Derivative of aminocarbon acid and application of said substances for medical purposes

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

 

The technical field to which the invention relates

The present invention relates to a compound able to bind with the receptor, sphingosine-1-phosphate (hereinafter denoted by the abbreviation “S1P”), which can be used as drugs and medicinal product containing the specified connection as the active ingredient.

In particular, an object of the present invention is:

(1) the compound represented by formula (I):

where all the symbols have the following values; its salt, N-oxide, MES or prodrug;

(2) pharmaceutical preparation containing as active ingredient a compound represented by the formula (I), its salt, N-oxide, MES or prodrug.

The level of technology

Sphingosine-1-phosphate (S1P), expressed by the formula (A), is a lipid synthesized in the intracellular metabolic metabolism of sphingolipids or intercellular secretory action sphingosines. Found that S1P acts as an intercellular and intracellular messenger (Biochem. Pharm., 58, 201 (1999)).

Known S1P receptors are EDG-1, which is a receptor associated G-protein, and similar molecules, EDG-3, EDG-5, EDG-6 and EDG-8 (also referred to as with therefore, its S1P 1, S1P3, S1P2, S1P4and S1P5). These receptors belong to the family of EDG together with receptors EDG-2, EDG-4 and EDG-7, which are receptors lysophosphatidic acid (LPA). The S1P receptors are associated with S1P and transmit signals into cells via G-protein associated with these receptors. Gs, Gi, Gq and G12/13etc. known as G-proteins, which can bind S1P receptor, it is considered that this receptor is involved in such reactions as increased cell proliferation, inhibition of cell proliferation, induction of chemotaxis of cells and inhibition of chemotaxis of cells.

When performing in vitro experiments it was found that the biological effects of S1P is expressed in the inhibition of migration of smooth muscle cells or cancer cells, platelet aggregation, induction of chemotaxis of cells, the inhibition of the chemotaxis of cells and similar processes, and based on the results of in vitro experiments, it was found that S1P is able to control blood pressure, stimulate the development of blood vessels, reduce blood flow to the kidneys, to inhibit fibrosis of the lungs, stimulate homing of lymphocytes in the lymph organs and so on. It is believed that the above-mentioned physiological effect mediated by S1P receptors present in the cell membrane. However, except for certain kuchipatchi not known what S1P receptor subtypes in fact mediate these effects.

The execution result of the study, which were used mice with absence of EDG-1, has recently been established with a high degree of certainty that S1P induces the development of blood vessels through the receptor EDG-1 (J. Clin. Invest., 106, 951 (2000)). Therefore, we can assume that the agonist EDG-1 can be used to treat diseases caused by the development of blood vessels. For example, the agonist can be used as a tool for the prevention and/or treatment of diseases of the peripheral arteries, such as obliterative arteriosclerosis, obliterating thromboangiitis, Buerger's disease, or diabetic neuropathy; varicose veins, such as hemorrhoids, fissure or fistula of the anus; dissecting aortic aneurysm, sepsis, inflammatory diseases such as vasculitis, nephritis or pneumonia, various edematous diseases that occur during ischemia in various organs and increase the penetrating ability of the blood, such as myocardial infarction, heart attack, brain, angina, disseminated intravascular coagulation (DIC), pleuritis, congestive heart failure, multiple failure of organs, the shock due to the incompatibility of blood during blood transfusion, and the like. Also what about the, agonist EDG-1 can also be used as a means to accelerate wound healing in the cornea, skin, in the digestive organs or the like or, for example, as a means for the prevention and/or treatment of decubitus ulcers, burns, ulcerative colitis, Crohn's disease, or the like. Agonist EDG-1 can also be used as a preoperative, postoperative and/or prognostic activator vessels in the transplantation of various organs, for example, as adhesion promoters of transplanted organs, in particular, heart transplant, kidney transplant, transplantation of skin or liver transplantation.

On the other hand, EDG-6 is localized and highly expressed in cells of the lymphatic and hematopoietic systems, including the spleen, leukocytes, lymph nodes, thymus, bone marrow, lungs and the like, from which it follows that EDG-6 is closely associated with the effects of S1P in inflammation or the immune system (Biochem. Biophys. Res. Commun., 268, 583 (2000)).

In addition, it is known that a polypeptide EDG-6 or its homolog mediates the immunomodulation, anti-inflammatory reactions and these processes are similar to EDG-1, which implies the potential use of these substances in the treatment of autoimmune diseases (such as systemic lupus erythematosus, revmatoidnyi arthritis, multiple sclerosis, myasthenia gravis, muscular dystrophy, and the like), allergic diseases (such as atopic dermatitis, hay fever, food allergies and allergies to chemicals (e.g., anesthetic, such as lidocaine), and the like), asthma, inflammatory diseases, infection, ulcer, lymphoma, malignant tumor (such as cancer and the like), leukemia, arteriosclerosis, diseases caused by infiltration of lymphocytes into tissues, such as multiple failure of organs and impaired reperfusion after ischemia, shock due to incompatibility of blood during blood transfusion and so similar.

It is known that EDG-8 expressed mainly in nerve cells, so EDG-8 can be used for treatment of various neurodegenerative diseases (such as Parkinson's disease, parkinsonovy syndrome, Alzheimer's disease and amyotrophic lateral sclerosis).

Thus, it is believed that the drug is affecting EDG-1, EDG-6 and/or EDG-8, can be used as a prophylactic and/or therapeutic agent in the case of transplant rejection, destruction of the transplanted organ, graft versus host (e.g., acute graft versus host during bone marrow transplantation, and the like), autoimmune Zabol the requirements (such as systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis and muscular dystrophy), allergic diseases (such as atopic dermatitis, hay fever, food allergies and allergies to chemicals (e.g., anesthetic, such as lidocaine), and the like), asthma, inflammatory diseases, infection, ulcer, lymphoma, malignant tumor (e.g., cancer), leukemia, arteriosclerosis, diseases caused by infiltration of lymphocytes into tissues, such as multiple failure of organs and impaired reperfusion after ischemia, shock due to incompatibility of blood during blood transfusion, neurodegenerative diseases (such as Parkinson's disease, parkinsonovy syndrome, Alzheimer's disease and amyotrophic lateral sclerosis), and the like.

In recent years in the scientific literature, it was noted that the agonist EDG-1 can be used as an immunosuppressant. However, no information about that as immunosuppressant can be used agonist or antagonist EDG-6 (see patent document 1: WO 03/061567).

On the other hand, it was found that the compound represented by formula (S):

where ArSmeans phenyl or naphthyl; ASmeans carboxy or similar group; nSmeans 2, 3 or 4; R1Sand R2Seach independently means a hydrogen atom, a halogen atom, is hydroxy, carboxy, C1-6 alkyl which may be substituted by 1-3 halogen atoms, or phenyl which can be substituted by 1-3 halogen atoms; R3Smeans a hydrogen atom or C1-4 alkyl which may be substituted by 1-3 hydroxy groups or halogen atoms; all R4Severy means independently hydroxy, halogen atom, carboxy or similar group; CSmeans C1-8 alkyl, C1-8 alkoxy, phenyl or similar group, or CSdoes not matter; and (BSmeans phenyl, C5-16 alkyl or a similar group (specified only the necessary part of the definition of symbols);

its pharmaceutically acceptable salt and hydrate, as well as

the compound represented by the formula (T):

where ArTmeans phenyl or naphthyl; AndTmeans carboxy or similar group; mTmeans 0 or 1; nTmeans 0 or 1; R1Tand R2Teach independently means a hydrogen atom, halogen atom, hydroxy, carboxy, C1-4 alkyl or phenyl which may be substituted by a halogen atom or the like; R3Tmeans a hydrogen atom or C1-4 alkyl which may be substituted by a hydroxyl group or a halogen atom or the like; all R4Tindependently denote a halogen atom, C1-4 alkyl, C1-3 alkoxy or the like; WithTmeans C1-8 alkyl, C1-8 alkoxy, phenyl or similar group who have, orThas no value; andTmeans phenyl, C5-16 alkyl or a similar group (specified only the necessary part of the definition of symbols);

its pharmaceutically acceptable salt and hydrate may be used as agonists EDG-1 (see patent document 2: WO 03/062248 and patent document 3: WO 03/062252).

On the other hand, it was found that the carboxylic acid derivative represented by the formula (Z):

where R1Zmeans C1-8 alkyl, C1-8 alkoxy, halogen atom, nitro or trifluoromethyl; ring AZmeans C5-7 monocyclic carbocyclic ring or a 5 - or 7-membered monocyclic heterocyclic ring containing one or two nitrogen atom, one oxygen atom and/or one sulfur atom; EZmeans-CH2-, -O-, -S - or-NR6Zwhere R6Zmeans a hydrogen atom or C1-8 alkyl; R2Zmeans C1-8 alkyl, C1-8 alkoxy, halogen atom, nitro or trifluoromethyl; R3Zmeans a hydrogen atom or C1-8 alkyl; R4Zmeans a hydrogen atom or C1-8 alkyl, or R2Zand R4Ztaken together may form-CH2CH2- or-CH=CH-; GZmeans-CONR7Z-, -NR7ZCO-, -SO2NR7Z-, -NR7ZSO2-, -CH2NR7Z- or-NR7ZCH2-where R7Zmeans a hydrogen atom, C1-8 alkyl, or similar group; Q means C1-4 alkylene or similar group: pZmeans 0 or an integer from 1 to 5; qZmeans an integer from 4 to 6; rZmeans 0 or an integer from 1 to 4; andmeans simple or double bond; its prodrug, or a non-toxic salt are agonists EDG-1 (see patent document 4: WO 02/092068).

In addition, it was found that the compound represented by formula (Y):

where ring AYmeans a cyclic group; ring BYmeans a cyclic group which may have one or more substituents; XYmeans bond or a spacer having a main chain containing 1 to 8 atoms, one atom of the spacer together with the substituent in ring BYmay form a ring group which may have one or more substituents; YYmeans bond or a spacer having a main chain containing 1-10 atoms, one atom of the spacer together with the substituent in ring BYmay form a ring group which may have one or more substituents; ZYmeans acidic group which may be protected; nY means 0 or 1, and when nY is 0, mY means 1, and R1Ymeans a hydrogen atom or a Deputy, and when nY is equal to 1, mY means 0 or an integer from 1 to 7, and R1Ymeans Zam is stitely, where, when mY is 2 or more, all R1Yhave the same or different values; its salt, MES or prodrug possess the ability to bind to the receptor S1P (see patent document 5: WO 2005/020882).

Patent document 1: WO 03/061567

Patent document 2: WO 2003/062248

Patent document 3: WO 2003/062252

Patent document 4: WO 2002/092068

Patent document 5: WO 2005/020882

Description of the invention

Objectives of the invention

Immunosuppressants are used for the prevention and/or treatment of inflammatory diseases, autoimmune diseases, allergic diseases and/or transplant rejection. However, immunosuppressive drugs and medicines for the treatment of autoimmune diseases, currently used, often cause serious side effects. In addition, many existing immunosuppressants are characterized by insufficient duration of action. Thus, it is desirable to obtain a new drug as an immunosuppressant and medicines for the treatment of autoimmune diseases, which is safe, has no effect on the metabolic enzyme, has a fairly long action and fewer side effects.

Means for solving the above problems

Auto is s of the present invention comprehensively investigated compounds the ability to communicate with the receptor, sphingosine-1-phosphate (S1P), with a view to their use as a medicine. In the results from these studies it was found that the compounds of the present invention have a strong agonistic action in respect of the S1P receptor, in particular EDG-1 and/or EDG-6. In addition, it was also found that some of the compounds of the present invention has an agonistic action on the receptor EDG-8; these compounds of the present invention reduced the number of lymphocytes in the peripheral blood and had an immunosuppressive effect; and an immunosuppressive effect of the compounds of the present invention was maintained even after 24 hours, which is not expected on the basis of activity in vitro. Very surprising was the fact that the compounds of the present invention had no side effects and are safe for many kinds of animals.

Objects of the present invention are:

[1] a compound represented by the formula (I)

where ring a represents a cyclic group;

the ring means In a cyclic group which may have one or more substituents;

X is a bond or a spacer having a main chain containing 1 to 8 atoms, one atom of the spacer together with the Deputy in Kohl is e may form a ring, which may have one or more substituents;

Y represents a bond or a spacer having a main chain containing 1-10 atoms, one atom of the spacer together with the substituent in the ring may form a ring which may have one or more substituents;

Z means an acid group which may be protected; and

n means 0 or 1 provided that when n is 0, m is 1, and R1means a hydrogen atom or a Deputy, and when n is 1, m is 0 or an integer from 1 to 7, and R1means the Deputy, when m is 2 or more, all R1can have the same or different values;

its salt, N-oxide, MES or prodrug;

[2] the compound according to above item [1], its salt, N-oxide, MES or prodrug, where Z means (1) a carboxyl group which may be protected; (2) a hydroxyl group which may be protected, (3) the group of the hydroxamic acid, which may be protected, (4) a sulfonic acid group which may be protected, (5) group Bronevoy acid, which may be protected, (6) carbamoyl group which may be protected, (7) sulfamoyl group which may be protected, (8) a group-P(=O)(OR2)(OR3), in which R2and R3each independently mean a hydrogen atom and C1-8 alkyl group, or R and R3taken together denote C2-4 alkylenes group, or (9) tetrazolyl group;

[3] the compound according to above item [1], its salt, N-oxide, MES or prodrug, where Y means

in which the carbon atom or the nitrogen atom may be substituted by an arbitrary number of substituents at arbitrary positions of the substituents, and turned to the right, the arrow indicates the communication with Z;

[4] the compound according to above item [1], its salt, N-oxide, MES or prodrug, where the ring b is a benzene ring which may have one or more substituents, or dihydronaphthalene ring which may have one or more substituents;

[5] the compound according to above item [1], its salt, N-oxide, MES or prodrug, where

in which R4, R4-1, R5, R5-1and R5-2each independently means a hydrogen atom, halogen atom, trifluoromethyl, triptoreline, C1-8 alkoxy or C1-8 alkyl; p is 0 or an integer from 1 to 4, and when p is 2 or more, all R4can have the same or different values; and right arrow means the communication with Z;

[6] the compound according to above [1] and [5], its salt, N-oxide, MES or prodrug, where

where all symbols have the values listed in the above paragraphs [1] and [5];

[7] the compound according to above item [1], its salt, N-oxide, MES or prodrug, where X means

in which R6and R7each independently means a hydrogen atom, halogen atom, hydroxyl group which may be protected, amino which may be protected, C1-8 alkyl or C1-8 alkyl, substituted hydroxyl group which may be protected; or R6and R7together with the carbon atom to which they are bound, may form a ring which may have one or more substituents; the symbolmean α-configuration; the symbolmean β-configuration; and the right arrow indicates the connection with the ring;

[8] the compound according to above item [7], its salt, N-oxide, MES or prodrug, where X means

in which all symbols have the values listed in the above item [7];

[9] the compound according to above item [8], its salt, N-oxide, MES or prodrug, where X means

in which all symbols have the values listed in the above item [7];

[10] the compound according to above item [1], Ecosol, N-oxide, MES or prodrug, where ring a is a benzene ring or a pyridine ring;

[11] the compound according to above item [1], its salt, N-oxide, MES or prodrug, where R1means halogen atom, C1-8 alkyl or C1-8 alkoxy;

[12] the compound according to above item [5], its salt, N-oxide, MES or prodrug, where

where all symbols have the values listed in the above paragraphs [1] and [5];

[13] the compound according to above item [12], its salt, N-oxide, MES or prodrug, where Z means carboxyl, which may be protected;

[14] the compound according to above item [12], its salt, N-oxide, MES or prodrug, where X means

which turned to the right, the arrow indicates the connection with the ring, and all other symbols have the values listed in the above item [7];

[15] the compound according to above item [12], its salt, N-oxide, MES or prodrug, where ring a is a benzene ring or a pyridine ring;

[16] the compound according to above item [12], its salt, N-oxide, MES or prodrug, where R1means halogen atom, C1-8 alkyl which may have one or more substituents, or C1-8 alkoxy which may have one or several mandated the residents;

[17] the compound according to above item [12], its salt, N-oxide, MES or prodrug represented by formula (IC-2):

where all symbols have the values listed in the above paragraphs [1] and [5];

[18] the compound according to above item [1], its salt, N-oxide, MES or a prodrug, which is 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({6-[(4-isobutyl-3-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({6-[(2-ethoxy-4-isobutylbenzene)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-[(6-{[4-isopropoxy-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-({1-chloro-6-[(2-methoxy-4-propylbenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({1-chloro-6-[(4-isobutyl-2-methoxybenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-[(1-chloro-6-{[(2S)-3-(2,4-differenl)-2-methylpropyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-[(6-{[4-ethoxy-2-(thrift rmutil)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-({6-[(4-ethyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-chloro-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-[(6-{[2-(deformedarse)-4-propylbenzyl]oxy}-1,5-dimethyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-[(6-{[4-ethoxy-3-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid or 1-({6-[(2-methoxy-6-propyl-3-pyridinyl)methoxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid;

[19] the compound according to above item [17], its salt, N-oxide, MES or a prodrug, which is 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid or 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid;

[20] the pharmaceutical composition containing the compound represented by formula (I)according to the above item [1], its salt, N-oxide, MES or prodrug;

[21] the pharmaceutical composition according to above item [20], which is an agonist of EDG-1 agonist EDG-6 and/or agonist EDG-8;

[22] the pharmaceutical composition according to the above the WMD above item [21], which is an agonist of EDG-1;

[23] the pharmaceutical composition according to above item [20], which is an agent for the prophylaxis and/or treatment of diseases caused EDG-1, EDG-6 and/or EDG-8;

[24] the pharmaceutical composition according to above item [23], where a disease caused by an EDG-1, EDG-6 and/or EDG-8, is a rejection in transplantation of an organ, tissue and/or cells, autoimmune disease, allergic disease, asthma, multiple failure of organs, impaired reperfusion after ischemia, cancer and/or neurodegenerative disease;

[25] the pharmaceutical composition according to above item [24], where the rejection in transplantation of an organ, tissue and/or cells is rejection in the transplantation of kidney, liver, heart, lung, skin graft, cornea, blood vessels, tendons, bone graft, bone marrow cells, neural cells and/or cells of pancreatic islet; autoimmune disease is collagen disorders, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, autoimmune diabetes, lung fibrosis and/or fibrosis, and allergic disease is atopic dermatitis, hay fever and/or food allergies;

[26] Pharm is citiesa the composition according to the above item [20], which is an immunosuppressant and/or means for causing lymphopenia;

[27] a preparation containing the compound represented by formula (I)according to the above item [1], its salt, N-oxide, MES or prodrug in combination with one or at least two means selected from the group comprising an antimetabolite, an alkylating agent, an inhibitor of the activation of T cells, calcineurin inhibitor, an inhibitor of proliferation signals, a steroid, an immunosuppressant, an antibody used to suppress the immune response, for the treatment of rejection, antibiotic, antiviral agent and antifungal agent;

[28] a method of prevention and/or treatment of diseases caused EDG-1, EDG-6 and/or EDG-8 in a mammal, comprising administration to the mammal of an effective amount of the compounds expressed by formula (I)according to the above item [1], its salt, N-oxide, MES or prodrugs;

[29] the method of suppressing the immune response and/or the induction of lymphopenia in a mammal, comprising administration to the mammal of an effective amount of the compounds expressed by formula (I)according to the above item [1], its salt, N-oxide, MES or prodrugs;

[30] the use of compounds expressed by the formula (I)according to the above item [1], its salt, N-oxide, MES or prodrugs for medium spans the VA for the prevention and/or treatment of disease, due to EDG-1, EDG-6 and/or EDG-8;

[31] the use of compounds expressed by the formula (I)according to the above item [1], its salt, N-oxide, MES or prodrugs for receiving immunosuppressant and/or causing lymphopenia;

[32] the method of obtaining the compounds expressed by formula (I)according to the above item [1], its salt, N-oxide, MES or prodrugs.

In the present description of the invention S1P means sphingosine-1-phosphate ((2S,3R,4E)-2-amino-3-hydroxyoctanoic-4-enyl-1-phosphate). EDG mean gene differentiation of the endothelium, which is a General term for EDG-1 - EDG-8. Among the genes differentiation of endothelial EDG-1, EDG-3, EDG-5, EDG-6 and EDG-8 (referred to respectively S1P1, S1P3, S1P2, S1P4and S1P5) are considered S1P receptors.

In the present description of the invention, the compounds having the ability to bind to the receptor, an agonist, antagonist and inverse agonist. The agonist can be a full agonist and partial agonist.

In the present invention, the preferred connection is able to connect with S1P receptor is an agonist of EDG-1, which may have agonistic activity against EDG-6 and/or agonist EDG-6, which may have agonistic activity against EDG-1.

In the present description of the invention examples of diseases caused EDG-1 and/ or EDG-6 include graft rejection, the destruction of the transplanted organ, graft-versus-host (for example, acute graft-versus-host during bone marrow transplantation, and the like), autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, and muscular dystrophy), allergic diseases (such as atopic dermatitis, hay fever, food allergies and allergies to chemicals (e.g., anesthetic, such as lidocaine), asthma, inflammatory disease, infection, ulcer, lymphoma, malignant tumor (e.g., cancer), leukemia, arteriosclerosis diseases caused by infiltration of lymphocytes in the tissue, the shock due to the incompatibility of blood during blood transfusion, acute heart failure, angina, apoplexy of the brain, traumatic lesions, genetic disease, peripheral artery disease, such as obliterative arteriosclerosis, obliterating thromboangiitis, Buerger's disease, diabetic neuropathy, sepsis, vasculitis, nephritis, pneumonia, heart attack, brain, myocardial infarction, edema disease, varicose veins, such as hemorrhoids, fissure or fistula of the anus, dissecting aneurysm of the aorta, disseminated intravascular coagulation (DIC), pleurisy, stagnation is th heart failure, multiple failure of organs, the shock due to the incompatibility of blood during blood transfusion, bedsores, burns, ulcerative colitis, Crohn's disease, osteoporosis, fibrosis (e.g., lung fibrosis and liver fibrosis), interstitial pneumonia, chronic hepatitis, cirrhosis, chronic renal failure and glomerular nephrosclerosis. In addition, EDG-1 is also preoperative, postoperative and/or prognostic activator vessels in the transplantation of various organs, tissues and/or cells, for example, adhesion promoters of transplanted organs, tissues and/or cells in heart transplant, kidney transplant, transplantation of skin or liver transplantation, and the like.

In the present description of the invention examples of diseases caused EDG-8, include neurodegenerative diseases. Neurodegenerative diseases are diseases caused by denaturation of the nerve, without limitation, the causes of such diseases. Neurodegenerative diseases the present invention also include violation of the nervous system. Preferred examples of neurodegenerative diseases are diseases of the Central nervous system such as Parkinson's disease, parkinsonovy syndrome, Alzheimer's disease, down's syndrome, side amyotrophies the th sclerosis, family amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington's disease, spinal and cerebellar ataxia, dentatorubral-pallidoluysian atrophy, olivopontocerebellar atrophy, corticobasal degeneration, familial dementia, fronto-temporal dementia, senile dementia, diffuse somatic disease Levi, degeneration of the striatum, choreoathetosis, dystonia, Meigs syndrome, late atrophy of the cerebral cortex, family spastic lower paraplegia, a disease of motor neurons disease Machado-Joseph syndrome Peak, neurological dysfunction after cerebral embolism (e.g., intracerebral hemorrhage, such as hypertensive intracerebral hemorrhage, infarction of the brain, such as cerebral thrombosis and cerebral embolism, transient ischemic stroke and subarachnoid hemorrhage), neurological dysfunction after spinal cord injury, demyelinizing disease (e.g. multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, acute cerebellar and transverse myelitis), brain tumor (e.g., astrocytoma), diseases of the brain and spinal cord, caused by infection (such as meningitis, brain abscess, CJD, als is homie, caused by AIDS) and mental disorder (for example, the syndrome is a common disorder, bipolar disorder, disease of the nervous system, psychosomatic disorder, and epilepsy). More preferred neurodegenerative diseases are, for example, Parkinson's disease, parkinsonovy syndrome, Alzheimer's disease, amyotrophic lateral sclerosis and the like. In addition, disorders of the nervous system include all disease and dysfunction of nerve cells. That is, these violations usually involve violations diagnosed as symptoms of disease. Examples of violations in the case of Parkinson's disease or parkinsonism syndrome are tremor, muscle tension, slow motion, impaired reflex provisions vegetatively violations, rapid movement, gait disturbance and neurological disorders. Alzheimer's disease include dementia. Amyotrophic lateral sclerosis and familial amyotrophic lateral sclerosis include muscle atrophy, muscle weakness, impaired function of the upper extremities, gait disturbance, dysarthria (slurred speech, dysphagia, and respiratory disorders.

In the present description of the invention exclusion encompasses acute rejection occurring within 3 months, chronic rejection, occurring later, and graft-versus-host (n is an example, acute graft-versus-host during bone marrow transplantation, and the like).

In the present description of the invention the graft means transplantirovannam organ (e.g. kidney, liver, heart, lung, and small intestine), transplantirovannam tissue (e.g. skin, such as a full-layer skin graft, epidermal graft, skin graft, and the graft Davis; cornea; vessels; the spinal marrow; bone graft; embryonic tissue, and the like) or transplanted cells (e.g. bone marrow cells, hematopoietic stem cells, stem cells peripheral blood stem cells, cord blood cells, pancreatic islet, part of which are the cells of the islet of Langerhans, hepatocytes, neurons and epithelial cells of the intestine). The preferred organs are kidney, liver, heart, and lung. Preferred tissues are skin, cornea, blood vessels, spinal cord and bone. Preferred cells are bone marrow cells, neurons, and cells of the pancreatic islet.

In the present description, the term “mediated by T-cells” means that the T-cell participates in one of the processes of emergence, escalation and development of the disease.

In the present description of the invention autoimmune Zab is levania includes collagenosis, systemic lupus erythematosus, Behcet's disease, rheumatoid arthritis, multiple sclerosis, nephrotic syndrome, lupus nephritis, Sjogren syndrome, scleroderma, dermatomyositis, psoriasis, inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease and the like), a complex disease of connective tissue, primary myxedema, Addison's disease lipoliticescuu anemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purple, the autoimmune trombopenia, autoimmune diabetes (such as diabetes type I), uveitis, antireceptor disease, myasthenia, muscle destroycontext, thyroiditis, Hashimoto's disease and the like.

In the present description of the invention allergic disease includes atopic dermatitis, rhinitis, conjunctivitis, hay fever, food allergies, and allergies to chemicals (e.g., anesthetic, such as lidocaine), and the like. Preferred allergic disease is atopic dermatitis, hay fever and food allergies.

In the present description of the invention immunosuppressant means a drug that is primarily used for the prevention and/or treatment of transplant rejection. As such drugs can be used, for example, an antimetabolite, alquiler is the tender agent, inhibitor of activated T cells (suppressor function of T-cells), a calcineurin inhibitor, an inhibitor of proliferation signals, a steroid, an antibody used to suppress the immune response, other tools against exclusion and the like. These medicinal products used in clinical trials for treatment of autoimmune diseases.

In the present description of the invention, means causing lymphopenia means a drug that reduces the number of lymphocytes in the peripheral blood, which reduces the number of lymphocytes in the bloodstream, reducing the number of penetrating lymphocytes, stimulating homing lymphocytes in secondary lymphatic tissue, the vast recirculation of lymphocytes from lymph nodes into the blood, and the like.

In the present description of the invention the secondary lymphatic tissue includes the lymph nodes, Peyer's patches (e.g., lymphatic tissue of the intestine, spleen and the like.

In the present description of the invention the stimulation of homing lymphocytes in secondary lymphatic tissue stimulation means migration of lymphocytes in secondary lymphatic tissue, enhancing the separation of lymphocytes in secondary lymphatic tissue, prolonged preservation of lymphocytes in secondary lymphatic tissue, and the like. Due to the above actions is to reduce the number of lymphocytes at the site of inflammation or rejection. Besides, this way you can protect lymphocytes in the peripheral blood during treatment of cancer. Protection of lymphocytes in the peripheral blood during treatment of cancer means the preliminary homing lymphocytes present in peripheral blood, in the secondary lymphatic tissue before cancer treatment (in particular, chemotherapy, radiation therapy etc). This effect includes the protection of lymphocytes in the previous transplant stage of introduction of a large number of anti-cancer tool. It is known that the treatment of cancer by chemotherapy or similar method using anti-cancer tool is accompanied by serious side effects such as hypofunction of hematopoietic cells, resulting in the entity is exposed to infections. Such side effects can be reduced as described above.

The compound of the present invention can be used as tools against exclusion, have antibacterial properties, because the connection is providing limfaticheskoi action, is unable to reduce the content of lymphocytes in vivo.

In the present description of the invention a side effect arising from the use of immunosuppressant, means a violation of function of kidneys, liver dysfunction, infection, lymphoma, resstr istwo circulation, such as bradycardia or hypertension, diarrhea, vomiting, alopecia, hirsutism, hyperlipidemia, respiratory disorders, disorder of the Central nervous system and the change in mass of the body.

In the present description of the invention ”cyclic group” means a “carbocyclic ring” or “heterocyclic ring”.

In the present description of the invention “carbocyclic ring” means, for example, “C3-15 carbocyclic ring”. “C3-15 carbocyclic ring” is a C3-15 monocyclic ring or polycyclic carbocyclic aryl ring, partially or fully saturated carbocyclic ring, a polycyclic carbocyclic ring, join Spiro connection, and polycyclic carbocyclic ring being connected to the transverse link. Examples of such rings are cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclodecane, cyclododecane, cycletrader, collaterality, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydroanthracene, azulene, pergerson, inden, palikonda, indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene, peridontal, 6,7-dihydro-5H-benzo[7]annulen, 5H-benzo[7]annulen, geptalen, PE is hydrocephalus, biphenylene, as-indocin, s-indocin, acenaphthylene, acenaphthene, fluorene, finale, phenanthrene, anthracene, Spiro[4.4]nonan, Spiro[4.5]decane, Spiro[5.5]undecane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]hept-2-ene, bicyclo-[3.1.1]heptane, bicyclo[3.1.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo[2.2.2]Oct-2-ene, adamantane and noradsanta.

In the present description of the invention C5-12 monocyclic ring or bicyclic carbocyclic ring” means a C5-12 monocyclic ring or bicyclic carbocyclic aryl ring or ring resulting from partial or complete saturation of the ring. Examples of such rings include cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclodecane, cyclododecane, cycletrader, collaterality, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydroanthracene, azulene, pergerson, inden, palikonda, indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene, peridontal, 6,7-dihydro-5H-benzo[7]annulen, 5H-benzo[7]annulen, geptalen and perheravintolan.

In the present description of the invention, the “C3-7 monocyclic carbocyclic ring” means a C3-7 monocyclic carbocyclic aryl ring or ring resulting from partial or complete us what their rings. Examples of such rings are cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene and benzene.

In the present description of the invention examples of the “C3-7 monocyclic saturated carbocyclic rings are cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane and Cycloheptane.

In the present description of the invention “heterocyclic ring” means “3-15 membered heterocyclic ring containing 1 to 5 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and sulfur atom”. “3-15 membered heterocyclic ring containing 1 to 5 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and sulfur atom” represents a 3 to 15-membered monocyclic ring or polycyclic heterocyclic aryl ring containing 1 to 5 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and sulfur atom, and the ring obtained by partially or fully saturated ring, a polycyclic heterocyclic ring, join Spiro connection, and polycyclic heterocyclic ring being connected to the transverse link. Examples of such rings are pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran oxepin, thiophene, thiopyran, tiepin, oxazol, isoxazol, thiazole, isothiazol, furazan, oxadiazole, oxazin, oxadiazon, oxazepine, oxadiazon, thiadiazole, teasin, thiadiazin, diazepin, thiadiazin, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, ditionally, indazole, quinoline, isoquinoline, hemolysin, purine, phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, chrome, benzocain, benzoxazepin, benzodiazepin, benzothiophen, benzodiazepin, benzodiazepin, benzazepin, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, β-carboline, acridine, fenesin, dibenzofuran, Xanten, dibenzothiophen, phenothiazines, phenoxazin, phenoxathiin, tianren, phenanthridine, phenanthroline, pyrimidin, aziridine, azetidine, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, oxiran, oxetan, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran is, dehydroacetic, tetrahydroazepine, perhydroxyl, thiran, tieton, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyran, dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazolidine), dihydrooxazolo, tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, indolin, isoindoline, dihydrobenzofuran, perhydroanthracene, dihydroisobenzofuran, peligrosamente, dihydrobenzofuran, targetobjecttype, dihydroisobenzofuran, peligrosamente, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahedrite inulin, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, benzocain, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, benzodioxepin, dihydroisoxazole, tetrahydrobenzaldehyde, dihydrocarvone, tetrahydrocarbazol, perhydrogenized, dihydrouridine, tetrahydrouridine, perhydrosqualene, dihydrobenzofuran, dihydroisobenzofuran, tetrahydroxybenzophenone, tetrahydrolipstatin, perhydrophenanthrene, perhydrophenanthrene, dioxolane, dioxane, ditiolan, Titian, dioksiinien, benzodioxan, chrome, chroman, benzodithiol, benzodithiol, azaspiro[4.4]nonan, oxazepine[4.4]nonan, dioxaspiro[4.4]nonan, azaspiro[4.5]decane, Diaspora[4.5]decane, Diaspora[4.5]decane, dioxaspiro[4.5]decane, oxazepine[4.5]decane, azaspiro[5.5]undecane, oxaspiro[5.5]undecane, dioxaspiro[5.5]undecane, azabicyclo[2.2.1]heptane, oxabicyclo[2.2.1]Hep C is an, azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane, azabicyclo[2.2.2]octane, diazabicyclo[2.2.2]octane, oxazepine[2.5]octane, 1,3,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane, 1,4,9-diazaspiro[5.5]undecane and azabicyclo[2.1.1]hexane.

In the present description of the invention “5-12-membered monocyclic or polycyclic heterocyclic ring containing 1-3 heteroatom selected from oxygen atom, nitrogen atom and sulfur atom, and the ring obtained by partially or fully saturated ring” means “5-12-membered monocyclic ring or polycyclic heterocyclic aryl ring containing 1-3 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and sulfur atom, and the ring obtained by partially or fully saturated ring, a polycyclic heterocyclic ring, join Spiro connection, and polycyclic heterocyclic ring being connected to the transverse communication”. Examples of such rings are pyrrole, imidazole, triazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, thiopyran, tiepin, oxazol, isoxazol, thiazole, isothiazol, furazan, oxadiazole, oxazin, oxadiazon, oxazepine, oxadiazon, thiadiazole, teasin, thiadiazin, diazepin, thiadiazin, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzo the Hairdryer, ditionally, indazole, quinoline, isoquinoline, hemolysin, phthalazine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, chrome, benzocain, dihydrobenzofuran, benzoxazepin, benzodiazepin, benzothiophen, benzodiazepin, benzodiazepin, benzazepin, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydroacetic, tetrahydroazepine, perhydroxyl, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyran, dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazolidine), Digi roaccutan, tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, indolin, isoindoline, dihydrobenzofuran, perhydroanthracene, dihydroisobenzofuran, peligrosamente, dihydrobenzofuran, targetobjecttype, dihydroisobenzofuran, peligrosamente, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, benzocain, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol,perhydroanthracene, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, benzodioxepin, dihydroisoxazole, tetrahydrobenzaldehyde, dioxolane, dioxane, ditiolan, Titian, dioksiinien, benzodioxan, chroman, benzodithiol, benzodithiol, azaspiro[4.4]nonan, oxazepine[4.4]nonan, dioxaspiro[4.4]nonan, azaspiro[4.5]decane, Diaspora[4.5]decane, diazaspiro[4.5]decane, dioxaspiro[4.5]decane, oxazepine[4.5]decane, azaspiro[5.5]undecane, oxaspiro[5.5]undecane, dioxaspiro[5.5]undecane, azabicyclo[2.2.1]heptane, oxabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane, azabicyclo[2.2.2]octane, diazabicyclo[2.2.2]octane, oxazepine[2.5]octane, 1,3,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane, 1,4,9-diazaspiro[5.5]undecane and azabicyclo[2.1.1]hexane.

In the present description of the invention “5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atom, one oxygen atom and/or one sulfur atom”, is a ring, the resulting saturation 5-7-membered monocyclic heterocyclic aryl ring containing 1-2 nitrogen atom, one oxygen atom and/or one sulfur atom, or a ring, resulting from partial or complete saturation of the ring. Examples of such rings are pyrrole, imidazole, pyrazole, pyrrolin, pyrrolidin, imidazolin, imidazolidin, pyrazoline, pyrazolidine, Digi properidine, the tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, tetrahydrooxazolo, tetrahydrooxazolo, tetrahydrothieno, tetrahydrocortisol, dihydroimidazole, tetrahydrooxazolo, dihydrocodiene, tetrahydrocortisol, tetrahydroimidazo, tetrahydrolipstatin, tetrahydroazepine, perhydroxyl, perhydroanthracene, tetrahydroazepine, targetrotation, targetrotation, morpholine and thiomorpholine.

In the present description of the invention “5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atom, one oxygen atom and/or one sulfur atom, which, together with the nitrogen atom to which it is attached, forms a 5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atom, one oxygen atom and/or one sulfur atom” is a ring, similar to the above “5 to 7 membered monocyclic heterocyclic ring containing 1-2 nitrogen atom, one oxygen atom and/or one sulfur atom”.

In the present description of the invention “cyclic group” in the definitions of “cyclic group which the traveler may have one or more substituents”, “cyclic group which may be substituted” and “substituted cyclic group” is a group similar to the above-mentioned “cyclic group”.

In the present description of the invention “Deputy” in the definition of “cyclic group which may have one or more substituents” does not have any restrictions if the specified group is Deputy. Examples of such a substituent are (1) C1-20 alkyl which may be substituted, (2) C2-20 alkenyl, which may be substituted, (3) C2-20 quinil, which may be substituted, (4) C1-20 alkylidene, which may be substituted, (5) a cyclic group which may be substituted, (6) oxo, (7) hydroxy, (8) C1-20 alkyloxy, which may be substituted, (9) C2-20 alkenylacyl, which can be substituted, (10) C2-20 alkyloxy, which may be substituted, (11) hydroxy, protected cyclic group which may be substituted, (12) C1-20 acyloxy, which may be substituted, (13) thioxo, (14) mercapto, (15) C1-20 alkylthio, which may be substituted, (16) C2-20 alkanity, which may be substituted, (17) C2-20 alkylthio, which may be substituted, (18) mercapto, substituted cyclic group which may be substituted, (19) C1-20 alkylsulfonyl, which may be substituted, (20) C2-20 alkanesulfonyl, which may be substituted, (21) C2-20 alkylsulfonyl, which can bytesneeded, (22) sulfinil, substituted cyclic group which may be substituted, (23) C1-20 alkylsulfonyl which may be substituted, (24) C2-20 alkanesulfonyl, which may be substituted, (25) C2-20 alkylsulfonyl, which may be substituted, (26) sulfonyl, substituted cyclic group which may be substituted, (27) sulfine, which may be substituted, (28) sulfo, which may be substituted, (29) sulfamoyl, which may be substituted (when there are two of these substituents, the substituents together with the nitrogen atom to which they are attached, may form a 5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atom, one oxygen atom and/or one sulfur atom (this heterocyclic ring may be substituted by C1-8 alkyl, hydroxy or amino)), (30) carbonyl which may be substituted, (31) carboxy which may be substituted, (32) C1-20 acyl which may be substituted, (33) carbarnoyl, which may be substituted (when there are two of these substituents, the substituents together with the nitrogen atom to which they are attached, may form a 5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atom, one oxygen atom and/or one sulfur atom (this heterocyclic ring may be substituted by C1-8 alkyl, hydroxy or amino)), (34) cyano, (35) amidino, which may be substituted (the ri, the presence of two substituents, these substituents together with the nitrogen atom, to which they are attached, may form a 5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atom, one oxygen atom and/or one sulfur atom (this heterocyclic ring may be substituted by C1-8 alkyl, hydroxy or amino)), (36) nitro, (37) nitroso, (38) imino which may be substituted, (39) amino which may be substituted (when there are two substituents, these substituents together with the nitrogen atom to which they are attached, may form a 5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atom, one oxygen atom and/or one sulfur atom (this heterocyclic ring may be substituted by C1-8 alkyl, hydroxy or amino)), (40) trifluoromethyl, (41) triptoreline, (42) a halogen atom and the like.

In the present description of the invention “Deputy” in the above “C1-20 alkyl which may be substituted” or similar group represents, for example, (1) C1-20 alkyl, (2) C2-20 alkenyl, (3) C2-20 quinil, (4) C1-20 alkylidene, (5) cyclic group, (6) C1-20 alkyl, substituted cyclic group, (7) oxo, (8) hydroxy, (9) C1-20 alkyloxy, (10) C2 20 alkenylacyl, (11) C2-20 alkyloxy, (12) hydroxy, protected cyclic group, (13) C1-20 atillio, (14) thioxo, (15) mercapto, (16) C1-20 alkylthio, (17) C2-20 alkanity, (18) C2-20 alkylthio, (19) mercapto, substituted cyclic group, (20)-20 alkylsulfonyl, (21) C2-20 alkanesulfonyl, (22) C2-20 alkylsulfonyl, (23) sulfinil, substituted cyclic group, (24) C1-20 alkylsulfonyl, (25) C2-20 alkanesulfonyl, (26) a C2-20 alkylsulfonyl, (27) sulfonyl, substituted cyclic group, (28) C1-20 alkylsulfonyl, substituted cyclic group, (29) sulfine, (30) sulfo, (31) sulfamoyl, (32) carboxy, (33) C1-20 acyl, (34) C1-20 acyl, substituted cyclic group, (35) carbonyl, substituted cyclic group, (36) carbarnoyl, (37) cyano, (38) amidino, (39) nitro, (40) nitroso, (41) imino, (42) amino, (43) mono(C1-8 alkyl)amino, (44) di(C1-8 alkyl)amino, (45) trifluoromethyl, (46) triptoreline, (47) a halogen atom or the like. These substituents can be in any positions of substitution when using any possible number of substituents.

