 methyl group,

R1' represents a hydrogen atom or a fluorine atom, which is located in the sixth or seventh position chineselanguage rings,

X1is-N(CH3)CH2CH2- or 1,3-pyrrolidinyl, which is located in the sixth or seventh position chineselanguage rings, and

Y11and Y12represent the combination of (Cl, Cl).

[10] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[2], in which in the formula (1), R12 and R13 each independently represents a hydrogen atom, methyl group or ethyl group, or N(R12)R13 represents 1-pyrrolidinyl group, 1-piperidinyl group or 4-morpholinyl group,

R14 represents methyl group or ethyl group,

R1' represents a hydrogen atom,

X1is-OCH(R1a)CH(R1b), where R1a and R1b each independently represents a hydrogen atom or methyl group, and

Y11and Y12are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).

[11] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[10], in which in the formula (1), R12 and R13 each independently represents a hydrogen atom, methyl group or ethyl group,

R14 represents a methyl group and

Y11and Y12represent the combination of (Cl, Cl).

[1] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[1], in which in the formula (1)

R11 represents a hydroxyl group or CNS group having 1-6 carbon atoms, which may have methoxy group (s) as a Deputy (deputies)

R12 represents a hydrogen atom or alkyl group having 1-6 carbon atoms,

R13 represents a hydrogen atom, methyl group or ethyl group, or

N(R12)R13 represents 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholine group, 3-tetrahydrocanabinol group or 1-piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms,

R14 represents a methyl group,

R1' represents a hydrogen atom,

X1represents-CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c) -, or-OCH(R1a)CH(R1b)-, which is located in the sixth position chineselanguage ring, where R1a, R1b and R1c each represents a hydrogen atom, and

Y11and Y12represent the combination of (Cl, Cl).

[13] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[1], in which in the formula (1)

R11 represents a hydroxyl group or CNS group having 1-6 carbon atoms,

R12 represents an alkyl group having 1-6 carbon atoms,

R13 represents a hydrogen atom, a methyl g is foam or ethyl group,

R14 represents a methyl group,

R1' represents a hydrogen atom,

X1represents-CH(R1a) -, or-CH(R1a)CH(R1b)-, which is located in the sixth position chineselanguage ring, where R1a and R1b each represents a hydrogen atom, and

Y11and Y12represent the combination of (Cl, Cl).

[14] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[1], in which in the formula (1)

R11 represents a hydroxyl group or CNS group having 1-6 carbon atoms,

R12 represents an alkyl group having 1-5 carbon atoms,

R13 represents a hydrogen atom,

R14 represents a methyl group,

R1' represents a hydrogen atom,

X1represents-CH(R1a)-, -CH(R1a)CH(R1b) -, or-CH(R1a)CH(R1b)CH(R1c)-, which is located in the sixth position chineselanguage ring, where R1a, R1b and R1c each represents a hydrogen atom, and

Y11and Y12represent the combination of (Cl, Cl).

[15] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[1], in which in the formula (1)

R11 represents a hydroxyl group or CNS group having 1-6 carbon atoms,

R12 represents methyl group or ethyl group,

R13 represents a hydrogen atom,

R14 represents a methyl group,

R1' represents a hydrogen atom,

X1represents-CH(R1a)-, -CH(R1a)CH(R1b) -, or-CH(R1a)CH(R1b)CH(R1c)-, which is located in the sixth position chineselanguage ring, where R1a, R1b and R1c each represents a hydrogen atom, and

Y11and Y12represent the combination of (Cl, Cl).

[16] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[1], in which in the formula (1)

R11 represents a hydroxyl group or CNS group having 1-6 carbon atoms,

R12 represents methyl group, ethyl group, isobutylene group, cyclopropylmethyl group, cyclobutyl group, sec-boutelou group or isopentyl group,

R13 represents a hydrogen atom,

R14 represents a methyl group,

R1' represents a hydrogen atom,

X1represents-CH(R1a)-, which is located in the sixth position chineselanguage ring, where R1a represents a hydrogen atom, and

Y11and Y12represent the combination of (Cl, Cl).

[17] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[1], in which in the formula (1)

R11 represents a hydroxyl group or CNS group having 1-6 carbon atoms,

R12 represents a hydrogen atom or alkyl group having 1-3 carbon atoms,

R13 represents a hydrogen atom, a methyl group is whether ethyl group, or

N(R12)R13 represents 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholine group, 3-tetrahydrocanabinol group or 1-piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms,

R14 represents a methyl group,

R1' represents a hydrogen atom,

X1represents-O-CH(R1a)CH(R1b) -, or-O-CH(R1a)CH(R1b)CH(R1c)-, which is located in the sixth position chineselanguage ring, where R1a, R1b and R1c each independently represents a hydrogen atom or methyl group, and

Y11and Y12represent the combination of (Cl, Cl).

[18] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to any one of the above paragraphs.[1]-[17], in which in the formula (1) R11 is a branched CNS group having 3-6 carbon atoms.

[19] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[1], represented by the following formula:

Preferred examples of each of the symbols in the formula (2)

R21 preferably represents a hydroxyl group, maxillo group, having 1-6 carbon atoms or morpholinoethoxy group, and especially preferably, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, bucalossi group or morpholinoethoxy group.

R22 preferably represents methyl group or ethyl group.

R24 is preferably a methyl group.

R2' preferably represents a hydrogen atom or a fluorine atom.

Replacement R2' preferably represents the sixth or seventh position chineselanguage rings.

X2represents preferably-CH2-, -NHCH2CH2- or-N(Me)CH2CH2-.

Replacement position X2represents preferably the sixth, seventh or eighth position chineselanguage ring, and preferable, his seventh or eighth position.

And Y21and Y22represent preferably a chlorine atom.

[21] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[20], in which in the formula (2)

R22 represents a methyl group or ethyl group,

R24 represents a methyl group,

R2' represents a hydrogen atom,

X2represents-CH2-located in the sixth, seventh or eighth position hin is zaindinova ring, and

Y21and Y22represent the combination of (Cl, Cl).

[22] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[20], in which in the formula (2)

R22 represents a hydrogen atom, methyl group or ethyl group,

R24 represents a methyl group,

R2' represents a hydrogen atom or a fluorine atom, which is located in the sixth or seventh position chineselanguage rings,

X2is-N(CH3)CH2CH2- or-NHCH2CH2-who is in the sixth or seventh position chineselanguage rings, and

Y21and Y22represent the combination of (Cl, Cl).

Preferred examples of each of the symbols in the formula (3)

R31 is preferably a hydroxyl group, CNS group having 1-6 carbon atoms or morpholinoethoxy group or benzyloxy group, and especially preferably, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, bucalossi group, pentyloxy group, morpholinoethoxy group or benzyloxy group.

R34represents preferably a methyl group.

R3' represents preferably a hydrogen atom.

The above formula (3-1) is preferably 4-morpholinyl group, 1-PIP is rosaniline group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms, or 1-imidazolidinyl group which may be substituted by methyl group, ethyl group or amino group. Communication in the formula (3-1) can be saturated or unsaturated. X3in the formula (3-1) is preferably an oxygen atom or a nitrogen atom. The above formula (3-1) is preferably 4-morpholinyl group, 4-methyl-1-piperazinilnom group or 2-amino-1-imidazolidinyl group.

And Y31and Y32represent preferably a chlorine atom.

[24] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[23]in which formula (3-1) represents the 4-morpholinyl group, 4-thiomorpholine group, 3-tetrahydrocanabinol group, 1-piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms, or 1-imidazolidinyl group which may be substituted by a methyl group or amino group.

where X3represents an oxygen atom, a nitrogen atom which may be substituted by an alkyl group having 1-3 carbon atom, or a sulfur atom.

[25] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[24], in which the GRF is ule (3)

R34represents a methyl group,

R3' represents a hydrogen atom,

Formula (3-1) represents the 4-morpholinyl group or 1-piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms, and

Y31and Y32represent the combination of (Cl, Cl).

[26] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[24], in which in the formula (3)

R34represents a methyl group,

R3' represents a hydrogen atom,

Formula (3-1) represents 2-amino-1-imidazolidinyl group, and

Y31and Y32represent the combination of (Cl, Cl).

[27] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[23], in which in the formula (3)

R34represents a methyl group,

R3' represents a hydrogen atom or a fluorine atom,

Formula (3-1) represents 1-imidazolidinyl group, the second position of which may be substituted methyl group or ethyl group, and

Y31and Y32represent the combination of (Cl, Cl).

Preferred examples of each of the symbols in the formula (4)

The ring is preferably a benzene ring, pyridine ring, thiophene ring, piperidine ring, the first state is which may be substituted by an alkyl group, having 1-3 carbon atoms, or pieperazinove ring, the first and/or fourth position of which may be substituted by an alkyl group having 1-3 carbon atom.

R41represents preferably a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or benzyloxy group, and especially preferably, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, bucalossi group, pentyloxy group, morpholinoethoxy group or benzyloxy group.

The ring is preferably a benzene ring, pyridine ring, the first position of which may be substituted by an alkyl group having 1-3 carbon atoms, or pieperazinove ring, the first and/or fourth position of which may be substituted by an alkyl group having 1-3 carbon atoms, and especially preferably, pieperazinove ring, the first and/or fourth position which may be substituted by a methyl group.

R44represents preferably a methyl group.

And Y41and Y42represent preferably a chlorine atom.

[29] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[28], in which in the formula (4) ring is pieperazinove ring, the first and/or fourth the e position of which may be substituted methyl group,

R44represents a methyl group and

Y41and Y42represent the combination of (Cl, Cl).

Preferred examples of each of the symbols in the formula (5)

R51represents preferably a hydroxyl group, CNS group having 1-6 carbon atoms, or morpholinoethoxy group, and especially preferably, hydroxyl group, methoxy group, ethoxy group, isopropyl group, bucalossi group or morpholinoethoxy group.

R54represents preferably a methyl group.

R5' represents preferably a hydrogen atom.

N(R5a)R5b represents preferably acylamino group or 1-pyrrolidinyloxy group.

And Y51and Y52represent preferably a chlorine atom.

[31] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[30], in which in the formula (5),

R54represents a methyl group,

R5' represents a hydrogen atom,

N(R5a)R5b represents acylamino group or 1-pyrrolidinyloxy group, and

Y51and Y52represent the combination of (Cl, Cl).

Preferred examples of each of the symbols in the formula (6)

R61represents preferably a hydroxyl group, CNS group having 1 to 6 atoms of plastics technology : turning & the Yes, morpholinoethoxy group or benzyloxy group, and especially preferably, hydroxyl group, methoxy group, ethoxy group, isopropyl group, bucalossi group, pentyloxy group, morpholinoethoxy group or benzyloxy group.

And preferably represents any of the formulas (6-1)to(6-6).

And Y61and Y62represent preferably a chlorine atom.

[33] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[32], in which in the formula (6)

And6represents any of the above formulas (6-1)to(6-4).

[34] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[32], in which in the formula (6)

R61represents a hydroxyl group, and Y61and Y62represent the combination of (Cl, Cl).

Preferred examples of each of the symbols in the formula (7)

R71represents preferably a hydroxyl group, CNS group having 1-6 carbon atoms, or morpholinoethoxy group, and especially preferably, hydroxyl group, methoxy group, ethoxy group, isopropyl group, bucalossi group or morpholinoethoxy group.

R74represents preferably a methyl group,

R7 represents preferably 2-PROPYNYL the ing group, cyclopropylmethyl group, through group or cyclopentyl group.

And Y71and Y72represent preferably a chlorine atom.

[36] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[35], in which in the formula (7)

R74represents a methyl group,

R7 is 2-propenyloxy group or cyclopropylmethyl group, and

Y71and Y72represent the combination of (Cl, Cl).

[37] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[35], in which in the formula (7)

R74represents a methyl group,

R7 is through the group, and

Y71and Y72represent the combination of (Cl, Cl).

Preferred examples of each of the symbols in the formula (8)

R81represents preferably a hydroxyl group, CNS group having 1-6 carbon atoms, or morpholinoethoxy group, and especially preferably, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, bucalossi group or morpholinoethoxy group.

R82represents preferably a methyl group.

R84represents preferably a methyl group.

n8represents preferably one of C the smaller the number 0 or 2, and particularly preferably 0.

S(=(0)n8R82is preferably a methylthio group or methanesulfonyl group.

Substitute S is a preferred sixth position chineselanguage rings.

And Y81and Y82represent preferably a chlorine atom.

[39] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[38], in which in the formula (8)

R81represents preferably a hydroxyl group, CNS group having 1-6 carbon atoms, and morpholinoethoxy group or a benzyloxy group which may be substituted by a methyl group (or groups) or methoxy group (or groups).

[40] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[38], in which in the formula (8)

R82represents preferably a methyl group.

R84represents preferably a methyl group.

n8represents preferably one of the whole number 0 or 2,

S located in the sixth position chineselanguage rings, and

Y81and Y82represent the combination of (Cl, Cl).

Preferred examples of each of the symbols in the formula (9)

R91represents preferably hydroximino group, CNS group having 1-6 carbon atoms, morpholinoethoxy group or benzyloxy group, and especially preferably, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, bucalossi group, pentyloxy group, morpholinoethoxy group or benzyloxy group.

R92represents preferably a hydroxyl group, a benzyloxy group, methoxy group, or amino group. CO-R92may be a carboxyl group in proletarienne form, which turns into a carboxyl group in vivo. Namely, R92represents preferably a hydroxyl group or a group which is substituted by a hydroxyl group in vivo.

Specific examples of the group (s)that are replaced with a hydroxyl group in vivo, above.

R94represents preferably a methyl group.

X9represents preferably an atomic bond.

Replacement position X9represents preferably the sixth position chineselanguage rings.

And Y91and Y92represent preferably a chlorine atom.

[42] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[41], in which in the formula (9),

X9represents-CH2CH2- or-CH=CH - and R92 represents a hydroxyl group,

or X9represents an atomic bond, and R92represents a benzyloxy group,

X9located in the sixth position chineselanguage rings,

R94represents a methyl group, and

Y91and Y92represent the combination of (Cl, Cl).

[43] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[41], in which in the formula (9),

X9represents an atomic bond, and R92represents a hydroxyl group, methoxy group or amino group,

X9located in the sixth position chineselanguage rings,

R94represents a methyl group, and

Y91and Y92represent the combination of (Cl, Cl).

Preferred examples of each of the symbols in the formula (10)

R101represents preferably CNS group having 2-4 carbon atoms, or morpholinoethoxy group, and especially preferably, ethoxy group, isopropoxy group, bucalossi group or morpholinoethoxy group.

R10 preferably represents methyl group or ethyl group, and particularly preferably ethyl group.

R104represents preferably a methyl group.

And Y101and Y102represent preferably an atom x is ora.

[45] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[44], in which in the formula (10), R10 is ethyl group.

Preferred examples of each of the symbols in the formula (11)

R111represents preferably CNS group having 1-4 carbon atoms, or morpholinoethoxy group, and especially preferably, methoxy group, ethoxy group, isopropoxy group, bucalossi group or morpholinoethoxy group.

R114represents preferably a methyl group.

And Y111and Y112represent preferably a chlorine atom.

Preferred examples of each of the symbols in the formula (12)

R121represents preferably CNS group having 1-4 carbon atoms, or morpholinoethoxy group, and especially preferably, methoxy group, ethoxy group, isopropoxy group, bucalossi group or morpholinoethoxy group.

R124represents preferably a methyl group,

But is preferably the formula (12-1).

Preferred examples of each of the symbols in the formula (13)

R131represents preferably CNS group having 1-6 carbon atoms, or benzyloxy group which may be substituted, m is a stylish group (or groups) or methoxy group (or groups), especially preferably, ethoxy group or benzyloxy group.

Replacement position ammonium side chain is preferably a sixth, seventh or eighth position chineselanguage ring, and preferably, its eighth position.

R13a and R13b are preferably methyl group or N(R13a)R13b represents preferably 1-pyrrolidinyloxy group.

Y131and Y132are preferably (Cl, Cl), (Cl, Me), or (Cl, F).

Preferred examples of each of the symbols in the formula (14)

R141represents preferably a hydroxyl group, CNS group having 1-6 carbon atoms, or morpholinoethoxy group, and especially preferably, ethoxy group or benzyloxy group.

R144represents preferably methyl group or ethyl group.

The alternate position of the hydroxyl group on hinazolinam the ring is preferably a sixth or seventh position of the ring, and preferably, its eighth position.

Y141and Y142are preferably (Cl, Cl), (Cl, Me), (Cl, F), (F, F) or (F, Me), and especially preferably (Cl, Cl), (Cl, Me), or (Cl, F).

[50] Preferred derivatives of phenylalanine or its pharmaceutically acceptable salt according to the above p.[49], in which the s in the formula (14), R144 represents a methyl group,

the hydroxyl group is located in the sixth position chineselanguage rings, and

Y141and Y142represent the combination of (Cl, Cl).

Preferred compounds of formulas (1)-1(14) are the compounds described in the "Examples"section. Especially preferred compounds are the compounds described in the examples 7, 8, 12, 21, 28, 30, 34, 37, 40, 46, 54, 59, 90, 91, 92, 99, 103, 106, 111, 116, 124, 136, 138, 139, 141, 142, 143, 144, 145, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 159, 162, 163, 164, 165, 166, 170, 171, 172, 173, 174, 176, 179, 181, 184, 185, 189, 191, 193, 196, 198, 201, 210, 213, 214, 216, 217, 218, 219, 220, 222, 223, 224, 225, 226, 229, 207, 230, 232, 233, 234 and 235.

Among the compounds of the formulas (1)to(14) is particularly preferably a compound of formula (1), and particularly, compounds where R11 represents a hydroxyl group; these compounds exhibit excellent antagonistic activity against the binding of α4β1, but also show very low total excretion from the body (CLtot). Therefore, the compounds have excellent characteristics as an active form for oral input antagonist of α4 integrin (prodrugs), which is effective at a lower dosage and with fewer doses.

In particular, compounds where R11 is a branched CNS group having 3-6 carbon atoms, are excellent duration in oral introduction.

When compounds of formulas (1)to(14) on astasia invention may form a salt, enough salt are pharmaceutically acceptable. When the compound has the formula acid group such as carboxyl group, the salt may be an ammonium salt, or their salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and their salts with aluminum, and their salts with zinc, and their salts with organic amines, such as triethylamine, ethanolamine, morpholine, piperidine and dicyclohexylamine, and their salts with basic amino acids such as arginine and lysine. When the compound has a basic group in the formula, the salt may be a salt with inorganic acids, for example hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and Hydrobromic acid; salts with organic carboxylic acids, for example acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, gyventojai acid, pambou acid, enanthic acid, decanoic acid, tolovaj acid, salicylic acid, lactic acid, oxalic acid, almond acid, and malic acid; and salt organosulfur acids, for example methanesulfonic acid, bansilal is about acid, and p-toluensulfonate acid. Salt can be formed by mixing the compounds of formulas (1)to(14) with the desired acid or base in an appropriate ratio in a solvent or dispersing the compound, or the reaction of cation exchange or anion exchange with another salt.

Compounds of the present invention also includes a solvate of the compounds of formulas (1)to(14), such as hydrates and alcohol adducts.

Compounds of the present invention can be modified in Proletarskoye form. The prodrug in the present invention means the connection (connection), which is converted into compounds of the present invention in vivo. For example, when the active compound contains a carboxyl group, phosphate group and the like, in connection proletarienne modifications include their esters, amides and the like compounds. When the active compound contains an amino group, compounds in proletarienne modifications include their amides, carbamates and the like compounds. When the active compound contains hydroxyl group, the compounds in proletarienne modifications include their esters, carbonates, carbamates and the like compounds. When the compounds of the present invention are modified in Proletarskoye forms, connections can connect to the amino acids of the Il is the sugars.

The present invention also includes metabolites of compounds of the present invention. Metabolites of the compounds of the present invention mean compounds in which compounds of the present invention have been converted to metabolic enzymes, etc. in vivo. Their examples are compounds where the hydroxyl group was introduced in a benzene ring metabolism; compounds where CNS group was converted into a hydroxyl group metabolism; and compounds where the alkyl group on the nitrogen atom was dialkylamino metabolism. Further, they include compounds where glucuronic acid, glucose, amino acid or sulfuric acid, combined with carbonatites part of the compounds of the present invention, with hydroxylgroups part of the compounds of the present invention or with hydroxylgroups part, introduced by the metabolism.

Compounds of the present invention have excellent antagonistic effect against the adhesion of cells by α4 integrins and have excellent bioavailability and stability after oral administration. In addition, they have excellent stability even at parenteral administration. These characteristics reflect a great affinity to the α4 integrins, plasma protein binding, solubility, full withdrawal from the organization is ISM or permeability through the mucous membrane of the intestinal tract.

In particular, since the compounds of the present invention have high antagonistic activity against α4 integrins even in the conditions of existence of plasma protein, when introduced in vivo can be an effective low dosage of the compounds of the present invention.

In addition, the total excretion of compounds of the present invention is low, and therefore they have excellent, long-lasting pharmacodynamic profile in plasma. These characteristics give the opportunity to reduce the dosage and number of doses. In addition, it is possible to maintain the level of the compounds of the present invention in plasma, and, therefore, can effectively inhibit cell adhesion occurring through α4 integrin.

Compounds of the present invention have a high permeability through the membrane and a larger area under the curve of the dynamics in time of the concentration in plasma (AUC) and high bioavailability with oral administration.

In addition, the compounds of the present invention have high safety.

In particular, the compound of formula (1) from compounds of formulas (1)to(14) exhibits high solubility and is useful.

Therefore, new derivatives of phenylalanine according to the present invention and their salts provide excellent antagonists α4 integrin, therapeutic the ski tools or prophylaxis against diseases in which pathology is involved, the process of adhesion-dependent α4 integrin, such as inflammatory diseases such as rheumatoid arthritis, inflammatory intestinal diseases (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus, multiple sclerosis, Sjogren syndrome, asthma, psoriasis, Allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, metastasis of tumors, and transplant rejection.

They also provide a therapeutic agent or a prophylactic against diseases such as preeclampsia, ischemic cardiovascular disorders (including cerebral infarction), scleroderma, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, giant cell arteritis diagnostics, uveitis, pneumosclerosis, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer's disease, spinal cord injury, traumatic brain injury, primary sclerosing cholangitis, cirrhosis of the liver caused by hepatitis C, chronic active hepatitis, sacroiliitis, ankylosing spondylitis, episcleritis, iritis, uveitis, nodular erythema, pyoderma gangrenosum, and autoimmune hepatitis.

In addition, they provide a therapeutic agent or a prophylactic agent against not only the criminal code is related to the above diseases, but also diseases in which α4 integrins may be involved in the development of pathology.

The dose of the compounds of the present invention or its salts, used for the purposes described above, varies, depending on the connection, the intended therapeutic effect, the route of administration, duration of treatment and age and body weight of the patient. The dose is usually from 1 μg to 5 g/d for adults in oral introduction and to 0.011 μg to 5 g/d for adults when administered parenterally (e.g. intravenously, subcutaneously, intramuscularly, in the form of suppositories, barium enema, ointments, adhesive pads on the skin, sublingually in the form of eye drops).

Compounds of the present invention have a high stability in acidic or alkaline solution, and they are useful because they can be used in various pharmaceutical forms.

Compounds of the present invention or its salt is introduced to the patient in pure form or in the form of various pharmaceutical compositions with a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers include, for example, various organic or inorganic materials carriers, usually used as materials for pharmaceutical preparations. Their examples are diluents, lubricants, binders, raznyh Italy, water-soluble polymers and the basic inorganic salt in solid preparations; and solvents, solubilizing agents, suspendresume agents, isotonic agents, sautereau agents and softening agents in liquid solutions. In addition, if necessary, you can use additives such as antiseptic agents, antioxidants, coloring agents, sweetening agents, acidifying agents, foaming agents and flavouring materials.

Dosage forms of pharmaceutical compositions are, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, covered sugar pills, depo-form, syrups, suspension tools, emulsions, trosha, sublingual form, applied to the skin lining, collapsing when oral administration tools (tablets), inhalation means, barium enema, ointments, plasters and eye drops. You can get them with the usual tools used in the manufacture, use normal way.

The pharmaceutical compositions of the present invention can be obtained by methods commonly used in the field of technology of obtaining compositions and, for example, by methods described in the Japanese Pharmacopoeia. Methods of obtaining described in detail below.

For example, when compounds of the present invention produces the t in the form of oral medication, they added diluents and, if necessary, binder, loosening agents, lubricants, coloring agents, flavouring agents. Then the usual ways they can be molded in the form of, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, covered sugar pills, depo-forms, syrups, suspension agents, emulsions, trosha, sublingual funds, collapsing when oral administration tools (tablets), inhalants. As diluents are used, for example, lactose, corn starch, sucrose, glucose, sorbitol and crystalline cellulose; as connecting means are used, for example, polyvinyl alcohol, polyvinyl simple ether, ethylcellulose, methylcellulose, acacia, tragakant, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethyl and polyvinylpyrrolidone; as loosening agents are used, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextran and pectin; as lubricating agents are magnesium stearate, talc, polyethylene glycol, silicon dioxide, gidrirovannoe vegetable oil and the like; materials that are approved for addition to drugs, are used as coloring is hentov; and as flavouring agents are used, for example, cocoa powder, menthol, aromatic acid, peppermint oil, borneol powder and cinnamon. These tablets and granules may be coated with sugar, gelatin and the like materials.

When you get the injection means to them, if necessary, add pH regulators, sautereau agents, stabilizing agents and preservatives, and then their usual ways get as subcutaneously, intramuscularly and intravenously administered funds.

Derivatives of phenylalanine (1) of the present invention can be obtained, for example, the methods described below. Derivatives of phenylalanine (2)-(14) can be obtained by the same methods as the methods described below.

Suitably protected carboxylic acid, (S-1) is loaded into the resin in the usual way. Deputy Q carboxylic acid (S-1) has the structure of a 2-Y11-6-Y12-Ph-CO, as described above with reference to formula (1), he is a Deputy, which can be converted into a 2-Y11-6-Y12-Ph-CO at any stage of the synthesis, or it represents a protective group of amino group. Deputy R carboxylic acid (S-1) has the structure of a substituent which can be converted into NH2or are adequately protected from the group of NH2.

<> Regarding the reaction of boot, then the reaction can be performed using, if necessary, a suitable additive such as HOAt (1-hydroxy-7-asobancaria), HOBt (1-hydroxybenzotriazole) or DMAP (dimethylaminopyridine), and a condensing agent such as DIC (diisopropylcarbodiimide), DCC (dicyclohexylcarbodiimide) or EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) in an organic solvent, such as dichloromethane, DMF (N,N-dimethylformamide) or NMP (N-methyl-2-pyrrolidone). For example, when Wang resin is used, the reaction is carried out in the presence of DIC and DMAP in DMF to obtain the complex ester (S-2).

When Q represents, for example, the protective group E (S-3) amino group, the protective group can be removed, depending on the protective group E in appropriate circumstances, to obtain the amine (S-4). For example, in the case of the Fmoc group (group 9-fertilityscore group) as E, the protective group can be removed with a base such as piperidine in a solvent such as DMF. Amide (S-5) can be obtained by the interaction of the amine (S-4) with the corresponding carboxylic acid by using a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt or HOBt in an organic solvent, such as DMF, NMP or dichloromethane. Amide (S-5) you can also obtain cooperation is receiving the appropriate acid chloride in the presence of a base.

Ester (S-2) can be replaced by Amin (S-6) in suitable conditions, depending on the substituent R. for Example, when the nitro group is used as R, ester (S-2) can be replaced by Amin (S-6) in the presence of a reducing agent, such as SnCl2or its hydrate in a solvent such as NMP, DMF or ethanol. In the case of amine protected by a Fmoc group (9-fertilityscore group) (FmocNH), the protective group can be removed with a base such as piperidine in a solvent such as DMF, to obtain the amine (S-6).

Hintlinin (S-9) can be synthesized by the following method. First, the amide (S-7) can be obtained by the interaction of the amine (S-6) with a halide of benzoic acid having a nitro group in the ortho position, in the presence of 2,6-lutidines of the base restoritive, such as NMP, or interacting with a carboxylic acid having a nitro group in the ortho position, activated by using a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt or HOBt in an organic solvent, such as DMF, NMP or dichloromethane. Then Amin (S-8) receive recovery nitro group SnCl2or its hydrates and cyclist such reagents as CDI (carbonyldiimidazole), triphosgene or p-nitrophenylphosphate to obtain chineselanguage (S-9).

As other methods of synthesis hintlinin (S-9) can also be obtained in the following way. First, the amide (S-8) can be obtained by the interaction of the amine (S-6) with a carboxylic acid having the amino group in the ortho position, activated by using a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt or HOBt in an organic solvent, such as DMF, NMP or dichloromethane. Then amide (S-8) cyclized in the same way as above, to obtain chineselanguage (S-9).

The substituents R' R' in the formula (S-7)to(S-9) represent groups that are derivatives of benzoic acid used in the above reaction. They represent R1' or-X1-N(R12)R13, described in the formula (1), or groups that can be converted into R1' or-X1-N(R12)R13, at any stage of the synthesis.

In the formula (S-10) compounds where R” is represented by a methyl group, can be obtained by Mitsunobu reaction with hinazolinam (S-9), using methanol, diisopropylethylamine acid and similar compounds. They can also be obtained by the interaction of methyliodide in the presence of a base such as potassium carbonate.

Thus obtained ester (S-10) is cleaved from the resin in suitable conditions to obtain the carboxylic acid (S-1).

For example, when using Wang resin, complex ether (S-10), each of Q, R', R” and R”' if necessary, into 2-Y11-6-Y12-Ph-CO, -X1-N(R12R13, methyl group, or R1'or groups that turn into a 2-Y11-6-Y12-Ph-CO, , -X1-N(R12R13, methyl group, or R1' in terms of removing the resin. Then, ester (S-10) treated with acidic solution, including, for example, added TFA (triperoxonane acid) to obtain a solution of carboxylic acid (1: R1 = OH), where in the formula (1) R1 presents a hydroxyl group. Next, clean carboxylic acid (1: R1 = OH) can be obtained by applying well-known methods of separation and purification such as concentration, extraction, crystallization, column chromatography, HPLC and recrystallization in the thus obtained carboxylic acid (1: R1 = OH).

In addition, carboxylic acid (1: R1 = OH) can also be obtained by application of the methods of synthesis on solid phase to liquid-phase method, where you select a suitable protective group and is used by well-known methods of isolation and purification.

In the carboxylic acid (S-11), each of Q, R', R” and R”' represents a 2-Y11-6-Y12-Ph-CO, -X1-N(R12R13, methyl group, or R1'or groups that may turn into a 2-Y11-6-Y12-Ph-CO, , - 1-N(R12R13, methyl group, or R1' in the following ways. The carboxyl group in the formula (S-11) can be transformed into the group-CO-R11 where R11 represents CNS group) well-known esterification. More specifically, the methods are the following. Carboxyl group treated with the appropriate alcohol under conditions of dehydration in the presence of an acid catalyst; it is treated with O-alkylating agents, such as alkylated, if necessary, in the presence of a base or acid, if necessary, it is treated with a suitable alcohol in the presence of base, after conversion into the acid halide with thionyl chloride, and similar compounds; more specifically, process it, for example, etelcharge.com in the presence of base to convert the anhydride of the acid. Then the reaction substance is optionally treated with a suitable alcohol in the presence of base. Further, it is treated with a suitable alcohol in the presence of condensing agent, such as dicyclohexylcarbodiimide, and, if necessary, a catalyst such as dimethylaminopyridine.

After these methods, the compounds of the present invention (1 : R1 represents a CNS group) can be obtained if necessary transformation Q, R', R” and R”'.

Fo the mule (1), for example, the compound (S-15), where X1is CH2be synthesized as follows. In the formula R11a represents R11 or functional group that can be converted into R11 at any stage of the synthesis.

The nitro compound (S-12), which is a starting material, can be obtained, for example, by the synthesis procedure, such as procedure synthesis of complex isopropyl ether (S)-2-(2,6-dichloraniline)-3-(4-nitrophenyl)propionic acid in Method 1 of Reference example 4. The nitro compound (S-12) is restored in the aniline compound interaction with SnCl2, the hydrogenation reaction in the presence of a metal catalyst and the like. More specifically, the corresponding aniline compounds can be obtained, for example, by the synthesis procedure, such as procedure synthesis of complex isopropyl ether (S)-2-(2,6-dichloraniline)-3-(4-AMINOPHENYL)propionic acid in Method 2 of Reference example 4. After condensation of the thus obtained aniline compounds and Anthranilic acid, substituted Ha (Ha is a halogen atom, a group of triflate and the like) using a suitable condensing agent (agents), the cyclization is performed with reagents such as CDI (carbonyldiimidazole), ethylchloride and triphosgene to obtain (S-13). Other ways sex is possible (S-13) is the following. The above aniline compounds interact with the chloride of 2-nitrobenzoic acid, substituted Ha, in the presence of a suitable base; and then the nitro group is restored SnCl2, the hydrogenation reaction in the presence of a metal catalyst and the like and cyclists reagents such as CDI, ethylchloride and triphosgene. Additional another way to obtain (S-13) is the following. Urea bond is formed between the above aniline compounds and complex Anthranilic acid, substituted Ha, using CDI, ethylchloride and triphosgene and the like; and then, if necessary, the reaction mixture cyclist interaction with a suitable base. Then R14 is introduced by such methods as the interaction of the compound (S-13) alkylhalides in the conditions of existence of a suitable base and a Mitsunobu reaction using alcohol. Then Ha is transformed into a carboxylic acid, for example, by reaction of transformation, using a palladium catalyst and carbon monoxide. Carboxylic acid into an alcohol compound (S-14, Xb = OH) in such a way as restorative reaction through a mixed anhydride of the acid. Next, Xb is transformed into a leaving group (Xb = the group of halogen, a triflate group, the group mesilate, a group of tosylate etc) using podhodyashego the halide acid, sulfanilamide, tinyglide, phosphorylcholine and the like. Then there is the reaction of their replacement by using suitably substituted amine to obtain the target compound (S-15).

This connection provides compounds having antagonistic activity against α4 integrin, or their pharmaceutically acceptable salts. These compounds can be used for treatment or prevention of diseases, pathology participates in the process of adhesion-dependent α4 integrin, such as inflammatory diseases, rheumatoid arthritis, inflammatory intestinal diseases (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus, multiple sclerosis, Sjogren syndrome, asthma, psoriasis, Allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, metastasis of tumors, and transplant rejection.

These compounds can also be used for treatment or prevention of pre-eclampsia, ischemic cardiovascular disorders (including cerebral infarction), scleroderma, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, giant cell arteritis diagnostics, uveitis, pneumosclerosis, chronic obstructive pulmonary disease, osteoarthritis, Alzheimer's disease, damage spin is on the brain, traumatic injuries of the brain, primary sclerosing cholangitis, cirrhosis caused by hepatitis C, chronic active hepatitis, sacroiliitis, ankylosing spondylitis, episcleritis, iritis, uveitis, nodular erythema, pyoderma gangrenosum and autoimmune hepatitis. In addition, the compounds of the present invention can be used for the treatment or prevention of not only the above diseases, but also diseases in which α 4 integrins may participate in the pathology.

EXAMPLES

The following examples will further illustrate the present invention, which are only preferred embodiments of the invention, and which in no way limit the invention.

In the following examples, although salt alleged connections can not be described, they are obtained in the form of salts triperoxonane acid (TFA) in the case of compounds capable of its TFA salt. This is because the expected compound were obtained by cleaning with a solvent containing 0.1% TFA, and lyophilized in the final process.

Example 1. The synthesis of compounds of the following formula (E-1), which has a Deputy (deputies) of example 1, table 1

The process 1. Download tar

Fmoc-Phe(4-nitro)-(25 g), DIC (8,9 ml), DMAP (281 mg) and DMF (193 ml) are added to the Wang resin (1,2 IMO the e/g, 19.3 g) and stirred at room temperature for 3 hours After removal of excess solvent, the resin was washed with DMF, methanol, dichloromethane and DMF 3 times each. For kupirovaniya unreacted hydroxyl groups on the resin, the resin is treated with acetic anhydride (19.6 ml), pyridine (16,8 ml) and DMF (193 ml) within 2 hours After removal of excess solvent, the resin was washed with DMF, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 2. Removal of the Fmoc group

Solution in DMF 20% piperidine (200 ml) is added to the resin obtained in process 1, and the interaction continued for 15 minutes the Reaction mixture is then interacts with a solution in DMF 20% piperidine (200 ml) within 15 min After removal of solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 3. The acylation reaction

2,6-dichlorobenzophenone (10.3 ml), 2,6-lutidine (13,7 ml) and NMP (120 ml) is added to the resin obtained in process 2, and the interaction continued for 14 hours After removal of solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 4. Recovery nitro

SnCl2·2H2O (150 g), NMP (300 ml) and EtOH (15 ml) is added to the resin obtained in process 3, and vzaimodeystviya within 14 PM After removal of solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 5. The acylation reaction

5-fluoro-2-nitrobenzoic acid (1.63 g), DIC (675 ml), HOAt (1.2 g) and NMP (25 ml) are mixed and stirred for 1 h and then added to 1 g of the resin obtained in process 4, and the interaction continued for 14 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 6. The substitution of fluorine groups Amin

Morpholine (400 μl) and NMP (2 ml) are added to 200 mg of the resin obtained in process 5, and interaction continued for 14 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 7. The restoration of the nitro group

The restoration of the nitro group is carried out in the resin obtained in process 6, the same procedure as in process 4 in example 1.

Process 8. Design chineselanguage ring carbonyl diimidazol

Carbonyldiimidazole (400 mg) and NMP (2 ml) is added to the resin obtained in process 7, and stirred at 95°C for 14 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process . Alkylation

Triphenylphosphine (520 mg), methanol (80 ml), 40% solution diisopropylperoxydicarbonate acid in toluene (1 ml) and dichloromethane (2 ml) is added to the resin obtained in process 8, and stirred for 14 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

The process 10. Cleavage from the resin

The resin obtained in process 9 process triperoxonane acid containing 5% water for 1 h After filtering, the filtrate is concentrated under reduced pressure. The residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

MS(ESI MH+): 597

Examples 2-6. The synthesis of compounds of the following formula (E-1), which has a Deputy (deputies) of examples 2-6 table 1

Compounds of examples 2-6 table 1 the following formula (E-1), which has a Deputy (deputies), synthesized by the same procedure as in example 1, except that in the process 6 of example 1 using the appropriate amines.

Example 7. The synthesis of compounds of the following formula (E-2), which has a Deputy (deputies) of example 7 table 2

The process 1. The acylation reaction

1 g of the resin obtained in process 4 of example 1, acelerou the same procedure, and so the technique of process 5 in example 1, except that in the process using 2-amino-5-nitrobenzoic acid.

Process 2. Design chineselanguage rings

Design chineselanguage ring is held in the resin received in the process 1, the same procedure as the procedure of the process 8 in example 1.

Process 3. Alkylation

Methyliodide (1 ml), diisopropylethylamine (1 ml) and NMP (5 ml) is added to the resin obtained in process 2, and stirred for 14 hours After removal of solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 4. The restoration of the nitro group

The restoration of the nitro group is carried out in the resin obtained in process 1, the same procedure as in process 4 in example 1.

Process 5. 2-nitrosodiphenylamine

2-nitrosodiphenylamine (1 g), 2,6-di-tert-butyl-4-methylpyridine (1 ml) and dichloromethane (15 ml) is added to the resin obtained in process 4, and stirred at 4°C for 24 h After removal of solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 6. Alkylation

Propyliodide (400 μl), diisopropylethylamine (400 μl) and NMP (2 ml) are added to 200 mg of the resin obtained in process 5, and stirred for 14 hours After removal of solvent, the resin was washed with NMP, methanol and dichlo the methane 3 times each and dried under reduced pressure.

Process 7. Remove 2-nitromethylene group

2-mercaptoethanol (200 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (100 μl) and NMP (2 ml) is added to the resin obtained in process 6, and stirred for 1 h After removal of solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 8. Cleavage from the resin, cleaning

Cleavage from the resin and purification of the resin obtained in process 7, perform the same procedure as in process 10 in example 1 to obtain 38 mg of the desired compound.

MS(ESI MH+): 569

Examples 8-12. The synthesis of compounds of the following formula (E-2), which have a Deputy (deputies) of examples 8-12 table 2

Compounds of examples 8-12 table 2 the following formula (E-2), which have a Deputy (deputies), synthesized by the same procedure as in example 7, except that in the process 6 of example 7 using the appropriate halide.

Example 13. The synthesis of compounds of the following formula (E-3), which have a Deputy (deputies) of example 13 table 3

The process 1. The acylation reaction

1 g of the resin obtained in process 4 of example 1, acelerou the same procedure as the procedure of the process 5 in example 1, except that in the process using 2-amino-4,5-differentyou acid.

Process 2. Design chineselanguage rings

Carbonyldiimidazole (3 g) and NMP (15 ml) is added to the resin obtained in process 1, and stirred for 14 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 3. The substitution of fluorine groups Amin

N,N,N'-trimethylethylenediamine (400 μl) and NMP (2 ml) are added to 200 mg of the resin obtained in process 2, and stirred at 90°C for 14 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 4. Alkylation

The resin obtained in process 3, alkylate the same procedure as the procedure of the process 9 of example 1.

Process 5. Cleavage from the resin, cleaning

Cleavage from the resin and purification of the resin obtained in process 4, carry out the same procedure as in process 10 in example 1, to obtain 39 mg of the desired compound.

MS(ESI MH+): 630

Examples 14-15. The synthesis of compounds of the following formula (E-3), which have a Deputy (deputies) of examples 14-15 table 3

Compounds of examples 14-15 table 3 the following formula (E-3), which have a Deputy (deputies), synthesized by the same procedure as in example 13, except that in the process 3 of example 13 using the appropriate amines.

Example 16. The synthesis of compounds of the following forms of the crystals of (E-4)

The process 1. The acylation reaction

200 mg of the resin obtained in process 4 of example 1, acelerou the same procedure as the procedure of the process 5 in example 1, except that in the process using 2-amino-4,5-differentyou acid.

Process 2. The substitution of fluorine groups Amin

The substitution of the fluorine-group with the amine is carried out in the resin obtained in process 1, the same procedure as process 6 of example 1, except that in the process using N-methylethylamine.

Process 3. The restoration of the nitrogroup, designing chineselanguage rings, alkylation, cleavage from the resin, cleaning

The restoration of the nitro group is carried out in the resin obtained in process 2, the same procedure as the procedure of process 4 in example 1; the design chineselanguage ring is held in the resin, the same procedure as the procedure of the process 8 in example 1; the alkylation is carried out in the resin, the same procedure as the procedure of the process 9 in example 1, and then the cleavage from the resin and purification resin conduct the same procedure as the procedure of the process 10 in example 1, to obtain 59 mg of the desired compound.

MS(ESI MH+): 617

Example 17. The synthesis of compounds of the following formula (E-5)

The process 1. The substitution of fluorine groups Amin

The substitution of the fluorine-group with the amine is carried out in 200 mg of the resin obtained in process is 1 of example 16, the same procedure as the procedure of process 3 in example 13, except that in the process of using N,N'-dimethylethylenediamine.

Process 2. The restoration of the nitrogroup, designing chineselanguage rings, alkylation, cleavage from the resin, cleaning

The restoration of the nitro group is carried out in the resin obtained in process 1, the same procedure as the procedure of process 4 in example 1; the design chineselanguage ring is held in the resin by the same procedure as the procedure of the process 8 in example 1; the alkylation is carried out in the resin by the same procedure as the procedure of the process 9 in example 1; and then spend cleavage from the resin and purification resin conduct the same procedure as the procedure of the process 10 in example 1, to obtain 16 mg of the desired compound.

MS(ESI MH+): 596

Example 18. The synthesis of compounds of the following formula (E-6)

The process 1. The acylation reaction

200 mg of the resin obtained in process 4 of example 1, acelerou the same procedure as the procedure of the process 5 in example 1, except that in the process of using 1-methyl-5-nitro-1H-pyrazole-4-carboxylic acid.

Process 2. The restoration of the nitrogroup, designing chineselanguage rings, alkylation, cleavage from the resin, cleaning

The restoration of the nitro group is carried out in the resin obtained in process 1, the same proced the swarm, as the process 4 in example 1; the design chineselanguage ring is held in the resin by the same procedure as the procedure of the process 8 in example 1; the alkylation is carried out in the resin by the same procedure as the procedure of the process 9 in example 1; and then spend cleavage from the resin and purification resin conduct the same procedure as the procedure of the process 10 in example 1, to obtain 15 mg of the desired compound.

MS(ESI MH+): 516

Example 19. The synthesis of compounds of the following formula (E-7)

The process 1. The acylation reaction

1 g of the resin obtained in process 4 of example 1, acelerou the same procedure as the procedure of the process 5 in example 1, except that in the process using 2-amino-4-nitrobenzoic acid.

Process 2. Design chineselanguage rings, alkylation, reduction of nitrogroup

Design chineselanguage ring is held in the resin obtained in process 1 by the same procedure as the procedure of the process 8 in example 1; the alkylation is carried out in the resin by the same procedure as the procedure of process 3 in example 7; and then restore the nitro group is carried out in the resin by the same procedure as the procedure of process 4 in example 1.

Process 3. Alkylation

Ethyliodide (200 μl), potassium carbonate (200 mg) and NMP (4 ml) are added to 400 mg of the resin obtained in process 2, and the mix is at 80°C for 9 hours After removal of solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 4. Cleavage from the resin, cleaning

Cleavage from the resin and its cleaning is performed in the resin obtained in process 3, the same procedure as the procedure of the process 10 in example 1 to obtain 43 mg of the desired compound.

MS(ESI MH+): 555

Example 20. The synthesis of compounds of the following formula (E-8)

The process 1. The substitution of fluorine groups Amin

The substitution of the fluorine-group with the amine is carried out in 200 mg of the resin obtained in process 5 of example 1, the same procedure as process 6 of example 1, except that in the process using 2-(methylamino)ethanol.

Process 2. Protection of the hydroxyl group of the acetyl group

Acetic anhydride (200 μl), pyridine (200 μl) and NMP (2 ml) is added to the resin obtained in process 1, and stirred for 14 hours After removal of solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 3. The restoration of the nitrogroup, designing chineselanguage ring alkylation

The restoration of the nitro group is carried out in the resin obtained in process 2, the same procedure as the procedure of process 4 in example 1; the design chineselanguage ring is held in the resin of the same process shall Urai, that process 8 in example 1; and then the alkylation is carried out in the resin by the same procedure as the procedure of the process 9 in example 1.

Process 4. Cleavage from the resin, removal of acetyl groups from the protective group

The resin obtained in process 3, process triperoxonane acid containing 5% water for 1 h After filtering, the filtrate is concentrated under reduced pressure. 4M solution of the hydrochloride dioxane (3 ml) and water (600 μl) is added to the obtained residue and stirred at 90°C. for 1.5 hours Then the residue purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 42 mg of the desired compound.

MS(ESI MH+): 585

Example 21. The synthesis of compounds of the following formula (E-9), which has a Deputy (deputies) of example 21 table 4

The process 1. Methylesterase

2M solution in hexane (4.5 ml) trimethylsilyldiazomethane added to a mixture of 2-nitro-3-methylbenzoic acid (1.6 g) and acetone (15 ml) and stirred for 3 hours After removal of the solvent the residue is diluted with ethyl acetate and washed accordingly 1M aqueous solution of hydrate of sodium, water and saturated aqueous sodium chloride. Then, the resulting substance is concentrated and dried to obtain methyl-2-nitro-3-methylbenzoate.