In the present description of the invention, the “C1-20 alkyl” means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, Needell, icosyl and their isomers.

In the present description of the invention, the “C1-8 alkyl” means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomers.

In the present description of the invention “C2-20 alkenyl” means ethynyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonanal, decanal, undecanal, dodecanal, tridecanal, tetradecanol, p is ntalianis, hexadecanyl, heptadecanol, octadecanol, nonadecane, costil and their isomers.

In the present description of the invention “C2-20 quinil” means ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl, heptenyl, octenyl, nonini, decenyl, undecenyl, dodecenyl, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecane, tosini and their isomers.

In the present description of the invention, the “C1-20 alkylidene” means methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, reptilian, actinidin, nonelite, deciliter, undecided, dodecyltin, tredecillion, tetrabutyltin, pentadecylic, hexadezimalen, heptageniidae, octadecylamine, nondecision, isosilybin and their isomers.

In the present description of the invention, the “C1-20 alkyloxy” means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecylamine, tetradecenoic, pentadecylic, hexadecylamine, heptadecenoic, octadecylamine, nonadecanoic, tosyloxy and their isomers.

In the present description of the invention, the “C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and their isomers.

In the present description of the invention “C2-20 alkenylacyl” means adenylate, propenyloxy, butenyloxy, pentyloxy, Huck is enyloxy, heptyloxy, octenoate, nonyloxy, deaniacs, undecyloxy, dodecyloxy, tridecanoate, tetradecenoic, pentadecenoic, hexadecenoic, heptadecenoic, octadecanoyloxy, nonadecanoic, kosenlose and their isomers.

In the present description of the invention “C2-20 alkyloxy” means itineracy, propenyloxy, butenyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, desenlace, undecyloxy, dodecyloxy, tridecanoate, tetradecenoic, pentadecenoic, hexadecenoic, heptadecenoic, octadecanoyloxy, nonadecanoic, casinolux and their isomers.

In the present description of the invention, the “C1-20 alkylthio” means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, Reptilia, octylthio, nonillion, decillia, undecillion, dodecylthio, tredecillion, tetradecyl, pentadecyl, hexadecimal, heptadecyl, octadecyl, nomadicity, easilty and their isomers.

In the present description of the invention “C2-20 alkanity” means etenity, property, butylthio, pentylthio, hexanite, gattelli, actinistia, nonenity, detentio, undecenyl, dodecenyl, tripartitie, tetradecanol, pentadecanolide, hexadecanethiol, heptadecanol, octadecanol, nonideality, yosemitie and their isomers.

In the present description of the invention“C2-20 alkylthio” means etenity, propylthio, butylthio, pentylthio, hexylthio, Latinity, actinistia, nominally, destinity, undecenyl, dodecylthio, traditinally, tetradecanol, pentadecanol, hexadecimally, heptadecanol, octadecanethiol, nonadditivity, casinelli and their isomers.

In the present description of the invention, the “C1-20 alkylsulfonyl” means methylsulfinyl, ethylsulfinyl, propylsulfonyl, butylsulfonyl, pentasulfide, exisulind, heptylaniline, octylsilane, noninsulin, decimalfield, undersurface, dodecylsulfonate, tridecylamine, tetradecyltrimethyl, pentadecanolide, hexadecylsulfate, heptanesulfonic, octadecylsilyl, noncellular, ecosecurities and their isomers.

In the present description of the invention “C2-20 alkanesulfonyl” means etailsolution, propylsulfonyl, butylsulfonyl, pentanesulfonic, hexanesulfonic, heptanesulfonic, octanesulfonyl, nonteleological, detailsoriginal, underanalysis, dodecanesulfonyl, tridecylalcohol, tetradecanoylphorbol, pentadecanolide, hexadecanesulfonyl, heptadecanoyl, octadecylsilyl, nonelectrolytes, Kostyshyn and their isomers.

In the present description of the invention “C2-20 alkylsulfonyl” means ethniccultural, provinical the Nile, butylsulfonyl, pentanesulfonic, hexanesulfonic, heptanesulfonic, octanesulfonyl, noninsulin, detailsoriginal, underinsuring, dodecanesulfonyl, tridecylalcohol, tetradecyltrimethyl, pentadecanolide, hexadecanesulfonyl, heptanesulfonic, octadecylsilyl, nondecisions, casinosonline and their isomers.

In the present description of the invention, the “C1-20 alkylsulfonyl” means methylsulphonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, peterculter, hexylsilane, septinsular, octylsilane, nonalcoholic, decimalpoint, undersurface, dodecylsulfonate, tridecylalcohol, tetradecylammonium, pentanesulfonic, hexadecacarbonyl, heptanesulfonic, octadecylsilane, noncellulosic, ecosilver and their isomers.

In the present description of the invention “C2-20 alkanesulfonyl” means atenololbuy, propylsulfonyl, butylsulfonyl, pentanesulfonic, hexanesulfonic, heptanesulfonic, octanesulfonyl, nonanalytic, decanesulfonate, undecalactone, dodecanesulfonyl, tridecylalcohol, tetradecanoylphorbol, pentadactylon, hexadecanesulfonyl, heptadecanoyl, octadecylsilane, nonelectrolytes, costimulatory and their isomers.

In esteem the description of the invention “C2-20 alkylsulfonyl” means ethniccultural, propylsulfonyl, butylsulfonyl, pentanesulfonic, hexanesulfonic, heptanesulfonic, octanesulfonyl, noninsulin, decentrality, underinsulated, dodecanesulfonyl, tridecylalcohol, tetradecyltrimethyl, pentanesulfonic, hexadecanesulfonyl, heptanesulfonic, octanesulfonyl, noncellulosic, casinossilver and their isomers.

In the present description of the invention, the “C1-20 acyl” means methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, deletion, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanoic, emosanal and their isomers.

In the present description of the invention, the “C1-20 acyloxy” means metanoiax, ethanolate, propenyloxy, butanoyloxy, pentanoate, hexanoate, heptanoate, octanoate, nonanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanolide, hexadecanoate, heptadecanoic, octadecanoyloxy, nonadecanoic, ecosanoids and their isomers.

In the present description of the invention “mono(C1-8 alkyl)amino” means methylamino, ethylamino, propylamino, butylamino, pentylamine, hexylamine, heptylamine, octylamine and their isomers.

In the present described and the invention of the “di(C1-8 alkyl)amino” means dimethylamino, diethylamino, dipropylamino, dibutylamino, methylethylamine, methylpropylamine, ethylpropylamine and their isomers.

In the present description of the invention “protective group” in the definitions of “acidic group which may be protected”, “carboxyl group which may be protected”, “hydroxyl group which may be protected”, a “group of hydroxamic acid, which may be protected”, “sulfonic acid group which may be protected”, “group Bronevoy acid, which may be protected”, “carnemolla group which may be protected”, “Altamarena group which may be protected” and “amino group which may be protected” is a group similar to the “Deputy” in the above definition, “which may be substituted (Deputy)”.

In the present description of the invention, the “halogen atom” means fluorine, chlorine, bromine and iodine.

In the present description of the invention “communication” means direct coupling of atoms without any other intermediate atom.

In the present description of the invention “spacer having a main chain containing 1-10 atoms”means the period occupied 1-10 atoms, sequentially connected in the main circuit. In this case, the number of atoms forming the main chain”, should be considered as minimalinvasive atoms in the main chain. For example, the number of atoms in the 1,2-cyclopentene is set to 2, and the number of atoms in 1,3-cyclopentadiene to be equal to 3. The “spacer having a main chain containing 1-10 atoms”represents a divalent group with 1-10 atoms in the main chain, which consists of 1 to 4 combinations selected from the group comprising C1-10 alkylene, which may be substituted, C2-10 albaniles, which may be substituted, C2-10 akinyan, which may be substituted, a nitrogen atom (-NH-), which may be substituted, -CO-, -O-, -S-, -SO-, -SO2-, -(carbocyclic ring which may be substituted)-, -(heterocyclic ring which may be substituted)-, and the like.

In the present description of the invention, the “C1-10 alkylene” means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptameron, octamethylene, nonmotile, decamethrin and their isomers.

In the present description of the invention “C2-4 alkylene” means ethylene, trimethylene, tetramethylene and their isomers.

In the present description of the invention, the “C2-10 albaniles” means ethenylene, propylen, butylen, penttinen, hexarelin, heptenyl, hoktanyan, nonpenile, decoiler and their isomers.

In the present description of the invention, the “C2-10 akinyan” means ethynylene, propylen, Butyrin, pentikinen, geksanalem, Eptingen, actinidin, noninert, decisoin and their isomers.

This is the General description of the invention “spacer, having a main chain containing 1-9 atoms”means the period occupied 1-9 atoms, sequentially connected in the main circuit. In this case, the number of atoms forming the main chain”, should be considered as the minimum number of atoms in the main chain. For example, the number of atoms in the 1,2-cyclopentene is set to 2, and the number of atoms in 1,3-cyclopentadiene to be equal to 3. The “spacer having a main chain containing 1-9 atoms”represents a divalent group with 1-9 atoms in the main chain, which consists of 1 to 4 combinations selected from the group comprising C1-9 alkylene, which may be substituted, C2-9 albaniles, which may be substituted, C2-9 akinyan, which may be substituted, a nitrogen atom (-NH-), which may be substituted, -CO-, -O-, -S-, -SO-, -SO2-, -(carbocyclic ring which may be substituted)-, -(heterocyclic ring which may be substituted)-, and the like.

In the present description of the invention “S1-9 alkylene” means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptameron, octamethylene, nonmotile and their isomers.

In the present description of the invention “C2-9 albaniles” means ethenylene, propylen, butylen, penttinen, hexarelin, heptenyl, hoktanyan, nonpenile and their isomers.

In the present description of the invention “C2-9 akinyan” means Tinian, propylen, Butyrin, pentikinen, geksanalem, Eptingen, actinidin, noninert and their isomers.

In the present description of the invention “spacer having a main chain containing 1 to 8 atoms”means the period occupied 1-8 atoms, sequentially connected in the main circuit. In this case, the number of atoms forming the main chain”, should be considered as the minimum number of atoms in the main chain. For example, the number of atoms in the 1,2-cyclopentene is set to 2, and the number of atoms in 1,3-cyclopentadiene to be equal to 3. The “spacer having a main chain containing 1 to 8 atoms”represents a divalent group with 1 to 8 atoms in the main chain, which consists of 1 to 4 combinations selected from the group comprising C1-8 alkylene, which may be substituted, C2-8 albaniles, which may be substituted, C2-8 akinyan, which may be substituted, a nitrogen atom (-NH-), which may be substituted, -CO-, -O-, -S-, -SO-, -SO2-, -(carbocyclic ring which may be substituted)-, -(heterocyclic ring which may be substituted)-, 1,2,4-oxadiazole, which may be substituted, and the like.

In the present description of the invention, the “C1-8 alkylene” means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptameron, octamethylene and their isomers.

In the present description of the invention “C2-8 albaniles” Osnach is that attilan, propylen, butylen, penttinen, hexarelin, heptenyl, hoktanyan and their isomers.

In the present description of the invention “C2-8 akinyan” means ethynylene, propylen, Butyrin, pentikinen, geksanalem, Eptingen, actinidin and their isomers.

In the present description of the invention “spacer having a main chain containing 1 to 7 atoms”means the period occupied 1-7 atoms, sequentially connected in the main circuit. In this case, the number of atoms forming the main chain”, should be considered as the minimum number of atoms in the main chain. For example, the number of atoms in the 1,2-cyclopentene is set to 2, and the number of atoms in 1,3-cyclopentadiene to be equal to 3. The “spacer having a main chain containing 1 to 7 atoms, a represents a bivalent group with 1 to 7 atoms in the main chain, which consists of 1 to 4 combinations selected from the group comprising C1-7 alkylene, which may be substituted, C2-7 albaniles, which may be substituted, C2-7 akinyan, which may be substituted, a nitrogen atom (-NH-), which may be substituted, -CO-, -O-, -S-, -SO-, -SO2-, -(carbocyclic ring which may be substituted)-, -(heterocyclic ring which may be substituted)-, 1,2,4-oxadiazole, which may be substituted, and the like.

In the present description of the invention, “C1-7 alkylene” means methylene, ethylene, trimethyl is h, tetramethylene, pentamethylene, hexamethylene, heptamethine and their isomers.

In the present description of the invention, the “C2-7 albaniles” means ethenylene, propylen, butylen, penttinen, hexarelin, heptenyl and their isomers.

In the present description of the invention, the “C2-7 akinyan” means ethynylene, propylen, Butyrin, pentikinen, geksanalem, Eptingen and their isomers.

In the present description of the invention examples of the acid group include the following groups which may be protected: (1) carboxyl group, (2) hydroxyl group, forming acid (e.g., phenolic hydroxyl group), (3) group of the hydroxamic acid, (4) a sulfonic acid group, (5) group Bronevoy acid, (6) carnemolla group, (7) Altamarena group, (8) group-P(=O)(OH)2, (9) the group-P(=O)(OR2)(OR3(in this group, R2and R3have the above values) and (10) tetrataenia group.

In the present description of the invention “ring which may have one or more substituents containing one atom of the spacer, denoted by the symbol X, and the substituent in the ring, is a ring that may have one or more substituents, formed by one atom spacer, denoted by the symbol X, together with one substituent in ring C. Ring which may have one or a few is to surrogates”, is a ring, similar to the above “cyclic group which may have one or more substituents”.

In the present description of the invention “ring which may have one or more substituents containing one atom of the spacer, denoted by Y, and the substituent in the ring, is a ring that may have one or more substituents, formed by one atom spacer, denoted by the symbol Y, together with one substituent in the ring Century example of the “ring which may have one or more substituents”is the “nitrogen-containing heterocyclic ring which may have one or more substituents”. An example of a “nitrogen-containing heterocyclic ring” in the definition of “nitrogen-containing heterocyclic ring which may have one or more substituents”is “3-15 membered heterocyclic ring containing one nitrogen atom, which may optionally include 1 to 4 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and sulfur atom”. “3-15 membered heterocyclic ring containing one nitrogen atom, which may optionally include 1 to 4 heteroatoms, each of which is selected from oxygen atom, nitrogen, nitrogen and sulfur atom”, is a 3 to 15-membered monocyclic ring or polycyclic who heterocyclic aryl ring, containing one nitrogen atom, which may optionally include 1 to 4 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and sulfur atom, and may be partially or fully saturated polycyclic heterocyclic ring connected Spiro connection, and polycyclic heterocyclic ring being connected to the transverse link. Examples of such rings are pyrrole, imidazole, triazole, tetrazole, pyrazole, azepin, diazepine, indole, isoindole, indolizine, indazole, quinoline, isoquinoline, hemolysin, phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, purine, benzoxazole, benzothiazole, benzoxazepin, benzodiazepin, benzodiazepin, benzodiazepin, benzofurazan, benzothiadiazole, benzotriazole, pyrrolopyridine, benzimidazole, benzazepin, benzodiazepine, benzotriazol, carbazole, β-carboline, acridine, fenesin, phenothiazines, phenoxazin, phenanthridine, phenanthroline, pyrimidin, pyrazoloquinoline, personafied, periodontal, indolizinyl, aziridine, azetidine, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, perhydro is ridazin, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazolidine), dihydrooxazolo, tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, indolin, isoindoline, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydro insulin, tetrahydropyrimidin, dihydroindole, tetrahydroindole, permitiendoles, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, dihydroisoxazole, tetrahydrobenzaldehyde, dihydrocarvone, tetrahydrocarbazol, perhydrogenized, dihydrouridine, tetrahydrouridine, perhydrosqualene, retroperitoneally, dihydro-β-carbolin, tetrahydro-β-carbolin, dehydrodimerization, hexahydroazepin, tetrahydropyrazino, tetrahydrobiopterin, dihydrodipicolinate, hexahydroazepin, dihydropyrimidinase, hexahydropyridine, tetrahydropyrimidines, dihydrothebainone, tetrahydrocannabinol, dihydroxyindole, tetrahydrocannabinol, hexahydrocannabinol, dehydrohalogenation, octahydronaphthalene, hexahydropyridine, hexahydropyrazino, azaspiro[4.4]nonan, oxazepine[4.4]nonan, oxazepine[2.5]octane, azaspiro[4.5]decane, 1,3,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane, 1,4,9-diazaspiro[5.5]undecane, oxazepine[4.5]decane, azaspiro[5.5]undecane, azabicyclo[2.2.1]GE is tan, azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane, azabicyclo[2.2.2]octane, azabicyclo[2.1.1]hexane.

In the present description of the invention “9-15-membered polycyclic heterocyclic ring containing one nitrogen atom, which may optionally include 1 to 4 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and sulfur atom”, is a “9-15-membered polycyclic heterocyclic ring containing one nitrogen atom, which may optionally include 1 to 4 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and sulfur atom, and may be partially or fully saturated”. Examples of such rings are indole, isoindole, indolizine, indazole, quinoline, isoquinoline, hemolysin, purine, phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzoimidazole, benzoxazepin, benzodiazepin, benzodiazepin, benzodiazepin, benzazepin, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, β-carboline, acridine, fenesin, phenothiazines, phenoxazin, phenanthridine, phenanthroline, pyrimidin, indolin, isoindoline, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphtho is in, tetrahydronaphthalen, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, dihydroisoxazole, tetrahydrobenzaldehyde, dihydrocarvone, tetrahydrocarbazol, perhydrogenized, dihydro-β-carbolin, tetrahydro-β-carbolin, dihydrouridine, tetrahydrouridine, perhydrosqualene, azaspiro[4.4]nonan, oxazepine[4.4]nonan, azaspiro[4.5]decane, oxazepine[4.5]decane, azaspiro[5.5]undecane.

In the present description of the invention “Deputy”, denoted by the symbol R1has the same meaning as “Deputy” in the above definition “which may have one or more substituents”.

In the present description of the invention R4and R4-1have the same meaning as “Deputy” in “cyclic group which may have one or more substituents”, the Century ring

In the present description of the invention R5, R5-1and R5-2have the same value what I that and “Deputy” in the “spacer having a main chain containing 1-10 atoms, one atom of which may form a ring which may have one or more substituents, together with the substituent in the ring”, denoted by the symbol Y.

In the present description of the invention “ring which may have one or more substituents”, denoted by the symbols R6and R7together with the carbon atom to which they are attached shall have the same meaning as the above “cyclic group which may further have one or more substituents”.

In the present invention, it is preferable to any ring group and the atom, represented respectively by ring A, ring B, X, Y, Z, R1, R2, R3,

R4, R4-1, R5, R5-1, R5-2, R6and R7. The following are the preferred groups, rings, atoms. It should be noted that all of the symbols used in the present description of the invention, have the same meanings as above characters.

In the present invention the ring And is preferably a “C3-15 carbocyclic ring or 3-15 membered heterocyclic ring containing 1-5 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and sulfur atom, more preferably a C3-7 monocyclic carbocyclic ring is or a 5-7 membered monocyclic heterocyclic ring, containing 1-2 nitrogen atom, one oxygen atom and/or one sulfur atom”, or particularly preferably a benzene ring or a pyridine ring.

In the present invention “cyclic group” in the definition of “cyclic group which may optionally have one or more substituents”, the ring is preferably a “C3-15 carbocyclic ring or 3-15 membered heterocyclic ring, more preferably a C5-12 monocyclic or bicyclic carbocyclic ring” and “5-to 12-membered monocyclic or polycyclic heterocyclic ring containing 1-3 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and sulfur atom, which may be partially or fully saturated, or particularly preferably a benzene ring, dihydronaphthalene ring, pyrazol ring, pyridine ring and benzothiophene ring.

In the present invention “ring” in the definition of “ring which may have one or more substituents, formed by one atom spacer, denoted by the symbol Y, together with the substituent in the ring, preferably is from 3 to 15-membered heterocyclic ring containing one nitrogen atom, which may optionally include 1 to 4 heteroatoms, each of which is selected from oxygen atom, nitrogen atom and the Ohm sulfur”, more preferably “9-15-membered polycyclic heterocyclic ring containing one nitrogen atom, which may further include 1-4 heteroatoms selected from oxygen atom, nitrogen, nitrogen and sulfur atom”, or particularly preferably tetrahydroisoquinolinium ring and tetrahydro-β-carbolineum ring.

In the present invention, X preferably denotes a divalent group which has a main chain containing 1 to 8 atoms, and consists of a combination of 1-4 groups selected from C1-8 alkalinous group which may be substituted, C2-8 alkenylamine group which may be substituted, -CO-, -S-, -O -, and 1,2,4-oxadiazole group which may be substituted, more preferably

where all the symbols have the above meanings; more preferred

where all the symbols have the above meanings; or particularly preferably

where all the symbols have the above values.

In the present invention Y preferably denotes a divalent group having a main chain containing 1-10 atoms, which consists of a combination of 1-4 groups selected from the group comprising C1-10 alkylenes group which may be substituted, C2-10 alkenylamine group which may be substituted, a nitrogen atom (-NH-)to the th may be substituted, -CO-, -O-, -S-, -(aziridine, which may be substituted)-, -(azetidin, which may be substituted)-, -(pyrrolidin, which may be substituted)-, -(piperidine which may be substituted)-, -(piperazine which may be substituted) -, and -(tetrahydropyridine, which may be substituted)-, more preferably-CH2-NH-(CH2)2-, -CH2(azetidin)-, -CH2-(piperidine)-(CH2)2-, -tetrahydropyridine)-(CH2)2-, -CH=CH-CH2-NH-(CH2)2and CR5-1=CR5-2-CH2(azetidin)-(R5-1and R5-2have the above values), most preferably-CH2(azetidin)-.

In the present invention, Z is preferably means an acid group which may be protected, more preferably a carboxyl group which may be protected, a hydroxyl group which may be protected (for example, -OP(=O)(OR2)(OR3) (R2and R3have the above values), group, hydroxamic acid, which may be protected, a sulfonic acid group which may be protected, a group Bronevoy acid, which may be protected, carbamoyl group which may be protected, sulfamoyl group which may be protected, -OP(=O)(OR2)(OR3) (R2and R3have the above values) or t is trusolino group, particularly preferably a carboxyl group which may be protected.

In the present invention “protective group” in the definition of “acidic group which may be protected by a protective group”denoted by the symbol Z, is preferably C1-20 alkyl group which may be substituted. In addition, the case where Z means unprotected group is also preferred.

In the present invention R1preferably means a halogen atom, C1-8 alkyl which may be substituted, C1-8 alkoxy which may be substituted, and the like, and more preferably a chlorine atom, a fluorine atom, ethyl group, through the group, isopropyl group, isobutylene group, sec-boutelou group, triptorelin group, metaxylene group, diplomatically group, isopropoxy or second-butoxypropyl and the like.

In the present invention R2preferably means hydrogen atom or C1-8 alkyl which may be substituted, and the like, and more preferably a hydrogen atom or methyl group, and the like.

In the present invention R3preferably means hydrogen atom or C1-8 alkyl which may be substituted, and the like, and more preferably a hydrogen atom or methyl group, and the like.

In the present invented and R 4and R4-1preferably denote a hydrogen atom, halogen atom, C1-8 alkyl, C1-8 alkoxy, triptorelin group, triptoreline group and the like, and more preferably a hydrogen atom, chlorine atom, methyl group, metaxylene group, triptorelin group and the like.

In the present invention R5, R5-1and R5-2preferably denote a hydrogen atom, halogen atom, C1-8 alkyl, triptorelin group, triptoreline group and the like, and more preferably a hydrogen atom, chlorine atom, methyl group, triptorelin group and the like.

In the present invention R6preferably means hydrogen atom, halogen atom, C1-8 alkyl, hydroxyl group which may be protected, amino which may be protected, C1-8 alkyl, substituted hydroxyl group which may be protected, and more preferably a hydrogen atom, methyl group, metaxylene group and the like.

In the present invention R7preferably means hydrogen atom, halogen atom, C1-8 alkyl, hydroxyl group which may be protected, amino which may be protected, C1-8 alkyl, substituted hydroxyl group which may be protected, and more preferably a hydrogen atom, methyl group, metaxylene gr the foam and the like.

In the present invention “ring which may have one or more substituents”, denoted by R6and R7together with the carbon atom to which they are attached, is preferably a “C3-7 monocyclic carbocyclic ring, more preferably a C3-7 monocyclic saturated carbocyclic ring” or particularly preferably cyclopropane ring and cyclobutanone ring.

In the present invention preferably m is 0, 1 or 2, and more preferably 2.

In the present invention preferably n is 0 or 1, and more preferably 1.

In the present invention, R preferably denotes 0, 1 or 2.

In the present invention, preferred is a compound represented by formula (I), which contains a combination of the above as preferred groups, preferred rings and preferred atoms. More preferred is a compound expressed by any of the following formulas, its salt, N-oxide, MES or prodrug:

formula (IA-1):

where all the symbols have the above meanings;

formula (IA-2):

where all the symbols have the above meanings;

formula (IA-3):

where all symbols have specified the above values;

formula (IA-4):

where all the symbols have the above meanings;

formula (IA-5):

where all the symbols have the above meanings;

and formula (IA-6):

where all the symbols have the above values.

Especially preferred is the compound expressed by any of the following formulas, its salt, N-oxide, MES or prodrug:

formula (IB-1):

where all the symbols have the above meanings;

formula (IB-2):

where all the symbols have the above meanings;

formula (IB-3):

where all the symbols have the above meanings;

formula (IB-4):

where all the symbols have the above meanings;

formula (IB-5):

where all the symbols have the above meanings;

and the formula (IB-6):

where all the symbols have the above values.

Even more preferred is a compound expressed by any of the following formulas, its salt, N-oxide, MES or prodrug:

formula (IC-1):

where all the symbols have the above meanings;

formula (IC-2):

where all the symbols have the above meanings;

formula (ID-1):

where all the symbols have the above meanings;

formula (ID-2):

where all the symbols have the above values.

Most preferred is a compound expressed by any of the following formulas, its salt, N-oxide, MES or prodrug:

formula (IC-1-1):

where all the symbols have the above meanings;

formula (IC-2-1):

where all the symbols have the above meanings;

and the formula (ID-2-1):

where all the symbols have the above values.

In the above formula (IC-1), (IC-2), (IC-1-1) and (IC-2-1) preferably m is 2, and all R1have the same or different values. In addition, the provisions substitutions preferably are positions 2 and 4, clauses 3 and 4, positions 3 and 5, particularly preferably with positions 2 and 4.

In the present invention all compounds described in the examples and their salts, N-oxides, solvate and prodrug are the preferred compounds. Particularly preferred examples of such compounds are 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidin Urbanova acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({6-[(4-isobutyl-3-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({6-[(2-ethoxy-4-isobutylbenzene)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-[(6-{[4-isopropoxy-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-({1-chloro-6-[(2-methoxy-4-propylbenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({1-chloro-6-[(4-isobutyl-2-methoxybenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-[(1-chloro-6-{[(2S)-3-(2,4-differenl)-2-methylpropyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-[(6-{[4-ethoxy-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-({6-[(4-ethyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({6-[(2-deformedarse-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-chloro-3,4-dihydro-2-Naftali who yl)methyl]-3-azetidinone acid, 1-[(6-{[2-(deformedarse)-4-propylbenzyl]oxy}-1,5-dimethyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-[(6-{[4-ethoxy-3-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid and 1-({6-[(2-methoxy-6-propyl-3-pyridinyl)methoxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, and their salts, N-oxides, solvate and prodrug. Even more preferred examples of such compounds are 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-({1-chloro-6-[(2-methoxy-4-propylbenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-({1-chloro-6-[(4-isobutyl-2-methoxybenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-chloro-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-[(6-{[2-(deformedarse)-4-propylbenzyl]oxy}-1,5-dimethyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, 1-[(6-{[4-ethoxy-3-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid and 1-({6-[(2-methoxy-6-propyl-3-pyridinyl)methoxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid, and their salts, N-oxides, solvate and is alacarte. The most preferred examples of such compounds are 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid and 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, and their salts, N-oxides, solvate and prodrug.

Isomers

Except where otherwise stated in the scope of the present invention includes all isomers. For example, alkyl, alkenyl, quinil, acyloxy, alkoxy, alkenylacyl, alkyloxy, alkylthio, alkylsulfonyl, alkylsulfonyl, alkylen, albaniles, akinyan, acyl, acyloxy include groups with straight and branched chain. In addition, the scope of the present invention includes all isomers by the presence of a double bond, ring and condensed ring (E-, Z-, CIS - and TRANS-forms), the isomers in the presence of an asymmetric carbon atom or the like (R-, S-, α - and β-configuration, enantiomers and diastereoisomers), optically active substances to rotate the plane of polarized light (D-, L-, d - and l-forms), polar compounds obtained by chromatographic separation (more polar compounds and less polar compounds), equilibrium compounds, rotamer, mixtures of such compounds in any ratio, and a racemic mixture. In the scope of the present invention includes all tautomers.

As due is to be clear to the person skilled in the art, in the present invention except where otherwise noted symbolmean α-configuration, the symbolmean β-configuration, and the symbolmeans a mixture of α-configuration and β-configuration at an arbitrary ratio. It should be noted that in the present invention, the connection with all the above-mentioned configuration is not limited to the configuration that is essentially pure and homogeneous, if this configuration is prevalent in this connection.

Salt, N-oxide and MES

Salts of the compounds of the present invention expressed by the formula (I)include all pharmaceutically acceptable salts. These salts are preferably non-toxic and water soluble. Salts of the compounds of the present invention expressed by the formula (I)preferably include salts of alkaline metal (such as potassium, sodium and lithium), salts of alkaline earth metal (such as calcium and magnesium), ammonium salts (such as salt Tetramethylammonium and tetrabutylammonium salt), salts of organic amine (such as triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Tris(hydroxymethyl)methylamine, lysine, arginine and N-methyl-D-glucamine), and acid-salt additive (t the such as inorganic salts (for example, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate)and organic acid salts (e.g. acetate, triptorelin, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, aconsultant, bansilalpet, toluensulfonate, isetionate, glucuronate and gluconate) or the like. Among the above-mentioned preferred salts are sodium salt, potassium salt, calcium salt or hydrochloride.

These salts further include a salt of Quaternary ammonium. The Quaternary ammonium salt is a compound represented by the formula (I), in which the nitrogen atom quaternion group, R0. The group R0is C1-8 alkyl which may be substituted by phenyl.

N-oxide of the compound expressed by formula (I), represents the form in which the nitrogen atom of the compounds of formula (I) is oxidized. In addition, the N-oxide of the present invention may be a salt of alkali (alkaline earth) metal salt, ammonium salt, organic amine and an acid additive salt.

Examples of the corresponding MES compounds expressed by the formula (I)include a solvate as hydrate and alcoholate (such as methanolate and ethanolate). The solvate each preferably are non-toxic and water-soluble compounds and, for example, preferably represent monohydrate. In addition, Solvay is s compounds according to the present invention includes a solvate salts of alkali metals, salts of alkaline earth metals, ammonium salts, salts of organic amines, acid additive salts and N-oxides of the aforementioned compounds of the present invention.

The compound represented by formula (I)may be converted into any of the above salts and solvate standard methods.

Prodrugs

The prodrug compounds expressed by the formula (I), its salt, N-oxide or MES is a compound that is transformed into a compound of formula (I) as a result of interaction with the enzyme, acid gastric juice or similar substance in the body of the subject. For example, prodrugs of the compounds expressed by formula (I), the compound of formula (I)containing an amino group, acelerou, alkylate or phosphorylate (e.g., in the position of the amino group of compounds of formula (I) impose eicosanol, Alamillo, intramyocardially, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidinyl, pivaloyloxymethyl, acetoxymethyl or tert-boutelou group); a compound of formula (I)containing a hydroxyl group, acelerou, alkylate, phosphorylate or bareroot (for example, in the position the hydroxyl group of the compounds of formula (I) is administered acetyl, Palmitoyl, propanolol, pivaloyloxy, cuccinello, fumarello, Alamillo is or dimethylaminomethylphenol group); the compound of formula (I)containing a carboxyl group, etherification or lidiruyut (for example, carboxyl group, the compounds of formula (I) is transformed into a complex of ethyl ether complex phenyl ether complex carboxymethylate ether complex dimethylaminomethylene ether complex pivaloyloxymethyl ether complex ethoxycarbonylmethylene ether complex Caligraphy ether complex (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester, complex cyclohexyloxycarbonyloxy ether or methylamide). These compounds can be obtained by standard methods. The prodrug compounds expressed by the formula (I)may be a hydrate or dehydrator. The prodrug compounds expressed by the formula (I), can also be a compound that is transformed into a compound of formula (I) under physiological conditions as described in “Iykuhin no kaihatsu”, vol.7 “Binshi-dekkei”, pp. 163-198 (Hirokawa-Shoten), 1990. In addition, the compound represented by formula (I)can also be tagged with a radioactive isotope (such as3H,14C,35S125I and so on).

Compounds of the present invention expressed by the formula (I), their salts, N-oxide, solvate or prodrug (hereinafter briefly referred to as “compounds of the present invention”) is perfectly dissolved and absorbed when administered orally, characterized by prolonged pharmaco is ogicheskom action (for example, stimulating activity against homing lymphocytes and immunosuppressive effects on lymphocytes), practically not exposed to enzymes mediating the metabolism of drugs, and have low toxicity. These characteristics are the most important physical, chemical, and pharmaceutical properties required when creating medicines. Satisfying the above requirements, the compounds of the present invention, apparently, are very valuable drugs (see The Merck Manual of Diagnosis and Therapy, 17thEd., Merck & Co.).

The fact that the compound of the present invention, which dissolves and is absorbed when administered orally, characterized by a prolonged pharmacological effect, is safe and has a high safety index (SI), suitable for use as a drug, you can explore the methods described in the following experimental systems or biological examples, or modified methods. In addition, the compounds of the present invention such excellent characteristics as a long half-life of serum resistance in the gastrointestinal tract, absorption when administered orally, the bioavailability and the like, you can easily identify known methods, for example using the method described in “Yakubutsu bioavailability (Hyouka to kaizen no depending)”, July 6, 1998, Gendaiiryou-sha, or similar methods.

(I) Experiments are performed to assess the connection properties

Evaluation of the solubility of the compounds of the present invention

[Experimental method]

Approximately 3-5 mg of the test compound, heated to 37°C (temperature measured by thermometer), placed in the tube. Then add solvent (official solution I included in the Japanese Pharmacopoeia, the official solution II, included in the Japanese Pharmacopoeia, and the official solution II with the addition of bovine bile acids in artificial bile (0.5 percent (wt./wt.), SIGMA), buffer solution with pH 7.4 (from the 4-fold dilution with buffer Mac-Elvina), buffer solution with pH 4.0 (obtained from 4-fold dilution with buffer Mac-Elvina), purified water and saline solution, heated to 37°C in a water bath until it reaches a concentration equal to 1.5 mg/ml, the Mixture is stirred at a constant temperature equal to 37°C. for 30 minutes, filtered through a filter (usually DISMIC-13cp, cellulose acetate, hydrophilic, 0,20 μm, Advantec). Immediately after filtration, the filtrate is diluted 2 times in an organic solvent in which the test compound is highly soluble (acetonic the sludge or methanol), and mix. The solubility of the test compounds can be determined, calculating the concentration of an external standard method using HPLC.

The study of absorption of the compounds of the present invention when administered orally dog

[Experimental method]

Hungry adults short-legged hounds intramuscularly (i.m.) injected pentagastrin (10 µg/kg). Fifteen minutes later, orally administered the test compound (100 mg/animal) with water (20 ml). After another fifteen minutes intramuscularly (i.m.) injected pentagastrin (10 µg/kg). Then after 15 and 30 minutes and 1, 2, 3, 4, 6, 8 and 10 hours after administration of the test compound to the animal take blood samples and extracted with acetonitrile. The concentration in plasma was measured by high-performance liquid chromatography (internal standard method). Measuring plasma concentrations obtained in this way, you can determine the area under the curve of plasma concentration (AUC), µg/ml/min) and maximum plasma concentration (Cmax, ng/ml).

(II) an Experimental system for determining the effectiveness of the compounds according to the present invention

(pathological model)

The fact that the compound of the present invention has an immunosuppressive effect, you can confirm using the following systems is. For example, the ability of the compounds to exert a therapeutic effect on graft rejection can be confirmed using the model of transplantation of heart, kidney, liver, pancreas, lung, bone marrow, skin or the like. Below is an example model description heart transplant.

Model ectopic transplantation of the heart in rats

[Experimental method]

The heart is removed from rats donor and transplanted into the abdominal cavity of the rat recipient. Rats orally administered the test compound in the preventive purposes, determine the number of days during which the heart remains viable after transplantation, and thus determine therapeutic effect of the drug.

The fact that the compound of the present invention provides a prophylactic and/or therapeutic effect on autoimmune disease can be confirmed by the following experiments. For example, the ability of the compounds to provide a prophylactic and/or therapeutic effect on a disease of the nervous system (such as multiple sclerosis) can be confirmed by the following experiment.

The model of experimental allergic encephalomyelitis (EAE)

[Experimental method]

In rats Levi called experimental allergic what encephalomyelitis, using different antigens, in particular the spinal cord or MOG (glycoprotein oligodendrocyte myelin). Comparing the group oral test was administered connection with the control group, it is possible to identify a therapeutic or prophylactic effect.

(III) Experiments to assess the toxicity of the compounds according to the present invention

The determination of the activity of the compounds of the present invention in relation to the current IKrhERG

[Experimental method]

In accordance with the description given in Zou, et al., Biophys. J., 74, 230-241 (1998), using HEK293 cells, sverkhekspressiya ether-a-go-go-related gene human (hERG), using the patch-clamp it is possible to measure and register the maximum current IKrhERG tail induced pulse depolarization and subsequent repolarization pulse. The rate of change (the ratio of inhibition) is calculated by comparing the maximum current in the tail before the introduction of the test compound and 10 minutes after the injection. The effect of the test compound to the current IKrhERG can be determined on the basis of the relationship of inhibition.

The title compounds of the present invention was determined using a computer program ACD/NAME™, was developed by Advanced Chemistry Development for mechanical assign the name in the IUPAC nomenclature. For example, PR is below the connection was named 1-{[1-chloro-6-(3-cyclohexylpropionic)-3,4-dihydronaphthalene-2-yl]methyl}azetidin-2-carboxylic acid.

Methods for obtaining compounds of the present invention

The compound of the present invention can be obtained through appropriate modification of the known method such as the method described in WO 02/092068, Synth. Commun., vol. 33(19), 3347 (2003) or Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2ndEd. (by Richard C. Larock, John Wiley & Sons Inc. (1999)), the following method and/or manner consistent with the following method, and the method described in the example. It should be noted that in each of the following methods source compound can be in the form of a salt. As such a salt using salt of the above compound of formula (I).

The compound of the present invention can be obtained by the methods discussed below in paragraphs (A)-(H).

(A) Compound of the present invention, in which X is linked to the ring via an oxygen atom, i.e. a compound represented by formula (I-1-A):

where Xqmeans bond or a spacer having a main chain containing 1 to 7 atoms, and other symbols have the above meanings, can be obtained by the methods described in paragraphs (1) or (a-2).

(A-1) a Compound represented by the formula (2):

where all the symbols have the above meanings;

soedinenii, represented by formula (3):

where all the symbols have the above meanings;

subjected to the reaction of Mitsunobu and then, if necessary, removing the protective group in the resulting compound represented by the formula (I-1-A).

The reaction Mitsunobu known in this field, is performed, for example, in an organic solvent (such as dichloromethane, dimethyl ether, tetrahydrofuran, acetonitrile, benzene or toluene) in the presence of azo compounds (such as diethylazodicarboxylate (DEAD), diisopropylcarbodiimide, 1,1'-(azodicarbon)piperidin or 1,1'-azobis(N,N-dimethylformamide)and phosphine compounds such as triphenylphosphine, tributylphosphine, trimethylphosphine or triphenylphosphine on the polymer carrier) at a temperature of from about 0 to 60°C. the Reaction of removing the protective group of carboxyl group, hydroxyl group, hydroxamic acid, sulphonic acid, Bronevoy acid, carbamoyl group, sulfamoyl group, phosphonic acid, phosphoric acid and tetrazolyl group can be performed in a known manner, for example by the method described in WO 02/092068, corresponding method and/or a method described in Protective Groups in Organic Synthesis (T.W. Greene, John Wiley & Sons Inc. (1999)). The protective group does not have any restrictions, if such a group can be easily and elected the part removed.

(A-2) a Compound represented by the formula (2)and the compound represented by formula (4):

where L means the deleted group, such as halogen atom, methysulfonylmethane (group OMs), toluensulfonate (group OTs), triftormetilfullerenov (OTf group), allylthiourea, alkylsulfonyl group, alkylsulfonyl group and hydroxysultaine group, and other symbols have the above meanings;

or a compound represented by the formula (5):

where all the symbols have the above meanings;

and the compound represented by formula (3), is subjected to the esterification reaction and then, if necessary, removing the protective group in the resulting compound represented by the formula (I-1-A).

Substantial, well-known in this field, is performed, for example, in an organic solvent (such as N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran or tert-butyl methyl ether) in the presence of alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide or lithium hydroxide), a hydroxide of alkaline earth metal (such as barium hydroxide or calcium hydroxide), a carbonate (such as sodium carbonate, potassium carbonate or cesium carbonate), water RA the solutions or mixtures, at a temperature of from about 0 to 100°C. The protective group can be removed as described above.