Process 2. Bromination

Benzoyl is eroxia added to a mixture of methyl-2-nitro-3-methylbenzoate (1.6 g), N-bromosuccinimide (2.0 g) and benzene (15 ml) and stirred at 90°C during the night. After removal of solvent the residue is diluted with ethyl acetate and washed respectively with an aqueous solution of sodium thiosulfate, 1M aqueous solution of hydrate of sodium, water and saturated aqueous sodium chloride. Then, the resulting substance is concentrated and dried, and the crude material purified by chromatography on a column of silica gel to obtain methyl 3-methyl bromide-2-nitrobenzoate.

Process 3. Amination

Methyl-3-methyl bromide-2-nitrobenzoate (1.6 g) dissolved in methanol (5 ml). Added a 2M solution of dimethylamine in methanol (6 ml) and stirred over night. After removal of solvent the residue is diluted 1M hydrochloric acid and washed with ethyl acetate. The aqueous layer was omelicheva aqueous solution of sodium hydrate and extracted with ethyl acetate. Spend the usual procedure for obtaining methyl-3-dimethylaminomethyl-2-nitrobenzoate.

Process 4. Hydrolysis of ester

A mixture of methyl-3-dimethylaminomethyl-2-nitrobenzoate (0,72 g) and 6M hydrochloric acid was stirred at 100°C during the night. After cooling the mixture to room temperature, the precipitated crystals are filtered, washed with simple diethyl ether and dried under reduced pressure to obtain the hydrochloride of 3-dimethyl shall aminomethyl-2-nitrobenzoic acid.

H-NMR(DMSO) δ 2,70 (C, 6N), or 4.31 (s, 2H), to 7.84 (m,1H), 8,07 (1H, d, J=7.8 Hz), 8,32 (1H, d, J=7.5 Hz).

Process 5. The formation of the acid chloride

A mixture of the hydrochloride of 3-dimethylaminomethyl-2-nitrobenzoic acid (0.1 g) and thionyl chloride (5 ml) was stirred at 80°C for 3 hours the Solvent is removed, and the residue is dried to obtain 3-dimethylaminomethyl-2-nitrobenzotrifluoride.

Process 6. The acylation reaction

3-dimethylaminomethyl-2-nitrobenzoate (0,69 g), 0.11 g of the resin obtained in process 4 of example 1, 2,6-lutidine (0.04 ml) and NMP (1.5 ml) are mixed and interaction produce during the night. After removal of excess solvent, the residue was washed with NMP, methanol and dichloromethane for 3 times each and dried under reduced pressure.

Process 7. Recovery nitro

The restoration of the nitro group is carried out in the resin obtained in process 6, the same procedure as the procedure of the process 7 of example 1.

Process 8. Design chineselanguage ring carbonyl diimidazol

Design chineselanguage ring is held in the resin obtained in process 7, the same procedure as in process 8 in example 1.

Process 9. Alkylation

The resin obtained in process 8, alkylate the same procedure as the procedure of the process 9 in example 1.

The process 10. Cleavage from the resin

Cleavage from the resin, polucen is in process 9, conduct the same procedure as the procedure of the process 10 in example 1 to obtain 12 mg of the desired compound.

MS(ESI MH+): 569

Example 22. The synthesis of compounds of the following formula (E-9), which has a Deputy (deputies) of example 22 table 4

Methyl-3-(1-pyrrolidinyl)-2-nitrobenzoate get using pyrrolidine instead of dimethylamine in process 3 of example 21. Then the desired connection receive the same procedures as the procedures processes 4-10 in example 21.

MS(ESI MH+): 595

Example 23. The synthesis of compounds of the following formula (E-9), which has a Deputy (deputies) of example 23 table 4

A mixture of 4 mg of the compound of example 21, ethanol (3 ml) and a 4M solution of the hydrochloride/dioxane (2 ml) was stirred at 85°C for 5 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 3.6 mg of the desired compound.

MS(ESI MH+): 597

Example 24. The synthesis of compounds of the following formula (E-9), which has a Deputy (deputies) of example 24 table 4

A mixture of 4 mg of the compound of example 21, dichloromethane (2 ml), triethylamine (10 ml), isopropanol (1 ml), HOBt (15 mg) and EDC hydrochloride (20 mg) is stirred over night. After removal of solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing the th of 0.1% TFA) to obtain 3.6 mg of the desired compound.

MS(ESI MH+): 611

Examples 25-27. The synthesis of compounds of the following formula (E-9), which has a Deputy (deputies) of example 25-97 table 4

Compounds synthesized by the same procedure as the procedure of example 24, except that the corresponding alcohols are used instead of isopropanol.

Example 28. The synthesis of compounds of the following formula (E-10), which has a Deputy (deputies) of example 28 table 5

The desired connection get the same procedure as the procedure of example 21, except that in the source material, using 2-nitro-5-methylbenzoic acid.

MS(ESI MH+): 569

Examples 29-33. The synthesis of compounds of the following formula (E-10), which has a Deputy (deputies) of examples 29-33 table 5

The desired connection get the same procedure as the procedure of example 23 or 24, except that as the starting material using the compound of example 28.

Example 34. The synthesis of compounds of the following formula (E-11), which has a Deputy (deputies) of example 34 table 6: Synthesis of N-(2,6-dichlorobenzoyl)-4-[7-[(dimethylamino)methyl]-1-methyl-2,4-hintlinin-3-yl]-L-vanillaninjaofficial

The process 1. The synthesis of compound methyl ester 4-(hydroxymethyl)-2-nitrobenzoic acid

of 0.51 ml (are 5.36 mmol) of ethylchloride added to a mixture of 1.0 g (4,46 mmol) 4-methoxycarbonyl-3-Latrobe what sainoi acid, 15 ml of tetrahydrofuran and 1.55 ml in (11.2 mmol) of triethylamine in terms of cooling with ice. After stirring for 30 min the precipitated salt is filtered and to the filtrate is added 0.17 g (4,46 mmol) of sodium borohydride and 2 g of ice. After stirring the mixture at room temperature overnight the solvent is removed, and the remainder hold the usual procedure. Then, the resulting material is purified by chromatography on a column of silica gel (30% ethyl acetate/hexane) to obtain specified in the connection header. Yield: 0.64 g (totaling 3.04 mmol), 68%.

Process 2. Synthesis of the hydrochloride of 4-[(dimethylamino)methyl]-2-nitrobenzotrifluoride

0.64 g (totaling 3.04 mmol) of the compound obtained in process 1, dissolved in 10 ml of methylene chloride and 0,635 ml (4,56 mmol) of triethylamine, and thereto is added dropwise under conditions of cooling with ice add 0,282 ml (of 3.64 mmol) methanesulfonanilide. After stirring for 2 h, and conduct routine processing of the mixture in accordance with a customary method to obtain the crude material. The crude material is treated with the same procedures as the procedures processes 3, 4 and 5 in example 21 to obtain specified in the connection header.

Yield: 0.64 g (2,20 mmol), 75%

Process 3

Consistently conduct the same procedure as the procedure of process 6 of example 21 and processes 7, 8, 9 and 10, the example1, using the acid chloride obtained in the process 2, and the resin obtained in process 4 of example 1, to obtain specified in the connection header.

MS(ESI MH+): 569

Example 35. The synthesis of compounds of the following formula (E-11), which has a Deputy (deputies) of example 35 table 6: Synthesis of triptoreline N-(2,6-dichlorobenzoyl)-4-[1-methyl-7-(pyrrolidin-1-ylmethyl)-2,4-hintlinin-3-yl]-L-phenylalanine

The process 1. Synthesis of hydrochloride of 2-nitro-4-(pyrrolidin-1-ylmethyl)of benzoyl chloride

Specified in the header of the connection receives the same procedure as the procedure of example 34, except that as an amine instead of dimethylamine in process 2 of example 34 using Amin.

Process 2. Synthesis of triptoreline N-(2,6-dichlorobenzoyl)-4-[1-methyl-7-(pyrrolidin-1-ylmethyl)-2,4-hintlinin-3-yl]-L-phenylalanine

Consistently conduct the same procedure as the procedure of process 6 of example 21 and processes 7, 8, 9 and 10 in example 1 using the acid chloride obtained in the process 1, and the resin obtained in process 4 of example 1, to obtain specified in the connection header.

MS(ESI MH+): 595

Example 36. The synthesis of compounds of the following formula (E-12): Synthesis of N-(2,6-dichlorobenzoyl)-4-[1-methyl-2,4-dioxo-1,2,3,4-tetrahydrobenzo[g]hinzelin-3(2H)-yl)]-L-phenylalanine

Specified in the header of the connection will receive the same procedures as procedure p is of acesso 5, 8, 9 and 10 in example 1, except that as starting materials using 3-amino-2-naphthaleneboronic acid and the resin obtained in process 4 of example 1.

MS(ESI MH+): 562

Example 37. The synthesis of compounds of the following formula (E-13), which has a Deputy (deputies) of example 37 table 7: Synthesis of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-(methylthio)-2,4-hintlinin-3-yl]-L-phenylalanine

The process 1. Synthesis of 5-methylthio-2-nitrobenzotrifluoride

2.5 ml of 15% aqueous solution of nitromethylene added to a mixture of 1.0 g (5.40 mmol) of 5-fluoro-2-nitrobenzoic acid and 5 ml of ethanol and stirred for 2 hours Then add 10 ml of water and the pH of the mixture was adjusted to 1 with concentrated hydrochloric acid. After separation by filtration of precipitated compounds, it is washed with water, simple ether and hexane and dried to obtain the crude material 5-methylthio-2-nitrobenzoic acid. 3 ml of thionyl chloride are added to the crude material and stirred for 5 hours thionyl chloride is removed to obtain specified in the connection header.

Process 2. N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-(methylthio)-2,4-hintlinin-3-yl]-L-phenylalanine

Specified in the header of the connection will receive the same procedures as the procedures of the process 6 of example 21 and processes 7, 8, 9 and 10 of example 1, except that, as the IP is adnych materials using acid chloride, obtained in the process 1, and the resin obtained in process 4 of example 1.

MS(ESI MH+): 558

Example 38. The synthesis of compounds of the following formula (E-13), which has a Deputy (deputies) of example 38 table 7: Synthesis of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-(methylsulphonyl)-2,4-hintlinin-3-yl]-L-phenylalanine

The process 1. Oxidation

The interaction of a mixture of 130 mg of the resin in the process 2 of example 37 before conducting the same procedure as the procedure of the process 10 in example 1 (cleavage from the resin), 1.5 ml of methylene chloride and 0.20 g of meta-chloroperbenzoic acid should be performed within 24 hours of the Obtained resin was washed with NMP, and mixed with an aqueous solution of sodium bicarbonate and sodium thiosulfate, methanol and methylene chloride 3 times each and dried under reduced pressure.

Process 2. Synthesis of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-(methylsulphonyl)-2,4-hintlinin-3-yl]-L-phenylalanine

The resin obtained in process 1, process the same procedure as the procedure of the process 10 in example 1, to obtain specified in the connection header.

MS(ESI MH+): 590

Example 39. The synthesis of compounds of the following formula (E-14), which has a Deputy (deputies) of example 39 table 8: Synthesis of triptoreline N-(2,6-dichlorobenzoyl)-4-[1-methyl-7-(morpholine-4-yl)-2,4-hintlinin-3-yl]-L-phenylalanine

The process 1. Synthesis of 4-fluoro-2-nitrobenzotrifluoride

5 ml of thionyl chloride add auth to 0.5 g of 4-fluoro-2-nitrobenzoic acid and stirred over night. Thionyl chloride is removed to obtain specified in the connection header.

Process 2. Synthesis of triptoreline N-(2,6-dichlorobenzoyl)-4-[1-methyl-7-(morpholine-4-yl)-2,4-hintlinin-3-yl]-L-phenylalanine

Specified in the header of the connection will receive the same procedures as the procedures of the process 6 of example 21 and processes 6, 7, 8, 9 and 10 of example 1, using as starting materials the acid chloride obtained in the process 1, and the resin obtained in process 4 of example 1.

MS(ESI MH+): 596

Example 40. The synthesis of compounds of the following formula (E-14), which has a Deputy (deputies) of example 40 table 8: Synthesis of triptoreline N-(2,6-dichlorobenzoyl)-4-[1-methyl-7-(pyrrolidin-1-yl)-2,4-hintlinin-3-yl]-L-phenylalanine

Specified in the header of the connection will receive the same procedures as the procedures of example 39, except that pyrrolidin used instead of the research when conducting the same procedure as process 6 of example 1 and the process 2 of example 39.

MS(ESI MH+): 581

Examples 41-42. The synthesis of compounds of the following formula (E-15), which have a Deputy (deputies) of examples 41-42 tabl

Compounds of the following formula (E-15), which have a Deputy (deputies) of examples 41-42 table, synthesize the same procedure as the procedure of example 1, except that in the process 6 of example 1 using the appropriate am the us.

Example 43. The synthesis of compounds of the following formula (E-16), which has a Deputy (deputies) of example 43 table 10

The process 1. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[(2-amino-5-Ioganson)amino]-L-phenylalanine

The complex mixture of methyl ester of N-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine (2,22 g), EDC/HCl (960 mg), HOBT (675 mg), triethylamine (834 μl), 2-amino-5-identies acid (1.3 g) and dichloromethane (100 ml) is stirred over night. The mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain a raw material of the desired connection.

Process 2. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[6-iodine-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in process 1, DMF (120 ml) and carbonyldiimidazole (4.5 g), stirred at 80°C for 4 h the Mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain specified in the connection header.

Process 3. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-iodine-2,4-hintlinin-3-yl]-L-phenylalanine

DMF (20 ml), potassium carbonate (648 mg) and methyliodide (176 μl) are added to the crude material obtained in process 2, and stirred at room temperature overnight. The mixture is extracted with ethyl acetate and treated in accordance with the usual way./p>

Process 4. N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-iodine-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in process 3 (20 mg), 4M solution hydrochloridecan (1 ml) and water (100 ml), stirred at 90°C for 4 h After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 3 mg of the desired compound.

MS(ESI MH+): 638

Example 44. The synthesis of compounds of the following formula (E-16), which has a Deputy (deputies) of example 44 table 10

The process 1. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-cyano-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in process 3 of example 43 (220 mg), DMF (2 ml), tetrakis(triphenylphosphine)palladium (5 mg) and cyanide zinc (79 mg), stirred at 90°C for 4 h the Mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain specified in the connection header.

Process 2. N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-cyano-2,4-hintlinin-3-yl]-L-phenylalanine

The crude material obtained in process 1 (60 mg), treated with the same procedure as the procedure of process 4 in example 43 to obtain specified in the connection header.

MS(ESI MH+): 537

Examples 45 and 46. The synthesis of compounds of the following formula (E-16), to the which have a Deputy (deputies) of examples 45-46 tab.10

The process 1. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-benzyloxycarbonyl-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in process 3 of example 43 (311 mg), palladium acetate (10 mg), benzyl alcohol (99 μl) and triethylamine (134 μl) is stirred in the presence of carbon monoxide at 100°C for 3 hours the Mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain the crude material specified in the connection header.

Process 2. N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-benzyloxycarbonyl-2,4-hintlinin-3-yl]-L-phenylalanine and N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-carboxy-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in process 1 (60 mg), 4M solution hydrochloridecan (1 ml) and water (100 ml), stirred at 90°C for 4 h After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired compound, 6-carboxyl group of compound (5 mg) and 6-benzyloxycarbonylamino compounds (1 mg).

MS(ESI MH+): 556 (6-carboxylic connection)

MS(ESI MH+): 646 (6-benzyloxycarbonyl connection)

Example 47. The synthesis of compounds of the following formula (E-17)

The process 1. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[2,4-d is oxo-1,2,3,4-tetrahydro-3-(2H)pyrido[3,2-d]pyrimidinyl]-L-phenylalanine

Specified in the header of the connection will receive the same procedures as the procedures of the process 1 in example 43, except that the use of 2-carboxy-3-aminopyridine instead of 2-amino-5-identies acid, and then process 2 of example 43.

Process 2. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)pyrido[3,2-d]pyrimidinyl]-L-phenylalanine

A mixture of the crude material obtained in process 1, triphenylphosphine (61 mg), methanol (15 ml), 40% solution in toluene (118 mg) diisopropylperoxydicarbonate acid and dichloromethane (2 ml) is stirred over night. The mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain specified in the connection header.

Process 3. N-(2,6-dichlorobenzoyl)-4-[1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)pyrido[3,2-d]pyrimidinyl]-L-phenylalanine

The crude material obtained in process 2 (20 mg), treated with the same procedure as the procedure of process 4 in example 43 to obtain specified in the connection header.

MS(ESI MH+): 513

Example 48. The synthesis of compounds of the following formula (E-18)

Connection get the same procedure as the procedure of example 47, except that use 3-amino-4-carboxamidine instead of 2-carboxy-3-aminopyridine in process 1 of example 47.

Example 49. Synthesis of compound words by the blowing of the formula (E-19), which has a Deputy (deputies) of example 49 tabl

The process 1. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-(2-t-butoxycarbonylamino)-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in process 3 of example 43 (630 mg), DMF (5 ml), palladium acetate (22 mg), t-butyl acrylate (283 μl) and triethylamine (270 μl) was stirred at 70°C for 3 hours the Mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain specified in the connection header.

Process 2

A mixture of the crude material obtained in process 1, dichloromethane and TFA was stirred at room temperature for 1 h After removal of the solvent mixture of the crude material, 4M solution hydrochloridecan water and stirred at 90°C for 4 h After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 10 mg of the desired compound.

MS(ESI MH+): 582

Example 50. The synthesis of compounds of the following formula (E-19), which has a Deputy (deputies) of example 50 tabl

The process 1. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-(trimethylsilylethynyl)-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in about the Jesse 3 of example 43 (6,58 mg), DMF (5 ml), palladium acetate (226 mg), trimethylsilylethynyl (2,9 ml) and triethylamine (2.8 ml) is stirred in the presence of carbon monoxide at 50°C during the night. The mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain specified in the connection header.

Process 2. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-carboxy-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in process 1 (4,2 g), tetrahydrofuran (100 ml) and tetrabutylammonium fluoride (3.3 grams) was stirred at room temperature for 2 hours the Mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain specified in the connection header.

Process 3

The triethylamine (70 μl) and ethylchloride (28 μl) are added to a mixture of the crude material obtained in process 2 (142 mg), and tetrahydrofuran (50 ml) under conditions of cooling with ice and stirred for 30 minutes After adding ammonia water (1 ml) in a reaction solvent and warming it to room temperature, the reaction mixture is stirred for 2 hours Then the mixture is extracted with ethyl acetate and treated in accordance with the usual method. A mixture of the crude material, 4M solution hydrochloridecan (2 ml) and water (200 μl) was stirred at 90°C for 4 hours of Posiadania of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 7 mg of the desired compound.

MS(ESI MH+): 555

Example 51. The synthesis of compounds of the following formula (E-19), which has a Deputy (deputies) of example 51 tabl

The process 1. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-(2-t-butoxycarbonylmethyl)-2,4-hintlinin-3-yl]-L-phenylalanine

Mix number 5/6 of the crude material obtained in process 1 of example 49, methanol (10 ml), Nickel-chloride-6-hydrate (191 mg) and sodium borohydride (62 mg) was stirred at room temperature for 6 hours the Mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain specified in the connection header.

Process 2. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-(2-carbonylethyl)-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in process 1, dichloromethane (2 ml) and TFA (2 ml) was stirred at room temperature for 1 h the Solvent is removed to obtain the crude material desired connection.

Process 3

A mixture of the crude material obtained in process 2, 4M solution hydrochloridecan water and stirred at 90°C for 4 h After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to receive the deposits of the desired connection.

MS(ESI MH+): 584

Example 52. The synthesis of compounds of the following formula (E-19), which has a Deputy (deputies) of example 52 table

The triethylamine (190 μl) and ethylchloride (80 μl) is added to the mixture quantity 5/6 of the crude material obtained in process 2 of example 51, and tetrahydrofuran (20 ml) under conditions of cooling with ice and stirred for 30 minutes After adding two or three pieces of ice and sodium borohydride (20 mg) to the reaction solvent and warming it to room temperature, the reaction mixture is stirred for 2 hours Then the mixture is extracted with ethyl acetate and treated in accordance with the usual method. The crude material dissolved in a 4M solution hydrochloridecan (2 ml) and water (200 μl) and stirred at 90°C for 4 h After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 7 mg of the desired compound.

MS(ESI MH+): 570

Example 53. The synthesis of compounds of the following formula (E-20), which has a Deputy (deputies) of example 53 table

The process 1. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-hydroxymethyl-2,4-hintlinin-3-yl]-L-phenylalanine

The triethylamine (970 μl) and ethylchloride (400 μl) is added to a mixture of the crude material obtained in process 2 of the example 50 (142 mg), and tetrahydrofuran (100 ml) under conditions of cooling with ice and stirred for 30 minutes After filtration, to the filtrate add 2 or 3 slices of ice and sodium borohydride (160 mg). After warming it to room temperature, the reaction mixture is stirred for 2 hours Then the mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain the desired connection.

Process 2. N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-chloromethyl-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in process 1, 4M solution hydrochloridecan (4 ml) and water (400 μl), stirred at 80°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 7 mg of the desired compound.

Process 3

The mixture of substances obtained in process 2 (20 mg), acetonitrile (1 ml) and research (6 ml) was stirred at room temperature for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 3 mg of the desired compound.

MS(ESI MH+): 611

Examples 54-58. The synthesis of compounds of the following formula (E-20), which have a Deputy (deputies) of examples 54-58 tabl

These compounds are synthesized that W is the procedure as the process 3 of example 53, except that in the process instead of the research using the appropriate amines.

These NMR of the compound of example 54:

1H-NMR (DMSO-d6) δ 9,13 (d, 1H, J=8,4 Hz), 8,69-8, 97 (user., 2H), 8,23 (d, 1H, J=2.1 Hz), 7,86 (DD, 1H, J= 8,6, 2,l Hz), EUR 7.57 (d, 1H, J=8.7 Hz), 7,34-the 7.43 (m, 6H), 7,18 (d, 2H, J=8,4 Hz), 4,70-4,78 (m, 1H), 4,22-4.26 deaths (m, 2H), 3,53 (s, 3H), up 3.22 (DD, 1H, J=14,2, 4,3 Hz), 2.91 in-3,00 (m, 3H), 1,19 (t, 3H, J=7,3 Hz).

Example 59. The synthesis of compounds of the following formula (E-21)

Process 1

A mixture of the crude material obtained in process 3 of example 43, DMSO (2 ml), copper iodide (11 mg), potassium carbonate (273 mg) and aminoimidazole (273 mg) was stirred at 130°C for 2 hours the Mixture is extracted with ethyl acetate and treated in accordance with the usual method. After removal of solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) and carry out the hydrolysis of ester by the same procedure as the procedure of process 4 in example 43 to obtain specified in the connection header.

MS(ESI MH+): 593

Example 60. The synthesis of compounds of the following formula (F-22), which have a Deputy (deputies) of example 60 table 13

The complex mixture of methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-hydroxymethyl-2,4-hintlinin-3-yl]-L-phenylalanine (7 mg), which is produced by the same procedure as the procedure of the process 1 in which the Rimera 53, and purification by high-performance liquid chromatography, tetrahydrofuran (1 ml), water (1 ml) and lithium hydroxide (1.2 mg) was stirred at room temperature for 2 hours the Mixture is extracted with ethyl acetate, treated in accordance with the usual way and purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 1 mg of the desired compound.

MS(ESI MH+): 542

Example 61. The synthesis of compounds of the following formula (F-22), which have a Deputy (deputies) of example 61 table 13

The mixture of substances obtained in process 2 of example 53 (40 mg), methanol (1 ml) and 40% solution of sodium methoxide in methanol (1 ml) was stirred at room temperature for 2 hours the Mixture was worked up in accordance with the usual way and purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 4 mg of the desired compound.

MS(ESI MH+): 556

Example 62. The synthesis of compounds of the following formula (E-23), which have a Deputy (deputies) of example 62 table 14

The process 1. The acylation reaction

3-dimethoxymethyl-2-nitrobenzoic acid (160 mg), DIC (58 μl), HOAt (101 mg) and NMP (1.5 ml) are mixed and stirred for 3 hours Then the mixture was added to 200 mg of the resin obtained in process 4 in example 1, and the interaction is carried out for 17 hours After removal and Bytca solvent, the resin was washed with NMP, methanol and dichloromethane for 3 times each and dried under reduced pressure.

Process 2. Recovery nitro

SnCl2·2H2O (1.5 g), NMP (3 ml) and EtOH (150 μl) is added to the resin obtained in process 1, and the interaction is carried out at room temperature for 16 hours After removal of solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 3. Design chineselanguage ring carbonyl diimidazol

Carbonyldiimidazole (400 mg) and NMP (2 ml) is added to the resin obtained in process 2, and stirred at 90°C for 21 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 4. Alkylation

Methyliodide (200 μl), tetramethylguanidine (200 μl) and NMP (2.5 ml) is added to the resin obtained in process 3, stirred for 1 h and washed with methanol and NMP 3 times each after removal of excess solvent. After repeating each of these processes on 3 times, the resin is washed with methanol and dichloromethane for 3 times each and dried under reduced pressure.

Process 5. Cleavage from the resin

The resin obtained in process 4, process triperoxonane acid containing 5% water for 1 h After filtering Phi is Trat concentrated under reduced pressure. The residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

MS(ESI MH+): 556

Example 63. The synthesis of compounds of the following formula (E-23), which have a Deputy (deputies) of example 63 table 14

The desired connection get the same procedure as the procedure of example 62, except that 4-methoxymethyl-2-nitrobenzoic acid is used instead of 3-methoxymethyl-2-nitrobenzoic acid.

MS(ESI MH+): 556

Example 64. The synthesis of compounds of the following formula (E-24)

The process 1. Nitration

Β-picoline-N-oxide (10 mg) is added slowly to a mixed concentrated sulfuric acid (35 ml) and concentrated nitric acid (27.5 ml) at 0°C, gradually warm up to 105°C and stirred for 4 h the Reaction solvent, cooled to room temperature, poured into ice (100 g) and added sodium carbonate (60 g). After separation by filtration of the precipitate, the reaction mixture was washed with water and dried under reduced pressure to obtain of 5.83 g of 3-methyl-4-nitropyridine-N-oxide.

Process 2. Oxidation

The substance obtained in process 1 (of 5.83 g), and dihydrobromide sodium (11.4 g) is slowly added to concentrated sulfuric acid (39,5 ml) at 0°C and hold interaction at room temperature for 4 h Re is clanny solvent was poured into ice (80 g) and thereto is added slowly to water (100 ml). Then to it add the sodium hydrosulphate to the disappearance of the orange color of hexavalent chromium, and the precipitate was separated by filtration. The filtered solid matter added ethyl acetate and 1 N. hydrochloric acid, extracted and washed. The ethyl acetate layer concentrated under reduced pressure to obtain a powder of 4-nitronicotinic acid-N-oxide (3,23 g).

Process 3. Catalytic reduction

Water (75 ml), 28% ammonia water (1.2 ml) and 10% Pd/C (0.8 g) is added to the substance obtained in process 2 (1.5 g), and stirred in hydrogen atmosphere (3.8 kg/cm2within 8 hours the Reaction solvent is filtered and the filtrate concentrated under reduced pressure, so that its liquid measure was Add 15 ml. of 1 N. hydrochloric acid to the solvent became slightly acid, and the precipitated insoluble materials are filtered off. The residue is washed with water and dried under reduced pressure to obtain a powder of 4-aminonicotinic acid (620 mg).

Process 4. The acylation reaction

The substance obtained in process 3 (207 mg), DIC (116 μl), HOAt (204 mg), DIEA (131 μl) and NMP (3 ml)are mixed and stirred for 10 hours Then the mixture was added to 200 mg of the resin obtained in process 4 in example 1, and the interaction continued for 14 hours After removal of excess solvent, the resin washed the t NMP, methanol and dichloromethane for 3 times each and dried under reduced pressure.

Process 5. Design chineselanguage ring carbonyl diimidazol

Carbonyldiimidazole (400 mg) and NMP (2 ml) is added to the resin obtained in process 4, and stirred at 90°C for 18 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 6. Alkylation

Triphenylphosphine (520 mg), methanol (80 ml), 40% solution diisopropylperoxydicarbonate acid in toluene (1 ml) and dichloromethane (2 ml) is added to the resin obtained in process 5, and stirred for 19 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane for 3 times each and dried under reduced pressure.

Process 7. Cleavage from the resin

The resin obtained in process 6 process triperoxonane acid containing 5% water for 1 h After filtering, the filtrate is concentrated under reduced pressure. The residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 28 mg of the desired compound.

MS(ESI MH+): 513

Examples 65-81. The synthesis of compounds of the following formula (E-25), which have a Deputy (deputies) of examples 65-81 table-1 and 15-2

The desired compounds are obtained from edowski ways And With:

And (Melastomataceae)

The corresponding carboxylic acid is added to a mixture of methanol and thionyl chloride and stirred over night. After removal of solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired compounds (compounds).

C. a Mixture of the corresponding carboxylic acid, in a suitable solvent (solvents, such as DMF and dichloromethane, a suitable organic bases (bases), such as triethylamine and diisopropylethylamine corresponding alcohols, if necessary, HOBt and EDC hydrochloride is stirred over night. After concentration, the mixture was purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired compounds (compounds).

C. a Mixture of the corresponding carboxylic acids, the corresponding alcohols and 4M solution hydrochloridecan, stirred at 90°C for several hours. After removal of solvent the crude material purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired compounds (compounds).

Examples 82-86. The synthesis of compounds of the following formula (E-26), which have a Deputy (deputies) of examples 82-86 table 16

The desired connection is in receive the same procedures, as the procedure of any of paragraphs a, b, C in the above examples.

Examples 87-88. The synthesis of compounds of the following formula (E-27), which have a Deputy (deputies) of examples 87-88 table 17

Example 87

The substance obtained in process 2 of example 50, clear high performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

MS(ESI MH+): 570

Example 88

Methanol (2 ml) and 2M solution trimethylsilyldiazomethane in hexane (1 ml) is added to the substance obtained in process 2 of example 50, and stirred for 3 hours After removal of the solvent the resulting material purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

MS(ESI MH+): 584

Example 89. The synthesis of compounds of the following formula (E-28)

The process 1. Methyl ester of N-(2,6-dichlorobenzoyl)-4-[1-methyl-6-(hydroxymethylamino)-2,4-hintlinin-3-yl]-L-phenylalanine

A mixture of the crude material obtained in process 3 of example 43 (100 mg), dimethylacetamide (2 ml), copper iodide (3 mg), aminoethanol (0,011 ml) and carbonate potassium (41 mg) was stirred at 80°C during the night. After extracting the mixture with ethyl acetate and removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, is each, containing 0.1% TFA) to obtain the desired connection.

Process 2.

A mixture of the crude material obtained in process 2, 4M solution hydrochloridecan (2 ml) and water (200 μl), stirred at 90°C for 4 h After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 1 mg of the desired compound.

MS(ESI MH+): 571

Example 90. The synthesis of compounds of the following formula (E-29)

A mixture of 40 mg of carboxylic acid, obtained in example 34, 5 ml ethanol and 5 ml of dioxane containing 4 M hydrochloride, stirred at 90°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

MS(ESI MH+): 597

H-NMR (DMSO) δ of 1.20 (3H, t), 2,80 (6H, s), 2.95 and is 3.25 (2H, m), 3,55 (3H, s)to 4.15 (2H, square), of 4.45 (2H, s), 4,80 (1H, m), 7,20 (2H, d), 7,35 is 7.50 (6H, m), of 7.70 (1H, s), 8,15 (1H, d), a 9.25 (1H, d).

Example 91. The synthesis of compounds of the following formula (E-30)

A mixture of 50 mg of carboxylic acid, obtained in example 54, 0.5 ml of benzyl alcohol and 1 ml of dioxane containing 4 M hydrochloride, stirred at 90°C for 4 h After concentration of the reaction solvent mixture purified by high-performance liquid chromatography (water/acetonitrile, each containing 1% TFA) to obtain the desired connection.

MS(ESI MH+): 659

H-NMR (DMSO) δ of 1.20 (3H, s), 2,90 is 3.40 (4H, m), 3,55 (3H, s), 4,25 (2H, t), of 4.90 (1H, m), 5,20 (2H, s), 7,20 (2H, d), 7,30 is 7.50 (10H, m), 7,60 (1H, d), of 7.90 (1H, d), of 8.25 (1H, d), 8,80 (2H, usher.), of 9.30 (1H, d).

Example 92. The synthesis of compounds of the following formula (E-31)

The process 1. The acylation reaction

A mixture of 600 mg of N-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine obtained in process 4 of example 1, where the carboxyl group is linked to Wang resin, 730 mg of 2-amino-4,5-diferential acid, 320 μl of DIC (diisopropylcarbodiimide), 570 mg of HOAt (1-hydroxy-7-isobenzofuranone) and 6 ml of NMP (N-methylpyrrolidone) is shaken at room temperature overnight. After removal of solvent the residue was washed with NMP, methanol, dichloromethane and simple diethyl ether and dried under reduced pressure.

Process 2. Design chineselanguage ring carbonyl diimidazol

Carbonyldiimidazole (600 mg) and NMP (4,9 ml) is added to the resin obtained in process 1, and stirred at room temperature for 13 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane to 4 times each and dried under reduced pressure. Carbonyldiimidazole (600 mg) and NMP (4,9 ml) is added to the resin and stirred at room temperature for 16 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane to 4 times each and dried under reduced pressure what to eat.

Process 3. The substitution of fluorine groups Amin

The imidazole (600 mg), diisopropylethylamine (600 μl) and NMP (3 ml) are added to 340 mg of the resin obtained in process 2, and the interaction is carried out in the course of 14.5 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane to 4 times each and dried under reduced pressure.

Process 4. Alkylation

Triphenylphosphine (780 mg), methanol (120 ml), 40% solution diisopropylperoxydicarbonate acid in toluene (1.5 ml) and dichloromethane (3 ml) is added to the resin obtained in process 3, and stirred for 18,5 hours After removal of excess solvent, the resin was washed with NMP, methanol and dichloromethane to 4 times each and dried under reduced pressure.

Process 5. Cleavage from the resin, cleaning

Cleavage from the resin and purification of the resin obtained in process 4, carry out the same procedure as in process 10 in example 1, to obtain 95 mg of the desired compound.

MS(ESI MH+): 596

1H-NMR (DMSO-d6) δ 2,94 totaling 3.04 (1H, m), 3,20-of 3.27 (1H, m), 4,71-4,80 (1H, m), 7.23 percent (2H, d, J=8,4 Hz), 7,39-7,47 (5H, m), 7,58 (1H, s), 7,87 (1H, d, J=6.0 Hz), 8,04-8,10 (2H, m), 8,96 (1H, s)to 9.15 (1H, d, J=8,l Hz), 12,80 (1H, users).

Example 93. The synthesis of compounds of the following formula (F-32)

The process 1. Methyl ester of N-(tert-butoxycarbonyl)-4-(6-dimethylamino-2,4-hintlinin-3-yl)-L-phenylalanine

3 g complex methyl ester of N-(t-butoxycarbonyl)--amino-L-phenylalanine, 2,73 g of the dihydrochloride methyl-2-amino-5-(dimethylamino)benzoate, 1,65 g CDI (carbonyldiimidazole) and 50 ml of acetonitrile is stirred at room temperature. Then added to 2.8 ml of triethylamine and stirred at 60°C over night. After removal of solvent, the obtained residue is extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. After removal of solvent, the obtained residue is purified by chromatography on a column of silica gel to obtain 2 g specified in the connection header.

Process 2. Synthesis dihydrochloride difficult methyl ester 4-(6-dimethylamino-1-methyl-2,4-hintlinin-3-yl)-L-phenylalanine

A mixture of 500 mg of chineselanguage obtained in the process 1, 0.3 ml of methanol, 0.4 g of triphenylphosphine, 0.7 ml of a 45% solution diisopropylperoxydicarbonate acid in toluene and dichloromethane is stirred overnight. After removal of solvent the residue is treated in accordance with the usual way, using dichloromethane as the extracting solvent to obtain the crude material difficult methyl ester of N-(t-butoxycarbonyl)-4-(6-dimethylamino-1-methyl-2,4-hintlinin-3-yl)-L-phenylalanine. A mixture of the crude material, 5 ml of dioxane containing 4 M hydrochloride and 5 ml of dichloromethane, stirred at room temperature within 5 hours After removal of solvent, the obtained residue was washed with dichloromethane to obtain the crude material specified in the connection header.

Process 3. The synthesis of compound methyl ester trifenatate N-(2-chloro-6-perbenzoic)-4-(6-dimethylamino-1-methyl-2,4-hintlinin-3-yl)-L-phenylalanine

A mixture of 100 mg of the amine of the crude material obtained in process 2, 80 mg of 2-chloro-6-tormentilla, 100 μl of triethylamine and 4 ml of DMF (dimethylformamide) was stirred at room temperature and processed in accordance with a conventional method using ethyl acetate as the extracting solvent to obtain the crude material. The crude material is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 51 mg of the desired compound.

MS(ESI MH+): 553

Process 4. Synthesis of triptoreline N-(2-chloro-6-perbenzoic)-4-(6-dimethylamino-1-methyl-2,4-hintlinin-3-yl)-L-phenylalanine

A mixture of 15 mg of complex compounds methyl ester obtained in process 3 of example 93, 3 ml of dioxane containing 4 M hydrochloride and 2 ml of water was stirred at 80°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

p> MS(ESI MH+): 539

Example 94. The synthesis of compounds of the following formula (E-33)

The process 1. The acylation reaction

A mixture of 50 mg of the amine compounds obtained in process 2 of example 93, 38 mg 2,4-dichloropyridine-2-carboxylic acid, obtained by the same procedure as the procedure Eur. J. Org. Chem. 2001, 1371-1376, 30 mg of HOAt, 38 mg EDC/HCl (hydrochloride 1-dimethylaminopropyl-3-ethylcarbodiimide), 560 μl of triethylamine and 2 ml of DMF was stirred at 40°C. the Reaction solvent is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA (triperoxonane acid)) to obtain the desired connection.

MS(ESI MH+): 570

Process 2. Hydrolysis of ester

The desired connection get the same procedure as the procedure of process 4 in example 93, using the ester obtained in the process 1.

MS(ESI MH+): 556

Example 95. The synthesis of compounds of the following formula (E-34)

The desired connection get the same procedure as the procedure of process 4 in example 92, using the resin obtained by the same procedure as the process 2 of example 92.

MS(ESI MH+): 548

Example 96. The synthesis of compounds of the following formula (E-35)

Hydrochloride lithium (7 mg), methanol (3.5 ml), tetrahydrofuran (0.5 ml) and acetone (2.0 ml) is added to the compound obtained in example 88 (60 mg), and stirred at room temperature for 30 min. P is, after removal of excess solvent, the residue is purified by high-performance liquid chromatography (water/ acetonitrile, each containing 0.1% TFA) to obtain 6.3 mg of the desired compound.

MS(ESI MH+): 570

Example 97. The synthesis of compounds of the following formula (E-36):

The process 1. N-(2,6-dichlorobenzoyl)-4-(1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimido[4,5-d]pyrimidine-3(2H)-yl)-L-phenylalanine

The mixture of compounds obtained in example 131 (15 mg), 4M solution hydrochloridecan (1 ml) and water (200 μl) was stirred at 90°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/ acetonitrile, each containing 0.1% TFA) to obtain 12 mg of the desired compound.

MS(ESI MH+): 514

Examples 98-99. The synthesis of compounds of the following formula (E-37), which have a Deputy (deputies) of examples 98-99 tabl

Compounds synthesized by the same procedure as process 3 of example 53, except that, instead of the research, using the appropriate amines.

MS(ESI MH+) connection data of example 99: 555

These NMR of compound of example 99:

1H-NMR (DMSO-d6) δ of 2.58 (3H, t, J=5,1 Hz), 2,98 (1H, DD, J=14,1, 10,5 1H) 3,24 (1H, DD, J=14,1, and 4.5 Hz), 3,55 (3H, s), 4,22-to 4.28 (1H, m), 4,6l-4,80 (1H, m), 7,20 (2H, d, J=8,4 Hz), 7,39-7,46 (5H, m), 7,60 (1H, d, J=9.0 Hz), 7,88 (1H, d, J=6.9 Hz), 8,24 (1H, d, J=1.5 Hz), 8,80 (2H, users), to 9.15 (1H, d, J=8.7 Hz), 12,90 (1H, users)

Example 100. The synthesis of compounds of the following formula (E-38):

The process 1. Alkylation

Methyliodide (200 μl), the carbonate to the lia (200 mg) and NMP (4 ml) are added to the resin, obtained in process 2 of example 19 (400 mg), and stirred at 60°C for 9 h After removal of solvent, the resin was washed with NMP, methanol and dichloromethane 3 times each and dried under reduced pressure.

Process 2. Cleavage from the resin, cleaning

Cleavage from the resin and its cleaning is performed in the resin obtained in process 1, the same procedure as the procedure of the process 10 in example 1, to obtain 31 mg of the desired compound.

MS(ESI MH+): 555

Examples 101-121. The synthesis of compounds of the following formula (E-39), which have a Deputy (deputies) of examples 101-121 table 19-1, 19-2 and 19-3

The desired connections receive the following methods a to E:

And (Melastomataceae)

The corresponding carboxylic acid is added to a mixture of methanol and thionyl chloride and stirred over night. After removal of solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired compounds (compounds).

C. a Mixture of the corresponding carboxylic acid, in a suitable solvent (solvents, such as DMF and dichloromethane, a suitable organic bases (bases), such as triethylamine and diisopropylethylamine corresponding alcohols, if necessary, HOBt and EDC hydrochloride is stirred over night. After concentration of the mixture cleans vsokoaffinny the Noah liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired compounds (compounds).

C. a Mixture of the corresponding carboxylic acids, the corresponding alcohols and 4M solution hydrochloridecan, stirred at 90°C for several hours. After removal of solvent the crude material purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired compounds (compounds).

D. a Mixture of the corresponding carboxylic acid, methyl alcohol and 2.0m solution trimethylsilyldiazomethane in hexane was stirred at room temperature for several minutes. After removal of solvent the crude material purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired compounds (compounds).

That is, the Mixture of the corresponding carboxylic acids, ethylene glycol, EDC/HCl, HOAt and dichloromethane is stirred. After removal of solvent the crude material purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired compounds (compounds).

These NMR of compound of example 111:

1H-NMR (DMSO-d6) δ 9,23 (d, 1H, J=8,l Hz), 8,64-8,79 (user., 2H), 8,23 (d, 1H, J=2.2 Hz), 7,86 (DD, 1H, J=2,l Hz, J=8.7 Hz), EUR 7.57 (d, 1H, J=8.7 Hz), 7,35-7,45 m, 6H), 7,19 (d, 2H, J=8,3 Hz), 4,93 (Sept., 1H, J=6.3 Hz), and 4.75 (m, 1H), 4,24 (m, 2H), 3,53 (s, 3H), 3,17 (DD, 1H, J=5.0 Hz, J=14,5 Hz), 2,94-3,00 (m, 3H), of 1.21 (d, 3H, J=6.2 Hz), 1,19 (t, 3H, J=7,3 Hz)of 1.17 (d, 3H, J=6.2 Hz).

The corresponding carboxylic acid, which is a synthetic raw material of the compound of example 111, is a compound of example 54.

In addition, the compound of example 111 receive the same treatment as the process 3 of example 53, except that the connection process 1 in example 174 is used as a raw material, and ethylamine is used instead of the research.

Examples 122-123. The synthesis of compounds of the following formula (E-40), which have a Deputy (deputies) of examples 122-123 tabl

The desired connections get the same procedure as the procedure of any of paragraphs C or D in the above examples.

Example 124. The synthesis of compounds of the following formula (E-41)

The desired connection get the same procedure as the procedure of paragraph (D in the above examples, 101-121.

MS(ESI MH+): 610

Example 125. The synthesis of compounds of the following formula (E-42)

The desired connection get the same procedure as the procedure of paragraph (D in the above examples, 101-121.

MS(ESI MH+): 530

Examples 126-127. The synthesis of compounds of the following formula (E-43), which have a Deputy (deputies) of examples 126-127 table 21

Example 126

Neocide the hydrated material, obtained in process 2 of example 47, treat in accordance with a customary method to obtain specified in the connection header.

Example 127

Isopropanol (2 ml) and concentrated sulfuric acid (0.1 ml) is added to the substance obtained in example 47 (50 mg), and heated to boiling in a vessel under reflux for 2 hours After removal of solvent, the reaction mixture is treated in accordance with a customary method to obtain specified in the connection header.

Example 128. The synthesis of compounds of the following formula (E-44)

The desired connection get the same procedure as the procedure of paragraph (D in the above examples, 101-121.

MS(ESI MH+): 527

Example 129. The synthesis of compounds of the following formula (E-45)

The process 1. Methyl ester 4-[(4-aminopyrimidine-5-yl)carbonyl]amino-N-(2,6-dichlorobenzoyl)-L-phenylalanine

The complex mixture of methyl ester of N-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine (1.0 g), EDC/HCl (783 mg), HOAt (555 mg), triethylamine (747 μl), 4-aminopyrimidine-karbonovoi acid (417 mg) and dichloromethane (15 ml) is stirred over night. After dilution of the mixture with dichloromethane and wash with saturated sodium bicarbonate and water, the organic layer dried over sodium sulfate and concentrated. The residue was washed with dichloromethane to obtain 145 mg of the crude material indicated in the header is VCE connection.

Process 2. Methyl ester of N-(2,6-dichlorobenzoyl)-4-(2,4-dioxo-1,2,3,4-tetrahydropyrimido[4,5-d]pyrimidine-3-(2H)-yl)-L-phenylalanine

A mixture of the crude material obtained in process 1 (145 mg), DMF (10 ml) and carbonyldiimidazole (482 mg), stirred at 110°C for 24 h the Mixture is extracted with ethyl acetate and treated in accordance with a customary method to obtain the crude material specified in the connection header.

Process 3. Methyl ester of N-(2,6-dichlorobenzoyl)-4-(1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimido[4,5-d]pyrimidine-3-(2H)-yl)-L-phenylalanine

DMF (2 ml), potassium carbonate (62 mg) and methyliodide (40 μl) are added to the crude material obtained in process 2, and stirred at room temperature for 3 hours the Mixture is extracted with ethyl acetate and purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired compounds (compounds).

MS(ESI MH+): 528

Example 131. The synthesis of compounds of the following formula (E-46)

The desired connection get the same procedure as the procedure of paragraph (D in the above examples, 101-121.

MS(ESI MH+): 583

Example 132. The synthesis of compounds of the following formula (E-47)

The desired connection get the same procedure as the procedure of paragraph (C in the above examples, 101-121.

MS(ESI MH+): 624

The use of the s 133-134. The synthesis of compounds of the following formula (E-48), which have a Deputy (deputies) of examples 133-134 table 22

Example 133

A mixture of compound of example 54 (19 mg), acetonitrile (3 ml), triethylamine (18 μl) and methylchloroform (5 ml) was stirred at room temperature for 5 minutes After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 17 mg of the desired compound (compounds).

MS(ESI MH+): 641

Example 134

A mixture of compound of example 54 (26 mg), acetonitrile (3 ml), triethylamine (20 μl) and acetylchloride (6 ml) was stirred at room temperature for 10 minutes After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 22 mg of the desired compound (compounds).