(C) the Compound of the present invention, in which Y means

where Y2and Y3each independently means a bond or a spacer having a main chain containing 1 to 8 atoms (provided that the total number of atoms of the main chain in the Y2and Y3not more than 8), and R102means a hydrogen atom or a Deputy or a heterocyclic ring containing at least one nitrogen atom which may have one or more substituents formed by atom spacer, denoted by Y2together with R102,

that is, the compound represented by formula (I-1-B)

where all the symbols have the above meanings, can be obtained as follows.

The compound represented by formula (6):

where all the symbols have the above values,

and the compound represented by the formula (7):

where all the symbols have the above meanings, is subjected to reductive aminating and then, if necessary, removing the protective group.

Reductive amination known in this field, is performed, for example, in an organic solvent (such as N,N-dimethylformamide, dichloromethane, methanol and the and the mixed solvent, containing these solvents in any parts) in the presence or absence of a desiccant (such as trimethoxymethane or triethoxysilane), in the presence or absence of organic acid (such as acetic acid)in the presence or absence of a base (such as triethylamine, sodium bicarbonate or sodium hydroxide) using a reducing agent (such as triacetoxyborohydride, cyanoacrylate, tetrabutylammonium borohydride or sodium borohydride) at a temperature of from about 0 to 100°C. the Protective group can be removed as described above.

(C) the Compound of the present invention, in which Y means

where Y1and Y6each independently means a bond or a spacer having a main chain containing 1-9 atoms (provided that the total number of atoms of the main chain in the Y1and Y6does not exceed 9), and all symbols have the above values, that is, the compound represented by formula (I-1-C):

where all the symbols have the above meanings, can be obtained as follows.

The compound represented by the formula (8):

where all the symbols have the above values,

and the compound represented by the formula (9):

where all si the oxen have the above values,

or a compound represented by the formula (10):

where all the symbols have the above values,

and the compound represented by the formula (11):

where all the symbols have the above meanings, is subjected to alkylation and then, if necessary, removing the protective group.

Alkylation is known in this field, is performed, for example, in an organic solvent (such as N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran or tert-butyl methyl ether) in the presence of alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide or lithium hydroxide), a hydroxide of alkaline earth metal (such as barium hydroxide or calcium hydroxide), a carbonate (such as sodium carbonate, potassium carbonate or cesium carbonate), their aqueous solutions or mixtures, at a temperature of from about 0 to 100°C. the Protective group can be removed as described above.

(D) the Compound of the present invention, in which Y means:

where Y4means bond or a spacer having a main chain containing 1 to 7 atoms, R103, R104and R105independently mean a hydrogen atom or a Deputy, and other symbols have the above values,

that is, the group represented by formula I-1-D):

where all the symbols have the above meanings, can be obtained as follows.

The compound represented by formula (12):

where all the symbols have the above values, and

the compound represented by the formula (13):

where all the symbols have the above meanings, is subjected to the reactions of addition of amine and then, if necessary, removing the protective group.

The reaction accession amine known in this field, is performed, for example, in an organic solvent (such as methanol, ethanol, propanol, benzene, toluene, diethyl ether, tetrahydrofuran or dimethoxyethane) or without solvent in the presence or absence of a base (such as diisopropylethylamine) at a temperature from about -78°C to the boiling temperature under reflux. The protective group can be removed as described above.

(E) Compound of the present invention, in which Z denotes a hydroxyl group which may be protected, and Y means:

where Y5means bond or a spacer having a main chain containing 1-9 atoms, that is, the compound represented by formula (I-2-E):

where all symbols have the t above values

get subjecting compound, which can be obtained by the above method, where Z means a carboxyl group which may be protected, that is, the compound represented by formula (I-1):

where R101means a hydrogen atom or a protective group, similar to the “protective group” in the definition of “carboxyl group which may be protected”represented by the group Z, and the other symbols have the above values of reduction reaction with the subsequent introduction of a protective group, if necessary.

The reaction of recovery, known in this area, performed in an organic solvent (such as methanol, ethanol, tetrahydrofuran or diethyl ether) in the presence of a reductive agent (such as alumalite lithium, lithium borohydride, sodium borohydride complex with borane pyridine or complex with borane-tetrahydrofuran) at a temperature of from about -10°C. to the boiling temperature under reflux. The reaction of introducing a protective group of hydroxyl group can be performed by a method described in Protecrive Groups in Organic Synthesis (T.W. Greene, John Wiley & Sons, Inc, (1999)).

(F) the Compound of the present invention, in which Z stands for a group hydroxamic acid, which may be protected, that is, the compound represented by formula (I-3-F):

where R121and R122each independently means a hydrogen atom or a protective group, similar to the “protective group” in the definition of “group of the hydroxamic acid, which may be protected”represented by the group Z, and the other symbols have the above values, get, exposing the connection, which can be obtained by the above method, where Z denotes the carboxyl group, i.e. the compound represented by formula (I-1-1):

where all the symbols have the above values, and the compound represented by the formula (14):

where all the symbols have the above values, the amidation reaction with the subsequent removal of the protective group, if necessary.

The amidation reaction is known in this field, and examples of how to perform this reaction include (1) the method using gelegenheid, (2) the method using mixed anhydride and (3) the method using a condensing agent. The following describes these methods. For example, (1) the method using acid chloride perform the following: carboxylic acid is subjected to interaction with acid halogenation agent (such as oxacillin or thionyl chloride) in an organic solvent (such as chloroform, dichloromethane, di is tilby ether or tetrahydrofuran) or without a solvent at temperatures from about -20°C. to the boiling temperature under reflux; the resulting gelegenheid subjected to interaction with the amine in the presence of a base (such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or diisopropylethylamine) in an organic solvent (such as chloroform, dichloromethane, diethyl ether or tetrahydrofuran) at a temperature of from about 0 to 40°C. Alternative when performing this method, the obtained gelegenheid subjected to interaction with the amine in an organic solvent (such as dioxane or tetrahydrofuran), using an aqueous solution of an alkali metal (such as sodium hydrogen carbonate solution or sodium hydroxide solution) at a temperature of from about 0 to 40°C. for Example, (2) method with the mixed anhydride perform the following: carboxylic acid is subjected to interaction with galogenangidridy (such as pivaloyloxy, taillored or methylchloride) or acid derivative (such as ethylchloride or isobutylparaben) in an organic solvent (such as chloroform, dichloromethane, diethyl ether or tetrahydrofuran) or without a solvent in the presence of a base (such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or diisopropylethylamine) at a temperature of from about 0 to 40°C, and the resulting mixed anhydride is subjected to interaction with the amine in the organic will dissolve the Le (such as chloroform, dichloromethane, diethyl ether or tetrahydrofuran) at a temperature of from about 0 to 40°C. for Example, (3) the method using a condensing agent, perform the following: carboxylic acid and amine is subjected to interaction with each other at a temperature of from about 0 to 40°C in an organic solvent (such as chloroform, dichloromethane, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent in the presence or absence of a base (such as pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) using a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium or cyclic anhydride 1-papapostolou acid (PPA)and using 1-hydroxybenzotriazole (HOBt) or without it. All of these reactions (1), (2) and (3) is preferably performed in an atmosphere of inert gas (such as argon or nitrogen) in anhydrous conditions. The protective group can be removed as described above.

(G) the Compound of the present invention, in which Z signifies tetrazolyl group, i.e. the compound represented by formula (I-4-G):

where all the symbols have the above meanings, can be obtained by subjecting the compound represented by formula is (15):

where all the symbols have the above values, the formation tetrazole rings.

Reaction formation tetrazole rings known in this field, is performed, for example, in an organic solvent (such as dimethylformamide, dioxane or tetrahydrofuran) in the presence of azide compounds (such as sodium azide, trimethylsilyl or azide anti) at a temperature of from about -10 to 150°C.

(H) the Compound of the present invention, in which Z means-OP(=O)(OR2)(OR3), where R2and R3have the above values, that is, the compound represented by formula (I-5-H):

where all the symbols have the above meanings, can be obtained by any of the following ways [H-1] and [H-2].

(N-1) a Compound represented by formula (I-5-H), in which the elements of R2and R3each means a hydrogen atom, i.e. a compound represented by formula (I-5-H-1):

where all the symbols have the above values, get, exposing the interaction of the compound, which can be obtained by the above method, where Z denotes a hydroxyl group, i.e. the compound represented by formula (I-1-2):

and the connection of dialkylphosphinate, then p is obtained compound is subjected to oxidation reaction and then the reaction of recovery.

In this area known reaction between the compound of alcohol and connection of dialkylphosphinate and the oxidation reaction. The combination of alcohol is subjected to interaction with the connection of dialkylphosphinate (such as dibenzylpiperazine or N,N-diethyl-1,5-dihydro-2,4,3-benzodioxathiepin-3-amine) in an organic solvent (such as methylene chloride, toluene or tetrahydrofuran) in the presence of tetrazole. Then carry out the oxidation reaction using an oxidant such as m-chloroperbenzoic acid, iodine or hydrogen peroxide). The reaction of recovery, also known in this field, perform in a solvent [such as a simple ether (such as tetrahydrofuran, dioxane, dimethoxyethane or diethyl ether), an alcohol (such as methanol or ethanol), benzene (such as benzene or toluene), a ketone (such as acetone or methyl ethyl ketone), a nitrile (such as acetonitrile), amide (such as dimethylformamide), water, ethyl acetate, acetic acid or a mixed solvent containing these substances two or more types] in the presence of a hydrogenation catalyst (such as palladium carbon, palladium mobile, palladium, palladium hydroxide, platinum dioxide, platinized carbon, Nickel, Nickel of Ranea, ruthenium chloride or catalyst ASCA-2 (company N.E. CHEMCAT CORPORATION, catalyst from 4.5% palladium and 0.5% platinum on aktivirovannogo, see the Fine Chemical, Oct. 1, 2002, pp. 5 to 14)in the presence or absence of acid (such as hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetraberlinia acid, acetic acid, p-toluensulfonate acid, oxalic acid, triperoxonane acid or formic acid) in an atmosphere of hydrogen under normal or elevated pressure in the presence of ammonium formate or hydrazine at a temperature of from about 0 to 200°C. in Addition to the above method, all of the reaction between the compound of alcohol and connection of dialkylphosphinate, in particular the oxidation reaction and the reduction can also be performed by the method described in “Guide to Organic Chemistry Experiment 3-Synthesis Reaction [I]” (edited by Toshio Goto, Tetsuo Shiba, and Teruo Matsuura, Called-dojin Publishing Company, INC, 1990).

(H-2), the Compound represented by formula (I-5-H), in which R2and R3each is a hydrogen atom, i.e. a compound represented by formula (I-5-H-2):

where R2H-2and R3H-2have the same meaning as R2and R3provided, that none of these elements is not a hydrogen atom, can be obtained by subjecting the interaction of the compound represented by formula (I-1-2), and the compound represented by the formula (16):

where all the symbols have the above value is I.

The above reaction is known in this area, performed in an organic solvent (such as tetrahydrofuran or methylene chloride) in the presence of a base (such as pyridine, triethylamine or utility) at a temperature from about -78°C. to 40°C.

In the present invention the compounds used as starting substances and expressed by the formulas (1)to(16)are known compounds or can be obtained by any known method.

When performing each reaction described in the present description of the invention may be used in solid-phase reagent to the polymer carrier (such as polystyrene, polyacrylamide, polypropylene, or polyethylene glycol).

When performing each reaction described in the present description of the invention, the products obtained can be purified by standard methods of purification. For example, purification may be effected by distillation at atmospheric or reduced pressure, by high-performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion-exchange resins, acceptor resin column chromatography by washing or recrystallization. Cleaning can be done after each reaction or after several reactions.

As is well known to specialists in this field, reacts the I temperature considered in the present description the invention may be performed in a water bath, oil bath, sand bath, or when heated with microwave radiation.

Toxicity

Compounds of the present invention have sufficiently low toxicity, and therefore, they are considered safe enough for use as pharmaceuticals.

The use of pharmaceutical drugs

The compound of the present invention has the ability to contact the S1P receptor (in particular, EDG-1, EDG-6 and/or EDG-8, preferably EDG-1 and/or EDG-6). Therefore, the specified connection suitable for use as a prophylactic and/or therapeutic agent in the treatment of mammals (such as humans and animals, other than humans, such as monkeys, sheep, cows, horses, dogs, cats, rabbits, rats and mice) in cases such as graft rejection, destruction of the transplanted organ, graft-versus-host (e.g., acute graft-versus-host during bone marrow transplantation, and the like), autoimmune diseases (e.g. systemic lupus erythematosus, Behcet's disease, scleroderma, nephrotic syndrome, rheumatoid arthritis, ulcerative colitis, Crohn's disease, autoimmune hemolytic anemia idiopathic thrombocytopenic purpura, myasthenia gravis, muscular dystrophy and multiple sclerosis), allergic diseases (such as atopic dermatitis, hay fever, food Allergy, psoriasis and allergies to medications (e.g., anesthetic, such as lidocaine), inflammatory diseases (e.g., varicose veins, such as hemorrhoids, fissure or fistula of the anus, dissecting aortic aneurysm, or sepsis, vasculitis, nephritis, pneumonia and chronic active hepatitis), diseases of the respiratory tract (e.g., lung fibrosis, asthma, and interstitial pneumonia), diseases of metabolism and endocrine disease (such as diabetes type I), diseases of the circulatory system (for example, violation of reperfusion after ischemia, arteriosclerosis, peripheral arteriosclerosis, obliterating thromboangiitis, diabetic neuropathy, acute heart failure and angina), various edematous disorders caused by increased penetration of the blood (e.g., myocardial infarction, heart attack, brain, DIC, pleuritis, congestive heart failure and multiple failure of the authorities), traumatic lesions (eg, pressure ulcers and burns), osteoporosis, chronic hepatitis, fibrosis, such as liver fibrosis, chronic renal failure, glomerulosclerosis kidney, infection, ulcer, lymphoma, malignant SDA is ol (for example, cancer), leukemia, cerebral embolism, ischemic pathology of different organs, the shock due to the incompatibility of blood during blood transfusion, genetic diseases, neurodegenerative diseases (such as Parkinson's disease, parkinsonovy syndrome, Alzheimer's disease and amyotrophic lateral sclerosis), and the like. In addition, the compound of the present invention can be used not only in vivo but also in vitro as a regulatory agent, such as an activator of cell differentiation and the like.

The compound of the present invention or a combination drug containing the compound of the present invention and the other drug used to achieve the above objectives, is usually administered systemically or topically, orally or parenterally. Injected dose depending on the age, body weight, symptoms, desired therapeutic effect, the route of administration and duration of treatment. Dose intended for insertion adult, usually ranging from 1 ng to 100 mg when administered orally from one to several times per day, from 0.1 ng to 10 ng when injecting from one to several times per day or continuous infusion into a vein within 1-24 hours. As described above, the input dose depend on different condition the conditions. Therefore, there may be cases when the dose will be less or more than the above range.

The compound of the present invention or a combination drug containing the compound of the present invention and the other drug used in solid form for oral administration in liquid form for oral administration, injections, liquid, ointments, suppositories, eye drops, pharmaceutical forms for inhalation or the like for parenteral administration.

Solid forms for oral administration include tablets, pills, capsules, powders and granules. Capsules include hard and soft capsules. Tablets include sublingual tablets, tablets for slow resorption, rapidly disintegrating tablets for oral administration and the like. In addition, such solid forms for oral administration may contain one or more active substances in pure form or mixed with a carrier such as lactose, mannitol, glucose, microcrystalline cellulose or starch), a binder (such as hydroxypropylcellulose, polyvinylpyrrolidone or aluminate of metasilicate magnesium), disintegrants (such as glycolate, calcium cellulose), lubricating agents (such as magnesium stearate), stabilizing agent and solubilization agent (such as glucam the new acid or aspartic acid) and can be obtained by, well known in this field. Solid forms may optionally be applied to the covering agent (such as sucrose, gelatin, hydroxypropylcellulose or phthalate hydroxypropylmethylcellulose) or a coating of two or more layers. In addition, the coating may be applied to capsules made of absorbable materials such as gelatin.

Sublingual tablets get known method. For example, one or more active substances in the form of a pharmaceutical preparation obtained by methods well known in the field, mixed with a carrier such as lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica or starch), a binder (such as hydroxypropylcellulose, polyvinylpyrrolidone or alumosilicate magnesium), disintegrants (such as starch, L-hydroxypropylcellulose, karboksimetilcelljuloza, sodium croscarmellose, or a glycolate, calcium cellulose), lubricant (such as magnesium stearate), agent causing swelling (such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carbopol, carboxymethylcellulose, polyvinyl alcohol, xanthan gum or guar gum), auxiliary substance, causing swelling (such as glucose, fructose, mannitol, xylitol, aritra, maltose, trehalose, FOSFA is, citrate, silica, glycine, glutamic acid or arginine), a stabilizing agent, solubilizers agent (such as polyethylene glycol, propylene glycol, glutamic acid or aspartic acid), flavouring (such as orange, strawberry, mint, lemon or vanilla) and the like. In addition, if necessary, on these tablets may be coated covering agent (such as sucrose, gelatin, hydroxypropylcellulose or phthalate of hydroxypropylmethylcellulose) or a coating of two or more layers. In addition, when required in these tablets can be added usually used additives such as antiseptics, antioxidants, coloring and sweetener. Tablets for slow resorption make or receive a known method. For example, one or more active substances in the form of a pharmaceutical preparation obtained by methods well known in the field, mixed with a carrier such as lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica or starch), a binder (such as hydroxypropylcellulose, polyvinylpyrrolidone or alumosilicate magnesium), disintegrants (such as starch, L-hydroxypropylcellulose, carboxymethylcellulose, sodium croscarmellose, or a glycolate, calcium cellulose), MCA is yuushin substance (such as magnesium stearate), adhesive agent (such as hydroxypropylcellulose, hypromellose, carbopol, carboxymethylcellulose, polyvinyl alcohol, xanthan gum or guar gum), auxiliary adhesive substance (such as glucose, fructose, mannitol, xylitol, aritra, maltose, trehalose, phosphate, citrate, silica, glycine, glutamic acid or arginine), a stabilizing agent, solubilizers agent (such as polyethylene glycol, propylene glycol, glutamic acid or aspartic acid), flavouring (such as orange, strawberry, mint, lemon or vanilla) and the like. In addition, if necessary, on these tablets may be coated covering agent (such as sucrose, gelatin, hydroxypropylcellulose or phthalate of hydroxypropylmethylcellulose) or a coating of two or more layers. In addition, when required in these tablets can be added usually used additives such as antiseptics, antioxidants, coloring and sweetener. Rapidly disintegrating tablets for oral administration get known method. For example, one or more active substances in pure form or in the form of a pharmaceutical preparation obtained by methods well known in the field, by applying to the particles of the powdery or granular the data of the substance of the relevant covering agent (such as ethylcellulose, hydroxypropylcellulose, hypromellose or copolymer of acrylate and methacrylate) and a plasticizer (such as polyethylene glycol or triethylcitrate), is mixed with a carrier such as lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica or starch), a binder (such as hydroxypropylcellulose, polyvinylpyrrolidone or alumosilicate magnesium), disintegrants (such as starch, L-hydroxypropylcellulose, carboxymethylcellulose, sodium croscarmellose, or a glycolate, calcium cellulose), lubricant (such as magnesium stearate), auxiliary dispersant substance (such as glucose, fructose, mannitol, xylitol, atichart, maltose, trehalose, phosphate, citrate, silica, glycine, glutamic acid or arginine), a stabilizing agent, solubilizers agent (such as polyethylene glycol, propylene glycol, glutamic acid or aspartic acid), flavouring (such as orange, strawberry, mint, lemon or vanilla) and the like. In addition, if necessary, on these tablets may be coated covering agent (such as sucrose, gelatin, hydroxypropylcellulose or phthalate of hydroxypropylmethylcellulose) or a coating of two or more layers. In addition, when required in these tablets can be dobavleniya used additional substances, such as preservative, antioxidant, coloring and sweetener.

Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs. In liquid form one or more active substances can be dissolved, suspended or emulsified in the diluent normally used in this field (such as purified water, ethanol or their mixture). In addition, the liquid form may also contain wetting agents, suspendresume agents, emulsifiers, sweeteners, flavors, aromatic substance, preservative or buffer agent.

Means for parenteral administration may be in the form of an ointment, gel, creams, wet compresses, paste, liquid, ointment, aerosol, pharmaceutical forms for inhalation, spray, solution eye drops, solution for irrigation of the nasal cavity or the like. These products containing one or more active substances, get known methods or in accordance with commonly used technology of preparation of medicines.

Ointment get known or commonly used methods. For example, to obtain such ointments in the basis pound or dissolve one or more active substances. The basis for ointments selected from known or commonly used substances. For example, alone or in videominuto two or more substances can be used such substances, as higher aliphatic acids or esters of higher aliphatic acids such as myristic acid, palmitic acid, stearic acid, oleic acid, an ester of myristic acid, an ester of palmitic acid, ester of stearic acid and an ester of oleic acid), waxes (such as beeswax, whale wax and ceresin), surfactant (e.g., ester polyoxyethylenesorbitan acid), higher alcohols (e.g., cetanol, stearyl alcohol and cetostearyl alcohol), silicone oil (for example, dimethylpolysiloxane), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, purified lanolin, and liquid paraffin), glycols (e.g. ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol and macrogol), vegetable oils (e.g. castor oil, olive oil, sesame oil and terpentine oil), animal oils (e.g., mink oil, yolk oil, squalane oil and squalene oil), water, absorption accelerator, or an antiallergic agent. The base may further include a moisturizer, a preservative, a stabilizer, an antioxidant, Parfumerie substance or the like.

Gel get known or commonly used methods. For example, to obtain such a gel based RA is tworay one or more active substances. The basis for a gel selected from known or commonly used substances. For example, individually or in combination of two or more substances can be used such substances as lower alcohols (e.g. ethanol, isopropyl alcohol), gelatinase agent (e.g., carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and ethylcellulose), a neutralizing agent (for example, triethanolamine and diisopropanolamine), surfactant (for example, polyethylene glycol monostearate), gums, water, absorption accelerator, or an antiallergic agent. The basis for the gel may optionally include a preservative, an antioxidant, Parfumerie substance or the like.

Cream get known or commonly used methods. For example, to obtain such a cream based dissolve or emuleret one or more active substances. The basis for the cream selected from known or commonly used substances. For example, individually or in combination of two or more substances can be used such substances as ester of higher aliphatic acid, a lower alcohol, hydrocarbons, polyhydric alcohols (for example propylene glycol and 1,3-butyleneglycol), higher alcohols (e.g., 2-hexyldecanol and cetanol), emulsifiers (for example, a simple polyoxyethyleneglycol ether and ester Lam is practical acid), water, absorption accelerator, or an antiallergic agent. The basis for the cream may optionally include a preservative, an antioxidant, Parfumerie substance or the like.

Damp cloth get known or commonly used methods. For example, to obtain such a wet compress one or more active substances dissolved in the base, after which the stirred mixture is applied on a substrate. The basis for wet compress selected from known or commonly used substances. For example, individually or in combination of two or more substances can be used such substances as a thickener (for example, polyacrylic acid, polyvinylpyrrolidone, Arabian gum, starch, gelatin and methyl cellulose), wetting agent (such as urea, glycerin and propylene glycol), a filler (for example, kaolin, zinc oxide, talc, calcium and magnesium), water, solubilizers agent, agent for improving adhesiveness and anti-allergic agent. The basis for wet compresses may optionally include a preservative, an antioxidant, Parfumerie substance or the like.

Asterousia means get known or commonly used methods. For example, to obtain such asterousia means one or more active substances dissolved in the base and then applied to mean the ku. The basis for asterousia means selected from known or commonly used substances. For example, individually or in combination of two or more substances can be used such substances as the polymer base, the fat and oil, higher aliphatic acid, a substance for increasing the adhesiveness or antiallergic agent. The basis for asterousia means may additionally include a preservative, an antioxidant, Parfumerie substance or the like.

Liquid ointment get known or commonly used methods. For example, for receiving such liquid ointment one or more active substances are dissolved, suspended or emuleret in a single substance or in combination of two or more substances selected from water, alcohol (e.g. ethanol and polyethylene glycol), higher aliphatic acids, glycerine, soap, emulsifier, suspending agent and the like. Liquid ointment may optionally include a preservative, an antioxidant, Parfumerie substance or the like.

The aerosol formulation for inhalation and spray the solution may contain a stabilizer, such as hydrosulfite sodium, and a buffer to make the solution isotonic, such as an isotonic agent (e.g., sodium chloride, sodium citrate and citric acid).

Injectable drug for parenteral administration can is to be in the form of a solution, suspensions, emulsions or solid injection of the drug, subject to dissolution or suspendirovanie in solvent immediately prior to use. Injection of the drug is produced by dissolving, suspending or amblyraja one or more active substances in a solvent. As such a solvent, you can use distilled water for injection, saline, vegetable oil, alcohols such as propylene glycol, polyethylene glycol and ethanol, or the like, and combinations thereof. Injectable preparation may additionally include a stabilizer, solubilizers agent (for example, glutamic acid, aspartic acid, Polysorbate 80 (trade name)), suspendisse agent, emulsifying agent, soothing agent, a buffer, a preservative or the like. Injectable sterile at the final stage or get in aseptic conditions. Alternatively, you can use aseptic solid agent such as liofilizovannye product that make aseptic or dissolved in aseptic distilled water for injection or other solvent before use.

Eye drops for parenteral administration can be a liquid, suspension, emulsion or oil, or can be dissolved in a solvent immediately before use is to be neglected. These eye drops get known methods. For example, one or more active substances are dissolved, suspended or emuleret in the solvent. As a solvent for eye drops you can use sterilized purified water, saline and other aqueous or non-aqueous solvents for injection of the drug (e.g., vegetable oil), and combinations thereof. Eye drops may include isotonic agent (e.g., sodium chloride and concentrated glycerin), a buffering agent (such as sodium phosphate and sodium acetate), a surfactant (for example, Polysorbate 80 (trade name), polyxystra 40, castor oil, utverjdenie a polyoxyethylene), a stabilizer (for example, sodium citrate and edetate sodium), antiseptics (e.g., benzalkonium chloride and paraben) or the like, which, if necessary, should be selected accordingly. Eye drops are sterilized or receive under aseptic conditions at the final stage. Alternatively, you can use aseptic solid agent such as liofilizovannye product that make aseptic or dissolved in aseptic distilled water for injection or other solvent before use.

Pharmaceutical form inhalation designed to parentalinvolvement, can be a spray, a powder for inhalation or liquid for inhalation. Liquid for inhalation may be dissolved or suspended in water and the other acceptable medium immediately before use. These pharmaceutical forms for inhalation receive a known method. For example, a liquid for inhalation derived from compounds which, if necessary, appropriately selected from antiseptics (e.g., benzalkonium chloride and paraben), coloring agents, buffering agents (for example, sodium phosphate and sodium acetate), isotonic agents (e.g. sodium chloride and concentrated glycerin), thickeners (for example, carboxyvinyl polymer), absorption accelerators, and the like.

Powder for inhalation derived from compounds which, if necessary, appropriately selected from lubricants (e.g. stearic acid and its salts), binding agents (e.g. starch and dextrin), media (e.g., lactose and cellulose), dyes, antiseptics (for example, benzalkonium chloride and paraben), absorption accelerators or the like.

For the introduction of liquid for inhalation usually use the spray device (e.g., aerosol nebulizer and atomizer). For injection powder for inhalation usually use the inhaler.

Other examples of composers who s include suppositories for rectal administration and vaginal suppositories for vaginal insertion, obtained from a conventional method and containing one or more active substances.

The compound of the present invention can be introduced in the form of combined drug in combination with other drugs to achieve the following tasks:

1) supplementing and/or enhancing the preventive and/or therapeutic action of this compound;

2) improved pharmacokinetics and absorption and reduce doses input connections; and/or

3) reduction of side effects for this connection.

Combined preparation containing the compound of the present invention, can be entered together with other pharmaceuticals as a means of complicated structure, in which both components are mixed in a single drug or in separate preparations. Introduction in the form of individual drugs involves the simultaneous introduction and the introduction of specific intervals of time. With the introduction of intervals of time, first enter the compound of the present invention and then another pharmaceutical agent, or enter another pharmaceutical agent and then the compound of the present invention. Such drugs you can enter the same or different ways.

Combination medications that contain other pharmaceuticals, which Supplement and/or reinforce the t preventive and/or therapeutic effect of the compounds of the present invention, not limited to drugs that are listed as examples in the present description of the invention. In addition, a combination of drugs that contain other pharmaceuticals, which complement and/or enhance the preventive and/or therapeutic effect of the compounds of the present invention, include not only compounds detected up to the present time, but also compounds that will be discovered in the future based on the mechanisms described in this specification.

Diseases for which the above combination medicines have a preventive and/or therapeutic effect, do not have any restrictions. In particular, such diseases include diseases, the treatment of which can be supplemented and/or enhanced preventive and/or therapeutic effect of the compounds of the present invention. For example, to complement and/or enhance the preventive and/or therapeutic action in the case of transplant rejection due to EDG-1 and/or EDG-6, can be used with other immunosuppressants, antibiotics or a similar tool. To complement and/or enhance the preventive and/or therapeutic effect in the treatment of autoimmune diseases can be used steroids, non-steroidal anti-inflammatory drugs (SAID), Antirheumatic agents that modify the course of illness (DMARDs, cause a slow Antirheumatic drugs), other immunosuppressants, and inhibitors of T cells, anti-inflammatory enzymes that protect the cartilage tools, prostaglandins and inhibitors of prostaglandin synthase, inhibitors of IL-1 inhibitors, IL-6 (including protein drugs, such as antibody against the receptor for IL-6), inhibitors of TNF-α (including protein drugs, such as antibody against TNF-α), agonists, γ-interferon, phosphodiesterase inhibitors, inhibitors of metalloproteinases, and the like. Examples of drugs used to complement and/or enhance the preventive and/or therapeutic effects in the treatment of allergic diseases such as atopic dermatitis include immunosuppressants, steroids, non-steroidal anti-inflammatory drugs, prostaglandins, anti-allergic medicines, inhibitors of the release of mediators, antihistamine medications, drugs of Forskolin, phosphodiesterase inhibitors and stimulators receptor cannabinoid-2.

Examples of immunosuppressive agents include azathioprine (trade name: IMURAN and ASANIN), mizoribine (trade name: BRAININ), methotrexate (trade name: METHOTREXATE, RHEUMATREX), mycophenolate mofetil (trade name: CELLCEPT), cyclophosphamide (brand name: ENDOXAN R), cyclosporine a (trade name: NEORAL, SANDIMMUNE), tacrolimus (FK506, trade name: PROGRAF), sirolimus (RAPAMYCIN), everolimus (trade name: CERTICAN), prednisolone (trade name: PREDOMIN), methylprednisolone (brand name: MEDROL), ortolan ACT (trade name: MUROMONAB CD3), globulin against human lymphocytes (ALG, trade name: ALBUMIN), desoxypeganine (DSG, hydrochloride of gusperimus and trade name: CYANIDIN).

Examples of antibiotics include cefuroxime sodium, Meropenem trihydrate, netilmicin sulfate, sulfate sisomicin, ceftibuten, PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, sulfate astromicin or hydrochloride cafetalera. Examples of antibiotics that are used as medicinal forms for inhalation include PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, sulfate astromicin or hydrochloride cafetalera.

Examples of steroids used in preparations for external use include clobetasol propionate, diacetate diflorasone, fluocinonide, furancarboxylic mometasone, betamethasone dipropionate, butyrate-propionate betamethasone valerate betamethasone difluprednate, budesonide, valerate of diflucortolone, amcinonide, halcinonide, dexamethasone, propionate, dexamethasone, dexamethasone valerate, azeta the dexamethasone, the hydrocortisone acetate, hydrocortisone butyrate, butyrate-propionate hydrocortisone, propionate of depradine, valerate-prednisolone acetate, acetonide fluoqinolona, propionate, beclomethasone, triamcinolone acetonide, pialat flumetazon, dipropionate alklometazon, butyrate of clobetasone, prednisolone, beclomethasone propionate and fludroxycortide. Examples of drugs for internal use and injection include cortisone acetate, hydrocortisone, sodium phosphate hydrocortisone, sodium succinate hydrocortisone acetate of fludrocortisone, prednisolone, prednisolone acetate, sodium succinate prednisolone, butyl acetate prednisolone sodium phosphate prednisolone acetate of halogenfree, methylprednisolone, methylprednisolone acetate, sodium succinate methylprednisolone, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, sodium phosphate dexamethasone, dexamethasone palmitate, acetate of paramethasone and betamethasone. Examples of pharmaceutical forms for inhalation include propionate, beclomethasone, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasone palmitate, frankenbot mometasone, prasterone sulfonate, deflazacort, sulatan methylprednisolone and sodium succinate methylprednisolone.

Examples of non-steroidal anti-inflammatory when edst (NSAID) include aspirin, the sodium salicylate, aspirin, dealuminated aspirin, diflunisal, indomethacin, suprofen, openmath, dimethylethanolamine, bufexamac, felbinac, diclofenac, tolmetin-sodium, clinoril, fenbufen, nabumeton, proglumetacin, indomethacinum, acemetacin, maleate proglumetacin, amfenac sodium, movetalk, etodolac, ibuprofen, ibuprofenpaypal, naproxen, flurbiprofen, flurbiprofene, Ketoprofen, fenoprofen-calcium, tiaprofenic, oxaprozin, pranoprofen, loxoprofen sodium, looprope, zaltoprofen, methenamine acid, mefenamic aluminum, tolfenamic acid, floctafenine, ketovinylation, oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, cream-based mapagana, epirizole, hydrochloride tiaramide, hydrochloride tinoridine, emorfazone, sulpirid, Amigrenin, saridon, Sedes G, amipro N, Sorbon, antipyretics system Parinov, acetaminophen, phenacetin, mesilate dimethocaine composition simetrica and antipyretics system antipyrine.

Examples Antirheumatic drugs that modify the course of illness (DMARDs, cause a slow Antirheumatic drugs)include aurothioglucose, aurothiomalate sodium, auranofin, actarit, drugs D-penitsillamin, disodium-lobenzarit, bucillamine, hydroxychloroquine, salazosulfapiridin, methotrexate and Leflunomide.

An example of the anti-inflammatory enzyme preparations include lysozyme chloride, bromelain, Pranas, serrapeptase or streptokinase-streptodornase.

Examples of protecting cartilage funds include sodium hyaluronate, glucosamine sulphate and chondroitin polysulphate of glycosaminoglycan.

Examples of prostaglandins (hereinafter abbreviated as “PG”) include agonist of PG receptors and receptor antagonist PG. Examples of receptors include PG PGE receptor (EP1, EP2, EP3, EP4), PGD receptor (DP, CRTH2), PGF receptor (FP), PGI receptor (IP) or receptor TX (TR).

Examples of inhibitors of prostaglandin synthase include salazosulfapiridin, mesalazin, olsalazine, 4-aminosalicylic acid, JTE-522, auranofin, carprofen, divinename, flunoxaprofen, flurbiprofen, indomethacin, Ketoprofen, lornoxicam, loxoprofen, meloxicam, oxaprozin, parceled, piperoxan, piroxicam, peroxycarbonates, cinnamate piroxicam, indomethacin tropine, zaltoprofen and pranoprofen.

Examples of inhibitors of IL-1 (including protein drugs, such as receptor antagonist of human IL-1) include anakinra.

Examples of inhibitors of IL-6 (including protein drugs, such as antibody receptor, anti-IL-6) include the MRA.

Examples of inhibitors of TNF-α (including protein drugs, such as antibody anti-TNF-α) include infliximab, adalimumab and etanercept.

Examples of the phosphodiesterase inhibitor include rolipram, cilomilast (trading n the title: ariflo), Bay 19-8004, NIK-616, roflumilast (BY-217), cipamfylline (BGL-61063), atizoram (CP-80633), SCH-351591, YM-976, V-11294A, PD-168787, D-4396, IC-485, or ONO-6126 as an inhibitor of PDE-4.

Examples of inhibitors of the release of mediators include tranilast, sodium cromoglycate, amlexanox, reprint, ibudilast, casinolist and pemirolast-potassium.

Examples of antihistamine medications include ketotifen fumarate, meketaten, hydrochloride azelastina, oxatomide, terfenadine, the fumarate of emedastine, hydrochloride of epinastine, astemizole, Bastin, cetirizine hydrochloride, bepotastine, fexofenadin, loratadine, desloratadine, hydrochloride of olopatadine, SO-427, ZCR-2060, NIP-530, mometasone furoate, mizolastine, BP-294, andolast, auranofin, acrivastine.

The effect of the invention

The compound of the present invention has the ability to contact the S1P receptor (in particular, EDG-1, EDG-6 and/or EDG-8). Therefore, the specified connection suitable for use as a prophylactic and/or therapeutic agent in the treatment of mammals (such as humans and animals, other than humans, such as monkeys, sheep, cows, horses, dogs, cats, rabbits, rats and mice) in cases such as graft rejection, destruction of the transplanted organ, graft-versus-host (e.g., acute graft-versus-host during the trance is santali bone marrow and the like), autoimmune diseases (e.g. systemic lupus erythematosus, Behcet's disease, scleroderma, nephrotic syndrome, rheumatoid arthritis, ulcerative colitis, Crohn's disease, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, myasthenia gravis, muscular dystrophy and multiple sclerosis), allergic diseases (such as atopic dermatitis, hay fever, food Allergy, psoriasis and allergies to medications (e.g., anesthetic, such as lidocaine), inflammatory diseases (e.g., varicose veins, such as hemorrhoids, fissure or fistula of the anus, dissecting aortic aneurysm, or sepsis, vasculitis, nephritis, pneumonia and chronic active hepatitis), diseases of the respiratory tract (e.g., lung fibrosis, asthma, and interstitial pneumonia), metabolic diseases and endocrine diseases (such as diabetes type I), diseases of the circulatory system (for example, violation of reperfusion after ischemia, arteriosclerosis, peripheral arteriosclerosis, obliterating thromboangiitis, diabetic neuropathy, acute cardiac insufficiency and angina), various edematous disorders caused by increased penetration of the blood (e.g., myocardial infarction, heart attack, brain, disseminated intravascular of swertia is s (DIC), pleuritis, congestive heart failure, multiple failure of the authorities), traumatic lesions (eg, pressure ulcers and burns), osteoporosis, chronic hepatitis, fibrosis, such as liver fibrosis, chronic renal failure, glomerulosclerosis kidney, infection, ulcer, lymphoma, malignant tumor (e.g., cancer), leukemia, cerebral embolism, ischemic pathology of different organs, the shock due to the incompatibility of blood during blood transfusion, genetic diseases, neurodegenerative diseases (such as Parkinson's disease, parkinsonovy syndrome, Alzheimer's disease and amyotrophic lateral sclerosis), and the like.

The best option of carrying out the invention

The present invention will be described in more detail in the examples below. However, the present invention is not limited to these examples.

As for chromatographic separation or TLC, the solvent in parentheses matching using an eluting or manifesting the solvent, the ratio expressed in terms of volume. Used aqueous ammonia is commercially available 28% aqueous ammonia solution.

For measurement was used solvent indicated in parenthesis NMR data.

The diffraction pattern x-ray powder diffraction beam of the nd was obtained under the following conditions: device: BRUKER D8 DISCOVER with GADDS BRUKER axs; target: Cu; filter: none; voltage: 40 kV; electric current: 40 mA; exposure time: 5 minutes

The relative intensity specified in tables are expressed in percentage values relative to the largest peak (given equal 100%).

Differential scanning calorimetry (DSC) was performed under the following conditions: device: DSC 822e METTLER TOLEDO; cell for sample: aluminum open cell; the flow rate of gaseous argon: 40 ml/min; heating rate: specified in each example.

Example 1: 6-(benzyloxy)-3,4-dihydronaphthalene-1(2H)-he

To a solution of 6-hydroxy-3,4-dihydronaphthalene-1(2H)-she (24.3 g) in acetone (160 ml) was added benzylbromide (29,4 ml) and potassium carbonate (31.1 grams) at room temperature and was stirred at 40°C. for 3.5 hours. Insoluble substances were filtered off, the filtrate was concentrated, and the reaction product is washed with a mixed solvent consisting of tert-butyl methyl ether and hexane (1:4), while receiving specified in the header connection (34,5 g)having the following physical properties.

TLC: Rf of 0.38 (hexane:ethyl acetate = 3:1).

Example 2: 7-(benzyloxy)-4-methyl-1,2-dihydronaphthalene

To a solution of compound (34,5 g)obtained in example 1 in tetrahydrofuran (300 ml) was added methylmagnesium (3 mol/l solution in diethyl ether, 55 ml) at 0°C and stirred at room is based temperature for 1 hour. The reaction mixture was cooled to 0°C and poured into saturated ice water solution of ammonium chloride. Then added 2 mol/l hydrochloric acid, and the mixture was stirred at room temperature for 3 hours. The reaction product was extracted with ethyl acetate, the organic layer was sequentially washed with water and saturated salt solution, dried and concentrated. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate = 10:1), while receiving specified in the title compound (24.8 g)having the following physical properties.

TLC: Rf of 0.57 (hexane:ethyl acetate = 15:1).

Example 3: 6-(benzyloxy)-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde

To phosphorus oxychloride (26.7 g) at 0°C was added dropwise N,N-dimethylformamide (60 ml) and was stirred for 20 minutes. Then dropwise slowly added to the solution of compound (24.8 g)obtained in example 2 in methylene chloride (60 ml) and stirred at room temperature for 90 minutes. The reaction mixture was cooled to 0°C., poured into ice and left to stand for some time. Then the reaction product was extracted with a mixed solvent consisting of hexane and ethyl acetate (1:2). The organic layer was sequentially washed with water and saturated salt solution, dried and concentrated. The resulting solid matter is washed with tert-butylmethylamine ether, while receiving specified in the title compound (19.9 g)having the following physical properties.