MS(ESI MH+): 625

Reference example 1. Synthesis of 3-methoxymethyl-2-nitrobenzoic acid

The process 1. Methoxylamine

A solution of sodium methoxide (197 mg) in methanol (4,7 ml) is added dropwise to a mixture of methyl-3-methyl bromide-2-nitrobenzoate (1 g) and methanol (7 ml) under heating by boiling under reflux. After 2 min the mixture is cooled with ice, and added dropwise to 1.82 ml of 4M solution hydrochloridecan. After removal of the solvent add a simple di is tilby ether and water, and the organic layer dried over sodium sulfate. After removal of solvent, the obtained residue is purified by chromatography on a column of silica gel to obtain 621 mg methyl-3-methoxymethyl-2-nitrobenzoate.

Process 2. The hydrolysis of complex methyl ether

A mixture of 582 mg of the substance obtained in process 1, 10 ml of 1,4-dioxane and 10 ml of 6M hydrochloric acid was stirred at 80°C for two nights. After adding ethyl acetate and 1N hydrochloric acid to the reaction mixture and extraction, the organic layer was washed with aqueous solution of sodium hydroxide. Next, the aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. After removal of solvent the residue is dried under reduced pressure to obtain 288 mg specified in the connection header.

Reference example 2. Synthesis of 4-methoxymethyl-2-nitrobenzoic acid

The process 1. Recovery of carboxylic acids

A solution of 1.0m of a complex of borane-tetrahydrofuran in tetrahydrofuran is added dropwise to a solution of 2.25 g of 4-methoxycarbonyl-3-nitrobenzoic acid in tetrahydrofuran (45 ml) and stirred at room temperature for 48 hours To it add methyl alcohol (2 ml) and 1 N. hydrochloric acid (10 ml) and concentrated. After adding ethyl acetate and water carry out the separation of liquids. The PR is anceschi layer was washed with saturated sodium bicarbonate and dried over sodium sulfate. After removal of solvent the crude material purified by chromatography on a column of silica gel to obtain 1,33 g methyl-4-hydroxymethyl-2-nitrobenzoate.

Process 2. Chlorination

A mixture of 1.33 g of benzyl alcohol obtained in the process 1, 18 ml of tetrahydrofuran, 60 ml simple diethyl ether, 1.8 ml of thionyl chloride and 91 μl of pyridine was stirred at room temperature overnight. After adding ethyl acetate and 10 ml of 1 N. hydrochloric acid carry out the separation of liquids. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After removal of solvent, the mixture is dried under reduced pressure to obtain 1.29 g of methyl-4-chloromethyl-2-nitrobenzoate.

Process 3. Metacycline, hydrolysis of complex methyl ether

40 ml of methyl alcohol and 1.22 g of sodium methoxide is added to 1.29 g of benzylchloride obtained in the process 2, and stirred at 80°C. for 1.5 hours After cooling the reaction solution to room temperature, added with 10 ml water and stirred over night. Added ethyl acetate and water, an aqueous solution of 0.1 G. of sodium hydroxide and a saturated aqueous solution of sodium chloride and carry out the separation of liquids. The aqueous layer was acidified with hydrochloric acid and extracted with et is lacerata. After removal of solvent the crude material purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 450 mg of the desired compound.

Reference example 3. Synthesis of methyl 2-amino-5-(dimethylamino)benzoate/dihydrochloride

Process 1:

30.0 g (148 mmol) of 5-chloro-2-nitrobenzoic acid dissolved in 78 ml (744 mmol) of an aqueous solution of 50% dimethylamine in terms of cooling in an ice bath. The solution is heated at 60°C in a sealed tube for 23 hours, the Reaction solution is cooled, and its internal pressure is reduced to atmospheric. After checking the completion of the reaction analysis by HPLC, the reaction solution is placed in a container (using about 50 ml of water), and to it add 49,6 ml of concentrated hydrochloric acid and then 200 ml of water.

Yellow crystals precipitated by adding hydrochloric acid. After maturation, the crystalline solution at 10°C during the night, it is filtered off and dried under reduced pressure to obtain 30,95 g of 5-dimethylamino-2-nitrobenzoic acid (yield 99%).

1H-NMR (400 MHz, DMSO-d6): 8,88 (users, 1H), of 7.97 (d, 1H, J=9.4 Hz, the coupling of aryl = 1,76 Hz), 6,78 (d, 1H, J=9.4 Hz, the coupling of aryl = 2,84 and 1.92 Hz), of 6.71 (s, 1H, connection aryl = 2,88 and 1.60 Hz), is 3.08 (s, 6H).

13C NMR (100 MHz, DMSO-d 6): 168,58, 153,86, 133,94, 132,85, 127,03, 111,44, 109,69, 40,24.

MS (ESI): m/z 211,17 (m+H)+, 209,27 (M-N)-

Process 2:

40,0 g (190,30 mmol) of 5-dimethylamino-2-nitrobenzoic acid are suspended in 160 ml of methanol at 25°C. the Suspension is cooled in an ice bath and to it was added 53,6 ml of concentrated sulfuric acid. After adding concentrated sulfuric acid the temperature of the solution rises to about 30°C. the Solution in this state is placed in a bath at 60°C and stirred under the conditions of heating for 20 hours After check the progress of the reaction by HPLC and confirmation of disappearance of the starting material to the solution was added 400 ml of toluene and dilute. Then to it add 200 ml water and the aqueous sodium hydroxide solution (where 38,06 g of sodium hydroxide dissolved in 200 ml of water). Then the aqueous layer was extracted with 200 ml of toluene, and the toluene solution unite with him. The toluene layer was washed with 300 ml saturated aqueous sodium bicarbonate solution. Then the toluene layer concentrated under reduced pressure (at temperature in the bath 50°C) so that the content of the desired connection becomes about 20 wt.%. After removal of the solvent under reduced pressure, the crystals of the desired compound precipitated and spend their maturation at room temperature for 1 h To add 220 ml of n-heptane and additionally stirred at 5°C in accordance with is their night. The crystals separating suction filtration and washed with 100 ml of n-heptane. The wet crystals are dried under reduced pressure at 60°C for 3 h to obtain 34,82 g of yellow crystalline powder methyl-5-dimethylamino-2-nitrobenzoate. (Yield 82%).

1H-NMR (400 MHz, DMSO-d6): 8,02 (d, 1H, J=9,4, Hz), PC 6.82 (d, 1H, J=9,36 Hz, the coupling of aryl = 2,56, Hz), 6,78 (s, 1H, connection aryl = 2,4 Hz), 3,83 (s, 3H), 3,10 (s, 6H).

13C NMR (100 MHz, DMSO-d6): 167,70, 153,92, 132,71, 132,34, 127,24, 111,87, 110,07, 53,21, 40,28.

MS (FAB): m/z 224,24 (M)+

HR MS (FAB): m/z 224,0830 (M)+

Process 3:

10,06 g (of 44.9 mmol) of methyl-5-dimethylamino-2-nitrobenzoate added to 50 ml of methanol and suspended and added to 9.0 ml of 10M hydrochloric acid and 1.96 g (wet, 1 mol% to a substrate) 5% activated carbon with palladium. Contained in the reaction vessel air replaces the gaseous hydrogen and the contents stirred at room temperature overnight. After separation by filtration palladium catalyst by filtration through celite, the filtrate concentrated under reduced pressure so that he was reduced to half its quantity. To the solution was added 80 ml of acetone and concentrated under reduced pressure 3 times for the deposition of compounds of formula (12). After maturation, the connection at temperatures below 10°C the compound is dried under reduced the output pressure to obtain 11,16 g of methyl 2-amino-5-(dimethylamino)benzoate/ dihydrochloride. (Yield 93%).

1H-NMR (400 MHz, DMSO-d6): of 8.09 (s, 1H), 7,72 (d, 1H, J=9.0 Hz), of 6.96 (d, 1H, remaining 9.08 Hz), 5,50 users), 3,83 (s, 3H), 3.04 from (s, 6H).

13C NMR (100 MHz, DMSO-d6): 167,12, 131,64, 126,66, 123,29, 118,7, 108,88, 52,18, 45,84.

MS (FAB): m/z 195,3 (m+H)+

HR MS (FAB): m/z 195,1122 (m+H)+

Example 135. The synthesis of compounds of the following formula (E-49), which has a Deputy (deputies) of example 135 table

The process 1. Methyl ester of N-(t-butoxycarbonyl)-4-(6-iodine-1-methyl-2,4-hintlinin-3-yl)-L-phenylalanine

The complex mixture of methyl ester of N-(t-butoxycarbonyl)-4-amino-L-phenylalanine (of 10.25 g), 2-amino-5-identies acid (9,18 g), EDC/HCl (6.8 g), HOBT (4.8 g), triethylamine (6.6 ml) and tetrahydrofuran (300 ml) was stirred at 40°C during the night. Solution, where about half the amount of the solvent was removed, diluted with water and ethyl acetate, and conduct liquid separation. The organic layer is washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed to obtain 22 g of crude material. The crude material (22 g), CDI (carbonyldiimidazole) (17 g) and DMF (200 ml) was stirred at 80°C during the night. The reaction solution was diluted with water and ethyl acetate and conduct liquid separation. The body is ical layer washed with water and dried over anhydrous sodium sulfate. The solvent is removed to obtain and 23.4 g of crude material. The crude material (23,4 g), methyliodide (3 ml), potassium carbonate (10.0 g) and DMF (100 ml) was stirred at room temperature overnight. The reaction solution is diluted with water and ethyl acetate and conduct liquid separation. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvent is removed to obtain 15 g of the desired compound.

Process 2. Methyl ester of N-(2-chloro-6-perbenzoic)-4-(6-iodine-1-methyl-2,4-hintlinin-3-yl)-L-phenylalanine

The substance obtained in process 1 (5 g), triperoxonane acid (3 ml) and dichloromethane (100 ml), stirred at room temperature for 3 hours Then to it add triperoxonane acid (10 ml) and stirred at room temperature for 2 hours After removal of the solvent added a 4 n solution hydrochloridecan and concentrate. The residue was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is removed to obtain the crude material. The crude material chloride 2-chloro-6-Formentera (2.5 g), triethylamine (5 ml) and dichloromethane (100 ml) was stirred at room temperature overnight. The reaction solution was diluted with water and dichloromethane and hold liquid once the bookmark. The organic layer is washed with diluted hydrochloric acid, aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate. The solvent is removed to obtain the crude material. The crude material is purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain 2.7 g of the desired compound.

Process 3. Methyl ester of N-(2-chloro-6-perbenzoic)-4-(1-methyl-6-chloromethyl-2,4-hintlinin-3-yl)-L-phenylalanine

The substance obtained in process 2, process the same procedures as respectively the procedure process 1 and 2 in example 50, and process 1 and 2 in example 53 to obtain specified in the connection header.

Process 4

The mixture of substances obtained in process 3 (300 mg), tetrahydrofuran (20 ml) and 2M solution of ethylamine-tetrahydrofuran (14 ml), stirred at room temperature overnight. After removal of solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 70 mg of the desired compound.

MS(ESI MH+): 553

Example 136. The synthesis of compounds of the following formula (E-49), which has a Deputy (deputies) of example 136 table

The substance obtained in process 3 in example 135, communicates the same procedure as the procedure of process 4 in example 135, using the 2M solution of methylamine-tetrahydrofuran to obtain the desired connection.

MS(ESI MH+): 539

Example 137. The synthesis of compounds of the following formula (E-49), which has a Deputy (deputies) of example 137 table

The process 1. Methyl ester of N-(2-chloro-6-methylbenzoyl)-4-(6-iodine-1-methyl-2,4-hintlinin-3-yl)-L-phenylalanine

The substance obtained in process 1 of example 135 (5 g), triperoxonane acid (10 ml) and dichloromethane (100 ml) was stirred at room temperature for 2 hours After removal of the solvent the residue was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is removed to obtain the crude material. A mixture of the crude material, 2-chloro-6-methylbenzoic acid (2.2 g), EDC/HCl (2.7 g), HOBT (2.1 g) and DMF (20 ml) was stirred at room temperature overnight. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed to obtain the crude material. The crude material is purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain 1.1 g of the desired compound.

Process 2

The substance obtained in process 1, communicates the same procedure as the procedure of process 3 and 4 in example 135, to obtain 90 mg we wish what about the connection.

MS(ESI MH+): 549

Example 138. The synthesis of compounds of the following formula (E-51), which has a Deputy (deputies) of example 138 table

Complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-[6-ethylmethylamino-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

The mixture of substances obtained in process 2 of example 53 (250 mg), isopropanol (6 ml) and 4 n solution hydrochloridecan (6 ml) was stirred at 70°C for 3 hours After removal of the solvent to the mixture isopropanol (5 ml), acetonitrile (2 ml) and methylethylamine (0.4 ml) and stirred at room temperature for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 138 mg of the desired compound.

MS(ESI MH+): 625

Example 139. The synthesis of compounds of the following formula (E-49), which has a Deputy (deputies) of example 139 table:

N-(2,6-dichlorobenzoyl)-4-[6-ethylmethylamino-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

4 N. a solution of 250 mg), isopropanol (6 ml) and 4 n solution hydrochloridecan (2 ml) and water (200 μl) is added to the compound of example 138 (30 mg) and stirred at 80°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 15 mg of the desired compound.

MS(ESI MH+): 583

Example 140. The synthesis of compounds of the following formula (E-49), which has a Deputy (deputies) of example 140 table:

N-(2,6-dichlorobenzoyl)-4-[6-hydroxy-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

Add a mixture of 2-nitro-5-methoxybenzoic acid (4 g), tetrahydrofuran (200 ml), complex methyl ester N-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine (6 g), EDC/HCl (3.6 g), HOBT (3.0 g) and triethylamine (4.4 ml) and stirred at 40°C during the night. The mixture is extracted with ethyl acetate and treated in accordance with the usual method. The crude material was dissolved in ethyl acetate (20 ml) and to it was added 1 g of 10% activated carbon with palladium and stirred in a hydrogen atmosphere at room temperature overnight. After filtration through celite the residue is treated in accordance with the usual method. To the crude material added DMF (200 ml) and carbonyldiimidazole (5,2 g) and stirred at 80°C for 4 h the Mixture is extracted with ethyl acetate and treated in accordance with the usual method. To the crude material added DMF (200 ml), potassium carbonate (4.4 g) and methyliodide (1.2 ml) and stirred at room temperature overnight. The mixture is extracted with ethyl acetate and treated in accordance with the usual method. To the crude material added 1M solution of tribrom is Yes boron-dichloromethane (50 ml) and stirred at room temperature for 3 hours The mixture is extracted with dichloromethane and treated in accordance with the usual method. To the crude material add water/acetonitrile (1:1) and precipitated substance is filtered off to obtain 2.2 g of the crude desired material connection. The filtrate is concentrated and purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 138 mg of the desired compound.

MS(ESI MH+): 528

Example 141. The synthesis of compounds of the following formula (E-49), which has a Deputy (deputies) of example 141 table:

Complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-[6-((2S)-2-aminopropoxy)-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

The process 1. t-butyl(1S)-2-hydroxy-1-methylethylketone

Di-t-BUTYLCARBAMATE (17 g), triethylamine (9 ml) and dichloromethane (100 ml) is added to L-alaninol (5 g) and stirred at room temperature for 2 hours the Mixture is diluted with dichloromethane and washed with water, and the organic layer is dried over anhydrous magnesium sulfate. After removal of solvent the crude material purified by chromatography on a column of silica gel (ethyl acetate - hexane) to obtain 5.9 g specified in the connection header.

Process 2. t-butyl(1S)-2-chloro-1-methylethylketone

Methanesulfonanilide (3.1 ml), triethylamine (9.0 ml) and dichloromethane (150 ml) EXT the keys to the connection, obtained in process 1 (5.9 g), and stirred at 0°C for 2 hours the Mixture was diluted with dichloromethane and washed with water, and the organic layer is dried over anhydrous magnesium sulfate. After removal of the solvent to the crude material added lithium chloride (2.8 g) and DMF (100 ml) and stirred at 40°C during the night. The mixture is diluted with ethyl acetate and washed with water, and the organic layer is dried over anhydrous magnesium sulfate. After removal of solvent the crude material purified by chromatography on a column of silica gel (ethyl acetate - hexane) to obtain 3.6 g specified in the connection header.

Process 3

The compound obtained in process 2 (15 mg), DMF (2 ml) and potassium carbonate (14 mg) is added to the compound of example 154 (30 mg) and stirred at 90°C during the night. The mixture is extracted with ethyl acetate and treated in accordance with the usual method. The crude material was dissolved in 4 BC solution hydrochloridecan (2 ml) and stirred at room temperature for 2 hours To it add water (200 μl) and stirred at 80°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 10 mg of the desired compound.

MS(ESI MH+): 528

Example 142. The synthesis of compounds of the following formula Th-51), which has a Deputy (deputies) of example 142 table:

N-(2,6-dichlorobenzoyl)-4-[6-(2-dimethylaminoethoxy)-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

T-butyl-2-chlorethylene (157 mg), DMF (3 ml) and potassium carbonate (1384 mg) is added to the compound of example 154 (450 mg) and stirred at 90°C during the night. The mixture is extracted with ethyl acetate and treated in accordance with the usual method. The crude material was dissolved in 4 BC solution hydrochloridecan (2 ml) and stirred at room temperature for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 350 mg of the pure material. To the resulting purified material (170 mg) is added acetonitrile (5 ml), formalin (37 μl), acetic acid (26 μl) and triacetoxy-boron (98 mg) and stirred at room temperature for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 150 mg of the pure material. To the resulting purified material (20 mg) is added 4 n solution hydrochloridecan (1 ml) and water (200 ml) and stirred at 90°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (waters, the/acetonitrile, each containing 0.1% TFA) to obtain 11 mg of the pure material.

MS(ESI MH+): 599

Example 143. The synthesis of compounds of the following formula (E-50), which has a Deputy (deputies) of example 143 table:

N-(2,6-dichlorobenzoyl)-4-[7-ethylaminomethyl-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

The process 1. Methyl-4-[(t-butoxycarbonylamino)methyl]-2-nitrobenzoate

The triethylamine (1.9 ml) and ethylchloride (1.0 ml) are added to a mixture of 1-methyl-2-nitroterephthalate (2.0 g) and tetrahydrofuran (120 ml) under conditions of cooling with ice and stirred for 30 minutes To the reaction solution was added sodium borohydride (500 ml) and then 3 cubes of ice and stirred at room temperature for 2 hours the Mixture is extracted with ethyl acetate and treated in accordance with the usual method. The crude material (565 mg) was dissolved in dichloromethane (10 ml). To it in terms of cooling with ice add triethylamine (0,74 ml) and methanesulfonamide (0.25 ml) and stirred for 2 hours, the Mixture is extracted with dichloromethane and treated in accordance with the usual method. The crude material was dissolved in acetonitrile (20 ml) and to it add 2.0m solution monoethylamine in tetrahydrofuran (2,68 ml) and stirred at room temperature overnight. The mixture is extracted with ethyl acetate and treated in accordance with ordinary the m way. The crude material was dissolved in dichloromethane (10 ml). To it in terms of cooling with ice add triethylamine (0,74 ml) and di-t-BUTYLCARBAMATE (700 mg) and stirred for 2 hours, the Mixture is extracted with dichloromethane and treated in accordance with a customary method to obtain 520 mg specified in the connection header.

Process 2

The substance obtained in process 1 (520 mg), dissolved in tetrahydrofuran (20 ml), 1M aqueous sodium hydroxide solution (5 ml) and methanol (10 ml) and stirred at room temperature for 2 h and then at 40°C for 2 hours the Mixture is extracted with ethyl acetate and treated in accordance with the usual method. To it was added tetrahydrofuran (20 ml), methyl ester N-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine (563 mg), EDC/HCl (352 mg), HOBT (248 mg) and triethylamine (425 μl) and stirred at 40°C during the night. The mixture is extracted with ethyl acetate and treated in accordance with the usual method. The crude material was dissolved in ethyl acetate (20 ml) and to it added 20 mg of 10% activated carbon with palladium and stirred in the presence of hydrogen at room temperature overnight. After filtration through celite the residue is treated in accordance with the usual method. To the crude material added DMF (10 ml) and carbonyldiimidazole (374 mg) and n is remediat at 80°C for 4 h The mixture is extracted with ethyl acetate and treated in accordance with the usual method. To the crude material added DMF (10 ml), potassium carbonate (212 mg) and methyliodide (58 μl) and stirred at room temperature overnight. The mixture is extracted with ethyl acetate and treated in accordance with the usual method. The crude material was dissolved in 4 BC solution hydrochloridecan (2 ml) and stirred at room temperature for 4 hours After concentration of the solvent is added 4 n solution hydrochloridecan (2 ml) and water (200 μl) and stirred at 80°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 40 mg of the desired material.

MS(ESI MH+): 569

Example 144. The synthesis of compounds of the following formula (E-50), which has a Deputy (deputies) of example 144 table:

N-(2,6-dichlorobenzoyl)-4-[7-methylaminomethyl-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

The desired connection receive the same procedures as procedures for process 1 and 2 in example 143, except that instead of a 2.0m solution of monoethylamine in tetrahydrofuran use 2.0m solution monomethylamine in tetrahydrofuran.

MS(ESI MH+): 555

Example 145. The synthesis of compounds of the following formula (E-50), which is the OE has a Deputy (deputies) of example 145 table:

N-(2,6-dichlorobenzoyl)-4-[1-methyl-7-propylaminoethyl-2,4-hintlinin-3-yl]-L-phenylalanine

The desired connection receive the same procedures as procedures for process 1 and 2 in example 143, except that instead of a 2.0m solution of monoethylamine in tetrahydrofuran using Propylamine.

MS(ESI MH+): 583

Example 146. The synthesis of compounds of the following formula (E-50), which has a Deputy (deputies) of example 146 table:

N-(2,6-dichlorobenzoyl)-4-[1-methyl-7-diethylaminomethyl-2,4-hintlinin-3-yl]-L-phenylalanine

The desired connection receive the same procedures as procedures for process 1 and 2 in example 143, except that instead of a 2.0m solution of monoethylamine in tetrahydrofuran use diethylamin.

MS(ESI MH+): 597

Example 147. The synthesis of compounds of the following formula (E-51), which has a Deputy (deputies) of example 147 table:

The desired connection get the same procedure as the procedure of paragraph With the above-described examples 101-121 using the compound of example 54.

MS(ESI MH+): 652

Example 148. The synthesis of compounds of the following formula (E-51), which has a Deputy (deputies) of example 148 table:

The desired connection get the same procedure as the procedure of paragraph With the above-described examples 101-121 using the compound of example 54.

MS(ESI MH+): 625

Example 149. Synthesis with the unity of the following formula (E-51), which has a Deputy (deputies) of example 149 table:

The desired connection get the same procedure as the procedure of paragraph With the above-described examples 101-121 using the compound of example 54.

MS(ESI MH+): 597

Example 150. The synthesis of compounds of the following formula (E-51), which has a Deputy (deputies) of example 150 table:

The desired connection get the same procedure as the procedure of paragraph With the above-described examples 101-121 using the compound of example 99.

MS(ESI MH+): 583

Example 151. The synthesis of compounds of the following formula (E-51), which has a Deputy (deputies) of example 151 table:

The desired connection get the same procedure as the procedure of paragraph With the above-described examples 101-121 using the compound of example 99.

MS(ESI MH+): 597

1H-NMR (DMSO-d6) δ to 1.19 (3H, d, J=6.3 Hz), of 1.23 (3H, d, J=6.3 Hz), to 2.57 (3H, t, J=5,1 Hz), 3,0l (1H, DD, J=14,1, 9.9 Hz), 3,19 (1H, DD, J=14,1, 5,1 Hz), 3,55 (3H, s), 4,24 (2H, t, J=5.4 Hz), 4.72 in-4,82 (1H, m), of 4.95 (1H, Sept., J=6.3 Hz), 7,2l (2H, d, J=8,4 Hz), 7,37-of 7.48 (5H, m), to 7.59 (1H, d, J=8.7 Hz), 7,88 (1H, DD, J=8,7, and 2.1 Hz), 8,24 (1H, d, J=2,l Hz), 8,58 (2H, users), a 9.25 (1H, d, J=8,1 Hz).

Further, the compound of example 151 receive the same treatment as the process 3 of example 53, except that the connection process 1 in example 174 is used as a raw material and methylamine are used instead of the research.

Example 152 Synthesis of compounds of the following formula (E-51), which has a Deputy (deputies) of example 152 table:

The desired connection get the same procedure as the procedure of paragraph With the above-described examples 101-121 using the compound of example 99.

MS(ESI MH+): 611

Example 153. The synthesis of compounds of the following formula (E-51), which has a Deputy (deputies) of example 153 table:

The desired connection get the same procedure as the procedure of paragraph With the above-described examples 101-121 using the compound of example 140.

MS(ESI MH+): 556

Example 154. The synthesis of compounds of the following formula (E-51), which has a Deputy (deputies) of example 150 table:

The desired connection get the same procedure as the procedure of paragraph With the above-described examples 101-121 using the compound of example 140.

MS(ESI MH+): 570

Example 155. The synthesis of compounds of the following formula (E-51), which has a Deputy (deputies) of example 155 table:

Complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-[6-(2-dimethylaminoethoxy)-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

T-butyl-2-chlorethylene (157 mg), DMF (3 ml) and potassium carbonate (1384 mg) is added to the compound of example 154 (450 mg) and stirred at 90°C during the night. The mixture is extracted with ethyl acetate and treated in accordance with the usual method. The crude material dissolved in a 4 n solution is hydrochloridecan (2 ml) and stirred at room temperature for 2 hours After removal of solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 350 mg of the pure material. To the resulting purified material (170 mg) is added acetonitrile (5 ml), formalin (37 μl), acetic acid (26 μl) and triacetoxy-boron (98 mg) and stirred at room temperature for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 150 mg of the desired material.

MS(ESI MH+): 641

Example 156. The synthesis of compounds of the following formula (E-52), which has a Deputy (deputies) of example 156 table:

Complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-[7-ethylaminomethyl-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

4 N. the solution hydrochloridecan (2 ml) and isopropanol (2 ml) is added to the compound of example 143 (20 mg) and stirred at 80°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

MS(ESI MH+): 611

Example 157. The synthesis of compounds of the following formula (E-52), which has a Deputy (deputies) of example 157 table:

Complex cyclopentyloxy ester N-(2,6-dichlorobenzoyl)-4-[7-methylamino the Il-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

4 N. the solution hydrochloridecan (2 ml) and Cyclopentanol (2 ml) is added to the compound of example 144 (20 mg) and stirred at 80°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 15 mg of the desired compound.

MS(ESI MH+): 623

Example 158. The synthesis of compounds of the following formula (E-52), which has a Deputy (deputies) of example 158 table:

Complex isobutyl ester N-(2,6-dichlorobenzoyl)-4-[7-methylaminomethyl-1-methyl-2,4-hintlinin-3-yl]-L-phenylalanine

4 N. the solution hydrochloridecan (2 ml) and isobutyl alcohol (2 ml) is added to the compound of example 144 (20 mg) and stirred at 80°C for 2 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 12 mg of the desired compound.

MS(ESI MH+): 611

Example 159. The synthesis of compounds of the following formula (E-52), which has a Deputy (deputies) of example 159 table:

Complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-[1-methyl-7-propylaminoethyl-2,4-hintlinin-3-yl]-L-phenylalanine

4 N. the solution hydrochloridecan (2 ml) and isopropanol (2 ml) is added to the compound of example 145 (50 mg) and stirred at 80°C for 3 hours After removal of the solvent the residue is purified is high performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 25 mg of the desired compound.

MS(ESI MH+): 625

Example 160. The synthesis of compounds of the following formula (E-53), which has a Deputy (deputies) of example 160 table:

The desired connection get the same procedure as the procedure of example 92, except that instead of imidazole use 2-Mei.

MS(ESI MH+): 610

Example 161. The synthesis of compounds of the following formula (E-53), which has a Deputy (deputies) of example 161 table:

The desired connection get the same procedure as the procedure of example 92, except that instead of imidazole use 2-ethylimidazole.

MS(ESI MH+): 624

Example 162. The synthesis of compounds of the following formula (E-53), which has a Deputy (deputies) of example 162 table:

The desired connection get the same procedure as the procedure of paragraph (C in the above examples, 101-121, using the compound of example 92.

MS(ESI MH+): 638

1H-NMR (DMSO-d6) δ to 1.19 (3H, d, J=6.3 Hz), of 1.23 (3H, d, J=6.3 Hz), to 3.02 (1H, DD, J=14,1, 9.9 Hz), 3,20 (1H, DD, J=14,1, 5,4 Hz)and 3.59 (3H, s), 4.72 in-4,82 (1H, m), of 4.95 (1H, Sept., J=6.3 Hz), 7,24 (2H, d, J=8,l Hz), 7,38-of 7.48 (5H, m), 7,69 (1H, s), to $ 7.91 (1H, d, J=6.0 Hz), 8.07-a to 8.14 (2H, m)to 9.15 (1H, s), a 9.25 (1H, d, J=7,8 Hz).

Examples 163-173. The synthesis of compounds of the following formula (E-54), which has the substituents in the examples 163-173 table:

The compounds obtained in examples 163-173, Sintesi who have the same procedure, as the procedure of paragraph With examples 65-81.

Example 174. The synthesis of compounds of the following formula (E-55), which has a Deputy (deputies) of example 174 tablw:

The process 1. Complex isopropyl ester 4-[6-(chloromethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl]-N-(2,6-dichlorobenzoyl)-L-phenylalanine

A mixed solvent of methylene chloride (140 ml) and dimethylformamide (140 ml) cooled to 0°C. is added phosphorus oxychloride (4,1 ml) and stirred for 30 minutes, the Compound of example 234 (25,7 g) is added at 0°C and stirred at room temperature for 1 h To it then add phosphorus oxychloride (0.4 ml) and stirred for 1 h and Then added ethyl acetate (500 ml) and water saturated with sodium bicarbonate (100 ml), and actively mix. After adding ethyl acetate (500 ml) and water (200 ml) to separate it into layers, the organic layer washed with water, saturated sodium bicarbonate (200 ml), 1 n sodium hydroxide solution (100 ml) and saturated aqueous solution of sodium chloride (200 ml) and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to obtain the crude material. Specified in the title compound is obtained by crystallization from methylene chloride and hexane.

Output: 20,32 g

MS(ESI MH+): 602

Process 2. Isopropyl(2S)-3-[4-(6-(azidomethyl)-1-methyl-2,4-dioxo-1,2,3,4-t is trihydro-3-(2H)-hintline)phenyl]-2-[(2,6-dichlorobenzoyl)amino]propionate

Sodium azide (56 mg) and dimethylsulfoxide (5 ml) is added to the compound (400 mg)obtained in process 1, and stirred for 2.5 hours After dilution with ethyl acetate and washing with water, the organic layer is dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue purified by chromatography on silica gel (hexane - ethyl acetate) to obtain specified in the title compound (350 mg).

Process 3. Isopropyl(2S)-3-[4-(6-(aminomethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)-hintline)phenyl]-2-[(2,6-dichlorobenzoyl)amino]propionate

Triphenylphosphine (52 mg) and tetrahydrofuran (2 ml) is added to the compound (100 mg)obtained in process 2, and stirred for 30 minutes Water (200 μl) is added to the reaction solution, and then stirred over night. After removal of solvent, the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 76 mg of the desired compound.

Examples 175-183. The synthesis of compounds of the following formula (E-55), which have substituents of examples 175-183 tablw:

Compounds synthesized by the same procedure as process 3 of example 53, except that instead of the research as the source of material used, the connection process 1 in example 174 and the corresponding amines.

Example 184. Sin is ez compounds of the following formula (E-56), which has a Deputy (deputies) of example 184 table:

The process 1. Isopropyl(2S)-2-[(2,6-dichlorobenzoyl)amino]-3-[4-(7-fluoro-6-iodine-1-methyl-6-[(methylamino)methyl]-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)-hintline)phenyl]propanoate

Specified in the title compound synthesized by the same procedure as the procedure of processes 1-3 in example 43, except that complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-[(2-amino-5-Ioganson)amino]-L-phenylalanine obtained in process 1 of example 234, is used instead of a complicated methyl ester N-(2,6-dichlorobenzoyl)-4-[(2-amino-5-Ioganson)amino]-L-phenylalanine and 2-amino-4-fluoro-5-identies acid is used instead of 2-amino-5-identies acid.

Process 2. Isopropyl(2S)-2-[(2,6-dichlorobenzoyl)amino]-3-[4-(7-fluoro-1-methyl-6-[(methylamino)methyl]-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)-hintline)phenyl]propanoate

The compound obtained in process 1, process the same procedures as the procedures of the processes 4 and 5 in example 234, process 1 in example 174 and example 175 to obtain specified in the connection header.

Example 185 and 186. The synthesis of compounds of the following formula (E-56), which are the substituents of examples 185 and 186 table:

Compounds synthesized by the same procedure as the procedure of example 184, except that the corresponding amines used in the process 2 of example 184.

Example 87. The synthesis of compounds of the following formula (E-57), which have a Deputy (deputies) of example 187 .D:

The process 1. Methyl(2S)-2-amino-3-[4-(6-iodine-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)-hintline)phenyl]proparathyroid

4 N. the solution hydrochloridecan added to methyl(2S)-2-[(tert-butoxycarbonyl)amino-3-[4-(6-iodine-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)-hintline)phenyl]propanoate (5 g)obtained in process 1 of example 135, and stirred for 3 hours the Solvent is removed to obtain specified in the connection header (4,2 g).

Process 2. Methyl(2S)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(6-iodine-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)-hintline)phenyl]propanoate

2-Chloro-6-methylbenzoic acid (1.7 g), EDC/HCl (1.9 grams), HOAt (1.4 g), triethylamine (2.2 ml) and dichloromethane (42 ml) is added to the compound obtained in process 1 (2.1 g), and stirred overnight. After diluting the reaction mixture with ethyl acetate and washing 1 N. hydrochloric acid, water, saturated sodium bicarbonate and saturated aqueous sodium chloride, the organic layer is dried over anhydrous sodium sulfate. The solvent is removed to obtain the crude material specified in the connection header.

Process 3. Isopropyl(2S)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(6-iodine-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)-hintline)phenyl]propanoate/p>

4 N. the solution hydrochloridecan (30 ml) and water (6 ml) is added to the compound obtained in process 2, and stirred at 90°C during the night. After removal of the solvent to the residue add 4 N. the solution hydrochloridecan (25 ml) and isopropyl alcohol (25 ml) and stirred at 90°C. for 3.5 hours After diluting the reaction mixture with ethyl acetate and washing 1 N. hydrochloric acid, water, saturated sodium bicarbonate, and saturated aqueous sodium chloride, the organic layer is dried over anhydrous sodium sulfate. The solvent is removed to obtain the crude material specified in the connection header.

Process 4. Isopropyl(2S)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(1-methyl-6-[(methylamino)methyl]-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)-hintline)phenyl]propanoate

The compound obtained in process 3, process the same procedures as the procedures of the processes 4 and 5 in example 234, the process 1 in example 174 and example 175, to obtain specified in the connection header.

Example 188. The synthesis of compounds of the following formula (E-57), which has a Deputy (deputies) of example 188 .D:

The compound synthesized by the same procedure as the procedure of example 187, except that the corresponding amine used in the process 4 of example 187.

Example 189. The synthesis of compounds of the following formula (E-57) which has a Deputy (deputies) of example 189 .D:

The compound obtained in process 2 of example 135, treated with the same procedures as the procedures of the processes 4 and 5 in example 234, the process 1 in example 174 and example 175 to obtain specified in the connection header.

Example 190. The synthesis of compounds of the following formula (E-57), which has a Deputy (deputies) of example 190 .D:

The compound synthesized by the same procedure as the procedure of example 189, except that the corresponding amine used in example 189.

Examples 191-206. The synthesis of compounds of the following formula (E-58), which have substituents, examples 191-206 table:

Compounds synthesized by the same procedure as the procedure of the process 4 of example 43, except that the starting materials used compounds of examples 174-188 and 190.

Example 207. The synthesis of compounds of the following formula (E-59), which has a Deputy (deputies) of example 207 .F:

Methanesulfonamide (30 μl), triethylamine (80 μl) and dichloromethane (3 ml) is added to methyl(2S)-2-[(2,6-dichlorobenzoyl)amino]-3-[4-(6-(3-hydroxypropyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-(2H)-hintline)phenyl]propanoate (150 mg), which is a synthetic intermediate of the compound of example 52, and stirred at 0°C for 2.5 hours After dilution of the reaction solvent the ethyl acetate and washing 1 N. chloritoid the second acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, the organic layer is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The precipitate was dissolved in acetonitrile (6 ml)is added dropwise to a 2M solution of methylamine-tetrahydrofuran (9 ml) and stirred at 50°C during the night. After removal of the solvent to the residue add 4 N. the solution hydrochloridecan (6 ml) and water (1.2 ml) and stirred at 90°C for 2 hours After removal of the solvent the residue and purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 70 mg of the desired compound.

Examples 208 and 209. The synthesis of compounds of the following formula (E-59)which have substituents of examples 208 and 209 .F:

Compounds synthesized by the same procedure as the procedure of example 207, except that, instead of a 2M solution of methylamine-tetrahydrofuran, use a solution in tetrahydrofuran of each of the corresponding amine.

Example 210. The synthesis of compounds of the following formula (E-59), which has a Deputy (deputies) of example 210 .F:

4 N. the solution hydrochloridecan (2 ml) and isopropanol (2 ml) is added to the compound of example 207 (65 mg) and stirred at 90°C. for 3.5 hours After removal of the solvent the residue is purified high the effective liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 60 mg of the desired compound.

Examples 211 and 212. The synthesis of compounds of the following formula (E-59)which have substituents of examples 211 and 212 .F:

Compounds synthesized by the same procedure as the procedure of example 210 using the compounds obtained in examples 208 and 209.

Examples 213-218. The synthesis of compounds of the following formula (E-60)which have substituents of examples 213-218 .G:

Process 1. The crude material compound of example 140 (2,49 g), 4 n solution hydrochloridecan (50 ml) and isopropyl alcohol (50 ml) was stirred at 80°C for 1.5 h and from him remove the solvent. A mixture of the crude material, 1-bromo-2-chlorethane (3,92 ml), potassium carbonate (6,51 g) and acetone (100 ml) was stirred at 50°C for 3 hours After removal of the solvent the residue is diluted with water and ethyl acetate and conduct liquid separation. After washing the organic layer with a saturated aqueous solution of sodium chloride, the solvent is removed to obtain the crude material (2.85 g).

Process 2. The desired connection receive the following methods a, b and C.

A. a Mixture of alkylhalides in the process 1, the corresponding amine and a suitable solvent (solvents), such as acetonitrile, stirred at 80°C during the period from midnight to 3 hours After removal of the solvent the residue of imaut high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

C. a Mixture of alkylhalides in the process 1, the appropriate amine (or hydrochloride of the corresponding amine and reason (reason), such as triethylamine) and a suitable solvent (solvents), such as acetonitrile, stirred inclined pipe at 80°C during the period from midnight to 3 hours After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

C. a Mixture of alkylhalides in the process 1, the corresponding amine and a suitable solvent (solvents), such as acetonitrile, stirred at 50°C during the period from midnight to 3 days After removal of the solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

Examples 219-224. The synthesis of compounds of the following formula (E-60)which have substituents of examples 219-224 .G:

A mixture of the corresponding complex ester, 4 N. solution hydrochloridecan water and stirred at 80°C for a period of from several hours to night. After removal of solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired joint is.

Example 225. The synthesis of compounds of the following formula (E-61), which has a Deputy (deputies) of example 225 table:

The desired compound synthesized by the same procedures as the procedures of examples 213-218, except that, instead of 1-bromo-2-chlorethane, using 1-bromo-2-chloropropane.

Examples 226 and 227. The synthesis of compounds of the following formula (E-61), which have substituents of examples 226 and 227 table:

The desired compounds are synthesized by the same procedure as the procedure of examples 219-224.

Example 228. The synthesis of compounds of the following formula (E-62):

The process 1. The synthesis of complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-[7-fluoro-6-(2-hydroxyethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl]-L-phenylalanine

In the atmosphere of argon, palladium acetate (6.5 mg) and triphenylphosphine (30 mg) are suspended in 5 ml of simple diethyl ether and stirred for 10 min. After two conducting simple decantation with diethyl ether to the mixture of complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-[7-fluoro-1-methyl-2,4-dioxo-6-iodine-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl]-L-phenylalanine (374 mg), the complex of 2,4,6-trivinylcyclohexane-pyridine (138 mg), diethylformamide (5 ml) and an aqueous solution of 2M sodium carbonate (1,15 ml) and stirred at 90°C. for 1.5 hours After removal of insoluble materials by filtration through celite provocational processing to obtain the crude material (0.36 g). The crude material was dissolved in tetrahydrofuran (3 ml) and cooled to 0°C. Then added sodium borohydride (35 mg) and the complex of trevormoran - simple diethyl ether (81 μl) and stirred at 0°C for 1 h, the Reaction mixture was additionally stirred at room temperature for 1 h and again cooled to 0°C, and to him slowly add water (0,26 ml). After stirring the reaction mixture at room temperature for 1 h and again cooling to 0°C. to it was added an aqueous solution (5 ml) of Oxone (registered trademark) (1.3 g purchased from Sigma-Aldrich) and stirred at room temperature for 3.5 hours Next to it was added sodium bisulfite, extracted with ethyl acetate, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate to obtain the crude material. The crude material is purified by chromatography on a column of silica gel (gradient of chloroform : methanol = 49:1 to 4:1) to obtain specified in the connection header.

Output: 0,197 g (0.32 mmol, 60%)

MS(ESI MH+): 616

Process 2. The synthesis of complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-{7-fluoro-1-methyl-6-[2-(methylamino)ethyl]-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl}-L-phenylalanine

The compound obtained in process 1 (0,179 g), dissolved in methylene chloride (2 ml) and d is billaut the triethylamine (67 μl) and methanesulfonamide (32 ml) at 0°C. After stirring the mixture for 2 h hold regular processing to obtain the crude material.

A 2M solution of methylamine and acetonitrile (6 ml) in tetrahydrofuran (10 ml) heated to 50°C., and to it is slowly added dropwise a solution of acetonitrile (6 ml) of the crude material and stirred over night. After removal of the solvent under reduced pressure the residue purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain the desired connection.

Output: 51,7 mg

MS(ESI MH+): 629

Example 229. The synthesis of compounds of the following formula (E-63):

Synthesis of N-(2,6-dichlorobenzoyl)-4-{7-fluoro-1-methyl-6-[2-(methylamino)ethyl]-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl}-L-phenylalanine

4 N. the solution hydrochloridecan (4 ml) and water (0.8 ml) is added to the compound of example 228 (10 mg) and stirred at 90°C for 2 hours After removal of the solvent under reduced pressure the residue purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain specified in the connection header.

Output: 5.3 mg

MS(ESI MH+): 587

Example 230. The synthesis of compounds of the following formula (E-64):

Synthesis of N-(2,6-dichlorobenzoyl)-4-{1-methyl-6-[2-(methylamino)ethyl]-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl}-L-phenylalanine

Specified in segaloviciene receive the same procedures, as a procedure of processes 1 and 2 in example 228, and then of example 229, except that as starting material used methyl ester N-(2,6-dichlorobenzoyl)-4-(1-methyl-2,4-dioxo-6-iodine-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl)-L-phenylalanine.

MS(ESI MH+): 569

Example 231. The synthesis of compounds of the following formula (E-65):

The compound of example 52 (351 mg) was dissolved in dichloromethane (10 ml) and triethylamine (0.16 ml, 1.2 mmol). Thereto dropwise under conditions of cooling with ice add methanesulfonanilide (0,116 ml, 1.2 mmol) and stirred for 2 hours Normal processing is performed to obtain the crude material. To the crude material added acetonitrile (5 ml), potassium carbonate (170 mg) and 2M solution of dimethylaminohydrolase (616 μl) and stirred at room temperature overnight. After removal of solvent the residue is purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA) to obtain 40 mg of the desired compound.

MS(ESI MH+): 611

Example 232. The synthesis of compounds of the following formula (E-66):

4 N. the solution hydrochloridecan and isopropanol is added to the compound of example 144 and stirred at 80°C for 2 hours After removal of the solvent under reduced pressure the residue purified by high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TA) to obtain the desired connection.

MS(ESI MH+): 597

Example 233. The synthesis of compounds of the following formula (E-67):

The desired connection get the same procedure as the procedure of paragraph (C in the above examples 101-121, using a raw material compound of example 140.

MS(ESI MH+): 542

Example 234. The synthesis of compounds of the following formula (E-68):

The process 1. The synthesis of complex isopropyl ester 4-[(2-amino-5-Ioganson)amino]-N-(2,6-dichlorobenzoyl)-L-phenylalanine

Complex isopropyl ester 4-amino-N-(2,6-dichlorobenzoyl)-L-phenylalanine, 1-hydroxybenzotriazole (11.5g) and 5-japantravel acid (17.8 g) was dissolved in dimethylformamide (200 ml) and cooled to 0°C. thereto was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (13,7 g) and stirred at room temperature for 16 hours the Organic layer, to which is added ethyl acetate (1 l), washed with respectively 0.1 N. aqueous solution of sodium hydroxide (200 ml, 100 ml), water (100 ml), 0.1 N. hloristovodorodnykh acid (200 ml) and saturated aqueous sodium chloride (200 ml, 100 ml). After drying the organic layer over anhydrous sodium sulfate and removal of solvent, the solid material obtained from a mixed solvent of methylene chloride and hexane, filtered to obtain specified in the connection header.

Output: 37,06 g (57,88 mmol)

MS(ESI MH+): 640

Process 2. Sinlesslinks isopropyl ester N-(2,6-dichlorobenzoyl)-4-(6-iodine-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl)-L-phenylalanine

N,N-carbonyldiimidazole (28,16 g) dissolved in 150 ml of dimethylformamide and heated to 80°C. thereto are added dropwise to the solution in dimethylformamide (150 ml) of the compound obtained in process 1 (37,06 g), and stirred overnight. After cooling the mixture to room temperature and to it was added ethyl acetate (1 l) and water (500 ml) and the extraction is carried out. The obtained organic layer was washed with water (300 ml, 200 ml, 200 ml) and saturated aqueous sodium chloride (100 ml) and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the obtained solid material is suspended in methylene chloride and hexane. The obtained solid material was filtered and dried to obtain specified in the connection header.

Output: 33,06 g

MS(ESI MH+): 666

Process 3. The synthesis of complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-(6-iodine-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl)-L-phenylalanine

The compound obtained in process 2 (33,06 g), and potassium carbonate (14.5 g) are added to a dimethylformamide (200 ml), and then to him next, add logmean (10 ml) and stirred at room temperature for 4 hours After removal of insoluble materials by filtration through celite the filtrate add ethyl acetate (1 l) and water (300 ml) and the extraction is carried out. The obtained organic layer was washed with respectively 1 N. chloritoid is one acid (250 ml), water, saturated sodium bicarbonate (250 ml), and saturated aqueous sodium chloride (200 ml). After removal of solvent, the obtained solid material is suspended in methylene chloride and hexane. The obtained solid material was filtered and dried to obtain specified in the connection header.