TLC: Rf of 0.50 (hexane:ethyl acetate = 3:1).

Example 4: 6-hydroxy-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde

To thioanisole (35 ml) at 0°C was added triperoxonane acid (140 ml). Then portions were added the compound (9,17 g)obtained in example 3 and stirred at room temperature for 4 hours. The reaction mixture was poured on ice and added 5 mol/l aqueous solution of sodium hydroxide. The mixture was washed tert-butylmethylamine ether, the aqueous layer was added 1 mol/l hydrochloric acid and was extracted with ethyl acetate. The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate = 5:1 to 2:1), while receiving specified in the header connection (6,03 g)having the following physical properties.

TLC: Rf 0.26 (hexane:ethyl acetate = 3:1).

Example 5: 6-[3-(4-forfinal)propoxy]-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde

Did the method according to example 1, using the compound obtained in example 4, instead of 6-hydroxy-3,4-dihydronaphthalene-1(2H)-it and 1-bromo-3-(4-forfinal)propane instead of benzylbromide, resulting mentioned in the title compound having the following physical properties.

TLC: Rf of 0.40(hexane:ethyl acetate = 3:1).

1H-NMR (CDCl3): δ 10,32 (s, 1H), of 7.48 (d, J=8,50 Hz, 1H), 7,16 (DD, J=8,50, 5.50 Hz, 2H), 6,97 (t, J=8,50 Hz, 2H), 6,78 (DD, J=8,50, 2,50 Hz, 1H), 6.73 x (d, J=2,50 Hz, 1H), 3,99 (t, J=6,00 Hz, 2H), and 2.79 (t, J=7,50 Hz, 2H), 2,69-of 2.75 (m, 2H), 2,47-of 2.56 (m, 5H), 2,04 with 2.14 (m, 2H).

Example 6: methyl-1-({6-[3-(4-forfinal)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinol

To a solution of compound (5,04 g)obtained in example 5 in tetrahydrofuran (50 ml) was sequentially added triethylamine (4,33 ml), hydrochloride methylisatin-3-carboxylate (4.71 g, which was obtained in the following example 38) and triacetoxyborohydride (9.88 g) under cooling with ice. The reaction mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added water under ice cooling. The resulting mixture was concentrated, and the resulting solution was extracted with ethyl acetate. The extract was sequentially washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated salt solution. The reaction product was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate = 2:1 to 1:1 and 1:6), while receiving specified in the header connection (6,12 g)having the following physical properties.

TLC: Rf value of 0.52 (hexane:ethyl acetate = 1:3).

1H-NMR (CDCl ): δ 7,11-7,21 (m, 3H), 6,92-7,01 (m, 2H), 6,66-6,74 (m, 2H), 3,94 (t, J=6,13 Hz, 2H), 3,70 (s, 3H), 3,50-to 3.58 (m, 2H), 3,23 is 3.40 (m, 5H), 2,78 (t, J=7,50 Hz, 2H), 2,62-of 2.72 (m, 2H), 2,22-2,31 (m, 2H), 2,09 (, 3H), 2.00 in to 2.13 (m, 2H).

Examples 6-1 - 6-10

Did the method according to example 6, using the corresponding aldehydes instead of the compound obtained in example 5. Thus were obtained the compounds having the following physical properties.

Example 6-1: methyl-1-({6-[3-(4-chlorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinol

TLC: Rf of 0.34 (hexane:ethyl acetate = 1:3).

1H-NMR (CDCl3): δ 7,09-7,28 (m, 5H), 6,62 to 6.75 (m, 2H), 3,94 (t, J=6,13 Hz, 2H), 3,71 (s, 3H), 3,50-3,60 (m, 2H), 3,24-to 3.41 (m, 5H), 2,78 (t, J=at 7.55 Hz, 2H), 2,63-of 2.72 (m, 2H), 2,22 of-2.32 (m, 2H), 2,09 (s, 3H), 2,00-2,12 (m, 2H).

Example 6-2: methyl-1-({6-[2-(4-isopropylphenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinol

TLC: Rf 0,89 (chloroform:methanol = 9:1).

1H-NMR (CDCl3): δ 7,12-of 7.24 (m, 5H), 6,63-6,76 (m, 2H), 4.04 the-4,12 (m, 1H), 3,91 (t, J=9,00 Hz, 1H), 3,70 (s, 3H), 3,48-3,61 (m, 2H), 3,09-of 3.43 (m, 6H), 2,82-to 2.94 (m, 1H), 2,66 (t, J=9,00 Hz, 2H), 2,17-of 2.30 (m, 2H), 2,08 (, 3H), of 1.40 (d, J=6,95 Hz, 3H), 1,25 (d, J=6,95 Hz, 6H).

Example 6-3: methyl-1-[(6-{[(2R)-3-(4-forfinal)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinol

TLC: Rf and 0.46 (chloroform:methanol = 20:1).

1H-NMR (CDCl3): δ 7,06-of 7.23 (m, 3H), 6.89 in-7,02 (m, 2H), 6,63 to 6.75 (m, 2H), 3,76 (d, J=5,9 Hz, 2H), 3,71 (s, 2H), 3,51-3,59 (m, 2H), 3,22-to 3.41 (m, 6H), 2,84 (DD, J=13,5, 6.4 Hz, 1H), to 2.67 (t, J=7,3 Hz, 2H), 2,52 (DD, J=13,5, 7.9 Hz, 1H), 2,12-2,31 (m, 3H), of 2.09 (s, 3H), and 1.00 (d, J=6.8 Hz, 3H).

Example 6-4: methyl-1-[(6-{[(2S)-3-(4-forfinal)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinol

TLC: Rf 0.36 and (hexane:ethyl acetate = 1:1)

1H-NMR (CDCl3): δ 7.18 in (d, J=8,40 Hz, 1H), 7,08-7,16 (m, 2H), 6,91-7,01 (m, 2H), 6,64-6,74 (m, 2H), 3,76 (d, J=5,85 Hz, 2H), 3,71 (s, 3H), 3,43-3,61 (m, 2H), 3,23-to 3.41 (m, 5H), 2,84 (DD, J=13,45, 6,50 Hz, 1H), 2,61 is 2.75 (m, 2H,), 2,52 (DD, J=13,45, to 7.68 Hz, 1H), 2,12 is 2.33 (m, 3H), of 2.09 (s, 3H), and 1.00 (d, J=6,7 Hz, 3H).

Example 6-5: methyl-1-({1-chloro-6-[3-(4-forfinal)propoxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinol

TLC: Rf 0.83 (chloroform:methanol = 9:1).

1H-NMR (CDCl3): δ 7,51 (d, J=at 8.60 Hz, 1H), 7,11-7,19 (m, 2H), 6,91-7,02 (m, 2H), 6.73 x (DD, J=8,60, of 2.56 Hz, 1H), 6,66 (d, J=2,56 Hz, 1H), 3,95 (t, J=6.22 per Hz, 2H), 3,71 (s, 3H), of 3.57 (t, J=7,14 Hz, 2H), 3,28-3,47 (m, 5H), 2,78 (t, J=7,20 Hz, 2H), 2,75 (t, J=7,20 Hz, 2H), 2,43 (t, J=7,50 Hz, 2H), 1,99 and 2.13 (m, 2H).

Example 6-6: methyl-1-[(6-{[1-(4-terbisil)cyclopropyl]methoxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinol

TLC: Rf to 0.73 (chloroform:methanol = 9:1).

Example 6-7: methyl-1-{[6-[3-(4-forfinal)propoxy]-3-(trifluoromethyl)-1-benzothieno-2-yl]methyl}-3-azetidinol

TLC: Rf of 0.54 (hexane:ethyl acetate = 3:1).

1H-NMR (CDCl3): δ 7,70-7,80 (m, 1H), 7,11-7,29 (m, 3H), 6,92-to 7.09 (m, 3H), 3.95 to 4,07 (m, 4H), 3,66-of 3.77 (m, 5H), 3,34-3,51 (m, 3H), of 2.81 (t, J=7.5 Hz, 2H), 2,04-2,19 (m, 2H).

Example 6-8: methyl-1-[(6-{[(2S)-3-(2,4-differenl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidin rboxylic

TLC: Rf of 0.20 (hexane:ethyl acetate = 1:2).

1H-NMR (CDCl3): δ 7.18 in (d, J=8,50 Hz, 1H), 7,08-7,16 (m, 1H), 6,74-PC 6.82 (m, 2H), 6,66-6,72 (m, 2H), 3,78 (d, J=6,00 Hz, 2H), 3,71 (s, 3H), 3,50-to 3.58 (m, 2H), 3.25 to 3,37 (m, 5H), 2,85 (DD, J=14,00, 6,50 Hz, 1H), 2,64-a 2.71 (m, 2H,), to 2.57 (DD, J=14,00, 7,50 Hz, 1H), 2,17-2,31 (m, 3H), of 2.08 (s, 3H), 1,01 (d, J=6,50 Hz, 3H).

Example 6-9: methyl-1-[(6-{[(2S)-3-(4-chloro-2-forfinal)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinol

TLC: Rf of 0.20 (hexane:ethyl acetate = 1:2).

1H-NMR (CDCl3): δ 7.18 in (d, J=8,50 Hz, 1H), 7,01-7,14 (m, 3H), 6,65-6,72 (m, 2H), 3,78 (d, J=6,00 Hz, 2H), 3,71 (s, 3H), 3,51-to 3.58 (m, 2H), 3,24 is 3.40 (m, 5H), 2,85 (DD, J=14,00, 6,50 Hz, 1H), 2,64-a 2.71 (m, 2H), 2,58 (DD, J=14,00, of 8.00 Hz, 1H), 2,19-2,31 (m, 3H), of 2.09 (s, 3H), 1,01 (d, J=6,50 Hz, 3H).

Example 6-10: methyl-1-[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinol

TLC: Rf of 0.33 (chloroform:methanol = 20:1).

1H-NMR (CDCl3): δ 7.23 percent (d, J=8,4 Hz, 2H), 7,18 (d, J=8,4 Hz, 1H), 7,10 (d, J=8,4 Hz, 2H), 6,64-6,72 (m, 2H, in), 3.75 (d, J=5,9 Hz, 2H), 3,70 (s, 2H), 3,50-3,59 (m, 2H), 3,23-to 3.41 (m, 6H), 2,85 (DD, J=a 13.5, 6.5 Hz, 1H), 2,67 (t, J=7,1 Hz, 2H), 2,52 (DD, J=13,5, and 7.8 Hz, 1H), 2.13 and of-2.32 (m, 3H), of 2.09 (s, 3H), 0,99 (d, J=6.8 Hz, 3H).

Example 7: 1-({6-[3-(4-forfinal)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

To a solution of compound (6,02 g)obtained in example 6 in methanol (120 ml) was added dropwise 1 mol/l aqueous solution of sodium hydroxide (40 ml) under cooling with ice. Reacciona the mixture was stirred for 3 hours under ice cooling. To the mixture was added 1 mol/l hydrochloric acid (40 ml). The resulting insoluble matter was filtered, washed with water and dried. The obtained solid was recrystallized from water-tetrahydrofuran, while receiving specified in the header of the connection (of 5.55 g)having the following physical properties.

Melting point: 154,0 was 155.3°C.

TLC: Rf of 0.35 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,31 (d, J=at 8.60 Hz, 1H), 7,15-7,25 (m, 2H), 6,92-7,02 (m, 2H), 6.75 in (DD, J=8,60, of 2.56 Hz, 1H), of 6.71 (d, J=2,56 Hz, 1H), 4,10-4.26 deaths (m, 4H), 4,07 (s, 2H), 3,95 (t, J=6,13 Hz, 2H), 3,34-of 3.48 (m, 1H), 2,66-2,82 (m, 4H), 2,20-of 2.28 (m, 2H), measuring 2.20 (s, 3H), 1,98 is 2.10 (m, 2H).

Examples 7-1 - 7-10

Did the method according to example 7, using the compounds obtained in examples 6-1 - 6-10, instead of the compound obtained in example 6. If necessary, the reaction product was converted to the corresponding salt, while receiving specified in the headers of the compounds having the following physical properties.

Example 7-1: 1-({6-[3-(4-chlorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

Melting point: 165,4-166,9°C.

TLC: Rf of 0.32 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,31 (d, J=at 8.60 Hz, 1H), 7,16-7,28 (m, 4H), to 6.75 (DD, J=8,60, to 2.74 Hz, 1H), 6,70 (d, J=2,74 Hz, 1H), 4.09 to-4,24 (m, 4H), 4,07 (s, 2H), 3.96 points (t, J=6.22 per Hz,2H), 3,34-3,47 (m, 1H), 2,67-2,82 (m, 4H), 2,17-of 2.28 (m, 5H), 1,99-2,11 (m, 2H).

Example 7-2: hydrochloride 1-({6-[2-(4-isopropylphenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0,11 (1-butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ 7,31 (d, J=at 8.60 Hz, 1H), 7,12-of 7.23 (m, 4H), to 6.75 (DD, J=8,60, 2.65 Hz, 1H), 6,70 (d, J=2.65 Hz, 1H), 4,20-to 4.41 (m, 4H), to 4.15 (s, 2H), 4,07 (DD, J=of 9.30, 6,30 Hz, 1H), 3,98 (DD, J=of 9.30, to 7.50 Hz, 1H), 3,60 is 3.76 (m, 1H), of 3.10-3.20 (m, 1H), 2,79 of 2.92 (m, 1H), 2,67 was 2.76 (m, 2H), of 2.21 (s, 3H), 2,17-of 2.27 (m, 2H), 1,36 (d, J=6,95 Hz, 3H), of 1.23 (d, J=6,95 Hz, 6H).

Example 7-3: 1-[(6-{[(2R)-3-(4-forfinal)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.40 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,30 (d, J=8,42 Hz, 1H), 7,09-of 7.23 (m, 2H), 6.87 in-7,03 (m, 2H), 6,74 (DD, J=8,42, of 2.56 Hz, 1H), 6,69 (d, J=2,56 Hz, 1H), 4,12-4,27 (m, 4H), 4.09 to (s, 2H), 3,78 (d, J=6,04 Hz, 2H), 3,35-3,47 (m, 1H), and 2.83 (DD, J=13,45, 6,50 Hz, 1H), 2,67 is 2.75 (m, 2H), 2,54 (DD, J=13,45, for 7.78 Hz, 1H), measuring 2.20 (s, 3H), 2,09-to 2.29 (m, 3H), 0,99 (d, J=6,77 Hz, 3H).

Example 7-4: 1-[(6-{[(2S)-3-(4-forfinal)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

Melting point: 142,5-143,6°C.

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 5:1:0,1).

1H-NMR (CD3OD): δ 7,30 (d, J=8,42 Hz, 1H), 7,09-of 7.23 (m, 2H), 6.87 in-7,03 (m, 2H), 6,74 (DD, J=8,42, of 2.56 Hz, 1H), 6,69 (d, J=2,56 Hz, 1H), 4,12-4,27 (m, 4H), 4.09 to (s, 2H), 3,78 (d, J=6,04 G is, 2H), 3,35-3,47 (m, 1H), and 2.83 (DD, J=13,45, 6,50 Hz, 1H), 2,67 is 2.75 (m, 2H), 2,54 (DD, J=13,45, for 7.78 Hz, 1H), measuring 2.20 (s, 3H), 2,09-to 2.29 (m, 3H), 0,99 (d, J=6,77 Hz, 3H).

Example 7-5: 1-({1-chloro-6-[3-(4-forfinal)propoxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0,12 (chloroform:methanol:aqueous ammonia= 5:1:0,1).

1H-NMR (CD3OD): δ at 7.55 (d, J=at 8.60 Hz, 1H), 7,10-7,26 (m, 2H), 6,92-7,05 (m, 2H), 6,80 (DD, J=8,60, 2.38 Hz, 1H), 6,76 (d, J=2.38 Hz, 1H), 4,22 (d, J=8,40 Hz, 4H), 4,17 (s, 2H), 3,97 (t, J=6,13 Hz, 2H), 3,36-to 3.49 (m, 1H), 2,70-2,89 (m, 4H), 2,41-2,49 (m, 2H), 1,97-2,11 (m, 2H).

Example 7-6: 1-[(6-{[1-(4-terbisil)cyclopropyl]methoxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf 0.14 (chloroform:methanol:aqueous ammonia= 5:1:0,1).

1H-NMR (CD3OD): δ 7.29 trend (d, J=at 8.60 Hz, 1H), 7,13-7,22 (m, 2H), 6,88-6,98 (m, 2H), 6,65-of 6.73 (m, 2H), 4,10-4.26 deaths (m, 4H), 4,07 (s, 2H), 3,61 (s, 2H), 3,36-3,47 (m, 1H), 2,78 (s, 2H), 2,66 is 2.75 (m, 2H), 2,14-of 2.28 (m, 5H), of 0.52 and 0.68 (m, 4H).

Example 7-7: 1-{[6-[3-(4-forfinal)propoxy]-3-(trifluoromethyl)-1-benzothieno-2-yl]methyl}-3-azetidinone acid

TLC: Rf of 0.32 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,71 (DD, J=9,0, 1.4 Hz, 1H), 7,39 (d, J=2.4 Hz, 1H), 7,22 (DD, J=8,8, at 5.3 Hz, 2H), 7,05 (DD, J=9,0, 2.4 Hz, 1H), 6,98 (t, J=8,8 Hz, 2H), 4.09 to (d, J=2.0 Hz, 2H), was 4.02 (t, J=6.2 Hz, 2H), and 3.72 (t, J=8,2 Hz, 2H), 3,50 (t, J=8,2 Hz, 2H), 3,23-to 3.35 (m, 1H), 2,81 (t, J=7,3 Hz, 2H), 2,01-of 2.15 (m, 2H).

Example 7-8: 1-[(6-{[(2S)-3-(2,4-differenl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthaleneacetic]-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 80:20:4).

[α]D25: +30,6° (0,10; chloroform-ethanol, 1:1).

1H-NMR (CDCl3+CD3OD): δ 7,26 (d, J=8,50 Hz, 1H), 7,09-to 7.18 (m, 1H), 6.75 in-6,83 (m, 2H), 6.73 x (DD, J=8,50, 2,50 Hz, 1H), of 6.68 (d, J=2,50 Hz, 1H), or 4.31 (DD, J=10,00, 5,00 Hz, 2H), 4.00 points (t, J=10.00 Hz, 2H), 3,94 (s, 2H), 3,80 (d, J=6,00 Hz, 2H), 3,20-of 3.32 (m, 1H), 2,85 (DD, J=14,00, 6,50 Hz, 1H), 2,69-2,77 (m, 2H), 2,58 (DD, J=14,00, 7,50 Hz, 1H), measuring 2.20 to 2.35 (m, 3H), of 2.18 (s, 3H), of 1.02 (d, J=6,50 Hz, 3H).

Example 7-9: 1-[(6-{[(2S)-3-(4-chloro-2-forfinal)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 80:20:4).

[α]D25: +64,1° (0,10; chloroform-ethanol, 1:1).

1H-NMR (CDCl3+CD3OD): δ 7,26 (d, J=8,50 Hz, 1H), 7.03 is-to 7.15 (m, 3H), 6,72 (DD, J=8,50, 2,50 Hz, 1H), to 6.67 (d, J=2,50 Hz, 1H), 4,25 is 4.35 (m, 2H), 3,99 (t, J=10.00 Hz, 2H), 3,93 (s, 2H), 3,80 (d, J=6,00 Hz, 2H), 3,22-of 3.32 (m, 1H), of 2.86 (DD, J=14,00, 6,50 Hz, 1H), 2,69-2,77 (m, 2H), 2,59 (DD, J=14,00, 7,50 Hz, 1H), 2.21 are a 2.36 (m, 3H), of 2.18 (s, 3H), of 1.03 (d, J=6,50 Hz, 3H).

Example 7-10: 1-[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

Melting point: of 148.6-148,9°C.

[α]D25: +43,2° (0,50, ethanol).

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,31 (d, J=8.6 Hz, 1H), 7,24 (d, J=8.6 Hz, 2H) 7.15m (d, J=8.6 Hz, 2H), 6,66-of 6.78 (m, 2H), 4,12-to 4.28 (m, 4H), 4,10 (s, 2H), 3,78 (d, J=5,9 Hz, 2H), 3.33 and-a 3.50 (m, 1H), 2,84 (DD, J=a 13.5, 6.5 Hz, 1H), 2,65-2,77 (m, 2H), by 2.55 (DD, J=13,5, and 7.8 Hz, 1H), 2,12-2,31 (m, 6H), to 1.00 (d, J=6.8 Hz, 3H).

Example 8: 1-({6-[3-(4-chlorophenyl)propoxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

Azetidin-3-carboxylic acid (46 mg) and sodium hydroxide (18 mg) was dissolved in methanol (4 ml). To the resulting solution was sequentially added trimethoxymethane (0,050 ml) and a mixed solution of 6-[3-(4-chlorophenyl)propoxy]-3,4-dihydronaphthalene-2-carbaldehyde (100 mg) in tetrahydrofuran (1 ml) and methanol (1 ml) under cooling with ice. The reaction mixture was stirred for 3.5 hours under ice cooling. To the reaction mixture was added sodium borohydride (17 mg) under ice cooling. The reaction mixture was stirred under ice cooling for 20 minutes. Then to the reaction mixture was added 4 mol/l solution of hydrochloride/ethyl acetate to achieve a neutral value, and concentrated. The resulting residue was purified flash chromatography on a column of silica gel (chloroform:methanol:aqueous ammonia = 80:10:1 to 80:20:4), while receiving specified in the title compound (79 mg)having the following physical properties.

TLC: Rf 0.21 in (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ of 7.25 (d, J=8,50 Hz, 2H), 7,19 (d, J=8,50 Hz, 2H) 7,02 (d, J=9,00 Hz, 1H), 6,68-6,72 (m, 2H), 6,60 (s, 1H), 4,11-of 4.25 (m, 4H), of 3.94 (t, J=6,00 Hz, 2H), with 3.89 (s, 2H), 3,35-of 3.48 (m, 1H), 2,73-of 2.86 (m, 4H), 2,22-of 2.30 (m, 2H), 1,98 is 2.10 (m, 2H).

Examples 8-1 - 8-5

Did the method according to example 8, using the appropriate aldehyde instead of 6-[3-(4-chlorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde. If necessary, the reaction product was converted to the corresponding salt, while receiving specified in the headers of the compounds having the following physical properties.

Example 8-1: 1-({6-[4-(4-chlorophenyl)butoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

(free form)

TLC: Rf of 0.29 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,30 (d, J=8,50 Hz, 1H), 7,24 (d, J=8,50 Hz, 2H), 7,17 (d, J=8,50 Hz, 2H), 6,74 (DD, J=8,50, 2,50 Hz, 1H), 6,70 (d, J=2,50 Hz, 1H), 4.09 to 4,22 (m, 4H), 4,06 (s, 2H), 3.95 to as 4.02 (m, 2H), 3,34 is-3.45 (m, 1H), 2,63 was 2.76 (m, 4H), 2,18-of 2.28 (m, 5H), 1,74-of 1.81 (m, 4H).

(hydrochloride)

TLC: Rf of 0.29 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ to 7.32 (d, J=8,50 Hz, 1H), 7,25 (d, J=8,50 Hz, 2H), 7,18 (d, J=8,50 Hz, 2H), 6.75 in (DD, J=8,50, 2,50 Hz, 1H), of 6.71 (d, J=2,50 Hz, 1H), 4,19 is 4.45 (m, 4H), to 4.16 (s, 2H), 3.95 to as 4.02 (m, 2H), 3,64-of 3.78 (m, 1H), 2,62 was 2.76 (m, 4H), 2,19-of 2.28 (m, 5H), 1,74-of 1.81 (m, 4H).

Example 8-2: hydrochloride 1-({6-[3-(4-chlorophenyl)-2,2-DIMETHYLPROPANE]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.16 (1-butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ 7,3 (d, J=8,42 Hz, 1H), 7,16-7,22 (m, 2H), 7,07-7,11 (m, 2H), 6,74-PC 6.82 (m, 2H), 4,19-of 4.49 (m, 4H), 4,17 (s, 2H), 3,63-with 3.79 (m, 1H), 3,53 (s, 2H), 2,71 (s, 2H), 2,68-and 2.79 (m, 2H), of 2.23 (s, 3H), 2,18-2,31 (m, 2H), 1,01 (s, 6H).

Example 8-3: hydrochloride 1-[(6-{[1-(4-chlorbenzyl)cyclopropyl]methoxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf 0.14 (1-butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ 7,31 (d, J=at 8.60 Hz, 1H), 7,14-7,24 (m, 4H), of 6.71 (DD, J=8,60, is 2.40 Hz, 1H), to 6.67 (d, J=2,40 Hz, 1H), 4,18-4,43 (m, 4H), to 4.16 (s, 2H), 3,66-of 3.78 (m, 1H), 3,61 (s, 2H), 2,78 (s, 2H), 2,67 was 2.76 (m, 2H), 2,21 (s, 3H), 2,17-of 2.30 (m, 2H), by 0.54 to 0.69 (m, 4H).

Example 8.4: the hydrochloride of 1-[(6-{[(2E)-3-(4-chlorophenyl)-2-propenyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf to 0.17 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,41 (d, J=8,50 Hz, 2H), 7,35 (d, J=8,50 Hz, 1H), 7,31 (d, J=8,50 Hz, 2H), at 6.84 (DD, J=8,50, 2,50 Hz, 1H), 6,80 (d, J=2,50 Hz, 1H), 6,72 (dt, J=16,00, 1.50 Hz, 1H), 6,46 (dt, J=16,00, 5.50 Hz, 1H), 4,71 (DD, J=5,50, 1.50 Hz, 2H), 4,18-4,47 (m, 4H), to 4.16 (s, 2H), 3,65-of 3.78 (m, 1H), 2,72-2,78 (m, 2H), 2.21 are to 2.29 (m, 5H).

Example 8-5: hydrochloride 1-({6-[4-(4-forfinal)butoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.23 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,31 (d, J=8,50 Hz, 1H), 7,19 (DD, J=8,50, 5.50 Hz, 2H), of 6.96 (t, J=8,50 Hz, 2H), 6.75 in (DD, J=8,50, 2,50 Hz, 1H), of 6.71 (d, J=2,50 Hz, 1H), 4,20 is 4.45 (m, 4H), to 4.15 (s, 2H), 3.95 to as 4.02 (m, 2H), 3,63-of 3.78 (m, 1H), 2,62-2,77 (m, 4H), 2,18-of 2.30 (m, 5H), 1,72-to 1.82 (m, 4H).

Example 9: tert-is util-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylic

Using tert-butyl 4-oxopiperidine-1-carboxylate, 1,1,1-Cryptor-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolan, performed the same way as described in Tetrahedron Letters, 2000, 41, 3705-3708, resulting mentioned in the title compound having the following physical properties.

TLC: Rf to 0.63 (hexane:ethyl acetate = 3:1).

1H-NMR (CDCl3): δ 6,25-6,70 (m, 1H), 3,86-was 4.02 (m, 2H), 3,44 (t, J=5,58 Hz, 2H), 2,12-of 2.34 (m, 2H), 1,42-1,49 (m, 9H), 1.26 in (s, 12H).

Example 10: tert-butyl 4-[2-methyl-4-(3-phenylpropoxy)phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic

To a solution of 1-bromo-2-methyl-4-(3-phenylpropoxy)benzene (641 mg) in anhydrous N,N-dimethylformamide (10 ml) was sequentially added compound (620 mg)obtained in example 9, potassium carbonate (829 mg) and dichloro[(diphenylphosphino)ferrocene]palladium(II) (88 mg). The reaction mixture was stirred at 80°C for 3 hours. To the reaction mixture were added saturated aqueous solution of ammonium chloride (20 ml) and tert-butyl methyl ether (30 ml). The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified flash chromatography on a column (hexane:ethyl acetate = 20:1 to 1:1), while receiving specified in the title compound (180 mg)having the following physical properties.

TLC: Rf 050 (hexane:ethyl acetate = 5:1).

1H-NMR (CDCl3): δ 7.24 to 7,38 (m, 2H), 7,15-7,25 (m, 3H), 6,98 (d, J=8,23 Hz, 1H), 6,72 (d, J=2,56 Hz, 1H), of 6.68 (DD, J=8,23, of 2.56 Hz, 1H), 5,41-the ceiling of 5.60 (m, 1H), 3,98-4,06 (m, 2H), 3,95 (t, J=of 6.31 Hz, 2H), 3,60 (t, J=5,67 Hz, 2H), 2,74-2,87 (m, 2H), 2,27-2,39 (m, 2H, in), 2.25 (s, 3H), 2,02-2,17 (m, 2H), 1,50 (s, 9H).

Example 11: 4-[2-methyl-4-(3-phenylpropoxy)phenyl]-1,2,3,6-tetrahydropyrimidine

To a solution of compound (180 mg)obtained in example 10, in methylene chloride (0.5 ml) was added 4 mol/ml solution of the hydrochloride/1,4-dioxane (2.0 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated. To the resulting residue was added diisopropyl ether, and dried, thus obtaining specified in the title compound (140 mg)having the following physical properties.

TLC: Rf 0.28 in (chloroform:methanol:aqueous ammonia= 8:1:0,1).

1H-NMR (CD3OD): δ 7,08-to 7.32 (m, 5H), 7,00 (d, J=8,23 Hz, 1H), 6,74 (d, J=2.20 Hz, 1H), 6,70 (DD, J=8,23, 2.20 Hz, 1H), 5,54-5,62 (m, 1H), 3,93 (t, J=of 6.31 Hz, 2H), 3.72 points-a-3.84 (m, 2H), 3,34-to 3.49 (m, 2H), 2,73-and 2.83 (m, 2H), 2,46-of 2.64 (m, 2H), and 2.27 (s, 3H), 1,96 and 2.13 (m, 2H).

Example 12: tert-butyl 3-[4-[2-methyl-4-(3-phenylpropoxy)phenyl]-3,6-dihydro-1(2H)-pyridinyl]propanoate

To a solution of the compound (100 mg)obtained in example 11, in methanol (2 ml), was added tert-butyl acrylate (0,13 ml) and N,N-diisopropylethylamine (0,105 ml) at room temperature. The reaction mixture was stirred at room temperature is round for 20 hours. The mixture was concentrated. The resulting residue was purified flash chromatography on a column (hexane:ethyl acetate:triethylamine = 20:1:0 to 67:33:1), while receiving specified in the title compound (116 mg)having the following physical properties.

TLC: Rf 0,78 (hexane:ethyl acetate:triethylamine= 1:1:0,5).

1H-NMR (CDCl3): δ 7.24 to 7,34 (m, 2H), 7,13-7,24 (m, 3H), 7,00 (d, J=8,23 Hz, 1H), 6,69-of 6.73 (m, 1H), 6,63-6,69 (m, 1H), 5,44 is 5.54 (m, 1H), 3,94 (t, J=of 6.31 Hz, 2H), is 3.08-3,17 (m, 2H), 2,74-to 2.85 (m, 4H), 2,69 (t, J=5,58 Hz, 2H,), of 2.50 (t, J=7,50 Hz, 2H), 2,29-to 2.41 (m, 2H), and 2.26 (s, 3H), 2,04-of 2.15 (m, 2H), of 1.46 (s, 9H).

Example 13: triptorelin 3-[4-[2-methyl-4-(3-phenylpropoxy)phenyl]-3,6-dihydro-1(2H)-pyridinyl]propanoic acid

Triperoxonane acid (1.0 ml) was added to a solution of the compound (116 mg)obtained in example 12 in methylene chloride (0.5 ml) at room temperature. The reaction solution was stirred at room temperature for 2 hours. The mixture was concentrated. The resulting residue was dissolved in a solution of a mixture of water and acetonitrile. The solution was dried by freezing, while receiving specified in the title compound (100 mg)having the following physical properties.

TLC: Rf of 0.44 (chloroform:methanol:aqueous ammonia= 8:2:0,4).

1H-NMR (d6-DMSO): δ 7,11 and 7.36 (m, 5H), 7,01 (d, J=8,23 Hz, 1H), 6.75 in-is 6.78 (m, 1H), 6,70 to 6.75 (m, 1H), 5,48-to 5.56 (m, 1H), 3,98 (t, J=of 6.31 Hz, 2H), 3,81-3,90 (m, 2H), 3,40-to 3.52 (m, 4H), 2,82 (t, J=to 7.32 Hz,2H), 2,71-2,78 (m, 2H), 2,52-2,63 (m, 2H, in), 2.25 (s, 3H), 1,95-2,11 (m, 2H).

Examples 13-1 - 13-4

Did the method according to the examples 12-13, using a corresponding amine compound instead of the compound obtained in example 11. Thus were obtained the compounds having the following physical properties.

Example 13-1: triptorelin 3-[4-[3-(3-phenylpropoxy)phenyl]-3,6-dihydro-1(2H)-pyridinyl]propanoic acid

TLC: Rf of 0.44 (chloroform:methanol:aqueous ammonia= 8:2:0,4).

1H-NMR (d6-DMSO): δ 7,11-7,35 (m, 6H), 7,00-was 7.08 (m, 1H), 6,95-6,99 (m, 1H), 6,83-6,93 (m, 1H), 6,07-of 6.17 (m, 1H), a 4.03 (t, J=6,40 Hz, 2H), 3,84-3,95 (m, 2H), 3,36-of 3.53 (m, 4H), 2,69-2,87 (m, 6H), 1,98 and 2.13 (m, 2H).

Example 13-2: bestrefiratecom 3-[6-(3-phenylpropoxy)-3',6'-dihydro-3',4'-bipyridine-1'(2'H)-yl]propanoic acid

TLC: Rf of 0.44 (chloroform:methanol:aqueous ammonia= 8:2:0,4).

1H-NMR (d6-DMSO): δ 8,24 (d, J=2,56 Hz, 1H), 7,80 (DD, J=8,69, of 2.56 Hz, 1H), 7,11-7,34 (m, 5H), to 6.80 (d, J=8,69 Hz, 1H), 6,04-x 6.15 (m, 1H), or 4.31 (t, J=6,59 Hz, 2H), a 3.87-3,98 (m, 2H), 3,47-of 3.54 (m, 2H), 3,44 (t, J=7,32 Hz, 2H), 2,61-is 2.88 (m, 6H), 1,98 and 2.13 (m, 2H).

Example 13-3: bestrefiratecom 3-[4-[1-(4-phenylbutyl)-1H-pyrazole-4-yl]-3,6-dihydro-1(2H)-pyridinyl]propanoic acid

TLC: Rf of 0.44 (chloroform:methanol:aqueous ammonia= 8:2:0,4).

1H-NMR (d6-DMSO): δ 7,79 (s, 1H), to 7.59 (s, 1H), 7,20-to 7.32 (m, 2H), 7,08-7,20 (m, 3H), of 5.83-5,94 (m, 1H), 4,10 (t, J=6,86 Hz, 2H), 3,78-to 3.89 (m, 2H), 3,36-of 3.54 (m, 4H), and 2.79 (t, J=to 7.32 Hz, 2H), 2,54-2,70 (m, 4H), 1,72-1,89 (m, 2H), 1,50-of 1.66 (m, 2H).

Example 13-4: Proc. of the fluoroacetate 3-[6-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-3,4-dihydro-2(1H)-ethenolysis]propanoic acid

TLC: Rf to 0.19 (chloroform:methanol:aqueous ammonia= 8:2:0,4).

1H-NMR (CD3OD): δ to 8.12 (d, J=8,23 Hz, 2H), 8,00-8,10 (m, 2H), 7,35 is 7.50 (m, 3H), 4,58 (s, 2H), 3,65-of 3.77 (m, 2H), 3,60 (t, J=6,86 Hz, 2H), 3,29-3,39 (m, 2H), equal to 2.94 (t, J=6,86 Hz, 2H), 2,61 (d, J=6,95 Hz, 2H), 1,84-to 2.06 (m, 1H), 0,95 (d, J=6,59 Hz, 6H).

Example 14: 7-(benzyloxy)-2,3,4,9-tetrahydro-1H-β-carbolin

37% Aqueous formalin solution (of 0.18 ml) was added to a mixed solution of {2-[6-(benzyloxy-1H-indol-3-yl]ethyl}amine (520 mg) in methanol-tetrahydrofuran (1:1, 10 ml) under cooling with ice. The reaction solution was stirred for 2 hours and added phosphate buffer (pH 6.8) (1.0 ml). Then the reaction solution was stirred for 16 hours. The reaction mixture was filtered, washed with a solution of a mixture of water and methanol, thus obtaining specified in the title compound (300 mg)with the following properties.

TLC: Rf of 0.64 (chloroform:methanol:aqueous ammonia= 8:2:0,4).

1H-NMR (d6-DMSO): δ 10,48 (s, 1H), 7,42-7,52 (m, 2H), 7,33-7,41 (m, 2H), 7,26-7,34 (m, 1H), 7,22 (d, J=8,42 Hz, 1H), 6,86 (d, J=2.38 Hz, 1H), to 6.67 (DD, J=8,42, 2.38 Hz, 1H), to 5.08 (s, 2H), 3,66 (s, 2H), 3.33 and is 3.40 (m, 1H), 2,79-of 2.93 (m, 2H), 2.57 m)-2,70 (m, 2H).

Example 15: tert-butyl 7-(benzyloxy)-2-(3-tert-butoxy-3-oxopropyl)-1,2,3,4-tetrahydro-N-β-carbolin-9-carboxylate

Did the method according to example 12, using the compound obtained in example 14, instead of the compound obtained in example 11. The compound obtained was protected using dicret-BUTYLCARBAMATE, while receiving specified in the title compound having the following physical properties.

TLC: Rf of 0.45 (hexane:ethyl acetate = 3:1).

1H-NMR (CDCl3): δ 7,80-7,86 (m, 1H), 7,43-to 7.50 (m, 2H), 7,30-7,42 (m, 3H), 7,27 (d, J=8,42 Hz, 1H), 6,93 (DD, J=8,42, 2.38 Hz, 1H), 5,12 (s, 2H), 3,92 (s, 2H), 2,93 (t, J=7,50 Hz, 2H), 2,79-2,87 (m, 2H), 2,64-to 2.74 (m, 2H), of 2.54 (t, J=7,50 Hz, 2H), 1,65 (s, 9H), 1,45 (s, 9H).

Example 16: tert-butyl 2-(3-tert-butoxy-3-oxopropyl)-7-hydroxy-1,2,3,4-tetrahydro-N-β-carbolin-9-carboxylate

The catalyst ASCA-II (4,5% palladium and 0.5% platinum on coal) (140 mg) was added to a mixed solution of the compound (290 mg)obtained in example 15, in methanol-ethyl acetate (4:1, 5 ml) at room temperature in an atmosphere of gaseous argon. The reaction mixture was stirred in an atmosphere of hydrogen gas for 3 hours. Above the atmosphere was replaced by a gaseous atmosphere of argon. The mixture was filtered through celite (trade name) and the filtrate was concentrated. The resulting residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate = 1:1), while receiving specified in the title compound (203 mg)having the following physical properties.

TLC: Rf is 0.24 (hexane:ethyl acetate = 3:1).

1H-NMR (CDCl3): δ 7,54-to 7.68 (m, 1H), 7,20 (d, J=8,42 Hz, 1H), 6,76 (DD, J=8,42, to 2.29 Hz, 1H), 4,54 and 5.36 (m, 1H), 3,90 (s, 2H), 2,87-3,03 (m, 2H), 2.77-to is 2.88 (m, 2H), 2,60-2,77 (m, 2H), 2,45-of 2.58 (m, 2H), of 1.66 (s, 9H), 1,45 (, 9H).

Example 17: tert-butyl-2(3-tert-butoxy-3-oxopropyl)-7-(3-phenylpropoxy)-1,2,3,4-tetrahydro-N-β-carbolin-9-carboxylate

To a solution of compound (112 mg)obtained in example 16, in anhydrous tetrahydrofuran (2.0 ml), was added 3-phenylpropane-1-ol (0,074 ml), 1,1'-azobis(N,N'-dimethylformamide) (93 mg) and triphenylphosphine (141 mg) in an atmosphere of gaseous argon. The reaction solution was stirred at room temperature for 48 hours. To the reaction solution was added tert-butyl methyl ether (3 ml), the resulting insoluble matter was filtered, and the filtrate was concentrated. The resulting residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate = 5:1), while receiving specified in the title compound (84 mg)having the following physical properties.

TLC: Rf 0,71 (hexane:ethyl acetate = 1:1).

1H-NMR (CDCl3): δ 7,66-7,76 (m, 1H), 7,15-7,35 (m, 6H), 6,86 (DD, J=8,42, 2.20 Hz, 1H), was 4.02 (t, J=of 6.31 Hz, 2H), 3,91 (s, 2H), 2,93 (t, J=7,50 Hz, 2H), 2,78-2,89 (m, 4H), 2,64 is 2.75 (m, 2H), 2,54 (t, J=7,50 Hz, 2H), 2.05 is-2,20 (m, 2H), 1,65 (s, 9H), 1,45 (s, 9H).

Example 18: triptorelin 3-[7-(3-phenylpropoxy)-1,3,4,9-tetrahydro-2H-β-carbolin-2-yl]propanoic acid

Did the method according to example 13, using the compound obtained in example 17, instead of the compound obtained in example 12. Thus were obtained the compounds having the following physical properties.

TLC: Rf 0,12 (chloroform:methanol:aqueous ammonia= 8:2:0,4).

1H-NMR (CDsub> 3OD): δ 7,34 (d, J=at 8.60 Hz, 1H), 7,07-7,29 (m, 5H), 6,86 (d, J=2.20 Hz, 1H), 6,74 (DD, J=8,60, 2.20 Hz, 1H), 4.53-in (s, 2H), 3,97 (t, J=6.22 per Hz, 2H), 3,67-of 3.78 (m, 2H), 3,63 (t, J=6,95 Hz, 2H), 3,03-3,19 (m, 2H), to 2.94 (t, J=6,95 Hz, 2H), 2,75-2,87 (m, 2H), 2.00 in of 2.16 (m, 2H).

Example 18-1: 3-{7-[3-(4-chlorophenyl)propoxy]-1,3,4,9-tetrahydro-2H-β-carbolin-2-yl}propanoic acid

Did the method according to examples 17 and 18, using 3-(4-chlorophenyl)propan-1-ol instead of 3-phenylpropane-1-ol. If necessary, the reaction products were transformed into the hydrochloride, thus obtaining specified in the title compound having the following physical properties.

(triptorelin)

TAH: Rf 0,11 (chloroform:methanol:aqueous ammonia= 8:2:0,4).

1H-NMR (CD3OD): δ to 7.35 (d, J=at 8.60 Hz, 1H), 7,25 (d, J=8,79 Hz, 2H), 7,19 (d, J=8,79 Hz, 2H), 6,85 (d, J=a 2.01 Hz, 1H), 6,74 (DD, J=8,60, a 2.01 Hz, 1H), 4.53-in (s, 2H), 3.96 points (t, J=6,13 Hz, 2H), 3,67-of 3.80 (m, 2H), 3,63 (t, J=of 6.95 Hz, 2H), 3,02-and 3.16 (m, 2H), equal to 2.94 (t, J=6,95 Hz, 2H), 2,74-of 2.86 (m, 2H), 1,98-2,19 (m, 2H).

(hydrochloride)

TLC: Rf 0,11 (chloroform:methanol:aqueous ammonia= 8:2:0,4).

1H-NMR (CD3OD): δ 7,34 (d, J=8,78 Hz, 1H), 7,25 (d, J=8,78 Hz, 2H), 7,19 (d, J=8,78 Hz, 2H), 6,85 (d, J=2.20 Hz, 1H), 6.73 x (DD, J=8,78, 2.20 Hz, 1H), 4,40 with 4.65 (m, 2H), 3.96 points (t, J=6,13 Hz, 2H), 3,57-of 3.78 (m, 4H), 3,05-3,16 (m, 2H), equal to 2.94 (t, J=? 7.04 baby mortality Hz, 2H), 2,75-of 2.86 (m, 2H), 1,97-2,17 (m, 2H).

Example 19: 3-[6-(3-phenylpropoxy)-1,3,4,9-tetrahydro-2H-β-carbolin-2-yl]propanoic acid

Did the method according to examples 14, 12, and 13, using {2-[5-(3-phenylpropoxy)-1H-indol-3-yl]et the l}amine instead of {2-[6-(benzyloxy)-1H-indol-3-yl]ethyl}amine. The reaction product was purified by chromatography on silica gel, thus obtaining specified in the title compound having the following physical properties.

TLC: Rf of 0.16 (chloroform:methanol:aqueous ammonia= 8:2:0,4).

1H-NMR (CD3OD): δ 6,99-7,28 (m, 6H), 6,83 (d, J=to 2.29 Hz, 1H), 6,72 (DD, J=8,69, to 2.29 Hz, 1H), 4,33 (s, 2H), 3,88 (t, J=6,04 Hz, 2H), 3,51 (t, J=6,04 Hz, 2H), 3,36 (t, J=6,77 Hz, 2H), 2.95 points (t, J=6,04 Hz, 2H), 2,67-2,77 (m, 2H), 2.57 m (t, J=6,77 Hz, 2H), 1,90 e 2.06 (m, 2H).

Example 20: N'-hydroxy-4-(hydroxymethyl)benzoquinoneimine

A solution of hydroxylamine hydrochloride (5.2 g), 4-(hydroxymethyl)benzonitrile (5.0 g) and sodium bicarbonate (12,6 g) in methanol (50 ml) was heated under reflux for 20 hours. The reaction solution was cooled at room temperature and filtered through celite (trade name). The filtrate was concentrated, thus obtaining specified in the title compound having the following physical properties. The compound obtained was used in the next reaction without further purification.

TLC: Rf 0.21 in (chloroform:methanol:aqueous ammonia= 8:1:0,1).

1H-NMR (CDCl3): δ to 7.61 (d, J=8,10 Hz, 2H), 7,37 (d, J=8,10 Hz, 2H), br4.61 (s, 2H).

Example 21: {4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]phenyl}-methanol

The compound obtained in example 20 was dissolved in N,N-dimethylformamide (60 ml). To the resulting solution were added 4-isobutylbenzene the th acid (6.7 g), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (7,28 g) and the monohydrate of 1-hydroxybenzotriazole (5,1 g) at room temperature. The reaction solution was stirred at room temperature for 30 minutes and then stirred at 140°C for 2 hours. To the reaction mixture were added water (50 ml) and was extracted with a solution of a mixture of ethyl acetate and hexane (10:1). The extract was sequentially washed with 0.5 mol/l hydrochloric acid, saturated sodium hydrogen carbonate solution and water. The reaction product was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by chromatography on a column of silica gel (hexane - hexane: ethyl acetate = 1:1), while receiving specified in the header connection (4,14 g)having the following physical properties.

TLC: Rf of 0.54 (hexane:ethyl acetate = 1:1).

1H-NMR (CD3OD): δ 8,13 (d, J=at 8.60 Hz, 2H), 8,11 (d, J=8,42 Hz, 2H), 7,53 (d, J=at 8.60 Hz, 2H), 7,41 (d, J=8,42 Hz, 2H), 4,69 (s, 2H), 2,61 (d, J=7,14 Hz, 2H), 1,86-2,04 (m, 1H), 0,94 (d, J=6,59 Hz, 6H).

Example 22: 4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzaldehyde

Dimethyl sulfoxide (2,13 ml) was added to a solution of oxalicacid (1,74 ml) in methylene chloride (40 ml) at -78°C in an atmosphere of gaseous argon. The reaction mixture was stirred at -78°C for 10 minutes and was added the compound (2.14 g)obtained in example 21, and N,N-diisopropylethylamine (14,6 ml) at -78°C. actionnow the mixture was stirred at room temperature for 3 hours. The mixture was concentrated and the resulting residue was diluted with ethyl acetate. The resulting solution was sequentially washed with 0.5 mol/l solution of potassium hydrosulfate, 1 mol/l hydrochloric acid, saturated sodium hydrogen carbonate solution and water. The reaction product was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate = 5:1), while receiving specified in the title compound (1.4 g)having the following physical properties.

TLC: Rf and 0.61 (hexane:ethyl acetate = 3:1).

1H-NMR (CDCl3): δ 10,11 (s, 1H), at 8.36 (d, J=8,23 Hz, 2H), 8,13 (d, J=8,42 Hz, 2H), 8,03 (d, J=8,42 Hz, 2H), 7,34 (d, J=8,23 Hz, 2H), 2,59 (d, J=to 7.32 Hz, 2H), 1,82-2,07 (m, 1H), 0,94 (d, J=6,59 Hz, 6H).

Example 23: 2-({4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}amino)ethanol

To a solution (1.0 ml) of the compound (100 mg)obtained in example 22, in 1,2-dichloroethane containing 5% acetic acid, was added 2-aminoethanol (0,030 ml) and triacetoxyborohydride sodium (138 mg). The reaction mixture was stirred for 18 hours. The mixture was concentrated. The resulting residue was diluted with ethyl acetate and sequentially washed with a saturated solution of sodium bicarbonate and water. The reaction product was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified of HRO what ecografia on a column of silica gel (chloroform:methanol:aqueous ammonia = 160:10:1), while receiving specified in the title compound (75 mg)having the following physical properties.

TLC: Rf of 0.48 (chloroform:methanol:aqueous ammonia= 8:1:0,1).

1H-NMR (CD3OD): δ 8,12-8,16 (m, 4H), 7,58 (d, J=8,23 Hz, 2H), 7,41 (d, J=8,23 Hz, 2H), was 4.02 (s, 2H), of 3.73 (t, J=5.50 Hz, 2H), 2,88 (t, J=5.50 Hz, 2H), 2,60 (d, J=to 7.32 Hz, 2H), 1.91 a-2,04 (m, 1H), 0,94 (d, J=6,59 Hz, 6H).

Example 24: tert-butyl 3-(3-oxo-1-piperidinyl)propanoate

Did the method according to the examples 12-22 using piperidine-3-ol instead of the compound obtained in example 11. Thus were obtained the compounds having the following physical properties.

TLC: Rf 0,71 (chloroform:methanol:aqueous ammonia= 8:1:0,1).

1H-NMR (CDCl3): δ to 3.02 (s, 2H), by 2.73 (t, J=7,14 Hz, 2H), 2,64-2,70 (m, 2H), 2.40 a (t, J=7,14 Hz, 2H), 2,35 (t, J=6,77 Hz, 2H), 1,87 is 2.01 (m, 2H), of 1.44 (s, 9H).

Example 25: tert-butyl 3-{3-[4-(3-phenylpropoxy)benzylidene]-1-piperidinyl}propionate (a mixture of E - and Z-isomers)

Sodium hydride (60% dispersion in oil, 800 mg) was added at room temperature to dimethylsulfoxide (20 ml) in an atmosphere of gaseous argon. The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled at room temperature. Out of all the obtained solution of 1.3 ml) was added at room temperature to a solution of bromide salt of triphenyl[4-(4-phenylbutyl)benzyl]phosphonium (830 mg) in dimethyl sulfoxide (2.0 ml). The reaction mixture plumage is shivali at room temperature for 30 minutes, and the solution was added the compound (830 mg)obtained in example 24, in dimethyl sulfoxide (2.0 ml). The reaction mixture was stirred at 50°C for 18 hours. To the mixture was added water (10 ml) and was extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate = 3:1), while receiving specified in the title compound (112 mg)having the following physical properties.

TLC: Rf of 0.44 (hexane:ethyl acetate = 1:1).

1H-NMR (CDCl3): δ 7,16-to 7.35 (m, 5H),? 7.04 baby mortality-7,16 (m, 2H), at 6.84 (d, J=7.87 in Hz, 2H), 6,24-6,34 (m, 1H), 3,89-a 4.03 (m, 2H), 2,98-is 3.21 (m, 2H), was 2.76-2,89 (m, 2H), 2,60-of 2.75 (m, 2H), of 2.51-2,62 (m, 2H), 2,44-2,52 (m, 1H), 2,31-2,44 (m, 2H), 2,20-2,31 (m, 1H), 2,03-of 2.16 (m, 2H), 1,66-to 1.82 (m, 1H), 1,51-to 1.67 (m, 1H), 1,36-1,49 (m, 9H).

Examples 26-1 - 26-16

Did the method according to example 6, using the corresponding aldehydes instead of the compound obtained in example 5. Thus were obtained the compounds having the following physical properties.

Example 26-1: methyl-1-[(6-{[(2E)-3-(4-forfinal)-2-methylpropan-2-enyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylate

TLC: Rf of 0.27 (hexane:ethyl acetate = 1:3).

1H-NMR (CDCl3): δ 7,17-7,30 (m, 3H), 6,98-7,07 (m, 2H), 6,74-PC 6.82 (m, 2H), return of 6.58 (s, 1H), 4,55 (s, 2H), 3,71 (s, 3H), 3,50-3,61 (m, 2H), 3.25 to to 3.41 (m, 5H), 2,64-to 2.74 (m, 2H), 2,22 of-2.32 (m, 2H), 2,09 (s, 3H), of 1.94 (d, J=1,46 Hz, 3H).

b> Example 26-2: methyl-1-[(6-{[(2S)-2-(4-terbisil)butyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylate

TLC: Rf of 0.34 (chloroform:methanol = 9:1).

1H-NMR (CDCl3): δ 7,20 (d, J=8,42 Hz, 1H), 7,06-7,16 (m, 2H), 6,86-7,01 (m, 2H), 6,51-6,77 (m, 2H), 3,88-of 4.05 (m, 2H), 3,78 (d, J=4,94 Hz, 2H), 3,74 (s, 3H), 3,52-3,62 (m, 5H), 2,64 is 2.80 (m, 4H), 2.26 and-a 2.36 (m, 2H), 2,13 (, 3H), 1,89 is 2.01 (m, 1H), 1,39-of 1.56 (m, 2H), 0,97 (t, J=7,20 Hz, 3H).

Example 26-3: methyl-1-[(6-{[(2R)-2-(4-terbisil)-3-methylbutyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylate

TLC: Rf of 0.34 (chloroform:methanol = 9:1).

1H-NMR (CDCl3): δ 7,07-7,21 (m, 3H), 6,80-7,02 (m, 2H), of 6.49-6,72 (m, 2H), 3,80 (d, J=5,12 Hz, 2H), 3,71 (s, 3H), to 3.58-3,68 (m, 2H), 3,22-to 3.49 (m, 5H), 2.57 m-and 2.83 (m, 4H), 2,18-of 2.34 (m, 2H), 2,08 (s, 3H), 1,79 of 1.99 (m, 2H), 0,97-1,03 (m, 6H).

Example 26-4: 1-chloro-6-{[(2S)-3-(4-forfinal)-2-methylpropyl]oxy}-3,4-dihydronaphthalene-2-carbaldehyde

TLC: Rf of 0.60 (hexane:ethyl acetate = 10:1)

1H-NMR (CDCl3): δ 10,33 (s, 1H), 7,79 (d, J=8,78 Hz, 1H), 7,06-7,17 (m, 2H), 6.89 in? 7.04 baby mortality (m, 2H), 6,80 (DD, J=8,78, of 2.56 Hz, 1H), 6,72 (d, J=2,56 Hz, 1H), 3,81 (d, J=5,85 Hz, 2H), 2,75-2,89 (m, 3H), 2,47 of 2.68 (m, 3H), 2,10-2,32 (m, 1H), of 1.03 (d, J=6,77 Hz, 3H).

Example 26-5: methyl-1-[(6-{[(2S)-3-(4-forfinal)-2-methylpropyl]oxy}-4,4-dimethyl-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylate

TLC: Rf of 0.45 (chloroform:methanol = 20:1).

1H-NMR (CDCl3): δ 7,08-to 7.18 (m, 2H), 6.89 in-7,02 (m, 3H), 6,83 (d, J=2.2 Hz, 1H), 6,62 (DD, J=8,2, 2.2 Hz, 1H), 6,28 (s, 1H), 3,76 (d, J=5,9 Hz, 2H), 3,71, 2H), of 3.56 (t, J=6.2 Hz, 2H), 3,23-of 3.43 (m, 3H), of 3.13 (s, 2H), 2,86 (DD, J=13,4, 6.0 Hz, 1H), 2,52 (DD, J=13,4, 7.7 Hz, 1H), 2,07-of 2.26 (m, 4H), 1,22 (s, 6H), and 1.00 (d, J=6.8 Hz, 3H).

Example 26-6: methyl-1-({6-[3-(4-forfinal)propoxy]-1-benzothieno-2-yl}methyl)azetidin-3-carboxylate

TLC: Rf of 0.45 (chloroform:methanol = 20:1).

1H-NMR (CDCl3): δ 7,56 (d, J=8,8 Hz, 1H), 7.23 percent (d, J=2.4 Hz, 1H), 7,16 (DD, J=8,6, and 5.5 Hz, 2H), 6,88-7,06 (m, 4H), to 3.99 (t, J=6.2 Hz, 2H), 3,83 (s, 2H), 3,71 (s, 3H), 3,55-to 3.67 (m, 2H), 3,29 is-3.45 (m, 3H), 2,80 (t, J=7,3 Hz, 2H), 2,02-to 2.18 (m, 2H).

Example 26-7: methyl-1-{[1-chloro-6-(3-cyclohexylpropionic)-3,4-dihydronaphthalene-2-yl]methyl}azetidin-3-carboxylate

TLC: Rf of 0.40 (chloroform:methanol = 20:1).

1H-NMR (CDCl3): δ 7,51 (d, J=8.6 Hz, 1H), 6,74 (DD, J=8,6, 2.7 Hz, 1H), to 6.67 (d, J=2.7 Hz, 1H), 3,95 (t, J=6,7 Hz, 2H), 3,71 (s, 3H), of 3.57 (t, J=7,0 Hz, 2H), 3.27 to to 3.49 (m, 5H), was 2.76 (t, J=7,1 Hz, 2H), 2,43 (t, J=7,1 Hz, 2H), 1.60-to a 1.88 (m, 7H), 1,09-of 1.39 (m, 6H), 0,82-a 1.01 (m, 2H).

Example 26-8: methyl-1-({1-chloro-6-[3-(4-chlorophenyl)propoxy]-3,4-dihydronaphthalene-2-yl}methyl)azetidin-3-carboxylate

TLC: Rf of 0.36 (chloroform:methanol = 20:1).

1H-NMR (CDCl3): δ 7,51 (d, J=8.6 Hz, 1H), 7,25 (d, J=8,2 Hz, 2H), 7,13 (d, J=8,2 Hz, 2H), 6.73 x (DD, J=8,6, 2.7 Hz, 1H), 6,66 (d, J=2.7 Hz, 1H), 3,94 (t, J=6,1 Hz, 2H), 3,71 (s, 3H), of 3.56 (t, J=6.5 Hz, 2H), 3,28-3,47 (m, 5H), 2,70-and 2.83 (m, 4H), 2,43 (t, J=8,4 Hz, 2H), 2.00 in to 2.13 (m, 2H).

Example 26-9: methyl-1-[(1-chloro-6-{[(2S)-3-(4-chlorophenyl)-2-methyl-propyl]oxy}-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylate

TLC: Rf of 0.45 (chloroform:methanol = 20:1).

1H-NMR (CDCl3): the 7,51 (d, J=8.6 Hz, 1H), 7,24 (d, J=8,4 Hz, 2H), 7,10 (d, J=8,4 Hz, 2H), 6,72 (DD, J=8,6, 2.7 Hz, 1H), 6,65 (d, J=2.7 Hz, 1H), 3,76 (d, J=5,9 Hz, 2H), 3,71 (s, 2H), only 3.57 (t, J=7.2 Hz, 2H), 3,28-to 3.49 (m, 6H), 2,84 (DD, J=13,5, 6.3 Hz, 1H), 2,75 (t, J=7.5 Hz, 2H), 2,52 (DD, J=13,5, 7.7 Hz, 1H), 2,43 (t, J=7.5 Hz, 2H), 2,13-of 2.28 (m, 1H), and 1.00 (d, J=6.8 Hz, 3H).

Example 26-10: methyl-1-({6-[2-(4-pertenece)ethoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidin-3-carboxylate

TLC: Rf of 0.15 (hexane:ethyl acetate = 1:5).

1H-NMR (CDCl3): δ 7,19 (d, J=8,42 Hz, 1H), 6,84-7,01 (m, 4H), 6,70-6,79 (m, 2H), 4,23-4,34 (m, 4H), 3,70 (s, 3H), 3,50-3,59 (m, 2H), 3.25 to 3.40 in (m, 5H), 2,62-by 2.73 (m, 2H), 2,22-2,31 (m, 2H), 2,09 (s, 3H).

Example 26-11: methyl-1-({6-[2-(4-pertenece)propoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidin-3-carboxylate

TLC: Rf of 0.45 (hexane:ethyl acetate = 1:6).

1H-NMR (CDCl3): δ 7,19 (d, J=8,42 Hz, 1H), 6.87 in-7,01 (m, 4H), 6,67 to 6.75 (m, 2H), 4,56-4,69 (m, 1H), 4,14 (DD, J=9,79, 5,67 Hz, 1H), 3,99 (DD, J=9,79, to 5.03 Hz, 1H), 3,70 (s, 3H), 3,49-3,59 (m, 2H), 3,24 is 3.40 (m, 5H), 2,62-2,72 (m, 2H), 2.21 are 2,31 (m, 2H), 2,08 (s, 3H), of 1.42 (d, J=6,40 Hz, 3H).

Example 26-12: methyl-1-({6-[(4-isobutyl-1,3-oxazol-2-yl)methoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidin-3-carboxylate

TLC: Rf 0,12 (hexane:ethyl acetate = 1:2).

1H-NMR (CDCl3): δ 7,39 (t, J=1,00 Hz, 1H), 7,18 (d, J=8,50 Hz, 1H), 6,83 (DD, J=8,50, 2,50 Hz, 1H), 6,79 (d, J=2,50 Hz, 1H), 5,09 (s, 2H), 3,70 (s, 3H), 3,51 is 3.57 (m, 2H), 3.25 to 3,37 (m, 5H), 2,64 -2,71 (m, 2H), 2,39 (DD, J=7,00, 1,00 Hz, 2H), 2,22-of 2.30 (m, 2H), 2,08 (s, 3H), 1.91 a-2,03 (m, 1H), 0,93 (d, J=6,50 Hz, 6H).

Example 26-13: methyl-1-({6-[3-(4-methoxyphenyl)propoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azeti the Jn-3-carboxylate

TLC: Rf is 0.42 (chloroform:methanol = 20:1).

1H-NMR (CDCl3): δ 7.18 in (d, J=8,2 Hz, 1H), 7,12 (d, J=8.6 Hz, 2H), 6,83 (d, J=8.6 Hz, 2H), 6,66-6,74 (m, 2H), 3,94 (t, J=6.2 Hz, 2H), 3,79 (s, 3H), 3,70 (s, 2H), 3,50-to 3.58 (m, 2H), 3,22 is 3.40 (m, 6H), to 2.75 (t, J=7.5 Hz,, 2H), to 2.67 (t, J=7,3 Hz, 2H), and 2.26 (t, J=7.5 Hz, 2H), 1,99 and 2.13 (m, 5H).

Example 26-14: methyl-1-({6-[3-(4-pertenece)propoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidin-3-carboxylate

TLC: Rf 0.31 in (hexane:ethyl acetate = 1:5).

1H-NMR (CDCl3): δ 7,19 (d, J=8,42 Hz, 1H), 6,91-7,00 (m, 2H), to 6.80-6.87 in (m, 2H), 6.73 x (DD, J=8,42, to 2.74 Hz, 1H), 6,69 (d, J=2,74 Hz, 1H), 4,07-4,19 (m, 4H), 3,70 (s, 3H), 3,50-3,59 (m, 2H), 3,24-to 3.41 (m, 5H), 2,62-a 2.71 (m, 2H,), 2,18-2,31 (m, 4H), of 2.08 (s, 3H).

Example 26-15: methyl-1-({6-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-terbisil)propoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)-azetidin-3-carboxylate

TLC: Rf of 0.50 (chloroform:methanol = 9:1).

1H-NMR (CDCl3): δ 7,08-7,19 (m, 3H), 6.89 in-6,98 (m, 2H), 6,61-of 6.71 (m, 2H), a 3.87 (DD, J=5,67, 2.20 Hz, 2H), 3,70 (s, 3H), 3,59-3,68 (m, 2H), 3,50-to 3.58 (m, 2H), 3.27 to (s, 5H), 2,73 (d, J=7.68 per Hz, 2H), 2,62-2,70 (m, 2H), 2,11-2,30 (m, 3H), of 2.08 (s, 3H), of 0.89 (s, 9H), of 0.01 (s, 6H).

Example 26-16: methyl-1-[(2E)-3-(4-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}phenyl)but-2-enyl]azetidin-3-carboxylate

TLC: Rf of 0.18 (hexane:ethyl acetate = 1:3).

1H-NMR (CDCl3): δ 7,30 (d, J=9,00 Hz, 2H), 7,24 (d, J=8,50 Hz, 2H), 7,10 (d, J=8,50 Hz, 2H), PC 6.82 (d, J=9,00 Hz, 2H), 5,63 (TCEs, J=7,00, 1,00 Hz, 1H, in), 3.75 (d, J=6,00 Hz, 2H), and 3.72 (s, 3H), 3,54 of-3.60 (m, 2H), 3,30 -3,37 (m, 3H), 3,26 (d, J=7,00 Hz, 2H), 2,84 (DD, J=13,50, 6,50 Hz, 1H), 2,52 (DD, J=13,50, 7,50 Hz, 1H), 2,15-of 2.26 (m, 1H), 2,04 (d, J=1,00 Hz, 3H), 1.00 and d, J=7,00 Hz, 3H).

Examples 27-1 - 27-16

Did the method according to example 7, using the compound obtained in the examples 26-1 - 26-16, instead of the compound obtained in example 6. Thus were obtained the compounds having the following physical properties.

Example 27-1: 1-[(6-{[(2E)-3-(4-forfinal)-2-methylpropan-2-enyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylic acid

TLC: Rf of 0.23 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CDCl3): δ 7,13-7,24 (m, 3H), 6,88-6,98 (m, 2H), 6,74 (DD, J=8,40, of 2.54 Hz, 1H), of 6.68 (d, J=2,54 Hz, 1H), 6,50 (s, 1H), 4,49 (s, 2H), 4,10-is 4.21 (m, 2 H), 3.95 to 4,07 (m, 2H), 3,92 (s, 2H), 3,16-3,30 (m, 1H), 2,62-2,71 (m, 2H), 2,15 was 2.25 (m, 2H), 2,12 (s, 3H), of 1.86 (d, J=1,10 Hz, 3H).

Example 27-2: 1-[(6-{[(2S)-2-(4-terbisil)butyl]oxyl}-1-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylic acid

TLC: Rf 0,13 (1-butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ 7.29 trend (d, J=at 8.60 Hz, 1H), 7,10-7,19 (m, 2H), 6.90 to-7,01 (m, 2H), 6,72 (DD, J=8,60, of 2.56 Hz, 1H), to 6.67 (d, J=2,56 Hz, 1H), 4.09 to of 4.25 (m, 4H), 4,06 (s, 2H), 3,80 (d, J=5,12 Hz, 2H), 3,34-of 3.48 (m, 1H), 2,64-2,78 (m, 4H), of 2.20 (s, 3H), 2,15 of-2.32 (m, 2H), 1,83-2,03 (m, 1H), 1,37 is 1.58 (m, 2H), and 0.98 (t, J=7,50 Hz, 3H).

Example 27-3: 1-[(6-{[(2R)-2-(4-terbisil)-3-methylbutyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylic acid

TLC: Rf 0,13 (1-butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ 7,28 (d, J=8,42 Hz, 1H), 711-7,22 (m, 2H), 6,88-7,03 (m, 2H), of 6.68 (DD, J=8,42, of 2.56 Hz, 1H), 6,62 (d, J=2,56 Hz, 1H), 4,08-to 4.23 (m, 4H), 4,06 (s, 2H), 3,78-to 3.89 (m, 2H), 3,30-of 3.48 (m, 1H), 2,61-and 2.83 (m, 4H), are 2.19 (s, 3H), 2,16-of 2.27 (m, 2H), 1,80-1,97 (m, 2H), of 1.03 (d, J=6,30 Hz, 3H), 1,01 (d, J=6,60 Hz, 3H).

Example 27-4: 1-[(1-chloro-6-{[(2S)-3-(4-forfinal)-2-methylpropyl]oxy}-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylic acid

TLC: Rf of 0.16 (1-butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ at 7.55 (d, J=at 8.60 Hz, 1H), 7,10-7,25 (m, 2H), 6.90 to-7,03 (m, 2H), 6,80 (DD, J=8,60, 2.38 Hz, 1H), 6.75 in (d, J=2.38 Hz, 1H), 4,19-4,27 (m, 4H), 4,17 (s, 2H), 3.75 to 3,86 (m, 2H), 3,36-to 3.49 (m, 1H), 2.77 - to 2,90(m, 3H), by 2.55 (DD, J=made 13.36, to 7.68 Hz, 1H), 2,40-of 2.50 (m, 2H), 2,09-of 2.27 (m, 1H), 1,01 (d, J=6,77 Hz, 3H).

Example up 27-5: 1-[(6-{[(2S)-3-(4-forfinal)-2-methylpropyl]oxy}-4,4-dimethyl-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylic acid

TLC: Rf of 0.27 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,17 (DD, J=8,4, and 5.5 Hz, 2H), 7,05 (d, J=8,2 Hz, 1H), 6,97 (t, J=8,4 Hz, 2H), at 6.84 (d, J=2.2 Hz, 1H), of 6.68 (DD, J=8,2, 2.2 Hz, 1H), 6,60 (s, 1H), 4,08-4,27 (m, 4H), 3,88 (s, 2H), 3,79 (d, J=5.7 Hz, 2H), 3,34-to 3.50 (m, 1H), 2,84 (DD, J=13,5, and 6.6 Hz, 1H), 2,55 (DD, J=13,5, and 7.8 Hz, 1H), 2,08-of 2.27 (m, 3H), of 1.23 (s, 6H), and 1.00 (d, J=6.8 Hz, 3H).

Example 27-6: 1-({6-[3-(4-forfinal)propoxy]-1-benzothieno-2-yl}methyl)azetidine-3-carboxylic acid

TLC: Rf of 0.23 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ of 7.70 (d, J=8,8 Hz, 1H), 7,39 (s, 1H), 7,37 (d, J=2.2 Hz, 1H), 7,21 (DD, J=8,8, 5.5 Hz, 2H), 6,92-7,06 (m, 3H), 4,51 (s, 2H), 4,10-4,18 (m, 4H), to 4.01 (t, J=6.2 Hz, 2H), 3,32-3,47 (m, 1H) 2,80 (t, J=7.5 Hz, 2H), 2,01-of 2.15 (m, 2H).

Example 27-7: 1-{[1-chloro-6-(3-cyclohexylpropionic)-3,4-dihydronaphthalene-2-yl]methyl}azetidin-3-carboxylic acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ at 7.55 (d, J=8,4 Hz, 1H), 6.73 x-6,84 (m, 2H), 4,24 (d, J=8.1 Hz, 4H), 4,18 (s, 2H), 3,97 (t, J=6.5 Hz, 2H), 3,34-of 3.53 (m, 1H), 2,84 (t, J=7.5 Hz, 2H), 2,45 (t, J=7.5 Hz, 2H), 1.60-to of 1.84 (m, 7H), 1,13-of 1.41 (m, 6H), 0,83-1,02 (m, 2H).

Example 27-8: 1-({1-chloro-6-[3-(4-chlorophenyl)propoxy]-3,4-dihydronaphthalene-2-yl}methyl)azetidine-3-carboxylic acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ at 7.55 (d, J=8.6 Hz, 1H), 7,25 (d, J=8.6 Hz, 2H), 7,18 (d, J=8.6 Hz, 2H), 6,80 (DD, J=8,6, 2.7 Hz, 1H), 6.75 in (d, J=2.7 Hz, 1H), 4,23 (d, J=8,2 Hz, 4H), 4,17 (s, 2H), 3,97 (t, J=6.2 Hz, 2H), 3,35-3,51 (m, 1H), 2,72-is 2.88 (m, 4H), 2.40 a is 2.51 (m, 2H), 1,96-2,17 (m, 2H).

Example 27-9: 1-[(1-chloro-6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-3,4-dihydronaphthalene-2-yl)methyl]azetidin-3-carboxylic acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ at 7.55 (d, J=8,4 Hz, 1H), 7,25 (d, J=8,4 Hz, 2H), 7,15 (d, J=8,4 Hz, 2H), 6,79 (DD, J=8,4, and 2.6 Hz, 1H), 6,74 (d, J=2.6 Hz, 1H), 4,17-to 4.23 (m, 4H), 4,14 (s, 2H), 3,81 (d, J=5,9 Hz, 2H), 3,34-to 3.49 (m, 1H), 2.77-to 2,89 (m, 3H), by 2.55 (DD, J=13,4, 7.9 Hz, 1H), 2,40-of 2.50 (m, 2H), 2,12-of 2.28 (m, 1H), 1,01 (d, J=6.8 Hz, 3H).

Example 27-10: 1-({6-[2-(4-pertenece)ethoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidine-3-carboxylic acid

TLC: Rf of 0.29 (chloroform:methanol:in the hydrated ammonia solution= 80:20:4).

1H-NMR (CD3OD): δ 7,34 (d, J=at 8.60 Hz, 1H), 6.90 to-7,05 (m, 4H), 6,83 (DD, J=8,60, to 2.74 Hz, 1H), 6,79 (d, J=2,74 Hz, 1H), 4,13-4,37 (m, 8H), 4,10 (s, 2H), 3,34-to 3.49 (m, 1H), 2,68 is 2.80 (m, 2H), of 2.21 (s, 3H), 2,19-of 2.30 (m, 2H).

Example 27-11: 1-({6-[2-(4-pertenece)propoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidine-3-carboxylic acid

TLC: Rf 0.31 in (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ to 7.32 (d, J=at 8.60 Hz, 1H), 6,91-7,03 (m, 4H), 6,78 (d, J=8,60, to 2.74 Hz, 1H), 6.73 x (d, J=2,74 Hz, 1H), br4.61-of 4.75 (m, 1H), 4,00-4,30 (m, 8H), 3,34-to 3.49 (m, 1H), 2,65-2,78 (m, 2H), 2,18-of 2.30 (m, 2H), measuring 2.20 (s,3H), of 1.37 (d, J=6,40 Hz, 3H).

Example 27-12: 1-({6-[(4-isobutyl-1,3-oxazol-2-yl)methoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidine-3-carboxylic acid

TLC: Rf 0.14 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ the 7.65 (t, J=1,00 Hz, 1H), 7,33 (d, J=8,50 Hz, 1H), 6,86 (DD, J=8,50, 2,50 Hz, 1H), PC 6.82 (d, J=2,50 Hz, 1H), 5,12 (s, 2H), 4.09 to to 4.23 (m, 4H), 4,06 (s, 2H), 3,35-3,47 (m, 1H), 2,69-2,77 (m, 2H), 2,39 (DD, J=7,00, 1,00 Hz, 2H), 2,18-to 2.29 (m, 5H), 1,89-2,02 (m, 1H), 0,92 (d, J=6,50 Hz, 6H).

Example 27-13: 1-({6-[3-(4-methoxyphenyl)propoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidine-3-carboxylic acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,30 (d, J=8.6 Hz, 1H), 7,10 (d, J=8,8 Hz, 2H), for 6.81 (d, J=8,8 Hz, 2H), 6,74 (DD, J=8,6, 2.7 Hz, 1H), 6,70 (d, J=2.7 Hz, 1H), 4.04 the-is 4.21 (m, 4H), was 4.02 (s, 2 H), of 3.94 (t, J=6.3 Hz, 2H), 3,74 (s, 3H), 3,32-3,47 (m, 1H), 2,65-2,78 (m, 4H), 2,20-of 2.28 (m, 2H), 2,19 (s, 3 H), 1,95-of 2.08 (m, 2H).

Example 27-14: 1-({6-[3-(4-pertenece)propox is]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidine-3-carboxylic acid

TLC: Rf 0.28 in (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,31 (d, J=at 8.60 Hz, 1H), 6,85-7,02 (m, 4H), 6,79 (DD, J=8,60, of 2.56 Hz, 1H), 6,74 (d, J=2,56 Hz, 1H), 4,06-4,27 (m, 10H), 3,34-of 3.48 (m, 1H), 2,65 was 2.76 (m, 2H), measuring 2.20 (s, 3H), 2,14-to 2.29 (m, 4H).

Example 27-15: 1-({6-[2-(4-terbisil)-3-hydroxypropoxy]-1-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidine-3-carboxylic acid

TLC: Rf 0,17 (1-butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ 7,30 (d, J=at 8.60 Hz, 1H), 7,15-7,24 (m, 2H), 6,91? 7.04 baby mortality (m, 2H), 6,74 (DD, J=8,60, 2.38 Hz, 1H), 6,70 (d, J=2.38 Hz, 1H), 4.09 to 4.26 deaths (m, 4H), 4,07 (s, 2H), 3,91 (d, J=5,31 Hz, 2H), 3,63 (d, J=5,85 Hz, 2H), 3,34-to 3.52 (m, 1H), 2,65-and 2.79 (m, 4H), of 2.20 (s, 3H), 2,13-of 2.28 (m, 3H).

Example 27-16: 1-[(2E)-3-(4-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}phenyl)but-2-enyl]azetidin-3-carboxylic acid

TLC: Rf is 0.22 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,38 (d, J=8,50 Hz, 2H), 7,24 (d, J=8,50 Hz, 2H), 7,15 (d, J=8,50 Hz, 2H), 6.87 in (d, J=8,50 Hz, 2H), 5,64 (TCEs, J=7,50, 1.50 Hz, 1H), 4,10-4.26 deaths (m, 4H), 3,98 (d, J=7,50 Hz, 2H), 3,79 (d, J=6,00 Hz, 2H), 3,35-of 3.43 (m, 1H), 2,85 (DD, J=13,50, 6,50 Hz, 1H), 2,55 (DD, J=13,50, 7,50 Hz, 1H), 2,13 was 2.25 (m, 4H), 1,01 (d, J=7,00 Hz, 3H).

Example 28: 1-((2E)-3-{4-[3-(4-chlorophenyl)propoxy]phenyl}but-2-enyl)azetidin-3-carboxylic acid

Did the method according to example 8, using the appropriate aldehyde instead of 6-[3-(4-chlorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde. Thus was obtained is indicated in the header connect the tion, has the following physical properties.

TLC: Rf of 0.18 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CDCl3+CD3OD): δ 7,34 (d, J=9,00 Hz, 2H), 7,25 (d, J=8,50 Hz, 2H), 7,15 (d, J=8,50 Hz, 2H), 6.87 in (d, J=9,00 Hz, 2H), ceiling of 5.60-5,67 (m, 1H), 4,23 (DD, J=10,00, 6,00 Hz, 2H), of 4.05 (t, J=10.00 Hz, 2H), 3.96 points (t, J=6,00 Hz, 2H), 3,85-3,91 (m, 2H), 3,24-to 3.33 (m, 1H), and 2.79 (t, J=7,50 Hz, 2H), 2,15 (d, J=1,00 Hz, 3H), 2,04 with 2.14 (m, 2H).

Examples 29-1 - 29-5

Did the method according to examples 12 and 13 using a corresponding amine compound instead of the compound obtained in example 11. Thus were obtained the compounds having the following physical properties.

Example 29-1: triptorelin 3-[4-{4-[3-(4-chlorophenyl)propoxy]phenyl}-3,6-dihydropyridines-1(2H)-yl]propanoic acid

TLC: Rf 0.28 in (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,40 (d, J=8,97 Hz, 2H), 7,25 (d, J=at 8.60 Hz, 2H), 7,19 (d, J=at 8.60 Hz, 2H), make 6.90 (d, J=8,97 Hz, 2H), 5,97-between 6.08 (m, 1H), 3,90-4,01 (m, 4H), 3,55-3,63 (m, 2H), 3,51 (t, J=6,59 Hz, 2H), 2,82-of 2.93 (m, 4H), 2,74-and 2.83 (m, 2H), 1,95-2,15 (m, 2H).

Example 29-2: triptorelin 3-[4-(4-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}phenyl)-3,6-dihydropyridines-1(2H)-yl]propanoic acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,40 (d, J=8,97 Hz, 2H), 7,24 (d, J=to 8.41 Hz, 2H), 7,15 (d, J=to 8.41 Hz, 2H), 6.89 in (d, J=8,97 Hz, 2H), 5,94-6,11 (m, 1H), 3,86-4,00 (m, 2H), 3,79 (d, J=5,85 Hz, 2H), 3.45 points-to 3.64 (m, 4H), 2,79-of 2.93 (m, 5H), 2,44-of 2.66 (m, 1H), 2,10-of 2.33 (m, 1H), 1,01 (d, J=6,77 Hz, 3H).

When the EP 29-3: triptorelin 3-{7-[(5-fenilpentil)oxy]-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl}propanoic acid

TLC: Rf of 0.38 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,30 (d, J=8,23 Hz, 1H), 7,19-7,27 (m, 2H), 7,07-7,19 (m, 3H), 6,83 (d, J=2,56 Hz, 1H), 6,79 (DD, J=8,23, of 2.56 Hz, 1H), 4,42-to 4.52 (m, 2H), 3,97 (t, J=6,40 Hz, 2H), 3,41 at 3.69 (m, 2H), 3,14-3,39 (m, 2H), 2,93-a 3.06 (m, 2H), 2,82 (t, J=6,95 Hz, 2H), 2,55-2,70 (m, 2H), 1,86-2,19 (m, 2H), 1,74-of 1.85 (m, 2H), 1,61-of 1.73 (m, 2H), 1,42-of 1.57 (m, 2H).

Example 29-4: triptorelin 3-{7-[3-(4-chlorophenyl)propoxy]-9-methyl-1,3,4,9-tetrahydro-2H-β-carbolin-2-yl}propanoic acid

TLC: Rf of 0.27 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,37 (d, J=8,42 Hz, 1H), 7,25 (d, J=8,78 Hz, 2H), 7,20 (d, J=8,78 Hz, 2H), 6.87 in (d, J=a 2.01 Hz, 1H), 6,76 (DD, J=8,42, a 2.01 Hz, 1H), 4,55-4,69 (m, 2H), 4,01 (t, J=6,13 Hz, 2H), 3,62 (s, 3H), 3,57 is 3.76 (m, 4H), 3,06-3,17 (m, 2H), 2,98 (t, J=7,14 Hz, 2H), 2.77-to 2,89 (m, 2H), 2.00 in 2,17 (m, 2H).

Example 29-5: triptorelin 3-{5-[(5-fenilpentil)oxy]-1,3-dihydro-2H-isoindole-2-yl}propanoic acid

TLC: Rf 0.21 in (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,19-7,31 (m, 3H), 7,07-7,19 (m, 3H), 6,86-6,98 (m, 2H), 4,51-4,79 (m, 4H), of 3.97 (t, J=of 6.31 Hz, 2H), 3,69 (t, J=6,86 Hz, 2H), 2,88 (t, J=6,86 Hz, 2H), 2,56-2,69 (m, 2H), 1,74-of 1.88 (m, 2H), 1.60-to around 1.74 (m, 2H), 1,42-of 1.57 (m, 2H).