Output: 31,85 g

MS(ESI MH+): 680

Process 4. The synthesis of complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-(6-carboxy-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl)-L-phenylalanine

The compound obtained in process 3, is dissolved in dimethylformamide (140 ml), and added triethylamine (13.1 ml) and water (8.5 ml). After ozonation carbon monoxide add palladium acetate (52 mg) and stirred in an atmosphere of carbon monoxide at 70°C for 11 hours After removal of insoluble materials by filtration through celite dimethylformamide (about 100 ml) is removed under reduced pressure. Then added ethyl acetate (1 l) and 1 N. hydrochloric acid (300 ml) and the extraction is carried out. The obtained organic layer was washed with 1 N. hydrochloric acid (200 ml) and saturated aqueous sodium chloride (200 ml, 200 ml) and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the obtained solid material is suspended in methylene chloride and hexane. The obtained solid material is altroot and dried to obtain specified in the connection header.

Output: 27,23 g

MS(ESI MH+): 598

Process 5. The synthesis of complex isopropyl ester N-(2,6-dichlorobenzoyl)-4-[6-(hydroxymethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-(2H)-yl]-L-phenylalanine

The compound obtained in process 4, dissolved in tetrahydrofuran (200 ml). Added triethylamine (9,51 ml) and cooled to 0°C. added dropwise ethylchloride (4,56 ml) and stirred for 30 minutes After separation by filtration of insoluble materials, the filtrate is cooled to 0°C and add sodium borohydride (2.58 g) and ice (5 pieces) and stirred for 1 h Then to it add additional sodium borohydride (0.25 g) and stirred for 20 minutes add 1 N. hydrochloric acid (74,8 ml), ethyl acetate and water and the extraction is carried out. The organic layer is washed with 0.3 N. hydrochloric acid, water, saturated sodium bicarbonate, and saturated aqueous sodium chloride. After removal of solvent, the obtained solid material is suspended in methylene chloride and hexane. The obtained solid material was filtered and dried to obtain specified in the connection header.

Output: 25,69 g

MS(ESI MH+): 584

Example 235. The synthesis of compounds of the following formula (E-69):

The desired connection receive in the form of material a by-product of the compound of example 228.

MS(ESI MH+): 609

Example 26. The synthesis of compounds of the following formula (E-70):

The desired connection receive in the form of material a by-product of the compound of example 229.

MS(ESI MH+): 567

Reference example 4. The synthesis of complex isopropyl ester 4-amino-N-(2,6-dichlorobenzoyl)-L-phenylalanine (namely, the synthesis of isopropyl-(S)-2-(2,6-dichloraniline)-3-(4-nitrophenyl)propionate

Process 1: the Synthesis of complex isopropyl ester 4-nitro-N-(2,6-dichlorobenzoyl)-L-phenylalanine

Isopropanol (130 ml), tetrahydrofuran (50 ml) and sulfuric acid (of 0.44 ml) was added to 4-nitro-N-(2,6-dichlorobenzoyl)-L-phenylalanine (2,95 g of 7.70 mmol) and stirred at 50°C for 5 hours After removal of the solvent under reduced pressure, the obtained solid material was washed with water and dried to obtain 3.28 g of a white solid material.

MS(ESI) m/z 425(MH+)

Step 2: Synthesis of complex isopropyl ester 4-amino-N-(2,6-dichlorobenzoyl)-L-phenylalanine (namely, the synthesis of isopropyl-(S)-2-(2,6-dichloraniline)-3-(4-nitrophenyl)propionate

Isopropanol (6 ml), tetrahydrofuran (3 ml) and 3% Pt-S/C (20 mg) are added to the solid material obtained in process 1 (98 mg), and stirred under hydrogen atmosphere at room temperature overnight. After filtering the reaction solution, the filtrate is washed with isopropanol and removed under reduced pressure to obtain 92 mg of the specified header from the organisations.

MS(ESI) m/z 395(MH+)

Below shows the structural formulas of the compounds given in the examples.

Table 1

Table 2

Table 3

Connection examples 16-20

Table 4
Example-R-R'MC found (MH+)
21569
22595
23597
24611
25625
26639
27659

Table 5

Table 6

The compound of example 36

Table 7

Table 8

Table 9
Example-RMC found (MH+)
41578
42592

tr>
Table 10
Example-RMC found (MH+)
43-I638
44-CN537
45-COOCH2Ph646
46-COOH556

Connection examples 47 and 48

Table 11
Example-RMC found (MH+)
49582
50555
51 584
52570

Table 12

The compound of example 59

Table 13
Example-RMS found (MH+)
60-HE542
61-OMe556

Table 14
Example-RMS found (MH+)
62556
63556

The compound of example 64

Table 15-1

Table 15-2

Table 16

Table 17

Connection examples 89-97

Table 18

The compound of example 100

Table 19-1

Table 19-2

Table 19-3

Table 20

Connection examples 124 and 125

Table 21

Connection examples 128-132

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table And

Table

Table

Table D

Table E-1

Table E (continued)

Table F

Table G

Table H

Connection examples 228-236

Additionally, compounds characterized by the following structural formulas can be easily obtained by the same methods as the connection described above. Examples or methods of synthesizing such modifications, which are obvious to experts in the field relating to these methods.

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Example 1 test

Analysis of antagonistic activity against the binding of VCAM-1/α4β1 integrin in the presence of serum

Determine the ability of test substance to counteract binding of a line of T-cells, Jurkat (ATCC TIB-152), which are known to Express α4β1 integrin with VCAM-1.

50 µl/well of a solution (500 ng/ml) recombinant human VCAM-1/Fc (R&D systems) diluted with buffer A (0.1m NaHCO3pH 9,6) is added to 96-well ritrovato the microplate (Nunc Maxicorp.). After incubation at 4°C during the night and a single washing PBS add a buffer (buffer B), obtained by dilution of Block Ace (Snow Brand Milk Products Co., Ltd.) using PBS to a concentration of ½ in the amount of 150 μl/well. After incubation at room temperature for 2 h, the buffer is removed and the plate washed once by PBS.

The Jurkat cells washed once modified, Dulbecco medium Needle (SIGMA, hereinafter referred to as “DMEM”). The cells are then again suspended in binding buffer (DMEM containing 20 mm HEPES, 0.1% of BSA (bovine serum albumin), 2 mm MnCl2and 50% human serum (Sigma)) to bring the concentration up to 1×106to etoc/ml

60 μl of various concentrations of the test substance, obtained by breeding binding buffer, added to 96-well plate with a round bottom (IWAKI). Immediately after this, they add 60 μl of Jurkat cells (1×106cells/ml) and shaken on the vibrator for a tablet (IKA-Labortechnik, IKA-SCHUTTLER MTS-4) at 1000 rpm for 10 seconds In 120 µl of cell suspension, which is added to the test substance, each 100 μl is transferred onto coated with VCAM-1/Fc the plate and incubated in the dark at room temperature for 60 minutes After shaking on the vibrator to the plate at 1000 rpm for 30 s, the solution is immediately removed. Then the unbound cells are removed once their washing by PBS. In the plate type buffer (PBS containing 0,82% Triton X-100) in an amount of 70 μl/well. After shaking on the vibrator to the plate at 1000 rpm for 5 min, related Jurkat cells lyse. After centrifugation of the cells on a tablet centrifuge (SIGMA 4-15C) at room temperature at 2500 rpm for 5 min, 50 µl of them supernatant is transferred into a 96-well ritrovato the microplate (Nune Maxisorp). It added per 50 μl of substrate buffer (non-radioactive analysis of cytotoxicity Promega, CytoTox 96), shaken on the vibrator to the plate at 1000 rpm for 10 s and provide interaction in a dark place at room temperature during the 30 minutes Then they add each 50 μl of stopping solution (non-radioactive analysis of cytotoxicity Promega, CytoTox 96) and shaken on the vibrator to the plate at 1000 rpm for 10 seconds Its spectral absorption capacity at 490 nm determined by the device to read the tablet (Molecular Devices Vmax). Obtained in this way spectral absorption ability reveals the activity of lactate dehydrogenase (LDH), dissolved in the supernatant of each well. Namely, the spectral absorption capacity is proportional to the number of remaining cells Jurkat on the tablet by binding to VCAM-1. The test is carried out twice, and the rate of binding of each test substance in various concentrations, whereas, according to the measurement of the spectral absorption capacity of the wells without test substance is 100%and the spectral absorption capacity of the wells without cells Jurkat, by definition, is 0%. Calculate the concentration for inhibition of binding by 50%, IC50. The results obtained are shown in table 1 the results.

Table 1 results
Analysis antagonistically activity against the binding of VCAM-1/α4β1 (IC50nm)
Example IC50(nm)
11,7
222,9
414,0
510,8
68,9
1015,5
135,5
145,8
1722,9
1811,7
1923,5
2813,9
3410,5
357,9
3812,4
396,5
4715,7
483,6
5015,4
5323,3
5414,5
5514,2
5613,1
5716,6
6025,5
6310,8
6412,3
9818,1
9911,2
13610,5
1398,4
14112,2
14214,7
1437,0
144a 4.9
145the 3.8
1467,9
1609,4
16116,5
19112,9
192179
1938,2
1946,9
1956,4
1965,3
1976,3
198the 5.7
19918,0
20813,4 I
20915,2
21911,9
22016,9
22119,7
22219,5
22314,6
22412,4
2269,2
22914,7
23011,7
*148, 8 persons
*represents the compound of example 1 in WO 02/6329 (patent publication 14)

Example 2 test

Pharmacokinetic study of intravenous rat

After weighing scales compounds of the present invention, where R11-R141 represent a hydroxyl group, which are the active forms, their concentration was adjusted dimethylsulfoxide to 10 mg/ml To add the polyethylene glycol 400 and distilled water to obtain input solution with a concentration of 1 mg/ml of Injected solution with a concentration of 1 mg/ml is injected in the form of a single dose of the Wistar rat 1 ml/kg After 1, 5, 10, 30, 60 and 180 min of the drug concentration in the blood plasma obtained by drawing blood from her Central vein, determine in the dynamics under anesthesia using LC/MS (liquid chromatography/mass spectrometry). According to the obtained results the area under the curve changes over time in plasma concentrations from zero to infinity (AUCinf (iv)) shall be calculated in accordance with the trapezoidal method pharmacokinetic analysis. The total excretion of (CLtot, [L/h/kg]) is calculated as the rate of disappearance dose [mg/kg] of the drug in plasma and AUC [µg×h/ml], in accordance with the formula: CLtot = dose + AUCinf (iv). The results obtained are shown in table 2 results.

Table 2 achiev is tatou
The total excretion of
(CLtot, [L/h/kg])
ExampleCltot, [L/h/kg]
70,1
80,22
120,21
280,1
340,31
370,33
400,19
460,33
540,27
590,32
990,23
1350,17
1370,24
*1,89
* represents the compound of example 1 in WO 02/16329 (patent publication 14)

Example 3 test

Pharmacokinetic study using oral administration rat

After weighing in the balance connections this is the invention, where R11-R141 are radicals other than hydroxyl groups, which are proletarienne compounds, dissolved with dimethylsulfoxide to bring the concentration up to 100 mg/ml they added a mixed solution of polyethylene glycol 400 : propylene glycol = 1:1 to receive input solution with a concentration of 2.5 mg/ml 2.5 mg/ml injectate orally administered to male Wistar rats (aged 7-9 weeks) in an amount of 4 ml/kg Over 0,25, 0,5, 1, 2, 4, 6 or 8 hours take blood from his jugular vein under anesthesia syringe treated with dichlorvos, which is an inhibitor of esterase. The blood is then transferred into a test tube, treated with heparin, and centrifuged, getting the blood plasma. Acetonitrile containing the internal standard substance, add the two parts to the obtained blood plasma and the concentration of the corresponding active forms, where R11-R141 represent a hydroxyl group, define LC/MS/MS. The results calculatethe area under the curve changes over time in plasma concentrationsfrom zero time to infinity, namely, AUCinf (po). Bioavailability (BA) is calculated based on AUCinf (iv) the active form when administered intravenously, obtained in example 2 tests according to the following formula:

BA(%)=[AUCinf(po)/Dose(po)]/AUCinf(iv)/Dose(iv)]×100

AUCinf:the area under the curve of the dynamics of times the plasma concentration from zero time to infinity active forms for oral or intravenously administered

Dose: oral or intravenous dose (active form)

The results obtained are shown in table 3 of the results.

Table 3 results
Pharmacokinetic studies in oral introduction rat
ExampleBA(%)
12430
10326
12313
11113
10810
16214
*2,7
ExampleAUC0-∞ (µmol∙h/l)
10814,15
10612,48
12310,08
1058,77
1247,2
1116,63
1035,74
1195,08
1164,28
*0,27
* represents the compound of example 190, WO 02/16329 (patent publication 14) and corresponds to the complex compound methyl ester of example 1 in WO 02/16329 (patent publication 14)

Example 4 tests

Activity in increasing the number of lymphocytes in the peripheral blood in rats

After the introduction of a substance that inhibits communication between α4-integrin and VCAM-1, in vivo, in case of an effective inhibitory activity, it is assumed that the number of lymphocytes in the peripheral blood increases inhibition of adhesion of lymphocytes to the blood vessels of organs (not patent publication 45 and 47). Investigated the activity of the compounds of the present invention in terms of increasing the number of lymphocytes in the rat.

The injected solution was obtained by dissolving the compounds of the present invention dimethylsulfoxide, adding a mixed solution of polyethylene glycol 400 : propylene glycol = 1:1 and re-turning the tube up and down on the ohms. The final concentration of DMSO was brought to 2.5%.

The injected solution of the test substance (3 mg/kg, 10 mg/kg or 30 mg/kg) orally administered to male Wistar rats (aged 6 to 8 weeks) in an amount of 4 ml/kg At set time points after administration of blood taken from his large abdominal vein under anesthesia and stirred in a container, covered with EDTA-2K, for blood collection. Then the number of lymphocytes in peripheral blood was determined by an automated analyzer full set hematological parameters (SF-3000, Sysmex). The test is carried out in 5 animals, and calculate the ratio (%) in the number of lymphocytes in the peripheral blood of the group, which administered the test substance, the number of lymphocytes in group treated with medium (control group), while the average number of lymphocytes in the peripheral blood of the control group is defined as 100%.

The results obtained are shown in table 4 results.

Table 4 results
Analysis of the activity in terms of increasing the number of lymphocytes in the peripheral blood during oral introduction of the rat
Example No.3 mg/kg3 mg/kg10 mg/kg
after 1 hafter 6 hafter 6 hafter 12 h
WO 02/16329
The compound of example 190

(195%)

(≤ 100%)

(131%)

(120%)
71---
88---
90
91---
102- --
103---
104---
106--
107---
109---
111
112- --
113---
115--
116--
117---
118---
122---
124---
125---
129---
131--
30---
85---
121---
126---
127- --
128---
138---
147--
148---
149---
150---
151---
152---
153---
154---
155---
156---
157---
158---
159-- -
162--
163---
164---
165---
166---
167---
168---
169 ---
170---
171---
172---
173---
174---
176---
177---
178---
179---
180---
181---
182---
183---
184---
185-- -
186---
187---
188---
189---
190---
210---
211---
212 ---
213---
214---
215---
216---
217---
218---
225---
228---
232---
233---
234---
235---
Criterion195% or more125% or more150% or more150% or more
a positive result (the value of the criterion or more)
: a negative result (the value is less than the criterion)
- : not rated

1. About spodnie phenylalanine following formula (1) or their pharmaceutically acceptable salts

where R11represents a hydroxyl group, CNS group having 1-6 carbon atoms which may be substituted by a methoxy group, cycloalkyl group having 3-6 carbon atoms, or benzyloxy;
R12and R13each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12R13is 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group;
R14represents a methyl group;
R1' represents a hydrogen atom, a fluorine atom;
X1represents-CH(R1a)-, -CH(R1a)CH(R1b)-,
-CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinyl, where R1a, R1beach independently represents a hydrogen atom or a methyl group, a R1crepresents a hydrogen atom;
Y11and Y12are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F).

2. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 1, where in formula (1) R11represents a hydroxyl group, CNS group having 1-6 carbon atoms, which may be Zam is established by a methoxy group, or benzyloxy;
R12and R13each independently represents a hydrogen atom, alkyl group having 1-3 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12R13is 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; and
X1represents-CH(R1a)-, -CH(R1a)CH(R1b)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)- or 1,3-pyrrolidinyl.

3. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 2, where in the formula (1) X1represents-CH(R1a)-, -CH2CH2-, -N(R1a)CH2CH2- or 1,3-pyrrolidinyl, where R1arepresents a hydrogen atom or methyl group.

4. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 3, where in the formula (1) R12and R13each independently represents a hydrogen atom or alkyl group having 1-3 carbon atoms, or N(R12R13is 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group.

5. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 3, where in the formula (1) R12represents methyl group or ethyl group,
R13represents a hydrogen atom, methyl group or ethyl group, or
N(R12R13is pyrrolidinyloxy group, 1-piperidinyloxy group or 4-morpholinyl group,
R14represents a methyl group,
R1' represents a hydrogen atom,
X1represents-CH2-located in the sixth, seventh or eighth position chineselanguage rings, and
Y11and Y12are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F).

6. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 3, where in the formula (1) R13represents a hydrogen atom, methyl group or ethyl group,
X1represents-CH2-located in the sixth, seventh or eighth position chineselanguage rings, and
Y11and Y12represent the combination of (Cl, Cl).

7. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 6, where in the formula (1) R13represents a hydrogen atom, methyl group or ethyl group, and
X1represents-CH2-who is in the sixth position chineselanguage rings.

8. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 6, where in the formula (1) R13represents a hydrogen atom, a metal group or ethyl group, and
X1represents-CH2-who is in the seventh position chineselanguage rings.

9. Derivatives of phenylalanine or its pharmaceutically acceptable salt, n is 3, where in the formula (1) R12and R13each independently represents a metal group or ethyl group,
R14represents a methyl group,
R1' represents a hydrogen atom or a fluorine atom, which is located in the sixth or seventh position chineselanguage rings,
X1is-N(CH3)CH2CH2-and
Y11and Y12represent the combination of (Cl, Cl).

10. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 2, where in the formula (1) R12and R13each independently represents a hydrogen atom, a metal group or ethyl group, or N(R12R13is' 1-pyrrolidinyl group, 1-piperidinyl group or 4-morpholinyl group,
R14represents a methyl group,
R1' represents a hydrogen atom,
X1is-OCH(R1a)CH(R1b), in which R1aand R1beach independently represents a hydrogen atom or methyl group, and
Y11and Y12are any of the combinations, (Cl, Cl), (Cl, Me), (Cl, F).

11. Derivatives of phenylalanine or its pharmaceutically acceptable salt of claim 10, where in the formula (1) R12and R13each independently represents a hydrogen atom, a metal group or ethyl group,
R14represents a methyl group and
Y11and Y12represent the combination is, s (Cl, Cl).

12. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 1, where in formula (1) R11represents a hydroxyl group or CNS group having 1-6 carbon atoms, which can be a methoxy group as a substituent,
R12represents a hydrogen atom or alkyl group having 1-6 carbon atoms,
R13represents a hydrogen atom, methyl group or ethyl group, or
N(R12R13is 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group,
R14represents a methyl group,
R1' represents a hydrogen atom,
X1represents-CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c) -, or-OCH(R1a)CH(R1b)-, which is located in the sixth position chineselanguage rings, where each R1a, R1band R1crepresents a hydrogen atom, and
Y11and Y12represent the combination of (Cl, Cl).

13. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 1, where in formula (1)
R11represents a hydroxyl group or CNS group having 1-6 carbon atoms,
R12represents an alkyl group having 1-6 carbon atoms,
R13represents a hydrogen atom, methyl group or ethyl group,
R14represents a methyl group,
R1' p is ecstasy a hydrogen atom,
X1represents-CH(R1a) -, or-CH(R1a)CH(R1b)-, which is located in the sixth position chineselanguage rings, where each R1aand R1brepresents a hydrogen atom, and
Y11and Y12represent the combination of (Cl, Cl).

14. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 1, where in formula (1)
R11represents a hydroxyl group or CNS group having 1-6 carbon atoms,
R12represents an alkyl group having 1-5 carbon atoms,
R13represents a hydrogen atom,
R14represents a methyl group,
R1' represents a hydrogen atom,
X1represents-CH(R1a)-, -CH(R1a)CH(R1b)- or-CH(R1a)CH(R1b)CH(R1c), which is located in the sixth position chineselanguage rings, where each R1a, R1band R1crepresents a hydrogen atom, and
Y11and Y12represent the combination of (Cl, Cl).

15. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 1, where in formula (1)
R11represents a hydroxyl group or CNS group having 1-6 carbon atoms,
R12represents methyl group or ethyl group,
R13represents a hydrogen atom,
R14represents a methyl group,
R1' represents a hydrogen atom,
X1represents the t-CH(R 1a)-, -CH(R1a)CH(R1b)- or-CH(R1a)CH(R1b)CH(R1c), which is located in the sixth position chineselanguage rings, where each R1a, R1band R1crepresents a hydrogen atom, and
Y11and Y12represent the combination of (Cl, Cl).

16. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 1, where in formula (1)
R11represents a hydroxyl group or CNS group having 1-6 carbon atoms,
R12represents methyl group, ethyl group, isobutylene group, cyclopropylmethyl group, cyclobutyl group, sec-boutelou group or isopentyl group,
R13represents a hydrogen atom,
R14represents a methyl group,
R1' represents a hydrogen atom,
X1represents-CH(R1a)-, which is located in the sixth position chineselanguage ring, where R1arepresents a hydrogen atom, and
Y11and Y12represent the combination of (Cl, Cl).

17. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 1, where in formula (1)
R11represents a hydroxyl group or CNS group having 1-6 carbon atoms,
R12represents a hydrogen atom or alkyl group having 1-3 carbon atom,
R13represents a hydrogen atom, methyl group or atlookup, or
N(R12R13is 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group,
R14represents a methyl group,
R1' represents a hydrogen atom,
X1represents-O-CH(R1a)CH(R1b)- or-O-CH(R1a)CH(R1b)CH(R1c), which is located in the sixth position chineselanguage rings, where each R1a, R1bindependently represents a hydrogen atom or methyl group, and R1crepresents a hydrogen atom, and
Y11and Y12represent the combination of (Cl, Cl).

18. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to any one of claims 1 to 17, where in the formula (1) R11is branched CNS group having 3-6 carbon atoms.

19. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 1, represented by the following formulas





20. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to claim 3, where in the formula (1) R12represents methyl group or ethyl group,
R13represents a hydrogen atom, methyl group or ethyl group, or
N(R12R13is 1-pyrrolidinyl group, 1-piperidinyl group or 4-morpholinyl group,
R14represents a methyl group,
R1' represents a hydrogen atom,
X1represents-CH2-located in the sixth, seventh or eighth position chineselanguage rings, and
Y11and Y12represent the combination of (Cl, Cl).

21. A derivative of phenylalanine or its pharmaceutically acceptable salt according to claim 19, represented by the following formula
.

22. A derivative of phenylalanine or its pharmaceutically acceptable salt according to claim 19, presented after the ith formula
.

23. A derivative of phenylalanine or its pharmaceutically acceptable salt according to claim 19, represented by the following formula
.

24. A derivative of phenylalanine or its pharmaceutically acceptable salt according to claim 19, represented by the following formula
.

25. A derivative of phenylalanine or its pharmaceutically acceptable salt according to claim 19, represented by the following formula
.

26. A derivative of phenylalanine or its pharmaceutically acceptable salt according to claim 19, represented by the following formula
.

27. A derivative of phenylalanine or its pharmaceutically acceptable salt according to claim 19, represented by the following formula
.

28. A derivative of phenylalanine or its pharmaceutically acceptable salt according to claim 19, represented by the following formula
.

29. A derivative of phenylalanine or its pharmaceutically acceptable salt according to claim 19, represented by the following formula
.

30. A derivative of phenylalanine or its pharmaceutically acceptable salt according to claim 19, represented by the following formula
.

31. Derivatives of phenylalanine following formula (2) or their pharmaceutically acceptable salts

where R21represents a hydroxyl group, CNS group having 1-6 carbon atoms,
R22represents a hydrogen atom or alkyl group having 1-3 carbon atom,
R24represents a methyl group,
R1' represents a hydrogen atom,
X2represents-CH(R2a)-, -CH2CH2- or-N(R2a)CH2CH2-, where R2arepresents a hydrogen atom or methyl group, and
Y21and Y22are any of the combinations, (Cl, Cl).