Example 30: methyl-N-[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-yl)methyl]-β-alaninate

Did the method according to example 6, using 6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde instead of the compound obtained is example 5, and methyl-β-alaninate instead of hydrochloride of methylisatin-3-carboxylate. Thus was obtained is listed in the title compound having the following physical properties.

TLC: Rf and 0.62 (chloroform:methanol:aqueous ammonia= 80:10:1).

Example 31: N-[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-yl)methyl]-β-alanine

Did the method according to example 7, using the compound obtained in example 30, instead of the compound obtained in example 6. Thus were obtained the compounds having the following physical properties.

TLC: Rf of 0.27 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,28 (d, J=8.6 Hz, 1H), 7,24 (d, J=8.6 Hz, 2H), 7,15 (d, J=8.6 Hz, 2H), 6.73 x (DD, J=8,6, 2.8 Hz, 1H), 6,69 (d, J=2,8 Hz, 1H), 3,88 (s, 2H), 3,78 (d, J=5,9 Hz, 2H), 3,18 (t, J=6.3 Hz, 2H), 2,84 (DD, J=13,4, 6.4 Hz, 1H), 2,75 (t, J=7,3 Hz, 2H), 2,47-2,60 (m, 3H), 2,33 (t, J=7,3 Hz, 2H), 2,11-of 2.25 (m, 4H), and 1.00 (d, J=6.8 Hz, 3H).

Example 32: 2-(methoxyethoxy)-3-propylbenzoyl

Methoxymethane (8,4 ml) and potassium carbonate (30 g) was added to a solution of 3-propylene (10 g) in N,N-dimethylformamide (150 ml) at room temperature and was stirred at 50°C for one day. The reaction solution was poured into a mixture of ice water. The insoluble substance was filtered and was extracted with a mixed solvent consisting of hexane and ethyl acetate (1:1). The organic layer is successively washed is whether water and saturated salt solution. The reaction product was dried over magnesium sulfate and concentrated. The resulting residue was purified by chromatography on a column of silica gel (from one of hexane to hexane:ethyl acetate = 10:1), while receiving specified in the title compound (8.0 g)having the following physical properties.

TLC: Rf of 0.64 (hexane:ethyl acetate = 10:1).

1H-NMR (CDCl3): δ 7.18 in (DD, J=8,50, 7,50 Hz, 1H), 6,80-to 6.88 (m, 3H), 5,16 (s, 2H), 3,48 (s, 3H), of 2.56 (t, J=7,50 Hz, 2H), 1.56 to 1,71 (m, 2H), were 0.94 (t, J=7,50 Hz, 3H).

Example 33: 2-(methoxyethoxy)-4-propylbenzamide

Tert-utility (1.56 mol/ml solution in pentane, 33.9 ml) was added to a solution of compound (7,95 g)obtained in example 32, in hexane (100 ml) at 0°C and was stirred for 30 minutes. Then was added dropwise N,N-dimethylformamide (5,12 ml). To the reaction solution was added a saturated solution of ammonium chloride and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrated. The resulting residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate = 14:1 to 10:1), while receiving specified in the title compound (4.94 g)having the following physical properties.

TLC: Rf of 0.27 (hexane:ethyl acetate = 10:1).

1H-NMR (CDCl3): δ 10,44 (s, 1H), 7,76 (d, J=7.9 Hz, 1H), 7,01 (s, 1H), 6,91 (d, J=7.9 Hz, 1H), and 5.30 (s, 2H), 3,53 (s, 3H), 2,62 (t, J=7.5 Hz, 2H), 1,58 is 1.75 (m, 2H), of 0.96 (t, J=73 Hz, 3H).

Example 34: 2-hydroxy-4-propylbenzamide

4 mol/l solution of hydrochloride/1,4-dioxane (50 ml) was added to a solution of compound (4,50 g)obtained in example 33, in 1,4-dioxane (10 ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated, thus obtaining specified in the header connection (3,48 g)having the following physical properties.

TLC: Rf of 0.57 (hexane:ethyl acetate = 10:1).

1H-NMR (CDCl3): δ 11,04 (s, 1H), 9,83 (s, 1H), 7,45 (d, J=7.9 Hz, 1H), 6,83 (d, J=7.9 Hz, 1H), for 6.81 (s, 1H), 2,61 (t, J=7.5 Hz, 2H), 1,58-of 1.74 (m, 2H), of 0.95 (t, J=7,3 Hz, 3H).

Example 35: 2-methoxy-4-propylbenzamide

Potassium carbonate (3,79 g) and methyliodide (1,71 ml) was added to a solution of the compound (3.00 g)obtained in example 34, in N,N-dimethylformamide (40 ml) at room temperature and was stirred at 40°C for 2 hours. To the reaction solution was added water and was extracted with a mixed solvent consisting of hexane and ethyl acetate (3:1). The organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrated, thus obtaining specified in the title compound (8.0 g)having the following physical properties.

TLC: Rf of 0.40 (hexane:ethyl acetate = 10:1).

1H-NMR (CDCl3): δ 10,41 (s, 1H), of 7.75 (d, J=7.9 Hz, 1H), 6,86 (d, J=7.9 Hz, 1H), 6,78 (s, 1H), 3,93 (s, 3H), 2.63 in (t, J=7.5 Hz, 2H), 1,59-to 1.77 (m, 2H), 0,97 (t, J=7,3 Hz, 3H).

Example 36: -(hydroxymethyl)-2-methoxy-4-propylbenzoyl

Sodium borohydride (958 mg) was added to a solution of compound (3,02 g)obtained in example 35, in methanol (40 ml) at 0°C and stirred at room temperature for 1 hour. The reaction solution was concentrated, added water and was extracted with ethyl acetate. The organic layer was dried the over sodium sulfate and concentrated. The resulting residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate = 6:1 to 3:1), while receiving specified in the header connection (2,87 g)having the following physical properties.

TLC: Rf 0.31 in (hexane:ethyl acetate = 3:1).

1H-NMR (CDCl3): δ 7,16 (d, J=7.5 Hz, 1H), 6,76 (d, J=7.5 Hz, 1H), of 6.71 (s, 1H)and 4.65 (s, 2H), a 3.87 (s, 3H), 2,58 (t, J=7.5 Hz, 2H), 1,57-1,72 (m, 2H), of 0.95 (t, J=7,3 Hz, 3H).

Example 37: 1-({6-{[2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

Did the method according to examples 5, 6 and 7, using 1-(methyl bromide)-2-methoxy-4-propylbenzoyl (which was obtained by adding tribromide phosphorus to the compound obtained in example 36, in diethyl ether at 0°C, and interacting mixture at room temperature for 1 hour) instead of 1-bromo-3-(4-forfinal)propane, while receiving specified in the title compound having the following physical properties.

1H-NMR (CD3OD): δ 7,31 (d, J=8,4 Hz, 1H), 7,25 (d, J=7,Hz, 1H), 6.73 x-6,86 (m, 4H), 5,04 (s, 2H), 4,12-the 4.29 (m, 4H), 4,10 (s, 2H), of 3.84 (s, 3H), 3,34-to 3.50 (m, 1H), 2,72 (t, J=7,0 Hz, 2H), 2,59 (t, J=7,3 Hz, 2H), 2,15-2,31 (m, 5H), 1,57-of 1.74 (m, 2H), were 0.94 (t, J=7,4 Hz, 3H);

amorphous substance.

Examples 37-1 - 37-16

Did the method according to example 37, using the appropriate connection phenol instead of the compound obtained in example 4, and the corresponding connection of the alcohol instead of the compound obtained in example 36, the result of which was obtained is listed in the title compound having the following physical properties.

Example 37-1: 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.23 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ to 7.32 (d, J=at 8.60 Hz, 1H), 7,26 (d, J=7.68 per Hz, 1H), 6,83 (DD, J=8,60, to 2.74 Hz, 1H), 6,77-to 6.80 (m, 2H), of 6.71-6.75 in (m, 1H), 5,04 (s, 2H), 4,11-4,27 (m, 4H), 4.09 to (s, 2H), of 3.84 (s, 3H), 3,34-of 3.48 (m, 1H), 2,67-2,77 (m, 2H), 2,48 (d, J=to 7.32 Hz, 2H), measuring 2.20 (s, 3H), 2,18-of 2.28 (m, 2H), 1,81-of 1.95 (m, 1H), of 0.91 (d, J=6,77 Hz, 6H).

Example 37-2: 1-({6-[(4-isobutyl-3-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf to 0.17 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ to 7.32 (d, J=8,50 Hz, 1H), 7,05 (d, J=7,50 Hz, 1H), 6,98 (d, J=1.50 Hz, 1H), 6.90 to (DD, J=7,50, 1.50 Hz, 1H), 6,85 (DD, J=8,50, 2,50 Hz, 1H), for 6.81 (d, J=2,50 Hz, 1H), 5,04 (s, 2H), 4,12-4.26 deaths (m, 4H), 4,08 (s, 2H), 3,80 (s,3H), 3,34-3,47 (m, 1H), 2,69-2,77 (m, 2H), 2,46 (d, J=7,00 Hz, 2H), 2,19-to 2.29 (m, 5H), 1,81-of 1.95 (m, 1H), 0,86 (d, J=7,00 Hz, 6H).

Example 37-3: 1-({6-[(2-ethoxy-4-isobutylbenzene)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.32 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ to 7.32 (d, J=8.6 Hz, 1H), 7,25 (d, J=7.5 Hz, 1H), 6,68-to 6.88 (m, 4H), of 5.06 (s, 2H), 4,12-4,30 (m, 4H), 4,03-to 4.14 (m, 4H), 3,36-to 3.50 (m, 1H), 2,72 (t, J=6.6 Hz, 2H), 2,46 (d, J=7,1 Hz, 2H), 2,16-2,30 m, 5H), 1,78 is 1.96 (m, 1H), 1,38 (t, J=7.0 Hz, 3H), of 0.90 (d, J=6.6 Hz, 6H).

Example 37-4: 1-[(6-{[4-isopropoxy-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.23 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,58 (d, J=8,50 Hz, 1H), 7,33 (d, J=8,50 Hz, 1H), 7,19 (d, J=2,50 Hz, 1H), 7,17 (DD, J=8,50, 2,50 Hz, 1H), for 6.81 (DD, J=8,50, 2,50 Hz, 1H), 6,78 (d, J=2,50 Hz, 1H), 5,14 (s, 2H), 4,62-to 4.73 (m, 1H), 4,08-4,24 (m, 4H), 4,06 (s, 2H), 3,35-3,47 (m, 1H), 2,70-2,77 (m, 2H), 2,19-of 2.28 (m, 5H), of 1.33 (d, J=6,00 Hz, 6H).

Example 37-5: 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

1H-NMR (CD3OD): δ of 7.96-8,03 (m, 3H), of 7.36 (d, J=8,50 Hz, 1H), 6,82-to 6.88 (m, 2H), to 5.35 (s, 2H), 4,12-4,27 (m, 4H), 4.09 to (s, 2H), 3,37-to 3.49 (m, 1H), 2,70-and 2.79 (m, 2H), 2,19-of 2.30 (m, 5H);

amorphous substance.

Example 37-6: 1-({1-chloro-6-[(2-methoxy-4-propylbenzyl)oxy]-3,4-dihydro-2-naphtalene the}methyl)-3-azetidinone acid

TLC: Rf of 0.29 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ at 7.55 (d, J=8.6 Hz, 1H), 7,24 (d, J=7.7 Hz, 1H), 6,86 (DD, J=8,6, and 2.6 Hz, 1H), 6,80-6,84 (m, 2H), 6,76 (d, J=7.7 Hz, 1H), is 5.06 (s, 2H), 4,23 (d, J=8,2 Hz, 4H), 4,18 (s, 2H), of 3.84 (s, 3H), 3,35-3,51 (m, 1H), and 2.83 (t, J=7,3 Hz, 2H), 2,59 (t, J=7,3 Hz, 2H), 2,45 (t, J=7,3 Hz, 2H), 1.56 to around 1.74 (m, 2H), were 0.94 (t, J=7,3 Hz, 3H);

crystalline substance.

Melting point 157,9-to 158.0°C.

Example 37-7: 1-({1-chloro-6-[(4-isobutyl-2-methoxybenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.32 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,56 (d, J=8.6 Hz, 1H), 7,25 (d, J=7.5 Hz, 1H), to 6.88 (DD, J=8,6, and 2.6 Hz, 1H), at 6.84 (d, J=2.6 Hz, 1H), 6,79 (d, J=1.3 Hz, 1H), 6,74 (DD, J=7,5, 1.3 Hz, 1H), 5,07 (s, 2H), 4,24 (d, J=8,2 Hz, 4H), 4,19 (s, 2H), of 3.84 (s, 3H), 3,37-to 3.50 (m, 1H), 2,84 (t, J=7.7 Hz, 2H), 2,41-2,52 (m, 4H), 1,80-of 1.97 (m, 1H), of 0.91 (d, J=6.8 Hz, 6H);

amorphous substance.

Example 37-8: 1-[(1-chloro-6-{[(2S)-3-(2,4-differenl)-2-methylpropyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,53 (d, J=8.6 Hz, 1H), 7,15-7,31 (m, 1H), for 6.81-6,94 (m, 2H), of 6.71-for 6.81 (m, 2H), 3,97-4,18 (m, 6H), 3,83 (d, J=5,9 Hz, 2H), 3,31-of 3.46 (m, 1H), was 2.76 of 2.92 (m, 3H), at 2.59 (DD, J=14,1, 7.9 Hz, 1H), 2,44 (t, J=8.6 Hz, 2H), 2,15-2,31 (m, 1H), 1,01 (d, J=6.8 Hz, 3H).

Example 37-9: 1-[(6-{[4-ethoxy-2-(trifluoromethyl)Ben who yl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.33 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ to 7.59 (d, J=8,80 Hz, 1H) 7,34 (d, J=at 8.60 Hz, 1H) 7,21 (d, J=2,60 Hz, 1H) 7.15m (DD, J=8,60, 2,60 Hz, 1H) 6,74-6,87 (m, 2H) 5,14 (s, 2H) 4,11-or 4.31 (m, 4H) was 4.02-to 4.15 (m, 4H) 3,34-to 3.50 (m, 1H) 2,73 (t, J=6,80 Hz, 2H) 2,14 of-2.32 (m, 5H) of 1.40 (t, J=7,00 Hz, 3H).

Example 37-10: 1-({6-[(4-ethyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0.28 in (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,30 (d, J=8,50 Hz, 1H), 7,25 (d, J=7,50 Hz, 1H), 6,74-6,85 (m, 4H), 5,04 (s, 2H), 4,08-4,24 (m, 4H), 4,06 (s, 2H), 3,85 (s, 3H), 3,35-of 3.46 (m, 1H), 2,60 was 2.76 (m, 4H), 2,18-of 2.28 (m, 5H), 1,24 (t, J=to 7.50 Hz, 3H).

Example 37-11: 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf to 0.19 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,27 (d, J=7,50 Hz, 1H), 7,21 (d, J=8,50 Hz, 1H), 6,80-6,85 (m, 2H), 6,76 (DD, J=7,50, 1,00 Hz, 1H), of 5.05 (s, 2H), 4,10-of 4.25 (m, 4H), 4,07 (s, 2H), 3,85 (s, 3H), 3,35-of 3.46 (m, 1H), 2,70-2,77 (m, 2H), 2,56 2.63 in (m, 2H), 2,17-of 2.27 (m, 8H), 1,59-1,72 (m, 2H), of 0.95 (t, J=7,50 Hz, 3H).

Example 37-12: 1-({6-[(2-deformedarse-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.15 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD) δ 7,42 (d, J=7,50 Hz, 1H), 7,33 (d, J=8,50 Hz, 1H), 7,01-7,11 (m, 2H), PC 6.82 (t, J=74,00 Hz, 1H), 6,79-6,86 (m, 2H), to 5.08 (s, 2H), 4,10-of 4.25 (m, 4H), 4,08 (s, 2H), 3,35-to 3.49 (m, 1H), 2,69-2,77 (m, 2H), 2,61 (t, J=7,50 Hz, 2H), 2,19-of 2.28 (m, 5H), 1,58-1,72 (m, 2H), were 0.94 (t, J=7,50 Hz, 3H).

Example 37-13: 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-chloro-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.35 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,92-8,08 (m, 3H), to 7.61 (d, J=at 8.60 Hz, 1H), 6,86-of 6.96 (m, 2H), lower than the 5.37 (s, 2H), 4,07-of 4.25 (m, 6H), 3,36-to 3.49 (m, 1H), 2,79 of 2.92 (m, 2H), 2.40 a-2,52 (m, 2H);

crystalline substance.

Example 37-14: 1-[(6-{[2-(deformedarse)-4-propylbenzyl]oxy}-1,5-dimethyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ the 7.43 (d, J=7,50 Hz, 1H), 7.23 percent (d, J=8,50 Hz, 1H), was 7.08 (d, J=7,50 Hz, 1H), 7,02 (s, 1H), 6,85 (d, J=8,50 Hz, 1H), PC 6.82 (t, J=74,00 Hz, 1H), 5,09 (s, 2H), 4,10-of 4.25 (m, 4H), 4,08 (s, 2H), 3,34-3,47 (m, 1H), 2,70-2,77 (m, 2H), 2,58-of 2.66 (m, 2H), 2,17-of 2.28 (m, 8H), 1,59-1,72 (m, 2H), of 0.95 (t, J=7,50 Hz, 3H);

crystalline substance.

Example 37-15: 1-[(6-{[4-ethoxy-3-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ 7,58-to 7.64 (m, 2H), 7,33 (d, J=8,50 Hz, 1H), 7,15 (d, J=8,00 Hz, 1H), 6,85 (DD, J=8,50, 2,50 Hz,1H), for 6.81 (d, J=2,50 Hz, 1H), of 5.05 (s, 2H), 4,11-of 4.25 (m, 6H), 4,08 (s, 2H), 3,35-of 3.48 (m, 1H), 2,69-2,77 (m, 2H), 2,18-of 2.27 (m, 5H), of 1.41 (t, J=7,00 Hz, 3H);

crystalline substance.

Example 37-16: 1-({6-[(2-methoxy-6-propyl-3-pyridinyl)methoxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.40 (chloroform:methanol:aqueous ammonia= 80:20:4).

1H-NMR (CD3OD): δ a 7.62 (d, J=7,32 Hz, 1H), 7,22 (d, J=8,78 Hz, 1H), PC 6.82 (d, J=8,78 Hz, 1H), 6,77 (d, J=7,32 Hz, 1H), 5,00 (s, 2H), 4,08-4,24 (m, 4H), of 4.05 (s, 2H), 3.96 points (s, 3H), 3,34-of 3.48 (m, 1H), 2,69-2,77 (m, 2H), 2,61-2,69 (m, 2H), 2,14-to 2.29 (m, 8H), 1,64-of 1.85 (m, 2H), of 0.95 (t, J=7,41 Hz, 3H);

crystalline substance.

Example 38: hydrochloride methylisatin-3-carboxylate

Methanol (70 ml) was added dropwise to thionyl chloride (23,4 ml), stirring at 0°C, then added azetidine-3-carboxylic acid (CAS no 36476-78-5, 25 g) and stirred at room temperature for 2 hours. The reaction solution was concentrated, thus obtaining specified in the title compound (36 g)having the following physical properties.

TLC: Rf of 0.68 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 4,18-to 4.33 (m, 4H), 3.72 points-3,81 (m, 4H).

Example 38-1: hydrochloride utilisation-3-carboxylate

Did the method according to example 38, using ethanol instead of methanol. Thus was obtained is listed in the title compound, having the following the physical properties.

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (DMSO-d6): δ 9,19-9,59 (m, 1H), 9,01-9,26 (m, 1H), 4,13 (kV, J=7,1 Hz, 2H), 3.95 to to 4.15 (m, 4H), 3,60 is 3.76 (m, 1H), 1,20 (t, J=7,1 Hz, 3H).

Example 39 ethyl-1-benzyliden-3-carboxylate

Acetate tetrahydrate of tetraethylammonium (9,42 g) was added to a solution of diethyl-1-benzyliden-3,3-in primary forms (7,00 g, which was obtained by the method described in Synthetic Communications, volume 33, No. 19, page 3347, 2003) 1,3 dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 40 ml) and stirred at 130°C for 12 hours. To the reaction solution was added water and was extracted with a mixed solvent consisting of acetate and hexane (1:1). The organic layer was washed with water, hexane was added and was extracted with 0.5 mol/l hydrochloric acid. The aqueous layer was washed with tert-butylmethylamine ether, the pH was brought to 8 by using 5 mol/l aqueous solution of sodium hydroxide, and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrated, thus obtaining specified in the header connection (3,21 g)having the following physical properties.

TLC: Rf of 0.54 (hexane:ethyl acetate = 1:2).

1H-NMR (CDCl3): δ 7,11-7,41 (m, 5H), is 4.15 (q, J=7,1 Hz, 2H), 3,60 (s, 2H), 3.46 in-to 3.58 (m, 2H), 3,23-to 3.41 (m, 3H), of 1.26 (t, J=7,1 Hz, 3H).

Example 40: hydrochloride utilisation-3-carboxylate

p> 4 n solution of hydrochloride/dioxane (4.6 ml) was added to a solution of the compound (2.00 g)obtained in example 39, in 1,4-dioxane (5 ml). The mixture was stirred for some time and concentrated. The reaction product was added ethanol (30 ml) and 20% palladium hydroxide on coal (about 50% humidity, 200 mg) and stirred at 70°C for 7 hours in an atmosphere of hydrogen. The reaction solution was filtered, and the filtrate was concentrated, thus obtaining specified in the title compound (1.60 g)having the following physical properties.

TLC: Rf 0.14 (chloroform:methanol:aqueous ammonia= 80:10:1).

Example 41: 1-methoxy-4-propylene

Palladium on coal (5 wt.%, 54 mg) was added to a solution of eugenol (CAS no 97-53-0, 500 mg) in 2-propanol (2.5 ml) in an argon atmosphere. The resulting mixture was intensively stirred at an external temperature of 50°C in a stream of hydrogen for about 4.5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated, thus obtaining specified in the title compound (447 mg)having the following physical properties.

TLC: Rf of 0.55 (hexane:ethyl acetate = 6:1).

Example 42: 2-methoxy-4-propyltrichlorosilane

Pyridine (63,3 ml) was added to a solution of the compound (100.0 g)obtained in example 41 in acetonitrile (450 ml). The reaction solution was cooled to an internal temperature, avnoj -4°C, dropwise slowly added anhydride triftormetilfullerenov acid (108,6 ml) and stirred at an internal temperature of from about 0 to 10°C for about 30 minutes. To the reaction solution was added 0.5 mol/l hydrochloric acid (400 ml) and was extracted with toluene. The organic layer was sequentially washed with water and saturated salt solution, dried and concentrated, thus obtaining specified in the header connection (178,7 g)having the following physical properties.

TLC: Rf to 0.63 (hexane:ethyl acetate = 6:1).

1H-NMR (CDCl3): δ 7,10 (d, J=8,4 Hz, 1H), 6,83 (d, J=2.00 Hz, 1H), 6,76 (DD, J=8,40, 2.00 Hz, 1H), 3,90 (s, 3H), at 2.59 (t, J=7,60 Hz, 2H), 1,59-of 1.73 (m, 2H), of 0.96 (t, J=7,20 Hz, 3H).

Example 43: methyl 2-methoxy-4-propylbenzoate

To a mixed solution of the compound (5,00 g)obtained in example 42, in dimethyl sulfoxide (20 ml) and methanol (15 ml) was added triethylamine (4,70 ml), 1,3-bis(diphenylphosphino)propane (DPPP, 346 mg) and palladium acetate (94 mg) and intensively stirred at an internal temperature of about 70°C in an atmosphere of carbon monoxide for approximately 2.5 hours. The reaction solution was cooled, diluted simple tert-butylmethylamine ether (20 ml), was added 3,5% aqueous sodium bicarbonate solution (67,5 ml), ticinobuy acid (201 mg) and activated carbon (500 mg) and intensively stirred at room temperature for about 30 minutes. About the ADOC was filtered. The organic layer was sequentially washed with water and saturated salt solution, dried and concentrated, thus obtaining specified in the header connection (3,10 g)having the following physical properties.

TLC: Rf of 0.50 (hexane:ethyl acetate = 2:1).

1H-NMR (CDCl3): δ 7,73 (d, J=8,00 Hz, 1H), 6,77-PC 6.82 (m, 2H), 3,90 (s, 3H), a 3.87 (s, 3H), 2,61 (t, J=7,50 Hz, 2H), 1,59-of 1.73 (m, 2H), of 0.95 (t, J=7,50 Hz, 3H).

Example 44: (2-methoxy-4-propylphenyl)methanol

Solution red aluminum in toluene (content of 66.5%in 2,05 g)was slowly added to a solution of compound (1,00 g)obtained in example 43, in tetrahydrofuran (3 ml)at an internal temperature of 5°C, and stirred at an internal temperature of about 35°C for about 2.5 hours. To the reaction solution was added methanol (0.5 ml) at an internal temperature of 9°C. to terminate the reaction. The reaction solution was poured into 50% aqueous solution of tartrate tetrahydrate, potassium and sodium and were extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated salt solution, dried and concentrated, thus obtaining specified in the header connection (0,91 g)having the following physical properties.

TLC: Rf of 0.43 (hexane:ethyl acetate = 2:1).

1H-NMR (CDCl3): δ 7,16 (d, J=7,50 Hz, 1H), 6,76 (DD, J=7,50, 1.50 Hz, 1H), of 6.71 (d, J=1.50 Hz, 1H)and 4.65 (s, 2H), 3,86 (s, 3H), 2,58 (t, J=7,50 Hz, 2H), 2,20 (s, 1H), 1,58-1,72 (m, 2H), and 0.9 (t, J=7,50 Hz, 3H).

Example 45: 1-(chloromethyl)-2-methoxy-4-propylbenzoyl

Pyridine (79 ml) was added to a solution of compound (160 g)obtained in example 44, in dimethoxyethane (640 ml). Then, with stirring, dropwise slowly added thionyl chloride (71,3 ml) and the mixture was stirred for 30 minutes. The reaction solution was cooled, was added a mixture of ice water and was extracted with simple tert-butylmethylamine ether. The organic layer was sequentially washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried and concentrated, thus obtaining specified in the title compound (169 g)having the following physical properties.

TLC: Rf of 0.65 (hexane:ethyl acetate = 10:1).

1H-NMR (CDCl3): δ of 7.24 (d, J=7,50 Hz, 1H), 6,76 (DD, J=7,50, 1.50 Hz, 1H), of 6.71 (d, J=1.50 Hz, 1H), with 4.64 (s, 2H), a 3.87 (s, 3H), 2,53-of 2.64 (m, 2H), 1,57-1,72 (m, 2H), of 0.95 (t, J=7,50 Hz, 3H).

Example 46: 6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthaleneboronic

Potassium phosphate (189 g) was added to a solution of compound (146 g)obtained in example 4 and the compound (162 g)obtained in example 45, in N,N-dimethylacetamide (584 ml) and stirred at 60°C for 2 hours. The reaction solution was cooled and added to water. The precipitate was filtered and dried. The resulting crude substance (263 g) was recrystallized from a mixed solvent consisting of etelaat the TA (520 ml) and heptane (2600 ml), while receiving specified in the title compound (213 g)having the following physical properties.

TLC: Rf 0.25 in (hexane:ethyl acetate = 6:1).

1H-NMR (CDCl3): δ 10.30 a.m (s, 1H), 7,46 (d, J=8,50 Hz, 1H), 7,31 (d, J=7,50 Hz, 1H), 6.89 in (DD, J=8,50, 2,50 Hz, 1H), at 6.84 (d, J=2,50 Hz, 1H), 6,79 (DD, J=7,50, 1.50 Hz, 1H), 6.73 x (d, J=1.50 Hz, 1H), 5,10 (s, 2H), 3,86 (s, 3H), 2,68 was 2.76 (m, 2H), 2,56-2,63 (m, 2H), 2,47-of 2.54 (m, 5H), 1,58-of 1.73 (m, 2H), of 0.96 (t, J=7,50 Hz, 3H).

Example 46-1: 6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthaleneboronic

Did the method according to example 46, using 2,4-bis(trifluoromethyl)benzylchloride (CAS no 195136-46-0) instead of the compound obtained in example 45. Thus was obtained is listed in the title compound having the following physical properties.

TLC: Rf of 0.27 (hexane:ethyl acetate = 5:1).

1H-NMR (CDCl3): δ 10,33 (s, 1H), of 7.96 (s, 1H), 7,92 (d, J=9,00 Hz, 1H), a 7.85 (d, J=9,00 Hz, 1H), 7,50 (d, J=8,50 Hz, 1H), 6,82-to 6.88 (m, 2H), are 5.36 (s, 2H), 2.71 to 2,78 (m, 2H), 2,48 is 2.55 (m, 5H).

Example 47 ethyl-1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinol

The triethylamine (95,5 ml) and triacetoxyborohydride sodium (145 g) was added at 0°C. to a solution of the compound (200 g)obtained in example 46, in tetrahydrofuran (800 ml) and was stirred for 10 minutes. To the mixture was added dropwise a solution of compound (113 g)obtained in example 38-1, in acetonitrile (400 ml) and stirred at tempera what ur from 30 to 40°C for 1.5 hours. To the reaction solution was added an aqueous solution of sodium carbonate and was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium carbonate, dried and concentrated, thus obtaining specified in the title compound (281 g)having the following physical properties.

TLC: Rf 0.31 in (hexane:ethyl acetate = 1:1).

1H-NMR (CDCl3): δ 7,33 (d, J=7,50 Hz, 1H), 7,19 (d, J=8,50 Hz, 1H), 6,76-6,84 (m, 3H), 6,72 (s, 1H), is 5.06 (s, 2H), 4,16 (kV, J=7,00 Hz, 2H), 3,85 (s, 3H), 3,52-of 3.60 (m, 2H), 3.25 to to 3.38 (m, 5H), 2,64-of 2.72 (m, 2H), by 2.55 2.63 in (m, 2H), 2,22-of 2.30 (m, 2H), 2,09 (s, 3H), 1,58-1,72 (m, 2H), 1.26 in (t, J=7,00 Hz, 3H), of 0.95 (t, J=7,00 Hz, 3H).

Example 47-1: ethyl-1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinol

Did the method according to example 47, using the compound obtained in example 46-1, instead of the compound obtained in example 46. Thus was obtained is listed in the title compound having the following physical properties.

TLC: Rf of 0.13 (hexane:ethyl acetate = 2:1).

1H-NMR (CDCl3): δ to $ 7.91-of 7.97 (m, 2H), 7,83 (d, J=8,00 Hz, 1H), 7,20 (d, J=8,50 Hz, 1H), 6.73 x-6,79 (m, 2H), 5,32 (s, 2H), 4,16 (kV, J=7,00 Hz, 2H), 3,51-3,61 (m, 2H), 3,23-3,37 (m, 5H), 2,65-by 2.73 (m, 2H), 2,22 is 2.33 (m, 2H), of 2.09 (s, 3H), of 1.26 (t, J=7,00 Hz, 3H).

Example 48: 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

Water (135 ml) solution of sodium hydroxide (28 g) was added to a solution of the compounds is based (262 g), obtained in example 47, in methanol (1320 ml) and stirred at 40°C for 2 hours. To the reaction solution was added 5 mol/l hydrochloric acid (135 ml) and water (1050 ml)and the precipitate was filtered. The precipitate was washed with mixed solvent (470 ml)consisting of methanol and water, and dried. The resulting powder was suspended in acetone (2.0 l) and permissively at 60°C for 2 hours. The reaction solution was cooled. The precipitate was filtered and washed with acetone (390 ml), while receiving specified in the title compound (191 g)having the following physical properties.

Melting point 158-163°C.

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8,50 Hz, 1H), 7,25 (d, J=7,50 Hz, 1H), PC 6.82 (m, 2H), 6,77 (m, 2H), 5,04 (s, 2H), 4,18 (m, 4H), 4,08 (s, 2H), 3,85 (s, 3H), 3,41 (m, 1H), 2,72 (t, J=of 8.06 Hz, 2H), 2,59 (t, J=7,50 Hz, 2H), of 2.23 (m, 5H), of 1.65 (m, 2H), were 0.94 (t, J=7,50 Hz, 3H);

IR (KBr): 3418, 2957, 2931, 2820, 1605, 1500, 1382, 1250, 993, 489 cm-1

Range of powder x-ray diffraction: the measurement results are shown in table 1 and chart shown in figure 1.

Table 1
The d value (Å)The diffraction angle (2θ, °)Relative intensity (%)
d=10,483758,42767,8
d=9,489859,31224,9
d=8,4763110,428to 19.9
d=7,4722711,83448,0
d=6,9914212,65176,4
d=5,8513215,129the 10.1
d=5,2754216,79265,6
d=4,9867217,77249,7
d=4,8477518,286100,0
d=4,7236718,77134,0
d=4,6030519,26719,1
d=4,4554419,912of 37.8
d=4,1959721,15774,6
d=4,124972,525 34,5
d=3,9968922,22434,2
d=3,9113822,71627,2
d=3,7934723,43265,7
d=3,7178723,91542,7
d=3,5099525,35528,2
d=3,3712326,41716,4
d=3,2939327,04822,0

Differential scanning calorimetry (DSC, heating rate: 5°C/min)was confirmed by the presence of an endothermic peak at a temperature of about 170°C. the Diagram shown in figure 2.

Example 48-1: 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

Did the method according to example 48, using the compound obtained in example 47-1, instead of the compound obtained in example 47. Thus was obtained is listed in the title compound having the following physical properties.

Melting point: 155-165°C.

TLC Rf of 0.18 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,89-8,02 (m, 3H), 7,33 (d, J=8,43 Hz, 1H), 6,77-6,86 (m, 2H), 5,32 (s, 2H), 4,13-the 4.29 (m, 4H), 4.09 to (s, 2H), 3.33 and-to 3.49 (m, 1H), 2,68-and 2.79 (m, 2H), 2,17 is 2.33 (m, 5H);

Range of powder x-ray diffraction: the measurement results are shown in table 2 and chart shown in figure 3.

Table 2
The d value (Å)The diffraction angle (2θ, °)Relative intensity (%)
10,479918,43013,7
8,4205010,49711,1
7,3661212,00522,3
6,6849013,23317,2
5,6895815,56213,7
5,4178716,34764,1
5,2525516,86613,6
5,0287017,62231,6
4,8307518,350100,0
4,7563318,64043,4
4,5654519,42744,9
4,4933519,74229,9
4,3782520,26627,6
4,2162621,05329,1
4,1636421,32220,9
4,0144922,12444,6
3,9354322,57517,4
3,8321623,19134,6
3,7720523,56646,3
3,6971224,051of 31.4
3,5886624,78935,6

Differential scanning calorimetry (DSC, heating rate is: 10°C/min)was confirmed by the presence of an endothermic peak at a temperature of about 172°C. The diagram shown in figure 4.

Example 49: monohydrate of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

A mixed solvent consisting of methanol (150 ml) and water (15 ml), was added to the compound (3,10 g)obtained in example 48. The resulting mixture was heated to 60°C. until complete dissolution. To the resulting solution was added water (210 ml) and left to stand at 0°C for 1 hour. The precipitate was filtered. The precipitate was washed mixed solvent consisting of methanol and water (2:3), and dried, thus obtaining specified in the title compound (crystalline substance type a) (2,89 g)having the following physical properties.

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,30 (d, J=8.6 Hz, 1H), 7,24 (d, J=7.7 Hz, 1H), 6,70-6,87 (m, 4H), 5,04 (s, 2H), 4,12-to 4.28 (m, 4H), 4.09 to (s, 2H), of 3.84 (s, 3H), 3,34-to 3.50 (m, 1H), 2,72 (t, J=6,8 Hz, 2H), 2,59 (t, J=7,3 Hz, 2H), 2,16-of 2.30 (m, 5H), 1,57-of 1.74 (m, 2H), were 0.94 (t, J=7,3 Hz, 3H).

Range of powder x-ray diffraction: the measurement results are shown in table 3 and chart shown in figure 5.

Table 3
The d value (Å)The diffraction angle (2θ, °)Relative intensive the industry (%)
d=9,979908,854100,0
d=7,9333111,14418,9
d=7,6813911,51124,0
d=7,2886912,133the 13.4
d=6,6610613,28164,6
d=6,3271313,98628,7
d=6,1080814,490to 12.0
d=5,8001315,2646,1
d=5,0887917,41361,6
d=4,7706918,58422,7
d=4,7338018,73019,6
d=4,5988419,28514,2
d=4,4636119,87521,8
d=4,2432 20,96319,2
d=3,9970622,22352,3
d=3,9588522,44042,5
d=3,7294423,84022,2
d=3,7068323,98824,2
d=3,5730324,90024,0
d=3,5431625,11329,1

Differential scanning calorimetry (DSC, heating rate: 5°C/min)was confirmed by the presence of an endothermic peak at a temperature of about 123°C. and about 168°C. Chart shown in Fig.6.

To headline the compound (crystalline substance type a) (500 mg)obtained in this example was added a mixed solution (3.75 ml)consisting of methyl ethyl ketone and water (10:1). After complete dissolution of the mixture formed a first solution was left to stand at room temperature overnight and then at a low temperature (about 5°C) for 2 days. The formed solid substance was collected by filtration, dried at 40°C at Pont the leaders introduce pressure (about 6 mm Hg) for 4 hours, while receiving specified in the title compound (crystalline substance type) (305 mg) as a white solid having the following physical properties.

Range of powder x-ray diffraction: the measurement results are shown in table 4 and chart shown in Fig.7.

71,3
Table 4
The d value (Å)The diffraction angle (2θ, °)Relative intensity (%)
d=9,735479,07677,1
d=7,8710011,23331,7
d=7,5834411,66029,3
d=6,8379012,93671,2
d=6,4966813,619to 59.4
d=6,1815614,31713,9
d=5,6066015,79420,6
d=5,2414116,902
d=5,1025517,36686,8
d=4,9021618,08149,1
d=4,7192918,78827,4
d=4,4311420,022of 87.8
d=4,1403621,44430,5
d=4,1043021,63530,2
d=3,9673822,391100,0
d=3,9077022,73861,3
d=3,7945723,42532,7
d=3,7150023,93441,6
d=3,6227924,553of 31.4
d=3,5098125,35628,3
d=3,0541029,21828,8

The differential is Naya scanning calorimetry (DSC, heating rate: 5°C/min)was confirmed by the presence of an endothermic peak at a temperature of about 115°C. and about 167°C. Chart shown in Fig.

Example 49-1: monohydrate, 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

Did the method according to example 49, using the compound obtained in example 48-1, instead of the compound obtained in example 48. Thus was obtained is listed in the title compound having the following physical properties.

TLC: Rf of 0.18 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ to $ 7.91-8,03 (m, 3H), 7,35 (d, J=at 8.60 Hz, 1H), 6,79-to 6.88 (m, 2H), of 5.34 (s, 2H), 4,13-the 4.29 (m, 4H), 4,10 (s, 2H), 3.33 and-to 3.49 (m, 1H), 2,68-2,78 (m, 2H), 2,17 is 2.33 (m, 5H);

Range of powder x-ray diffraction: the measurement results are shown in table 5 and chart shown in Fig.9.

Table 5
The d value (Å)The diffraction angle (2θ, °)Relative intensity (%)
11,569447,63576,2
7,7505111,40738,0
7,4356 11,89959,1
6,9590412,71049,7
6,6947113,21420,1
6,4982013,61538,1
6,0485414,63314,3
5,8061915,24725,5
5,2818516,77136,8
5,1391417,24150,6
4,8900918,12620,7
4,6600219,029100,0
4,4468519,95075,8
4,3703220,30336,3
4,2659220,80596,7
4,1796221,240 18,8
4,0553921,89913,6
3,8752122,93064,0
3,7804723,51385,5
3,6459024,39423,1

Differential scanning calorimetry (DSC, heating rate: 10°C/min). The diagram shown in figure 2.

Example 50: hydrochloride 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

0.1 mol/l hydrochloric acid (5,54 ml) was gradually added to the bath with ice to a mixed solution of the compound (201 mg)obtained in example 48, in methanol (8 ml) and water (2 ml). The solution was dried by freezing, while receiving specified in the title compound (218 mg)having the following physical properties.

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CDCl3): δ 7,17-of 7.48 (m, 2H), 6,63-6,92 (m, 4H), of 5.05 (s, 2H), 3,23-4,71 (m, 12H), 2,65-2,82 (m, 2H), 2.57 m (t, J=7,41 Hz, 2H), 2,31 at 2.45 (m, 2H), 2,18 (s, 3H), 1,50-1,79 (m, 2H), of 0.95 (t, J=to 7.32 Hz, 3H).

Example 50-1: hydrochloride 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

Vypolnyaemogo for example, 50, using the compound obtained in example 48-1, instead of the compound obtained in example 48. Thus were obtained the compounds having the following physical properties.

TLC: Rf of 0.18 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,87-of 8.09 (m, 3H), 7,37 (d, J=8,05 Hz, 1H), 6,76-to 6.95 (m, 2H), to 5.35 (s, 2H), 4,21-4,50 (m, 4H), to 4.16 (s, 2H), 3,57-3,82 (m, 1H), 2,58-and 2.83 (m, 2H), 2,15-of 2.38 (m, 5H).

Example 51: 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinol sodium

To the compound (200 mg)obtained in example 48, was added 0.1 mol/l aqueous solution of sodium hydroxide (4,56 ml) and the resulting solution was dried by freezing. The resulting residue was dissolved in water and again dried by freezing, while receiving specified in the title compound (209 mg)having the following physical properties.