32. Derivatives of phenylalanine or its pharmaceutically acceptable salt p, where in the formula (2)
R22represents methyl group or ethyl group,
R24represents a methyl group,
R2' represents a hydrogen atom,
X2represents-CH2-located in the sixth, seventh or eighth position chineselanguage rings, and
Y21and Y22represent the combination of (Cl, Cl).

33. Derivatives of phenylalanine or its pharmaceutically acceptable salt p, where in the formula (2)
R22represents a hydrogen atom, methyl group or ethyl group,
R24represents a methyl group,
R2' represents a hydrogen atom,
X2is-N(CH3)CH2CH2- or-NHCH2CH2-who is in the sixth or seventh position hin is zaindinova ring, and
Y21and Y22represent the combination of (Cl, Cl).

34. Derivatives of phenylalanine following formula (3) or their pharmaceutically acceptable salts

where R31represents a hydroxyl group, CNS group having 1-6 carbon atoms,
R34represents a methyl group,
R3' represents a hydrogen atom or a fluorine atom,

formula (3-1) represents the 4-morpholinyl group, 1-piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms, or 1-imidazolidinyl group which may be substituted by methyl group, ethyl group or amino group, and
Y31and Y32represent the combination of (Cl, Cl).

35. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to clause 34, where in the formula (3) formula (3-1) represents the 4-morpholinyl group, 1-piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms, or 1-imidazolidinyl group which may be substituted by a methyl group or amino group.

36. Derivatives of phenylalanine or its pharmaceutically acceptable salt p, where in the formula (3)
R34represents a methyl group,
R3' represents a hydrogen atom,
formula (3-1), not only is no 4-morpholinyl group or 1-piperazinilnom group, the fourth position may be substituted by an alkyl group having 1-3 carbon atoms, and
Y31and Y32represent the combination of (Cl, Cl).

37. Derivatives of phenylalanine or its pharmaceutically acceptable salt p, where in the formula (3)
R34represents a methyl group,
R3' represents a hydrogen atom,
formula (3-1) represents 2-amino-1-imidazolidinyl group, and
Y31and Y32represent the combination of (Cl, Cl).

38. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to clause 34, where in the formula (3)
R34represents a methyl group,
R3' represents a hydrogen atom or a fluorine atom,
formula (3-1) represents 1-imidazolidinyl group, the second position of which may be substituted methyl group or ethyl group, and
Y31and Y32represent the combination of (Cl, Cl).

39. Derivatives of phenylalanine following formula (4) or their pharmaceutically acceptable salts

where R41represents a hydroxyl group, CNS group having 1-6 carbon atoms,
the ring represents a benzene ring, pieperazinove ring, the first and fourth position which is substituted by an alkyl group having 1-3 carbon atoms, or pyrolidine ring, the first position of which may be substituted by an alkyl group, had the soup of 1-3 carbon atom,
R44represents a methyl group, and
Y41and Y42are any of the combinations, (Cl, Cl).

40. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to § 39, where in the formula (4) ring is pieperazinove ring, the first and fourth position which is substituted by a methyl group,
R44represents a methyl group, and
Y41and Y42represent the combination of (Cl, Cl).

41. Derivatives of phenylalanine following formula (5) or their pharmaceutically acceptable salts

where R51represents a hydroxyl group, CNS group having 1-6 carbon atoms,
R54represents a methyl group,
R5' represents a hydrogen atom,
R5a represents a hydrogen atom or alkyl group having 1-3 carbon atoms, and R5brepresents an alkyl group having 1-3 carbon atoms, or
N(R5aR5bis 1-pyrrolidinyloxy group, and
Y51and Y52represent the combination of (Cl, Cl).

42. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to paragraph 41, where in the formula (5),
R54represents a methyl group,
R5' represents a hydrogen atom,
N(R5aR5bis 1-pyrrolidinyloxy group, and
Y51and Y52represent the combination of (Cl, Cl).

43. Proizvodi the e phenylalanine following formula (6) or their pharmaceutically acceptable salts

where R61represents a hydroxyl group, CNS group having 1-6 carbon atoms,
And6is any formula of the following formulas (6-1)to(6-6)


and Y61and Y62represent the combination of (Cl, Cl).

44. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to item 43, where in the formula (6) And6represents any of the above formulas (6-1)to(6-4).

45. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to item 43, where in the formula (6) R61represents a hydroxyl group, and Y61and Y62represent the combination of (Cl, Cl).

46. Derivatives of phenylalanine following formula (7) or their pharmaceutically acceptable salts

where R71represents a hydroxyl group, CNS group having 1-6 carbon atoms, morpholinoethoxy,
R74represents a methyl group,
R7is alkylamino group having 3-5 carbon atoms, cycloalkylcarbonyl group having 4-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, or through the group, and
Y71and Y72are combined is the situation (Cl, Cl).

47. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to item 46, where in the formula (7)
R74represents a methyl group,
R7is 2-propenyloxy group or cyclopropylmethyl group, and
Y71and Y72represent the combination of (Cl, Cl).

48. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to item 46, where in the formula (7)
R74represents a methyl group,
R7is through the group, and
Y71and Y72represent the combination of (Cl, Cl).

49. Derivatives of phenylalanine following formula (8) or their pharmaceutically acceptable salts

where R81represents a hydroxyl group, CNS group having 1-6 carbon atoms, or hydroxyethylene group,
R82represents a methyl group,
R84represents a methyl group,
n8represents an integer from 0 to 2, and
Y81and Y82represent the combination of (Cl, Cl).

50. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to § 49, where in the formula (8)
R81represents a hydroxyl group, CNS group having 1-6 carbon atoms.

51. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to § 49, where in the formula (8)
R82represents a methyl group,
R84 represents a methyl group,
n8represents one of integer numbers 0 or 2
S located in the sixth position chineselanguage rings, and
Y81and Y82represent the combination of (Cl, Cl).

52. Derivatives of phenylalanine following formula (9) or their pharmaceutically acceptable salts

where R91represents a hydroxyl group, CNS group having 1-6 carbon atoms,
R92represents a hydroxyl group, CNS group having from 1 to 6 carbon atoms, amino group or benzyloxy,
R94represents a methyl group,
X9represents an atomic bond, -CH2CH2- or-CH=CH-, and
Y91and Y92represent the combination of (Cl, Cl).

53. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to paragraph 52, where in the formula (9),
X9represents-CH2CH2- or-CH=CH-, and R92represents a hydroxyl group,
or X9represents the atomic valence, a R92is benzyloxy,
X9located in the sixth position chineselanguage rings,
R94represents a methyl group, and
Y91and Y92represent the combination of (Cl, Cl).

54. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to paragraph 52, where in the formula (9),
X9PR is dstanley atomic bond, and R92represents a hydroxyl group, a methoxy group or an amino group,
X9located in the sixth position chineselanguage rings,
R94represents a methyl group, and
Y91and Y92represent the combination of (Cl, Cl).

55. Derivatives of phenylalanine following formula (10) or their pharmaceutically acceptable salts

where R101is CNS group having 2-6 carbon atoms, or morpholinoethoxy,
R10represents methyl group or ethyl group,
R104represents a methyl group, and
Y101and Y102represent the combination of (Cl, Cl).

56. Derivatives of phenylalanine or its pharmaceutically acceptable salt according to § 55, where in the formula (10), R10represents ethyl group.

57. Derivatives of phenylalanine following formula (11) or their pharmaceutically acceptable salts

where R111is CNS group having 1-6 carbon atoms,
R114represents a methyl group, and
Y111and Y112represent the combination of (Cl, Cl).

58. Derivatives of phenylalanine following formula (12) or their pharmaceutically acceptable salts:

where R121is CNS group having 1-6 carbon atoms,
R124presented AET methyl group, and
And are any of the following formulas (12-1) and (12-2)

59. Derivatives of phenylalanine following formula (13) or their pharmaceutically acceptable salts

where R131is CNS group having 1-6 carbon atoms,
N(R13aR13bis 1-pyrrolidinyloxy group, and
Y131and Y132represent the combination of (Cl, Cl).

60. Derivatives of phenylalanine following formula (14) or their pharmaceutically acceptable salts

where R141represents a hydroxyl group, CNS group having 1-6 carbon atoms,
R144represents a methyl group,
hydroxyl group on hinazolinam the ring is in the sixth or seventh position of the ring, and
Y141and Y142represent the combination of (Cl, Cl).

61. Derivatives of phenylalanine or its pharmaceutically acceptable salt p, where in the formula (14),
R144represents a methyl group,
the hydroxyl group is located in the sixth position chineselanguage rings, and
Y141and Y142represent the combination of (Cl, Cl).

62. Pharmaceutical composition having antagonistic activity against α4-integrin-containing derivative of phenylalanine or its pharmaceutical the ski acceptable salt according to any one of claims 1 to 61 as an active ingredient and a pharmaceutically acceptable carrier.

63. Antagonist of α4 integrin containing a derivative of phenylalanine or its pharmaceutically acceptable salt according to any one of claims 1 to 61 as an active ingredient and optionally a carrier.

64. Therapeutic agent or a prophylactic agent against inflammatory diseases, pathology involving the process of adhesion-dependent α4 integrin containing a derivative of phenylalanine or its pharmaceutically acceptable salt according to any one of claims 1 to 61 as an active ingredient and optionally a carrier.

65. Therapeutic agent or a prophylactic agent against rheumatoid arthritis, inflammatory intestinal diseases (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus, multiple sclerosis, Sjogren syndrome, asthma, psoriasis, Allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, metastasis of tumors and transplant rejection, containing a derivative of phenylalanine or its pharmaceutically acceptable salt according to any one of claims 1 to 61 as an active ingredient and optionally a carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new condensed compounds (versions) or their pharmaceutically acceptable salts having inhibitory effect on HER2 and/or EGFR kinase, having the following formula, for example: or , where R1a is a hydrogen atom; R2a is a C1-8alkyl group, C2-8alkenyl group or C2-8alkynyl group, each of which is substituted with substitute(s), R3a is a hydrogen atom or C1-6alkyl group; or R1a and R2a are optionally bonded with formation or R2a and R3a are optionally bonded with formation of C2-4alkylene; Ba is a benzene ring optionally substituted with 1-4 substitutes selected from halogen and optionally halogenated C1-4alkyl; Ca is a phenyl group substituted with 1-5 substitutes selected from (i) halogen, (ii) optionally halogenated C1-4alkyl, (iii) hydroxy- C1-4alkyl, (iv) a 5-8-member heterocycle- C1-4alkyl, where the said 5-8-member heterocycle contains 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and optionally oxidised sulphur atom, (v) optionally halogenated C1-4alkyloxy, (vi) cyano and (vii) carbamoyl, optionally substituted with C1-8alkyl, and, respectively, R2e is a C1-4alkyl group optionally substituted with -O-(CH2)n-OH, where n is an integer from 1 to 4; R3e is a hydrogen atom; Be is a benzene ring optionally substituted with a halogen; and Ce is a phenyl group optionally substituted with halogenated C1-4alkyl.

EFFECT: obtained new compounds can be used for treating cancer.

22 cl, 2 tbl, 280 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.

EFFECT: increased effectiveness of using the compounds.

24 cl, 20 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to use of dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidzo[1,2-a]benzimidazole as a compound which inhibits erythrocyte aggregation and reduces blood viscosity, and also reduces insulin resistance and restores tolerance of the body to glucose. The invention also relates to a pharmaceutical composition based on the said dihydrochloride.

EFFECT: new potential of the of the said compound has been studied.

3 cl, 4 dwg, 9 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidine and pyrrolopyridine of general formula (I), substituted with a cyclic amino group (II), or their pharmaceutically acceptable salts having CRF antagonist properties. In general formula the cyclic amino group has formula , in which the cyclic amino group is a 6-member saturated cyclic amine, the said cyclic amine is substituted with a group of formula -(CH2)mX; in which X is -CO2H, -CONH2,-P(=O)(OH)2 or -S(=O)2OH; Y is N or CH; m is an integer selected from 1, 2 and 3; R4 is hydrogen; R5 is hydrogen; R6 is C1-5alkyl; R7 and R8 are identical or different and independently represent hydrogen, C1-5alkyl, Ar is phenyl which is unsubstituted or substituted with one or more substitutes which are identical or different and are selected from a group consisting of halogen, C1-5alkyl, C1-5alkoxy, C1-5alkylthio, trifluoromethyl and trifluoromethoxy.

EFFECT: compounds can be used for therapeutic or preventive treatment of diseases where CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension etc.

12 cl, 6 dwg, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a novel method of producing pyrrolo[2,3-d]pyrimidine derivatives of general formula V, which have protein kinase inhibiting properties, including a method of producing novel intermediate compounds. The method of producing compounds of formula V , where X1 is an activating group selected from chlorine, bromine, iodine, R1 is (C1-C6)alkyl; a is an integer from 0 to 4; R2 is hydrogen or (C1-C6)alkyl, involves linking an activated pyrrolopyrimidine compound of formula IIa , where L1 is a leaving group and X is an activating group selected from chlorine, bromine, iodide; with an amine of formula IIIa or its salt, where R1 is (C1-C6)alkyl; a is an integer from 0 to 4; R2 is hydrogen or (C1-C6)alkyl and P is a nitrogen protecting group labile to hydrogenolysis, such as benzyl; in the presence of a base to obtain a compound of formula IVa and subsequent removal from the obtained compound of formula IVa of the activating group X1 and the nitrogen protecting group P through hydrogenolysis in the presence of hydrogen or a hydrogen source and a catalyst in any order.

EFFECT: method increases output of the desired product.

26 cl, 8 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of modulating expression of a target gene induced by β-catenin using an agent which increases linkage of p300 with β-catenin and reduces linkage of CBP with β-catenin, involving bringing a composition containing β-catenin, CBP and p300, where β-catenin is more likely linked to CBP than p300, into contact with an agent in an amount which is effective for changing the probability of linking β-catenin to CBP compared to p300, where the said agent is a compound with a structure selected from formula (I), or its stereoisomers: where A represents -(C=O)-, B represents -(CHR4)-, D represents -(C=O)-, E represents -(ZR6)-, G represents -(XR7)n-> W represents (C=O)NH-, X represents nitrogen or CH, Z represents CH, n = 0 or 1. Values of substitutes R1 and R2 are indicated in the formula of invention. The invention also relates to a composition for modulating expression of a target gene induced by β-catenin.

EFFECT: novel compounds have useful biological properties.

9 cl, 7 tbl, 30 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) and their pharmaceutically acceptable salts which have PDE9A inhibition properties. In formula (I) R1 represents alkyl with 1-8 carbon atoms or cycloalkyl with 5-6 carbon atoms which, if necessary, can have up to three substitutes independently selected from: alkyl with 1-6 carbon atoms, hydroxy, halogen and trifluoromethyl, where the alkyl with 1-6 carbon atoms, if necessary, can be substituted with 1-3 substitutes independently selected from halogen and trifluoromethyl, R2 represents phenyl or aromatic mono- or bicyclic heteroaryl with 5-10 atoms in the ring and up to 5 heteroatoms selected from: sulphur, oxygen and/or nitrogen, where phenyl is substituted with 1-3 substitutes, and the heteroaryl, if necessary, can be substituted with 1-3 substitutes in each case independently selected from: alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, hydroxyl and halogen.

EFFECT: compounds can be used for preparing medicinal agents for enhancing perception, ability to concentrate, learning capability and memory enhancement.

9 cl, 1 dwg, 2 tbl, 78 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine-condensed derivatives of formula , where n is selected from 0, 1, 2, 3 and 4, Z1 is selected from N, C(O) and CR3, where R3 represents hydrogen, Z2 is selected from N and CR4, where R4 is selected from hydrogen and halogen, where the bond between Z1 and Z2 is selected from a single bond and a double bond, R1 is selected from C1-C4alkyl and C1-C4alkoxy, R2 is selected from NR5C(O)R6, C(O)NR5R6 and NR5R6, where R5 represents hydrogen, and R6 is selected from hydrogen, C1-C4alkyl and phenyl, where phenyl as R6 is optionally substituted with 1-2 radicals independently selected from a group comprising halogen(C1-C4)alkyl, heteroaryl(C0-C4)alkyl and heterocycloalkyl(C0-C4)alkyl, where any heteroaryl or heterocycloalkyl substitute R6 can be optionally substituted with a substitute independently selected from C1-C4alkyl and heterocycloalkyl, where the said heteroaryl and heterocyclyl represent a saturated or unsaturated 5-6-member ring containing 1 or 2 N atoms as a heteroatom, and to their pharmaceutically acceptable salts, hydrates, solvates and isomers. The invention also relates to a pharmaceutical composition base on a formula I compound and to use of formula I compound for preparing a medicinal agent which can be used for treating diseases or disorders associated with anomalous or disrupted kinase activity, primarily diseases or disorders related to anomalous activation of kinase Ab1, Bcr-Ab1, BMX, BTK, CHK2, c-RAF, CSK, c-SRC, Fes, FGFR3, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB.

EFFECT: novel compounds have useful biological properties.

7 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new imidazole derivatives of general formula I , where R1 is C1-C10alkyl or C3-C10cycloalkyl, each possibly and independently substituted with 1 substitute selected from C3-C10cycloalkyl or aryl or a heteroaryl group, possibly substituted with one or two halogens; aryl or heteroaryl; R2 is C1-C10alkoxy or C1-C10thioalkyl; R3 is C1-C10alkoxy, possibly substituted with one C1-C10alkoxy or nitrile, where the said alkoxy group can be cyclic or can contain one O heteroatom; R4 is C1-C10alkyl; C2-C10alkenyl; C1-C10alkoxy or C3-C10cycloalkyl, each possibly and independently substituted with 1 or 2 substitutes selected from C1-C10alkoxy, C3-C10cycloalkyl, carboxylic ester, or with one or two aryl or heteroaryl groups, possibly substituted with one substitute selected from C1-C10alkyl, C3-C10cycloalkyl, nitro or halogen; aryl or heteroaryl, each possibly and independently substituted with 1-3 substitutes selected from C1-C10alkyl, C3-C10cycloalkyl, C1-C10alkoxy, phenoxy, thiophenyl, halogen, nitro, nitrile or aryl group, possibly substituted with one halogen; where up to three hydrogen atoms of the alkyl group can be substituted with fluorine atoms; where the said cycloalkyl can independently have one or two carbon atoms substituted with O or N; where the said aryl denotes an aromatic ring having 6 to 10 carbon atoms, including mono- and bicyclic compounds; and where the said heteroaryl denotes an aromatic ring having 3 to 10 carbon atoms, including mono- and bicyclic compounds in which one to three ring atoms are oxygen, nitrogen or sulphur atoms; except compounds given in paragraph 1. The invention also pertains to use of the said compounds for making a medicinal agent, a treatment and prevention method, a compound of formula II (values of radicals are given in the formula of invention).

EFFECT: new imidazole derivatives having positive allosteric modulator effect on GABAB receptor are obtained.

30 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of a 5-hydroxy-4-thiomethylpyrazole compound, where a pyrazole compound of general formula is reacted with a sulphur compound of general formula X-S(O)n-R (2) in the presence of a base and formaldehyde to form a 5-hydroxy-4-thiomethyl compound of general formula , where radicals and symbols in the said formulae are defined in the formula of invention.

EFFECT: easier synthesis of the desired 5-hydroxy-4-thiomethylpyrazole compound with high output in mild conditions in a single step without using special equipment, expensive catalyst or a transition metal etc, where the process can be carried out virtually without formation of hazardous wastes from a catalyst etc; owing to this, the method is environmentally safe and can be used in industry.

6 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R is hydrogen or (lower)alkyl; R1 is a (lower)alkyl or (C3-C7)cycloalkyl; X is nitrogen while Y is carbon or Y is nitrogen while X is carbon; m equals 0 or 1; Z is C(O) or SO2; R2 is selected from a group consisting of (lower)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl substituted with (lower)alkyl, (lower)phenylalkyl, where the phenyl ring is not substituted or is mono- or disubstituted with (lower)alkoxy or halide, pyridyl which is mono- or disubstituted with a halide, and NR3R4 or when Z is C(O), R2 can also be a (lower)alkoxy; R3 is hydrogen or (lower)alkyl; R4 is selected from a group consisting of (lower)alkyl, (lower)alkoxyalkyl, (C3-C7)cycloalkyl, unsubstituted phenyl or phenyl which is mono-substituted with (lower)alkoxy, or (lower)phenylalkyl, where phenyl is not substituted or is mono- or disubstituted with a halide; or R3 and R4 together with the nitrogen atom to which they are bonded form a 5-, 6- or 7-member heterocyclic ring which optionally contains an additional heteroatom selected from oxygen, the said heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from (lower)alkyl, halide and alkyl halide, or is condensed with a phenyl or cyclohexyl ring, and to their pharmaceutically acceptable salts, as well as to pharmaceutical compositions containing these compounds.

EFFECT: obtaining novel compounds and pharmaceutical compositions based on the said compounds, which are suitable for treating and/or preventing diseases which are associated with modulation of H3 receptors.

25 cl, 2 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cycloalkene derivatives of formula (I) in which X and Y are a group, in which X and Y together with a carbon atom on ring B to which they are bonded form a ring A, X and Y together represent a ring B substitute, or each of X and Y is a hydrogen atom.

EFFECT: invention relates to a medicinal agent based on the said compounds, which has inhibitory effect on intracellular signal transduction or cell activation induced by an endotoxin.

21 cl, 3 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.

EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: novel compound is N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or its pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with CFTR activity modulation properties.

2 cl, 485 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-phenylpyrimidine-2-carbonitrile of formula

(values of R, R1, R2 are given in the formula of invention) or their pharmaceutically acceptable salts which have inhibition properties towards catepsin K and catepsin S. The invention also relates to use of derivatives of formula I for treating catepsin K and catepsin S related disorders, as well as to a pharmaceutical composition containing the said derivative.

EFFECT: improved properties of derivatives.

9 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new imidazole derivatives of general formula I , where R1 is C1-C10alkyl or C3-C10cycloalkyl, each possibly and independently substituted with 1 substitute selected from C3-C10cycloalkyl or aryl or a heteroaryl group, possibly substituted with one or two halogens; aryl or heteroaryl; R2 is C1-C10alkoxy or C1-C10thioalkyl; R3 is C1-C10alkoxy, possibly substituted with one C1-C10alkoxy or nitrile, where the said alkoxy group can be cyclic or can contain one O heteroatom; R4 is C1-C10alkyl; C2-C10alkenyl; C1-C10alkoxy or C3-C10cycloalkyl, each possibly and independently substituted with 1 or 2 substitutes selected from C1-C10alkoxy, C3-C10cycloalkyl, carboxylic ester, or with one or two aryl or heteroaryl groups, possibly substituted with one substitute selected from C1-C10alkyl, C3-C10cycloalkyl, nitro or halogen; aryl or heteroaryl, each possibly and independently substituted with 1-3 substitutes selected from C1-C10alkyl, C3-C10cycloalkyl, C1-C10alkoxy, phenoxy, thiophenyl, halogen, nitro, nitrile or aryl group, possibly substituted with one halogen; where up to three hydrogen atoms of the alkyl group can be substituted with fluorine atoms; where the said cycloalkyl can independently have one or two carbon atoms substituted with O or N; where the said aryl denotes an aromatic ring having 6 to 10 carbon atoms, including mono- and bicyclic compounds; and where the said heteroaryl denotes an aromatic ring having 3 to 10 carbon atoms, including mono- and bicyclic compounds in which one to three ring atoms are oxygen, nitrogen or sulphur atoms; except compounds given in paragraph 1. The invention also pertains to use of the said compounds for making a medicinal agent, a treatment and prevention method, a compound of formula II (values of radicals are given in the formula of invention).

EFFECT: new imidazole derivatives having positive allosteric modulator effect on GABAB receptor are obtained.

30 cl, 6 ex

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