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CDCl3): δ 7,21-7,30 (m, 2H), 6,99-to 7.15 (m, 1H), 6,59-of 6.78 (m, 3H), of 4.95 (s, 2H), 3,74 (s, 3H), 3.33 and-to 3.49 (m, 2H), 3,07-3,30 (m, 5H), 2,45-2,70 (m, 4H), 2.06 to of 2.20 (m, 2H), 1,95 (s, 3H), 1,51 by 1.68 (m, 2H), 0,92 (t, J=of 7.23 Hz, 3H).

Examples 51-2 - 51-5

Did the method according to example 51, using an aqueous solution of potassium hydroxide or an aqueous solution of calcium hydroxide instead of an aqueous solution of sodium hydroxide and the compound obtained in example 48-1, instead of the compound obtained in example 48, the cut is ltate which were obtained the corresponding compounds has the following physical properties.

Example 51-2: 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinol potassium

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CDCl3): δ 7,21-7,37 (m, 2H), 7,06 (d, J=9.15, with Hz, 1H), 6,50-6,87 (m, 3H), 4,94 (s, 2H), of 3.73 (s, 3H), 3,30-3,47 (m, 2H), 3,03-3,26 (m, 4H), 2,82-2,99 (m, 1H), 2,41 of 2.68 (m, 4H), 2.06 to of 2.20 (m, 2H), 1,95 (s, 3H), 1,46-1,71 (m, 2H), of 0.91 (t, J=to 7.32 Hz, 3H).

Example 51-3: genitallia salt of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CDCl3): δ 7,17-7,40 (m, 2H), 6,67-of 6.90 (m, 4H), of 5.05 (s, 2H), 3,94 was 4.42 (m, 4H), 3,90 (s, 2H), 3,83 (s, 3H), 3.27 to to 3.56 (m, 1H), 2,69 (t, J=7,3 Hz, 2H), 2,52-2,62 (m, 2H), 2,28-to 2.41 (m, 2H), 2,16 (s, 3H), 1,54-1,72 (m, 2H), of 0.95 (t, J=7,3 Hz, 3H).

Example 51-4: 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinol sodium

TLC: Rf of 0.18 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,89-8,10 (m, 3H), 7,18 and 7.36 (m, 1H), 6.73 x-6,85 (m, 2H), 5,33 (s, 2H), 3,51-to 3.73 (m, 2H), 3,35-of 3.48 (m, 4H), 3,17-3,26 (m, 1H), 2,56-2,78 (m, 2H), 2,17-of 2.34 (m, 2H), 2,10 (s, 3H).

Example 51-5: 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinol potassium

TLC: Rf of 0.18 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,84-8,12 (who, 3H), 7,16-7,38 (m, 1H), 6,65-6,87 (m, 2H), 5,33 (s, 2H), 3,55-3,70 (m, 2H), 3,35-to 3.50 (m, 4H), 3,13-of 3.27 (m, 1H), 2,62-2,77 (m, 2H), 2,18-of 2.30 (m, 2H), 2,10 (s, 3H).

Example 52: 1-oxide, ethyl-1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-apatitenephelite

M-chloroperbenzoic acid (57,3 mg) was added to the bath with ice to a solution of the compound (100 mg)obtained in example 47, in dichloromethane (2 ml) and was stirred for 30 minutes. To the reaction solution was added saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The organic layer was washed with saturated salt solution, dried and concentrated. The resulting amorphous substance (128 mg) was purified by chromatography on a column of silica gel (from a mixture of ethyl acetate:methanol = 4:1-mixture of dichloromethane:methanol = 10:1), separately highlighting specified in the title compound having the following physical properties.

The less polar compound

TLC: Rf 0.26 (ethyl acetate:methanol = 4:1).

1H-NMR (CDCl3): δ 7.24 to 7,38 (m, 2H), 6,65-6,92 (m, 4H), to 5.08 (s, 2H), 4,42-4,69 (m, 2H), 4,27-and 4.40 (m, 2H), 4,22 (kV, J=7.2 Hz, 2H), 3,86 (s, 3H), of 3.48 (s, 2H), 3,18-to 3.34 (m, 1H), of 2.51-to 2.85 (m, 6H), of 2.20 (s, 3H), 1,58-1,74 (m, 2H), 1,28 (t, J=7.2 Hz, 3H), of 0.96 (t, J=7,3 Hz, 3H).

The more polar compound

TLC: Rf of 0.13 (ethyl acetate:methanol = 4:1).

1H-NMR (CDCl3): δ 7,19-7,39 (m, 2H), 6,60-6,98 (m, 4H), to 5.08 (s, 2H), 4,49-of 4.67 (m, 2H), 4,03-4.26 deaths (m, 6H), 3,81-3,98 (m, 4H), 2,47-2,95 (m, 6H), to 2.18 (s, 3H, 1,55-of 1.74 (m, 2H), 1.26 in (t, J=7.4 Hz, 3H), of 0.96 (t, J=7.2 Hz, 3H).

Example 53: 1-oxide 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

5 mol/l aqueous sodium hydroxide solution (700 μl) was added to the bath with ice to mixed solution (2.8 ml) of the compound (less polar compound, 43 mg)obtained in example 52, in tetrahydrofuran and methanol (1:1) and was stirred for 30 minutes. The reaction solution was concentrated and purified by chromatography on a column of silica gel (dichloromethane:methanol:aqueous ammonia = 20:5:1), while receiving specified in the title compound (27 mg)having the following physical properties.

The less polar compound

TLC: Rf of 0.32 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CDCl3): δ 7,20-7,37 (m, 2H), 6,65-6,92 (m, 4H), of 5.05 (s, 2H), 4,82-5,00 (m, 2H), 4,40-4,59 (m, 2H), 4,27 (s, 2H), 3,83 (s, 3H), 3.27 to of 3.42 (m, 1H), 2,63-2,78 (m, 2H), 2,53-2,63 (m, 2H), 2,36 of $ 2.53 (m, 2H), 2,17 (s, 3H), 1,53 is 1.75 (m, 2H), 0,90 is 0.99 (m, 3H).

Compound (more polar compound)obtained in example 52, was subjected to the above interaction, while receiving specified in the title compound having the following physical properties.

The more polar compound

TLC: Rf of 0.30 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CDCl3): δ 7,21-7,35 (m, 2H), 6,66-of 6.90 (m, 4H), 5,04 (s, 2H), 4,49-of 4.77 (m, 6H), 3,82 (s, 3H), 3,52 at 3.69 (who, 1H), 2,37-2,77 (m, 6H), 2,22 (s, 3H), 1,52 is 1.75 (m, 2H), were 0.94 (t, J=7.2 Hz, 3H).

Example 54: Rel-1-({(1R,2R)-6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-1,2,3,4-tetrahydro-2-naphthalenyl}methyl)-3-azetidinone acid (CIS-isomer, RS-configuration is not yet defined)

10% palladium on coal (wet, 10 mg) was added to solution (8.0 ml) of the compound (100 mg)obtained in example 48, methanol, ethyl acetate and tetrahydrofuran (2:1:1) and stirred at room temperature in a stream of hydrogen for 12 hours. The reaction solution was filtered through celite (trade name) and concentrated. The resulting residue was purified by chromatography on a column of silica gel (chloroform:methanol:aqueous ammonia = 80:10:1 to 20:5:1), while receiving specified in the title compound (45 mg)having the following physical properties.

TLC: Rf of 0.43 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ of 7.24 (d, J=7.68 per Hz, 1H), 7,00 (d, J=at 8.60 Hz, 1H), 6,80 (s, 1H), 6,69-of 6.78 (m, 2H), 6,63-6,69 (m, 1H), to 4.98 (s, 2H), 4,12-4,30 (m, 4H), 3,83 (s, 3H), 3.33 and-a 3.50 (m, 1H), 3,23-3,29 (m, 1H), and 3.16 (DD, J=12,81, 8,23 Hz, 1H), 2,75-2,96 (m, 3H), of 2.51 2.63 in (m, 2H), 1,95-to 2.18 (m, 1H), 1,55-of 1.81 (m, 4H), of 1.09 (d, J=7,14 Hz, 3H), were 0.94 (t, J=to 7.32 Hz, 3H).

Example 55: 1-{[6-hydroxy-7-(2-methoxy-4-propylbenzyl)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinone acid (compound 55(a)) and 1-{[6-hydroxy-5-(2-methoxy-4-propylbenzyl)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetilirovaniu (compound 55(b))

To the compound (200 mg)obtained in example 48, was added to the first liquid (200 ml), specified in the description of the test raspadaemost described in the 14th edition of the Japanese Pharmacopoeia, and stirred at 37°C for one day. The reaction solution was cooled to 0°C, and brought the pH to 4-5, using an aqueous solution of sodium hydroxide. The precipitate was filtered. The resulting residue was purified by chromatography on a column of silica gel (chloroform: methanol:aqueous ammonia = 80:10:1 to 20:5:1), while receiving specified in the title compound 55(a) (60 mg) and indicated in the title compound 55(b) (9 mg)having the following physical properties.

Compound 55(a)

TLC: Rf is 0.22 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 6,98 (s, 1H), make 6.90 (d, J=7,50 Hz, 1H), 6.75 in (d, J=1,46 Hz, 1H), only 6.64 (DD, J=7,50, 1,46 Hz, 1H), to 6.57 (s, 1H), 4,08-4,24 (m, 4H), was 4.02 (s, 2H), 3,82 (s, 2H), 3,80 (s, 3H), 3,32 is-3.45 (m, 1H), 2,59-2,69 (m, 2H), 2.49 USD at 2.59 (m, 2H), 2,15-of 2.24 (m, 2H), 2.05 is (s, 3H), 1,55 was 1.69 (m, 2H), to 0.92 (t, J=to 7.32 Hz, 3H).

Compound 55(b)

TLC: Rf is 0.22 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,20 (d, J=8,45 Hz, 1H), 6,72 to 6.75 (m, 1H), 6.73 x (d, J=8,45 Hz, 1H), 6.48 in-6,56 (m, 2H), 4.04 the-4,24 (m, 4H), a 4.03 (s, 2H), 3,92 (s, 2H), a 3.87 (s, 3H), 3,30 is-3.45 (m, 1H), 2,42-to 2.57 (m, 4H), are 2.19 (s, 3H), 2,00 and 2.13 (m, 2H), 1,52 by 1.68 (m, 2H), of 0.91 (t, J=7,41 Hz, 3H).

Examples 56-1 - 56-9

Did the methods of examples 5 and 6, and, if necessary, the method according to example 7 using the appropriate connection benzylbromide instead of 1-bromo-3-(4-forfinal)propane and the corresponding connection of azetidine instead of hydrochloride of methylisatin-3-carboxylate, in the result that were obtained indicated in the title compound having the following physical properties.

Example 56-1: 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone

TLC: Rf of 0.38 (chloroform:methanol:aqueous ammonia= 280:30:1).

1H-NMR (CD3OD): δ of 7.25 (d, J=7,50 Hz, 1H), 7,19 (d, J=8,42 Hz, 1H), 6,68-for 6.81 (m, 4H), 5,02 (s, 2H), of 3.84 (s, 3H), 3,48-to 3.58 (m, 2H), 3,31-to 3.41 (m, 5H), 2,58-of 2.72 (m, 2H), 2,48 (d, J=7,14 Hz, 2H), 2,16-of 2.30 (m, 2H), 2,10 (s, 3H), 1,78-to 1.98 (m, 1H), of 0.91 (d, J=6,59 Hz, 6H).

Example 56-2: 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-N-methyl-3-azetidinone

TLC: Rf of 0.47 (chloroform:methanol:aqueous ammonia= 280:30:1).

1H-NMR (CD3OD): δ 7,26 (d, J=7.68 per Hz, 1H), 7,20 (d, J=8,23 Hz, 1H), 6,68-PC 6.82 (m, 4H), 5,02 (s, 2H), of 3.84 (s, 3H), 3.46 in-of 3.60 (m, 2H), 3,19-to 3.41 (m, 5H), of 2.72 (s, 3H), 2,60-2,70 (m, 2H), 2,48 (d, J=to 7.32 Hz, 2H), 2,15-2,30 (m, 2H), 2,11 (s, 3H), 1,81 is 1.96 (m, 1H), of 0.91 (d, J=6,59 Hz, 6H).

Example 56-3: N-hydroxy-1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 80:10:1).

1H-NMR (CD3OD): δ 7,26 (d, J=7.68 per Hz, 1H), 7,20 (d, J=8,42 Hz, 1H), 6,66-6,83 (m, 4H), 5,02 (s, 2H), of 3.84 (s, 3H), 3.46 in is 3.57 (m, 2H), 3,34-3,44 (m, 4H), 3,10-3,26 (m, 1H), 2,59-a 2.71 (m, 2H), 2,47 (d, J=to 7.32 Hz, 2H), 2,14-2,30 (m, 2H), 2,10 (s, 3H), 1,80 is 1.96 (m, 1H), of 0.91 (d, J=6,59 Hz, 6H).

Example 56-4: 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-2-naphthyl}methyl)-3-azetidin Urbanova acid

TLC: Rf 0.21 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD:CDCl3=3,6:1): δ 8,03 (d, J=10,06 Hz, 1H), 7,66 (d, J=at 8.60 Hz, 1H), 7.24 to 7,39 (m, 4H), 6.73 x-PC 6.82 (m, 2H), 5,17 (s, 2H), 4,56 (s, 2H), 4,11-of 4.25 (m, 4H), a 3.87 (s, 3H), 3,31-of 3.46 (m, 1H), 2,72 (s, 3H), 2,58 (t, J=of 7.70 Hz, 2H), 1,58-1,72 (m, 2H), were 0.94 (t, J=to 7.32 Hz, 3H).

Example 56-5: 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-2-naphthyl)methyl]-3-azetidinone acid

TLC: Rf 0.31 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ to 8.14 (d, J=9.15, with Hz, 1H), of 7.96-8,10 (m, 3H), 7,72 (d, J=at 8.60 Hz, 1H), 7,43 (d, J=at 8.60 Hz, 1H), 7,31-7,39 (m, 2H), 5,48 (s, 2H), 4,60 (s, 2H), 4,14-of 4.25 (m, 4H), 3.33 and-of 3.48 (m, 1H), 2,75 (s, 3H).

Example 56-6: 1-[(6-{[4-(2-hydroxypropyl)-2-methoxybenzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,33 (d, J=8,50 Hz, 1H), 7,28 (d, J=7,50 Hz, 1H), 6.87 in (d, J=1.50 Hz, 1H), 6,77-6,85 (m, 3H), of 5.05 (s, 2H), 4,13-of 4.25 (m, 4H), 4.09 to (s, 2H), 3,91-4,01 (m, 1H), 3,86 (s, 3H), 3,36-3,47 (m, 1H), 2,63-2,82 (m, 4H), 2,18-of 2.28 (m, 5H)and 1.15 (d, J=6,00 Hz, 3H).

Example 56-7: 1-[(6-{[4-(hydroxypropyl)-2-methoxybenzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf 0.14 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,26-7,35 (m, 2H), 7,00 (d, J=1,28 Hz, 1H), 6.89 in (DD, J=7,78, of 1.28 Hz, 1H), PC 6.82 (DD, J=to 8.41, to 2.74 Hz, 1H), 6,78 (d, J=2,74 Hz, 1H), is 5.06 (s, 2H), to 4.52 (t, J=6,50 Hz, 1H), 4.09 to 4.26 deaths (m, 4H), 4,06 (s, 2H), a 3.87 (s, 3H), 3.33 and-to 3.49 (m, 1H), 2,652,76 (m, 2H), 2,16-to 2.29 (m, 5H), 1,64 of-1.83 (m, 2H), of 0.90 (t, J=7,41 Hz, 3H).

Example 56-8: 1-({6-[(5-hydroxy-2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 20:5:1).

Example 56-9: 1-({6-[(3-hydroxy-2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

Examples 57-1 - 57-87

Did the methods of examples 5, 6 and 7, using the appropriate halide instead of 1-bromo-3-(4-forfinal)propane, resulting in the received specified in the title compound having the following physical properties.

Example 57-1: 1-{[6-(2-hydroxy-3-phenylpropoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinone acid

TLC: Rf 0,13 (butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8,42 Hz, 1H), 7,08-7,28 (m, 5H), 6,76 (DD, J=8,42, 2,70 Hz, 1H), 6,72 (d, J=2,70 Hz, 1H), 4,08-4,24 (m, 5H), 4,07 (s, 2H), 3,93 (DD, J=9,60, 3,90 Hz, 1H), 3,85 (DD, J=9,60, 5,70 Hz, 1H), 3,35-3,47 (m, 1H), 2,96 (DD, J=13,50, 6,30 Hz, 1H), 2,85 (DD, J=13,50, 7,20 Hz, 1H), 2,67 is 2.75 (m, 2H), measuring 2.20 (s, 3H), 2,17-of 2.28 (m, 2H).

Example 57-2: 1-({6-[3-(4-forfinal)-2-methoxypropane]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.15 (butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ to 7.32 (d, J=at 8.60 Hz, 1H), 7,19-7,29 (m, 2H), 6,92-7,05 (m, 2H), 6,76 (DD, J=8,60, of 2.56 Hz, 1H), of 6.71 (d, J=2,56 Hz, 1H), 4,12-4,27 (m, 4H), 4,10 (s, 2H), 3,99 (l is, J=9,90, 3,90 Hz, 1H), 3,89 (DD, J=9,90, 5,10 Hz, 1H), 3,67-with 3.79 (m, 1H), 3,40 (s, 3H), 3,37-of 3.48 (m, 1H), 2,83-3,00 (m, 2H), 2,65 was 2.76 (m, 2H), measuring 2.20 (s, 3H), 2,14-of 2.28 (m, 2H).

Example 57-3: 1-({1-chloro-6-[(4-isobutylphenyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ EUR 7.57 (d, J=8,4 Hz, 1H), 7,32 (d, J=8.1 Hz, 2H), 7,15 (d, J=8.1 Hz, 2H), 6.90 to (DD, J=8,4, and 2.6 Hz, 1H), 6,86 (d, J=2.6 Hz, 1H), is 5.06 (s, 2H), 4,23 (d, J=8.1 Hz, 4H), 4,18 (s, 2H), 3,36-3,51 (m, 1H), 2,84 (t, J=7.2 Hz, 2H), 2,41 is 2.51 (m, 4H), 1.77 in-of 1.94 (m, 1H), 0,89 (d, J=6.6 Hz, 6H).

Example 57-4: 1-[(2Z)-3-chloro-3-(4-{[(2S)-3-(4-forfinal)-2-methylpropyl]oxy}phenyl)-2-propenyl]-3-azetidinone acid

TLC: Rf 0,22 (butanol:acetic acid:water= 20:4:1).

1H-NMR (CDCl3): δ rate of 7.54 (d, J=9,00 Hz, 2H),? 7.04 baby mortality-to 7.15 (m, 2H), 6,95 (t, J=8,69 Hz, 2H), 6,85 (d, J=9,00 Hz, 2H), x 6.15 (t, J=6,86 Hz, 1H), 4,16-4,32 (m, 2H), 3,89-of 4.05 (m, 4H), of 3.78 (d, J=5,85 Hz, 2H), 3,18-to 3.35 (m, 1H), 2,82 (DD, J=13,50, 6,60 Hz, 1H), 2,54 (DD, J=13,50, 7,80 Hz, 1H), 2,08-of 2.30 (m, 1H), 1,01 (d, J=6,77 Hz, 3H).

Example 57-5: 1-({6-[2-(4-terbisil)-3-methoxypropane]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.15 (butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ 7,26 (d, J=8,42 Hz, 1H), 7,14-7,22 (m, 2H), 6,91? 7.04 baby mortality (m, 2H), 6,72 (DD, J=8,42, of 2.56 Hz, 1H), to 6.67 (d, J=2,56 Hz, 1H), 3.75 to as 4.02 (m, 7H), to 3.41 (d, J=5,85 Hz, 2H), 3.25 to to 3.38 (m, 5H), was 2.76 (d, J=7.68 per Hz, 2H,), 2,63-of 2.72 (m, 2H), 2,18-2,31 (m, 3H), of 2.16 (s, 3H).

Example 57-6: 1-({6-[(3-isobutylphenyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidin Urbanova acid

TLC: Rf of 0.29 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=at 8.60 Hz, 1H), 7.18 in-7,30 (m, 3H), 7,06-7,11 (m, 1H), at 6.84 (DD, J=8,60, to 2.74 Hz, 1H), 6,79 (d, J=2,74 Hz, 1H), of 5.05 (s, 2H), 4,12-4,27 (m, 4H), 4.09 to (s, 2H), 3,34-3,47 (m, 1H), 2,66 was 2.76 (m, 2H), 2,47 (d, J=to 7.32 Hz, 2H), 2,18-of 2.28 (m, 5H), 1.77 in-1,92 (m, 1H), from 0.88 (d, J=6,59 Hz, 6H).

Example 57-7: 1-[(2E)-3-(4-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-2-were)-2-butenyl]-3-azetidinone acid

TLC: Rf of 0.18 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ of 7.25 (d, J=8,50 Hz, 2H), 7,15 (d, J=8,50 Hz, 2H), of 6.96 (d, J=8,00 Hz, 1H), 6,65-6,72 (m, 2H), 5,23 (t, J=7,00 Hz, 1H), 4,15-4.26 deaths (m, 4H), of 3.97 (d, J=7,00 Hz, 2H, in), 3.75 (d, J=5.50 Hz, 2H), 3,37-3,44 (m, 1H), 2,82 (DD, J=13,50, 6,50 Hz, 1H), 2,55 (DD, J=13,50, 7,50 Hz, 1H), of 2.23 (s, 3H), 2,13-2,22 (m, 1H), 2.06 to (s, 3H), and 1.00 (d, J=7,00 Hz, 3H).

Example 57-8: 1-[(1-chloro-6-{[(2S)-3-(4-chloro-2-forfinal)-2-methylpropyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,51 (d, J=at 8.60 Hz, 1H), 7,21 (t, J=to 8.20 Hz, 1H), 7,06-7,17 (m, 2H), 6,76 (DD, J=8,60, 2,70 Hz, 1H), of 6.71 (d, J=2,70 Hz, 1H), a 3.87-of 3.97 (m, 2H), 3.75 to a 3.87 (m, 6H), 3,24-to 3.41 (m, 1H), 2,87 (DD, J=12,40, 5,30 Hz, 1H), and 2.79 (t, J=7,10 Hz, 2H), 2,60 (DD, J=12,40, of 8.00 Hz, 1H), 2,43 (t, J=7,10 Hz, 2H), 2,16-of 2.30 (m, 1H), 1,01 (d, J=to 6.80 Hz, 3H).

Example 57-9: 1-({6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-I Is R (CD 3OD): δ 7,26-7,39 (m, 5H), 6.75 in (DD, J=8,50, 2,70 Hz, 1H), 6,70 (d, J=2,70 Hz, 1H), a 4.83-4.92 in (m, 1H), 4,07-of 4.25 (m, 5H), Android 4.04 (s, 2H), 3,89-4,01 (m, 1H), 3.33 and-3,47 (m, 1H), 2,71 (t, J=7,00 Hz, 2H), 2.00 in to 2.29 (m, 7H).

Example 57-10: 1-[(2Z)-3-chloro-3-(4-{[(2S)-3-(4-forfinal)-2-methylpropyl]oxy}-2-were)-2-propenyl]-3-azetidinone acid

TLC: Rf 0,24 (butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ 7,12-7,21 (m, 3H), 6.89 in-7,03 (m, 2H), 6,67-of 6.78 (m, 2H), 5,79 (t, J=6,90 Hz, 1H), 4,16-4,32 (m, 4H), 4.09 to (d, J=6,90 Hz, 2H), 3,70-of 3.85 (m, 2H), 3,34-3,51 (m, 1H), 2,82 (DD, J=13,54, 6,40 Hz, 1H), 2,54 (DD, J=13,54, to 7.68 Hz, 1H), 2,33 (s, 3H), 2,10-of 2.25 (m, 1H), and 1.00 (d, J=6,77 Hz, 3H).

Example 57-11: 1-({6-[3-(4-chlorophenyl)-3-methoxypropane]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf is 0.22 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7.24 to 7,41 (m, 5H), 6,74 (DD, J=8,6, and 2.6 Hz, 1H), 6,69 (d, J=2.6 Hz, 1H), 4,42 (DD, J=7,9, 5.3 Hz, 1H), 4,06-to 4.23 (m, 5H), is 4.03 (s, 2H), 3,85-of 3.96 (m, 1H), 3,35-of 3.46 (m, 1H), 3,19 (s, 3H), 2,71 (t, J=7,3 Hz, 2H), 2,10-to 2.29 (m, 5H), 1,92-2,07 (m, 2H).

Example 57-12: 1-({1-chloro-6-[(3-isobutylphenyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf is 0.22 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,56 (d, J=8.6 Hz, 1H), 7.18 in-7,31 (m, 3H), 7,07-7,13 (m, 1H), 6,83-6,92 (m, 2H), to 5.08 (s, 2H), 4,21 (d, J=7.7 Hz, 4H), to 4.16 (s, 2H), 3,35-to 3.50 (m, 1H), and 2.83 (t, J=7,0 Hz, 2H), 2,41-2,52 (m, 4H), 1,78-of 1.93 (m, 1H), from 0.88 (d, J=6.6 Hz, 6H).

Example 57-13: 1-({6-[3-(4,4-diverticulosis)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-AZ is thinkabout acid

TLC: Rf 0.28 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7.29 trend (d, J=8,4 Hz, 1H), 6.75 in (DD, J=8,4, 2.8 Hz, 1H), 6,70 (d, J=2,8 Hz, 1H), 4,03-4,22 (m, 4H), of 4.00 (s, 2H), 3.96 points (t, J=6.4 Hz, 2H), 3,32-of 3.46 (m, 1H), 2,71 (t, J=7,1 Hz, 2H), 2,23 (t, J=7,1 Hz, 2H), 2,18 (s, 3H), 1,91-of 2.09 (m, 2H), 1,58-of 1.88 (m, 7H), 1,33-1,49 (m, 2H), to 1.14 to 1.31 (m, 2H).

Example 57-14: 1-({6-[(6-isobutyl-3-pyridinyl)methoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinol sodium

TLC: Rf of 0.15 (butanol:acetic acid:water= 20:4:1).

1H-NMR (CD3OD): δ 8,49 (d, J=1,46 Hz, 1H), 7,82 (DD, J=8,05, 1,46 Hz, 1H), 7,29 (d, J=8,05 Hz, 1H), 7,21 (d, J=8,23 Hz, 1H), 6,72-6,86 (m, 2H), 5,09 (s, 2H), 3,54 (t, J=to 7.59 Hz, 2H), 3,14-3,39 (m, 3H), 2,55-by 2.73 (m, 5H), 2,17-to 2.29 (m, 2H), 2,09 (s, 3H), 1,96-of 2.15 (m, 2H), 0,93 (d, J=6,59 Hz, 6H).

Example 57-15: 1-({6-[(2-fluoro-4-isobutylphenyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0.31 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31-7,42 (m, 2H), 6.90 to-7,01 (m, 2H), 6,86 (DD, J=8,50, 2,50 Hz, 1H), for 6.81 (d, J=2,50 Hz, 1H), 5,09 (s, 2H), 4,11-4,24 (m, 4H), 4,08 (s, 2H), 3,35-3,47 (m, 1H), 2,69-2,77 (m, 2H), 2.49 USD (d, J=7,00 Hz, 2H), 2,19-of 2.28 (m, 5H), 1,79-of 1.94 (m, 1H), 0,90 (d, J=6,50 Hz, 6H).

Example 57-16: 1-({6-[(5-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf to 0.19 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,30 (d, J=8,50 Hz, 1H), 7,14 (d, J=2.00 Hz, 1H), 7,05 (DD, J=8,50, 2.00 Hz, 1H), 6.89 in (d, J=8,50 Hz, 1H), PC 6.82 (DD, J=8,50, 2,50 Hz, 1H), 6,78 (d,J=2,50 Hz, 1H), 5,07 (s, 2H), 4,11-to 4.23 (m, 4H), 4,06 (s, 2H), of 3.84 (s, 3H), 3,36 is-3.45 (m, 1H), 2,66 was 2.76 (m, 2H), 2,39 (d, J=7,00 Hz, 2H), 2,18-of 2.28 (m, 5H), 1.70 to of 1.84 (m, 1H), 0,85 (d, J=6,50 Hz, 6H).

Example 57-17: 1-({6-[(2,4-dimethoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8,4 Hz, 1H), 7,26 (d, J=8,2 Hz, 1H), PC 6.82 (DD, J=8,4, and 2.6 Hz, 1H), 6,77 (d, J=2.6 Hz, 1H), 6,56 (d, J=2.4 Hz, 1H), 6,50 (DD, J=8,2, 2.4 Hz, 1H), 4,99 (s, 2H), 4,10-4,27 (m, 4H), 4.09 to (C, 2H), 3,83 (s, 3H), 3,79 (s, 3H), 3,34-of 3.48 (m, 1H), 2,72 (t, J=6.0 Hz, 2H), 2,17-of 2.30 (m, 5H).

Example 57-18: 1-[(6-{[4-(benzyloxy)-2-methoxybenzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7.23 percent-of 7.48 (m, 7H), PC 6.82 (DD, J=8,4, 2,9 Hz, 1H), 6,77 (d, J=2,9 Hz, 1H), only 6.64 (d, J=2.0 Hz, 1H), return of 6.58 (DD, J=8,3, 2.0 Hz, 1H), 5,09 (s, 2H), 5,00 (s, 2H), 4,10-the 4.29 (m, 4H), 4.09 to (s, 2H), 3,82 (s, 3H), 3,33-to 3.50 (m, 1H), 2,72 (t, J=5.7 Hz, 2H), 2,17-to 2.29 (m, 5H).

Example 57-19: 1-({6-[(3-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0.21 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ to 7.32 (d, J=8,50 Hz, 1H), 7,28 (DD, J=7,50, 2.00 Hz, 1H), 7,15 (DD, J=7,50, 2.00 Hz, 1H),? 7.04 baby mortality (t, J=7,50 Hz, 1H), 6,85 (DD, J=8,50, 2,50 Hz, 1H), 6,80 (d, J=2,50 Hz, 1H), 5,10 (s, 2H), 4,10-4,24 (m, 4H), 4,07 (s, 2H), 3,76 (s, 3H), 3,34-of 3.48 (m, 1H), 2,68 was 2.76 (m, 2H), 2,54 (d, J=7,00 Hz, 2H), 2,19-of 2.28 (m, 5H), 1,87-2,02 (m, 1H), of 0.91 (d, J=6,50 Hz, 6H).

Por the measures 57-20: 1-({6-[(4-isobutyl-2-methylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0.21 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8,50 Hz, 1H), 7,25 (d, J=7,50 Hz, 1H), 6,99 (s, 1H), 6,95 (d, J=7,50 Hz, 1H), 6,85 (DD, J=8,50, 2,50 Hz, 1H), 6,80 (d, J=2,50 Hz, 1H), 5,02 (s, 2H), 4,01-4,18 (m, 4H), to 3.99 (s, 2H), 3,34 is-3.45 (m, 1H), 2,69-2,77 (m, 2H), 2,44 (d, J=7,00 Hz, 2H), 2,33 (s, 3H), 2,18-to 2.29 (m, 5H), 1.77 in-of 1.93 (m, 1H), 0,90 (d, J=6,50 Hz, 6H).

Example 57-21: 1-({6-[(4-butyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.36 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8.6 Hz, 1H), 7,25 (d, J=7.5 Hz, 1H), 6,72-6,86 (m, 4H), 5,04 (s, 2H), 4,12-the 4.29 (m, 4H), 4,10 (s, 2H), of 3.84 (s, 3H), 3,34-to 3.49 (m, 1H), 2,72 (t, J=6,8 Hz, 2H), 2,61 (t, J=7.7 Hz, 2H), 2,15-2,31 (m, 5H), 1,54-to 1.67 (m, 2H), 1.30 and the 1.44 (m, 2H), were 0.94 (t, J=7,3 Hz, 3H).

Example 57-22: 1-[(6-{[4-(2,2-dimethylpropyl)-2-methoxybenzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.36 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ to 7.32 (d, J=8.6 Hz, 1H), 7,26 (d, J=7.5 Hz, 1H), 6,68-to 6.88 (m, 4H), of 5.05 (s, 2H), 4,12-to 4.28 (m, 4H), 4,10 (s, 2H), of 3.84 (s, 3H), 3.33 and-3,51 (m, 1H), 2,68-2,78 (m, 2H), of 2.51 (s, 2H), 2,16-of 2.30 (m, 5H)that is 0.92 (s, 9H).

Example 57-23: 1-({6-[(4-isopropoxy-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.36 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8.6 Hz, 1H), 7.23 percent (d, J=8,4 Hz, 1H), PC 6.82 (DD, J=8,6, 2.7 Hz, 1H), 6,77 (d, J=2.7 Hz, 1H), of 6.52 (d, J=2.4 Hz, 1H), and 48 (DD, J=an 8.4, 2.4 Hz, 1H), to 4.98 (s, 2H), 4.53-in-of 4.66 (m, 1H), 4,12-the 4.29 (m, 4H), 4,10 (s, 2H), 3,81 (s, 3H), 3,34-to 3.50 (m, 1H), 2,72 (t, J=7,0 Hz, 2H), 2,16-of 2.30 (m, 5H), of 1.30 (d, J=6.0 Hz, 6H).

Example 57-24: 1-({6-[(4-cyclohexyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.32 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ to 7.32 (d, J=8,4 Hz, 1H), 7,26 (d, J=7.7 Hz, 1H), 6.73 x-to 6.88 (m, 4H), 5,04 (s, 2H), 4,12-4,30 (m, 4H), 4,11 (s, 2H), 3,85 (s, 3H), 3,36-3,51 (m, 1H), 2,72 (t, J=7,0 Hz, 2H), 2.40 a-2,62 (m, 1H), 2,15-2,30 (m, 5H), 1,69-of 1.93 (m, 5H), 1,22-of 1.56 (m, 5H).

Example 57-25: 1-({6-[(4-isobutyl-2-isopropoxyphenyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.32 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8,4 Hz, 1H), 7,25 (d, J=7.7 Hz, 1H), 6,67-to 6.88 (m, 4H), to 5.03 (s, 2H), 4,57-4,70 (m, 1H), 4,12-the 4.29 (m, 4H), 4,10 (s, 2H), 3,35-to 3.50 (m, 1H), 2,72 (t, J=6,8 Hz, 2H), 2,45 (d, J=7,3 Hz, 2H,), 2,16-of 2.30 (m, 5H), 1.77 in-1,95 (m, 1H), 1,31 (d, J=5,9 Hz, 6H), of 0.90 (d, J=6.8 Hz, 6H).

Example 57-26: 1-[(6-{[4-isobutyl-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf to 0.17 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ a 7.62 (d, J=8,00 Hz, 1H), 7,51 (s, 1H), 7,42 (d, J=8,00 Hz, 1H), 7,34 (d, J=8,50 Hz, 1H), 6,78-6,85 (m, 2H), total of 5.21 (s, 2H), 4,11-of 4.25 (m, 4H), 4.09 to (s, 2H), 3,35-to 3.49 (m, 1H), 2,69-2,77 (m, 2H), 2.57 m (d, J=7,00 Hz, 2H), 2,19-of 2.27 (m, 5H), 1,84-of 1.97 (m, 1H), of 0.91 (d, J=6,50 Hz, 6H).

Example 57-27: 1-({6-[(2-chloro-4-isobutylphenyl)oxy]-1-methyl-3,4-d the hydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.23 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ the 7.43 (d, J=8,00 Hz, 1H), 7,34 (d, J=8,50 Hz, 1H), 7.23 percent (d, J=1.50 Hz, 1H), 7,11 (DD, J=8,00, 1.50 Hz, 1H), 6,85 (DD, J=8,50, 2,50 Hz, 1H), for 6.81 (d, J=2,50 Hz, 1H), 5,13 (s, 2H), 4,10-4,24 (m, 4H), 4,08 (s, 2H), 3,36-3,47 (m, 1H), 2,70-2,78 (m, 2H), 2,48 (d, J=7,00 Hz, 2H), 2,19-of 2.28 (m, 5H), 1,81-of 1.92 (m, 1H), 0,90 (d, J=6,50 Hz, 6H).

Example 57-28: 1-({6-[(2-methoxy-4-{[(1S)-1-methylpropyl]oxy}benzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.32 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8.6 Hz, 1H), 7.23 percent (d, J=8,4 Hz, 1H), PC 6.82 (DD, J=8,4, 2.7 Hz, 1H), 6,77 (d, J=2.7 Hz, 1H), 6,53 (d, J=2.2 Hz, 1H), 6.48 in (DD, J=8,6, 2.2 Hz, 1H), 4,99 (s, 2H), 4,29 is 4.45 (m, 1H), 4,11-4,28 (m, 4H), 4.09 to (s, 2H), 3,82 (s, 3H), 3.33 and-3,51 (m, 1H), 2,72 (t, J=6,8 Hz, 2H), 2,16-to 2.29 (m, 5H), 1,54-to 1.79 (m, 2H), 1.26 in (d, J=6.0 Hz, 3H), and 0.98 (t, J=7.5 Hz, 3H).

Example 57-29: 1-({6-[(2-methoxy-4-{[(1R)-1-methylpropyl]oxy}benzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.32 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8.6 Hz, 1H), 7.23 percent (d, J=8,4 Hz, 1H), PC 6.82 (DD, J=8,4, 2.7 Hz, 1H), 6,77 (d, J=2.7 Hz, 1H), 6,53 (d, J=2.2 Hz, 1H), 6.48 in (DD, J=8,6, 2.2 Hz, 1H), 4,99 (s, 2H), 4,29 is 4.45 (m, 1H), 4,11-4,28 (m, 4H), 4.09 to (s, 2H), 3,82 (s, 3H), 3.33 and-3,51 (m, 1H), 2,72 (t, J=6,8 Hz, 2H), 2,16-to 2.29 (m, 5H), 1,54-to 1.79 (m, 2H), 1.26 in (d, J=6.0 Hz, 3H), and 0.98 (t, J=7.5 Hz, 3H).

Example 57 within 30: 1-({6-[(3-isobutyl-5-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8,50 Hz, 1H), 6,78-6,86 (m, 4H), 6,62 of 6.66 (m, 1H), to 5.03 (s, 2H), 4,10-4.26 deaths (m, 4H), 4,07 (s, 2H), of 3.77 (s, 3H), 3,36-3,47 (m, 1H), 2,68 was 2.76 (m, 2H), 2,44 (d, J=7,00 Hz, 2H), 2,18-of 2.27 (m, 5H), 1,79 is 1.91 (m, 1H), from 0.88 (d, J=6,50 Hz, 6H).

Example 57-31: 1-({6-[(3-isobutyl-4-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,30 (d, J=8,50 Hz, 1H), 7,22 (DD, J=8,00, 2.00 Hz, 1H), 7,12 (d, J=2.00 Hz, 1H), make 6.90 (d, J=8,00 Hz, 1H), 6,83 (DD, J=8,50, 2,50 Hz, 1H), 6,78 (d, J=2,50 Hz, 1H), to 4.98 (s, 2H), 4,07-4,22 (m, 4H), of 4.05 (s, 2H), 3,80 (s, 3H), 3,35-of 3.46 (m, 1H), 2,66 was 2.76 (m, 2H), 2,46 (d, J=7,00 Hz, 2H), 2,18-of 2.27 (m, 5H), 1,81 is 1.96 (m, 1H), 0,86 (d, J=6,50 Hz, 6H).

Example 57-32: 1-[(1-methyl-6-{[4-propoxy-2-(trifluoromethyl)benzyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.33 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,60 (d, J=8,80 Hz, 1H), 7,34 (d, J=at 8.60 Hz, 1H), 7,22 (d, J=2,60 Hz, 1H), 7,15 (DD, J=8,60, 2,60 Hz, 1H), 6,74-6,87 (m, 2H), 5,14 (s, 2H), 4,12-the 4.29 (m, 4H), 4,10 (s, 2H), 3,99 (t, J=6,50 Hz, 2H), 3,34-to 3.49 (m, 1H), 2,73 (t, J=7,00 Hz, 2H), 2,16-of 2.30 (m, 5H), 1,74-1,89 (m, 2H), of 1.05 (t, J=7,40 Hz, 3H).

Example 57-33: 1-[(6-{[4-butoxy-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.33 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ to 7.59 (d, J=at 8.60 Hz, 1H), 7,34 (d, J=860 Hz, 1H), 7,21 (d, J=2,60 Hz, 1H), 7,15 (DD, J=8,60, 2,60 Hz, 1H), 6.75 in-6,86 (m, 2H), 5,14 (s, 2H), 4,12-the 4.29 (m, 4H), 4,11 (s, 2H), Android 4.04 (t, J=6,40 Hz, 2H), 3,36-to 3.50 (m, 1H), 2,73 (t, J=7,00 Hz, 2H), 2,16-2,31 (m, 5H), 1.70 to of 1.85 (m, 2H), 1,44 is 1.60 (m, 2H), 0,99 (t, J=7,40 Hz, 3H).

Example 57-34: 1-[(6-{[4-(cyclobutylamine)-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.33 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,58 (d, J=8,40 Hz, 1H), 7,34 (d, J=8,40 Hz, 1H), 7,13 (d, J=2,70 Hz, 1H), 7,06 (DD, J=8,40, 2,70 Hz, 1H), 6,74-6,86 (m, 2H), 5,14 (s, 2H), 4,68-to 4.81 (m, 1H), 4,11-or 4.31 (m, 4H), 4,11 (s, 2H), 3.33 and-3,51 (m, 1H), 2,73 (t, J=7,10 Hz, 2H), 2,39-to 2.57 (m, 2H), 2,04 of-2.32 (m, 7H), 1,65-of 1.97 (m, 2H).

Example 57-35: 1-[(6-{[4-(cyclopentyloxy)-3-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.33 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,58 (d, J=8,40 Hz, 1H), 7,34 (d, J=at 8.60 Hz, 1H), 7,18 (d, J=2,70 Hz, 1H), 7,13 (DD, J=8,60, 2,70 Hz, 1H), 6,74-6,87 (m, 2H), 5,14 (s, 2H) 4.80 to 4,94 (m, 1H), 4,12-4,30 (m, 4H), 4,11 (s, 2H), 3,35-to 3.50 (m, 1H), 2,73 (t, J=7,30 Hz, 2H), 2,16 of-2.32 (m, 5H), 1.56 to 2,07 (m, 8H).

Example 57-36: 1-[(6-{[4-isobutoxy-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.33 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,60 (d, J=9,00 Hz, 1H), 7,34 (d, J=8,40 Hz, 1H), 7,22 (d, J=2,60 Hz, 1H), 7,15 (DD, J=8,40, 2,60 Hz, 1H), 6.73 x-to 6.88 (m, 2H), 5,14 (s, 2H), 4,10-4,30 (m, 4H), 4,10 (s, 2H), 3,80 (d, J=6,40 Hz, 2H), 3.33 and-to 3.50 (m, H), by 2.73 (t, J=7,30 Hz, 2H), 2,16 of-2.32 (m, 5H), 1,99-of 2.16 (m, 1H), was 1.04 (d, J=6,60 Hz, 6H).

Example 57-37: 1-({6-[(2-chloro-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.15 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ the 7.43 (d, J=8,00 Hz, 1H), 7,34 (d, J=8,50 Hz, 1H), 7,26 (d, J=1.50 Hz, 1H), 7,14 (DD, J=8,00, 1.50 Hz, 1H), 6,85 (DD, J=8,50, 2,50 Hz, 1H), for 6.81 (d, J=2,50 Hz, 1H), 5,13 (s, 2H), 4,11-4.26 deaths (m, 4H), 4,08 (s, 2H), 3,36-to 3.50 (m, 1H), 2,69-2,78 (m, 2H), 2,59 (t, J=7,50 Hz, 2H), 2,18-of 2.28 (m, 5H), 1.56 to around 1.74 (m, 2H), were 0.94 (t, J=7,50 Hz, 3H).

Example 57-38: 1-[(1-methyl-6-{[4-(trifluoromethyl)benzyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf 0.14 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,66 (d, J=8,50 Hz, 2H), to 7.64 (d, J=8,50 Hz, 2H), 7,32 (d, J=8,50 Hz, 1H), PC 6.82-6.89 in (m, 2H), 5,19 (s, 2H), 4,10-of 4.25 (m, 4H), 4,07 (s, 2H), 3,35-3,47 (m, 1H), 2,69-2,78 (m, 2H), 2,18-of 2.28 (m, 5H).

Example 57-39: 1-({6-[(2,4-dimethylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.15 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,33 (d, J=8,50 Hz, 1H), 7.23 percent (d, J=7,50 Hz, 1H), 7,03 (s, 1H), 6,98 (d, J=7,50 Hz, 1H), 6,85 (DD, J=8,50, 2,50 Hz, 1H), 6,80 (d, J=2,50 Hz, 1H), 5,02 (s, 2H), 4,12-of 4.25 (m, 4H), 4,08 (s, 2H), 3,36-3,47 (m, 1H), 2,70-2,78 (m, 2H), 2,31 (s, 3H), to 2.29 (s, 3H), 2,19-of 2.28 (m, 5H).

Example 57-40: 1-[(6-{[2-fluoro-4-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.15 (chloroform:is ethanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,74 (DD, J=7,50, 7,50 Hz, 1H), 7,46-of 7.55 (m, 2H), 7,35 (d, J=8,50 Hz, 1H), to 6.88 (DD, J=8,50, 2,50 Hz, 1H), at 6.84 (d, J=2,50 Hz, 1H), 5,22 (s, 2H), 4,11-of 4.25 (m, 4H), 4,08 (s, 2H), 3,36-of 3.48 (m, 1H), 2.71 to 2,78 (m, 2H), 2,19-of 2.30 (m, 5H).

Example 57-41: 1-({6-[(2-isobutyl-6-methoxy-4-pyridinyl)methoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8,50 Hz, 1H), 6,78-6,85 (m, 3H), 6,63 (s, 1H), 5,07 (s, 2H), 4,10-of 4.25 (m, 4H), 4,07 (s, 2H), a 3.87 (s, 3H), 3,35-of 3.48 (m, 1H), 2,67-2,77 (m, 2H), 2,53 (d, J=7,00 Hz, 2H), 2,18-of 2.28 (m, 5H), 2,03-of 2.15 (m, 1H), 0,90 (d, J=6,50 Hz, 6H).

Example 57-42: 1-({6-[(5-chloro-6-isobutyl-3-pyridinyl)methoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 8,46 (d, J=2.00 Hz, 1H), of 7.90 (d, J=2.00 Hz, 1H), 7,34 (d, J=8,50 Hz, 1H), 6,82-6,91 (m, 2H), 5,13 (s, 2H), 4,11-of 4.25 (m, 4H), 4,08 (s, 2H), 3,37-of 3.46 (m, 1H), and 2.83 (d, J=7,50 Hz, 2H), 2.71 to 2,78 (m, 2H,), 2,11-to 2.29 (m, 6H), of 0.95 (d, J=6,50 Hz, 6H).

Example 57-43: 1-({6-[(2-fluoro-4-isopropoxyphenyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0.28 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,28-7,42 (m, 2H), 6,85 (DD, J=8,5, 2.7 Hz, 1H), 6,79 (d, J=2.7 Hz, 1H), 6,64-6,76 (m, 2H), 5,02 (s, 2H), 4.53-in-4,67 (m, 1H), 4,11-4,27 (m, 4H), 4.09 to (s, 2H), 3.33 and-a 3.50 (m, 1H), 2,73 (t, J=7,0 Hz, 2H), 2,16-of 2.30 (m, 5H), of 1.30 (d, J=6.0 Hz, 6H).

Example 57-44: 1-({6-[(4-isopropyl-2-methoxybenzyl is)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.18 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7.23 percent-7,33 (m, 2H), 6,74-to 6.88 (m, 4H), to 5.03 (s, 2H), 4,10-4,24 (m, 4H), 4,06 (s, 2H), 3,85 (s, 3H), 3,35-3,47 (m, 1H), 2,82-2,96 (m, 1H), 2,65-2,77 (m, 2H), 2.13 and of-2.32 (m, 5H), 1,25 (d, J=6,95 Hz, 6H).

Example 57-45: 1-({6-[(2-cyano-4-isopropoxyphenyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0.21 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ rate of 7.54 (d, J=8.6 Hz, 1H), 7,34 (d, J=8.6 Hz, 1H), 7,28 (d, J=2.7 Hz, 1H), 7,20 (DD, J=8,6, 2.7 Hz, 1H), 6.87 in (DD, J=8,6, and 2.6 Hz, 1H), 6,83 (d, J=2.6 Hz, 1H), 5,14 (s, 2H), 4,58-4,74 (m, 1H), 4.09 to 4.26 deaths (m, 4H), 4,08 (s, 2H), 3.33 and-of 3.48 (m, 1H), 2,74 (t, J=7,0 Hz, 2H), 2,17-2,31 (m, 5H), of 1.33 (d, J=6.0 Hz, 6H).

Example 57-46: 1-[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1,5-dimethyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf to 0.19 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7.18 in-7,26 (m, 3H), 7,15 (d, J=8,50 Hz, 2H), 6,70 (d, J=8,50 Hz, 1H), 4,10-of 4.25 (m, 4H), 4,08 (s, 2H), 3,79 (d, J=5.50 Hz, 2H), 3,35 is-3.45 (m, 1H), 2,88 (DD, J=13,00, 6,50 Hz, 1H), 2,70-2,77 (m, 2H), 2,60 (DD, J=13,00, 7,50 Hz, 1H), 2,18-of 2.28 (m, 9H), of 1.05 (d, J=7,00 Hz, 3H).

Example 57-47: 1-[(6-{[4-isobutyl-2-(methylsulphonyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,87 (d, J=1.80 Hz, 1H), 7,66 (d, J=of 7.90 Hz, 1H), 7,52 (DD, J=of 7.90, 1.80 Hz, 1H), was 7.36 (d, J=8,40 Hz, 1H), for 6.81-6,94 (m, 2H), 5,48 (s, 2H), 4,11-4,27 (who, 4H), 4.09 to (s, 2H), 3,34-to 3.50 (m, 1H), 3,20 (s, 3H), of 2.75 (t, J=7,10 Hz, 2H), 2,61 (d, J=7,10 Hz, 2H), 2,17-2,31 (m, 5H), 1,84 of 1.99 (m, 1H), 0,93 (d, J=6,60 Hz, 6H).

Example 57-48: 1-[(6-{[4-isopropoxy-2-(methylsulphonyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ a 7.62 (d, J=8,40 Hz, 1H), 7,56 (d, J=2,60 Hz, 1H), was 7.36 (d, J=8,40 Hz, 1H), 7.23 percent (DD, J=8,40, 2,60 Hz, 1H), to 6.88 (DD, J=8,40, is 2.40 Hz, 1H), at 6.84 (d, J=2,40 Hz, 1H), 5,41 (s, 2H), with 4.64-4,78 (m, 1H), 4.09 to 4.26 deaths (m, 4H), 4,07 (s, 2H), 3.33 and-to 3.49 (m, 1H), 3,20 (s, 3H), 2,74 (t, J=to 8.20 Hz, 2H), 2,17-of 2.30 (m, 5H), of 1.35 (d, J=6,00 Hz, 6H).

Example 57-49: 1-[(6-{[3-fluoro-5-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,60 (s, 1H), 7,49 (d, J=9,70 Hz, 1H), 7,30-the 7.43 (m, 2H), 6,80-6,93 (m, 2H), 5,19 (s, 2H), 4,10-4.26 deaths (m, 4H), 4.09 to (s, 2H), 3.33 and-to 3.49 (m, 1H), 2,74 (t, J=8,10 Hz, 2H), 2,14-2,31 (m, 5H).

Example 57-50: 1-[(6-{[4-fluoro-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,71-7,83 (m, 1H), 7,52 (DD, J=9,20, 2,70 Hz, 1H), 7,30-7,46 (m, 2H), 6,76-to 6.88 (m, 2H), with 5.22 (s, 2H), 4.09 to 4.26 deaths (m, 4H), 4,08 (s, 2H), 3.33 and-of 3.48 (m, 1H), 2,74 (t, J=6,60 Hz, 2H), 2,15-of 2.30 (m, 5H).

Example 57-51: 1-({6-[(3-fluoro-4-isopropoxyphenyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

The SH: Rf to 0.19 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=at 8.60 Hz, 1H), 7,10-7,20 (m, 2H), 7,05 (t, J=8,32 Hz, 1H), 6,76-6,87 (m, 2H), 5,00 (s, 2H), 4,50 with 4.64 (m, 1H), 4.09 to 4,27 (m, 4H), 4,07 (s, 2H), 3.33 and-to 3.49 (m, 1H), 2,67-2,78 (m, 2H), 2,19-2,28 (m, 2H), measuring 2.20 (s, 3H), 1,32 (d, J=6,04 Hz, 6H).

Example 57-52: 1-[(6-{[4-isopropoxy-3-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf 0.21 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,53-7,66 (m, 2H), 7,32 (d, J=at 8.60 Hz, 1H), 7,17 (d, J=at 8.60 Hz, 1H), 6,78-to 6.88 (m, 2H), 5,04 (s, 2H), 4,66-4,80 (m, 1H), 4,08-4,27 (m, 4H), 4,07 (s, 2H), 3,34-3,51 (m, 1H), 2,66-and 2.79 (m, 2H), measuring 2.20 (s, 3H), 2,18-to 2.29 (m, 2H), of 1.34 (d, J=6,04 Hz, 6H).

Example 57-53: 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1,7-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,28 (d, J=7,50 Hz, 1H), 7,18 (s, 1H), PC 6.82 (d, J=1.50 Hz, 1H), 6.75 in-6,79 (m, 2H), is 5.06 (s, 2H), 4,10-of 4.25 (m, 4H), 4,07 (s, 2H), 3,85 (s, 3H), 3,35-3,47 (m, 1H), 2,66-by 2.73 (m, 2H), 2,59 (t, J=7,50 Hz, 2H), 2,18-of 2.26 (m, 8H), 1,59-1,72 (m, 2H), of 0.95 (t, J=7,50 Hz, 3H).

Example 57-54: 1-[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1,7-dimethyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ of 7.25 (d, J=8,00 Hz, 2H), 7,14-to 7.18 (m, 3H), 6,60 (s, 1H), 4,10-4,24 (m, 4H), 4,07 (s, 2H), 3,80 (m, 2H), 3,35-3,47 (m, 1H), 2,86 (DD, J=13,50, 6,50 Hz, 1H), 2,64-of 2.72 (m, 2H), 2,59 (DD, J=13,50, 7,50 Hz, 1H), 2,18-of 2.26 (m, 9H), of 1.05 (d, J=7,00 Hz, 3H).

Example 57-55 1-[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-5-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ of 7.25 (d, J=8,2 Hz, 2H), 7,18 (d, J=8,2 Hz, 2H), 7,13 (d, J=8.6 Hz, 1H), 6,80 (d, J=8.6 Hz, 1H), 4,12-the 4.29 (m, 4H), 4,11 (s, 2H), 3,70-to 3.89 (m, 5H), 3,34-3,51 (m, 1H), 2,90 (DD, J=14,3, and 6.6 Hz, 1H), 2,72-2,84 (m, 2H), 2,58 (DD, J=14,3, 7.5 Hz, 1H), 2,12-of 2.30 (m, 6H), of 1.05 (d, J=6.6 Hz, 3H).

Example 57-56: 1-[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-7-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ of 7.24 (d, J=at 8.60 Hz, 2H), 7,17 (d, J=at 8.60 Hz, 2H), 7,00 (s, 1H), 6,69 (s, 1H), 4,12-to 4.28 (m, 4H), 4,10 (s, 2H), 3,85 (s, 3H), 3,81 (d, J=5,90 Hz, 2H), 3,34-to 3.50 (m, 1H), 2,87 (DD, J=13,40, to 6.80 Hz, 1H), 2,60-2,70 (m, 2H), by 2.55 (DD, J=13,40, of 7.70 Hz, 1H), 2,14-to 2.29 (m, 6H), 1,01 (d, J=to 6.80 Hz, 3H).

Example 57-57: 1-({5-methoxy-6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,30 (d, J=of 7.70 Hz, 1H), 7,13 (d, J=at 8.60 Hz, 1H), 6,92 (d, J=at 8.60 Hz, 1H), 6,83 (d, J=1,30 Hz, 1H), 6,77 (DD, J=7,70, 1,30 Hz, 1H), 5,09 (s, 2H), 4,13-to 4.28 (m, 4H), 4,10 (s, 2H), of 3.84 (s, 3H), of 3.77 (s, 3H), 3,34-to 3.49 (m, 1H), 2,72-to 2.85 (m, 2H), 2,59 (t, J=7,30 Hz, 2H), 2,11-of 2.27 (m, 5H), 1,57-of 1.74 (m, 2H), were 0.94 (t, J=7,30 Hz, 3H).

Example 57-58: 1-({7-methoxy-6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,27 (d, J=8,10 Hz, 1H), 6,99 (s, 1H), 6,79-6,84 (m, 2H), 6,76 (DD, J=8,10, 1.60 Hz, 1H), to 5.08 (s, 2H), 4,06-to 4.23 (m, 4H), Android 4.04 (s, 2H), of 3.84 (s, 3H), 3,83 (s, 3H), 3.33 and is-3.45 (m, 1H), 2,53-2,70 (m, 4H), 2,15-of 2.26 (m, 5H), 1,59-1,71 (m, 2H), were 0.94 (t, J=7,40 Hz, 3H).

Example 57-59: 1-({6-[(4-sec-butyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,22-7,35 (m, 2H), 6,72-6,87 (m, 4H), 5,04 (s, 2H), 4,10-of 4.25 (m, 4H), 4,07 (s, 2H), 3,85 (s, 3H), 3,35-3,47 (m, 1H), 2,66-2,78 (m, 2H), 2,54-of 2.64 (m, 1H), 2,14-2,31 (m, 5H), 1,53 was 1.69 (m, 2H), 1,23 (d, J=6,95 Hz, 3H), of 0.82 (t, J=to 7.32 Hz, 3H).

Example 57-60: 1-({1-chloro-6-[(4-ethyl-2-methoxybenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ at 7.55 (d, J=at 8.60 Hz, 1H), 7,25 (d, J=of 7.70 Hz, 1H), for 6.81-6.90 to (m, 3H), 6,78 (DD, J=7,70, 1.60 Hz, 1H), is 5.06 (s, 2H), 4,23 (d, J=8,20 Hz, 4H), 4,17 (s, 2H), 3,85 (s, 3H), 3,36-to 3.50 (m, 1H), and 2.83 (t, J=7,50 Hz, 2H), 2,64 (kV, J=7,50 Hz, 2H), 2,45 (t, J=7,50 Hz, 2H), 1,23 (t, J=7,50 Hz, 3H).

Example 57-61: 1-[(1-chloro-6-{[4-ethoxy-2-(trifluoromethyl)benzyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ to 7.59 (d, J=at 8.60 Hz, 1H), 7,58 (d, J=at 8.60 Hz, 1H), 7,22 (d, J=2,60 Hz, 1H), 7,16 (DD, J=8,60, 2,60 Hz, 1H), 6.87 in (DD, J=8,60, 2,60 Hz, 1H), 6,82-6,85 (m, 1H), 5,16 (s, 2H), 4,23 (d, J=8,10 Hz, 4H), 4,17 (s, 2H), 4,10 (kV, J=7,00 Hz, 2H), 3,36-to 3.50 (m, 1H), 2,85 (t, J=7,10 Hz, 2H), 2,46 (t, J=7,10 Hz, 2H), 1,41 (t, J=7,00 Hz, 3H.

Example 57-62: 1-[(1-chloro-6-{[4-isopropoxy-2-(trifluoromethyl)benzyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,52-to 7.64 (m, 2H), 7,19 (d, J=2.6 Hz, 1H), 7,15 (DD, J=8,6, and 2.6 Hz, 1H), to 6.88 (DD, J=8,2, 2.6 Hz, 1H), 6,82-6,85 (m, 1H), 5,16 (s, 2H), br4.61-of 4.75 (m, 1H), 4,23 (d, J=8,4 Hz, 4H), 4,18 (s, 2H), 3,36-3,51 (m, 1H), 2,85 (t, J=7,0 Hz, 2H), 2,46 (t, J=7,0 Hz, 2H), 1,33 (d, J=6.0 Hz, 6H).

Example 57-63: 1-({6-[(2-methoxy-4-methylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf to 0.19 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8,42 Hz, 1H), 7.23 percent (d, J=7,50 Hz, 1H), 6,69-to 6.88 (m, 4H), to 5.03 (s, 2H), 4,10-4.26 deaths (m, 4H), 4,07 (s, 2H), of 3.84 (s, 3H), 3.33 and-to 3.49 (m, 1H), 2,64-and 2.79 (m, 2H), 2,33 (s, 3H), 2,15-to 2.29 (m, 5H).

Example 57-64: 1-({6-[(4-chloro-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf to 0.19 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,28-7,38 (m, 2H), 7,03 (d, J=1.65 Hz, 1H), 6,95 (DD, J=8,14, 1.65 Hz, 1H), 6,76-6,85 (m, 2H), of 5.05 (s, 2H), 4.09 to-4,24 (m, 4H), 4,06 (s, 2H), a 3.87 (s, 3H), 3,35-to 3.49 (m, 1H), 2,64-2,78 (m, 2H), 2,14-2,31 (m, 5H).

Example 57-65: 1-({6-[(2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,21-the 7.43 (m, 3H), 6,97-7,03 (m, 1H), 6,88-of 6.96 (m, 1H), 6,77-to 6.88 (m, 2H), 5,09 (s, H), 4,08-4.26 deaths (m, 4H), of 4.05 (s, 2H), 3,86 (s, 3H), 3,35-to 3.49 (m, 1H), 2,64-2,82 (m, 2H), 2,12-2,31 (m, 5H).

Example 57-66: 1-{[6-(benzyloxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,22-7,46 (m, 6H), 6,85 (DD, J=8,72, to 2.74 Hz, 1H), for 6.81 (d, J=2,74 Hz, 1H), to 5.08 (s, 2H), 4,12-4,30 (m, 4H), 4.09 to (s, 2H), 3.33 and-3,51 (m, 1H), 2,66 is 2.80 (m, 2H), 2,17-2,31 (m, 5H).

Example 57-67: 1-({6-[(2-methoxy-6-propyl-3-pyridinyl)methoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf to 0.19 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ to 7.61 (d, J=7,50 Hz, 1H), 7,32 (d, J=at 8.60 Hz, 1H), 6.73 x-6,87 (m, 3H), free 5.01 (s, 2H), 4,10-the 4.29 (m, 4H), 4,08 (s, 2H), 3.96 points (s, 3H), 3,34-to 3.49 (m, 1H), 2.57 m-of 2.81 (m, 4H), 2,15-2,31 (m, 5H), 1,67-to 1.82 (m, 2H), of 0.95 (t, J=7,41 Hz, 3H).

Example 57-68: 1-[(6-{[6-isobutyl-4-(trifluoromethyl)-3-pyridinyl]methoxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf 0.21 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 8,80 (s, 1H), 7,60 (s, 1H), 7,37 (d, J=8,42 Hz, 1H), for 6.81-6,91 (m, 2H), 5,26 (s, 2H), 4,14-the 4.29 (m, 4H), 4,11 (s, 2H), 3,34-3,51 (m, 1H), 2,77 (d, J=to 7.32 Hz, 2H), 2,71 is 2.80 (m, 2H), 2,22 (s, 3H), 2,19-2,30 (m, 2H), 2,04-to 2.18 (m, 1H), 0,94 (d, J=6,59 Hz, 6H).

Example 57-69: 1-({6-[(4-chloro-6-isobutyl-3-pyridinyl)methoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0.21 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3 OD): δ 8,55 (s, 1H), 7,42 (s, 1H), was 7.36 (d, J=8,42 Hz, 1H), 6.89 in (DD, J=8,42, of 2.56 Hz, 1H), 6,85 (d, J=2,56 Hz, 1H), 5,20 (s, 2H), 4,12-to 4.28 (m, 4H), 4,10 (s, 2H), 3.33 and-a 3.50 (m, 1H), 2,70-and 2.79 (m, 2H), 2,66 (d, J=to 7.32 Hz, 2H), of 2.21 (s, 3H), 2,18-of 2.30 (m, 2H), 2.00 in to 2.13 (m, 1H), 0,93 (d, J=6,77 Hz, 6H).

Example 57-70: 1-[(6-{[2-methoxy-4-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf 0,11 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,58 (d, J=7,50 Hz, 1H), 7,33 (d, J=8,23 Hz, 1H), 7,19-7,28 (m, 2H), 6,76-of 6.90 (m, 2H), further 5.15 (s, 2H), 4,12-4,27 (m, 4H), 4.09 to (s, 2H), of 3.94 (s, 3H), 3,35-to 3.50 (m, 1H), 2,67-and 2.79 (m, 2H), 2,16-2,31 (m, 5H).

Example 57-71: 1-({6-[(5-chloro-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0,13 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7.29 trend-7,38 (m, 2H), 7,26 (DD, J=8,78, to 2.74 Hz, 1H), 6,98 (d, J=8,78 Hz, 1H), 6,78-6,86 (m, 2H), 5,07 (s, 2H), 4,13-the 4.29 (m, 4H), 4,10 (s, 2H), a 3.87 (s, 3H), 3,36-to 3.52 (m, 1H), 2,66-of 2.81 (m, 2H), 2,16-2,31 (m, 5H).

Example 57-72: 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.30 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ of 7.24 (d, J=of 7.70 Hz, 1H), 7,02 (d, J=9,00 Hz, 1H), 6,69-PC 6.82 (m, 4H), 6,59 (s, 1H), to 5.03 (s, 2H), 4,10-4,27 (m, 4H), to 3.89 (s, 2H), of 3.84 (s, 3H), 3.33 and-to 3.49 (m, 1H), 2,81 (t, J=8,10 Hz, 2H), 2,48 (d, J=7,10 Hz, 2H), and 2.26 (t, J=8,10 Hz, 2H), 1,79-of 1.97 (m, 1H), of 0.91 (d, J=6,80 Hz, 6H).

Example 57-73: 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-3,4-dihydro-2-naphthalenyl}met the l)-3-azetidinone acid

TLC: Rf of 0.30 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ of 7.24 (d, J=7,50 Hz, 1H), 7,01 (d, J=9,00 Hz, 1H), of 6.71-6,85 (m, 4H), 6,59 (s, 1H), 5,02 (s, 2H), 4,10-4,27 (m, 4H), to 3.89 (s, 2H), of 3.84 (s, 3H), 3.33 and-a 3.50 (m, 1H), 2,81 (t, J=8,10 Hz, 2H), 2,59 (t, J=7,10 Hz, 2H), and 2.26 (t, J=8,10 Hz, 2H), 1.56 to around 1.74 (m, 2H), were 0.94 (t, J=7,30 Hz, 3H).

Example 57-74: 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf 0.26 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,27 (d, J=7,50 Hz, 1H), 7,21 (d, J=8,50 Hz, 1H), 6,83 (d, J=8,50 Hz, 1H), 6,78 (d, J=1.50 Hz, 1H), 6.73 x (DD, J=7,50, 1.50 Hz, 1H), of 5.05 (s, 2H), 4,10-of 4.25 (m, 4H), 4,07 (s, 2H), 3,85 (s, 3H), 3,34-3,43 (m, 1H), 2,69-2,77 (m, 2H), 2,48 (d, J=7,00 Hz, 2H), 2,17-of 2.27 (m, 8H), 1,81-of 1.95 (m, 1H), 0,92 (d, J=6,50 Hz, 6H).

Example 57-75: 1-[(6-{[4-isopropoxy-3-(trifluoromethyl)benzyl]oxy}-1,5-dimethyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.20 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,58-the 7.65 (m, 2H), 7,24 (d, J=8,50 Hz, 1H), 7,18 (d, J=9,00 Hz, 1H), 6.87 in (d, J=8,50 Hz, 1H), is 5.06 (s, 2H), 4,68-to 4.81 (m, 1H), 4,11-4,24 (m, 4H), 4.09 to (s, 2H), 3,36-3,47 (m, 1H), 2,68-2,78 (m, 2H), 2,17-of 2.27 (m, 8H), of 1.34 (d, J=6,00 Hz, 6H).

Example 57-76: 1-[(1-methyl-6-{[4-(2,2,2-triptoreline)-3-(trifluoromethyl)benzyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.35 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,62-7,74 (m, 2H), 7,33 (d, J=8,4 Hz, 1H), 7,25 (d, J=8,8 Hz, 1H) 6,79-of 6.90 (m, 2H), 5,09 (s, 2H), 4,66 (kV, J=8,2 Hz, 2H), 4,13-the 4.29 (m, 4H), 4,10 (s, 2H), 3,35-3,51 (m, 1H), 2,74 (t, J=6.6 Hz, 2H), 2,15-of 2.30 (m, 5H).

Example 57-77: 1-[(1-methyl-6-{[4-{[(1S)-1-methylpropyl]oxy}-3-(trifluoromethyl)benzyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.35 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,53-to 7.64 (m, 2H), 7,33 (d, J=8,4 Hz, 1H), 7,14 (d, J=8,4 Hz, 1H), 6,77-6,89 (m, 2H), 5,04 (s, 2H), 4,46-4,60 (m, 1H), 4,12-the 4.29 (m, 4H), 4,10 (s, 2H), 3,34-to 3.50 (m, 1H), 2,73 (t, J=8,1 Hz, 2H), 2,17-2,30 (m, 5H), 1,61-of 1.81 (m, 2H), 1,30 (d, J=6.0 Hz, 3H), 0,99 (t, J=7.5 Hz, 3H).

Example 57-78: 1-[(6-{[6-isopropoxy-4-(trifluoromethyl)-3-pyridinyl]methoxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 8,39 (s, 1H), 7,35 (d, J=at 8.60 Hz, 1H), 7,01 (s, 1H), 6,85 (DD, J=8,60, of 2.56 Hz, 1H), 6,80 (d, J=2,56 Hz, 1H), 5,28-5,42 (m, 1H), 5,13 (s, 2H), 4,13-the 4.29 (m, 4H), 4,10 (s, 2H), 3,34-to 3.50 (m, 1H), 2,70-2,80 (m, 2H), 2,20-of 2.30 (m, 2H), 2,22 (s, 3H), of 1.35 (d, J=6.22 per Hz, 6H).

Example 57-79: 1-({6-[(4-chloro-6-isopropoxy-3-pyridinyl)methoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ to 8.20 (s, 1H), 7,33 (d, J=8,42 Hz, 1H), 7,13 (s, 1H), at 6.84 (DD, J=8,42, of 2.56 Hz, 1H), 6,80 (d, J=2,56 Hz, 1H), 5,04 (s, 2H), 4,78-to 4.87 (m, 1H), 4.09 to 4.26 deaths (m, 4H), 4,07 (s, 2H), 3,34-of 3.48 (m, 1H), 2,69-2,78 (m, 2H), measuring 2.20 (s, 3H), 2,18-of 2.30 (m, 2H), 1,37 (d, J=6,04 Hz, 6H).

Example 57-80: 1-[(6-{[4-(2-hydroxy-2-methylpropyl)-2-ethoxybenzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf of 0.25 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,31 (d, J=8,50 Hz, 1H), 7,27 (d, J=7,50 Hz, 1H), 6.89 in (d, J=1.50 Hz, 1H), 6,77-6,85 (m, 3H), of 5.06 (s, 2H), 4,11-of 4.25 (m, 4H), 4,08 (s, 2H), 3,86 (s, 3H), 3,35-of 3.46 (m, 1H), 2,68-2,77 (m, 4H), 2,19-2,28 (m, 5H), of 1.18 (s, 6H).

Example 57-81: 1-({1-tert-butyl-6-[(2-methoxy-4-propylbenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.27 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ to 7.35 (d, J=8,50 Hz, 1H), 7,26 (d, J=7,50 Hz, 1H), PC 6.82 (d, J=1.50 Hz, 1H), 6.73 x-6,79 (m, 3H), of 5.03 (s, 2H), 4,29 (s, 2H), 4,03-to 4.23 (m, 4H), 3,85 (s, 3H), 3.33 and-of 3.43 (m, 1H), 2,55-2,63 (m, 2H), 2,46-2,53 (m, 2H), 1,89 is 1.96 (m, 2H), 1,58-of 1.73 (m, 2H), 1,45 (s, 9H), were 0.94 (t, J=7,50 Hz, 3H).

Example 57-82: 1-[(1-methyl-6-{[4-(2,2,2-triptoreline)-2-(trifluoromethyl)benzyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf is 0.24 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ of 7.69 (d, J=at 8.60 Hz, 1H), 7,32-7,38 (m, 2H), 7,28 (DD, J=8,42, to 2.74 Hz, 1H), PC 6.82 (DD, J=8,60, of 2.54 Hz, 1H), 6,79 (d, J=2,54 Hz, 1H), 5,19 (s, 2H), with 4.64 (q, J=8,29 Hz, 2H), 4,10-4,27 (m, 4H), 4,10 (s, 2H), 3,34-to 3.50 (m, 1H), 2,68-and 2.79 (m, 2H), 2,19-to 2.29 (m, 2H), of 2.21 (s, 3H).

Example 57-83: 1-({6-[(4-methoxy-6-propyl-3-pyridinyl)methoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.27 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ of 8.28 (s, 1H), 7,33 (d, J=at 8.60 Hz, 1H), of 6.96 (s, 1H), 6,77-to 6.88 (m, 2H), is 5.06 (s, 2H), 4.09 to to 4.28 (m, 4H), 4,07 (s, 2H), of 3.94 (s, 3H), 3,3-of 3.48 (m, 1H), 2,67-2,78 (m, 4H), 2,15 of-2.32 (m, 5H), 1,65 of-1.83 (m, 2H), 0,97 (t, J=to 7.32 Hz, 3H).

Example 57-84: 1-({5-iodine-6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.38 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,44 (d, J=7,50 Hz, 1H), 7,37 (d, J=at 8.60 Hz, 1H), 6,86 (d, J=at 8.60 Hz, 1H), 6,74-6,83 (m, 2H), 5,14 (s, 2H), 4,12-4,27 (m, 4H), 4,10 (s, 2H), 3,86 (s, 3H), 3,36-to 3.49 (m, 1H), 2,87-to 2.99 (m, 2H), 2,53-2,65 (m, 2H), 2.13 and is 2.33 (m, 5H), 1,55-of 1.73 (m, 2H), of 0.95 (t, J=7,41 Hz, 3H).

Example 57-85: 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-iodine-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid

TLC: Rf 0.28 in (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 8,24-8,30 (m, 1H), 8,00-of 8.06 (m, 2H), 7,44 (d, J=at 8.60 Hz, 1H), to 6.88 (d, J=at 8.60 Hz, 1H), 5,44 (s, 2H), 4,15-4,32 (m, 4H), 4,14 (s, 2H), 3,36-to 3.50 (m, 1H), 2,90-a 3.01 (m, 2H), 2,23 is 2.33 (m, 2H), 2,22 (s, 3H).

Example 57-86: 1-{[1-ethyl-6-(4-phenylmethoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinone acid

TLC: Rf of 0.29 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD3OD): δ 7,30 (d, J=at 8.60 Hz, 1H), 7,08-7,27 (m, 5H), 6,74 (DD, J=8,60, 2,70 Hz, 1H), 6,70 (d, J=2,70 Hz, 1H), 4.09 to 4.26 deaths (m, 4H), of 4.05 (s, 2H), 3,92-4,01 (m, 2H), 3,34-3,47 (m, 1H), 2,60-2,77 (m, 6H), 2,15-of 2.24 (m, 2H), 1,72-of 1.81 (m, 4H), of 1.09 (t, J=7,41 Hz, 3H).

Example 57-87: 1-({6-[3-(4-chlorophenyl)propoxy]-1-ethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid

TLC: Rf of 0.30 (chloroform:methanol:aqueous ammonia= 20:5:1).

1H-NMR (CD 3OD): δ 7.29 trend (d, J=at 8.60 Hz, 1H), 7,19-7,26 (m, 2H), 7,13-7,19 (m, 2H), 6.73 x (DD, J=8,60, 2,70 Hz, 1H), 6,69 (d, J=2,70 Hz, 1H), 4,07-4,24 (m, 4H), was 4.02 (s, 2H), 3,93 (t, J=6,13 Hz, 2H), 3.33 and-of 3.46 (m, 1H), 2,63-2,79 (m, 6H), 2,15-of 2.26 (m, 2H), 1,95-of 2.08 (m, 2H), 1,09 (t, J=7,41 Hz, 3H).

Biological examples

The pharmacological activity of the compounds of the present invention was confirmed by the following biological examples. All operations were performed by standard methods by creating cells expressing genes at a high level, using basic techniques of genetic engineering. In addition, measurement methods used in the present invention for evaluating the compounds of the present invention were improved in terms of accuracy and/or sensitivity of the measurement. Below is a detailed description of the performed research. Histological specimens were obtained by standard methods using fundamental techniques of genetic engineering modified accordingly.

Biological example 1. Measurement of inhibitory activity of compounds of the present invention in relation to binding [3H]-PhS1P with EDG-6

Experimental method

The interaction was performed on 96-well analytical tablet, using the fraction of the cell membrane of the cells of the Chinese hamster ovary (CHO), sverkhekspressiya the soup EDG-6, and 1 mg protein/ml membrane fraction. To each well was injected with 80 μl of a solution of the carrier (DMSO), diluted to twice the volume of binding buffer (100 mmol/l Tris buffer, pH 7.5, 200 mm NaCl, 30 mm NaF, 1% BSA), or a solution of the ligand in two concentrations and 40 μl of 10 nmol/l [3H]-PhS1P (phytosphingosine-1-phosphate 5,5,6,6-tetralite received the following obrazom). Connection (anti-7: tert-butyl(4S)-4-[(1S,2R)-1-(benzyloxy)-2-hydroxyhexane-3-in-1-yl]-2,2-dimethyl-1,3-oxazolidin-3-carboxylate)obtained by the method described in Tetrahedron Lett., 38(34), 6027-6030 (1997)were subjected to interaction with benzylbromide in tetrahydrofuran in the presence of hexamethyldisilane potassium to protect the hydroxyl group. Then the specified connection was treated with a solution of hydrogen chloride/methanol to unlock the acetonide group. Thus obtained compound was subjected to interaction with N,N-diethyl-1,5-dihydro-2,4,3-benzodioxathiepin-3-amine in methylene chloride in the presence of tetrazole and then oxidized with m-chloroperbenzoic acid. The compound obtained was subjected to interaction in the presence of a catalyst ASCA-2 (company N.E. CHEMCAT CORPORATION, the catalyst containing 4.5% palladium and 0.5% platinum on active charcoal, see Fine Chemical, October 1, 2002, page 5-14) in methanol in the atmosphere of tritium. The compound obtained was treated with 4 N. solution of hydrogen chloride/1,4-dioxane in methylene chloride, p is the beam when the desired connection. Then add 40 μl of the membrane fraction solution and worked together at room temperature for 60 minutes. After the reaction, the reaction mixture was filtered by suction through the filter UNIFILTER 96-hole tablet, three times washed with 50 ml of wash buffer (50 mmol/l Tris buffer, pH 7.5, and 0.5% BSA) and dried at 60°C for 45 minutes. Then add 50 ál/well of MicroScint 20 and closed the tablet TopSeal-P. Radioactivity was measured using a device TopCount (the company Perkin Elmer Inc.).

Results

Compounds of the present invention were characterized by the presence of inhibitory activity against the binding of [3H]-PhS1P with EDG-6.

Biological example 2. Counting the number of lymphocytes in the blood

Experimental method

Compound oral was administered to male BALB/c mice or male rats Sprague-Dawley (Charles River Laboratories, Japan, Inc., at the age of 6 weeks during the study). Through 4-72 hours after injection the animals took the blood from the abdominal aorta under anesthesia simple ether. The total number of leukocytes, lymphocytes, neutrophils, erythrocytes and platelets in the blood and hematocrite number was measured using the multi-purpose automatic counter blood cells (SF-3000, the company Sysmex Corporation). When you measure the average number of blood cells in the group of animals which were injected nose is tel (control group), was set equal to 100% and calculated the percentage of the average number of blood cells in each group of animals that were administered the test compound, compared with the control group. On the basis of the doses of the test compounds and the percentage of the values obtained with the introduction of media and test compounds, the dose of a compound required to reduce the number of blood cells by 50%, were calculated as ED50.

Results

Compounds of the present invention significantly reduced the number of lymphocytes in the blood by oral administration of a dose of 10 mg/kg for Example, the values of the ED5024 hours after administration of the compounds obtained in example 27-7 and example 37, were, respectively, 1.6 mg/kg and 0,029 mg/kg

Biological example 3. Evaluation of agonistic activity of the compounds of the present invention against EDG by determining the changes in intracellular calcium ion concentration [Ca2+]

Experimental method

Cells SNO, sverkhekspressiya gene EDG-1, EDG-3, EDG-5 and EDG-8 man, were cultured in the medium of ham F12 (company GibcoBRL)containing 10% FBS (fetal bovine serum), penicillin/streptomycin and blasticidin (5 µg/ml). Cultured cells were incubated in 5 μm solution of Fura2-AM (Wednesday ham F12 containing 10% FBS, 20 mm HEPES buffer (pH 7.4) and 2.5 mm probenecid)at 37°C for 60 minutes. Cells were once washed with Hanks solution containing 20 mm HEPES buffer (pH 7.4) and 2.5 mm probenecid, after which the tablet was immersed in the same solution. Then the tablet was placed in the system for fluorescent screening of drugs (FDSS 6000; Hamamatsu Photonics K.K.) and measured the intracellular concentration of calcium ions without stimulation for 30 seconds. Added the test compound (final concentration: 1 nm to 10 µm solution in dimethylsulfoxide (DMSO)) and after 5 minutes was added S1P (final concentration: 100 nm). The increase of intracellular calcium ion concentration was measured before and after addition of S1P at intervals of 3 seconds (wavelength of excitation: 340 nm and 380 nm, the wavelength fluorescence: 500 nm).

Agonistic activity of compounds against each receptor EDG was determined using the maximum value obtained in the S1P-stimulation of wells containing DMSO instead of test compounds, as a reference value (A), for which the value obtained before adding the test compound, compared with a high value (B) in respect of fluorescence intensity after the addition was calculated ratio increase (%) intracellular calcium ion concentration [CA2+]ias the ratio of increase (%) = (b/a) × 100. Defined relationships increase caused by the connection in the s concentrations, and we calculated the value of the EU50.

Results

It was found that the compounds of the present invention have agonistic activity against EDG-1. For example, the values of the EU50compounds obtained in examples 18, 13-4, 29-1, 27-7, 37 and 37-6, were respectively equal to 662 nmol/l, 41 nmol/l, 133 nmol/l, 0.7 nmol/l, 1.0 nmol/l and 0.7 nmol/L.

Biological example 4. Model dermatitis in mice caused by constant exposure to the hapten

Experimental method

1% (wt./about.) a solution of 4-ethoxymethylene-2-phenyl-2-oxazoline-5-it (hereinafter referred to as the “axalon”) (20 μl) was applied on ear (right ear, both surfaces) mice (male BALB/c) for primary sensitization. Seven days after sensitization 1% (wt./about.) the solution okalona (20 μl) were applied to the ear to consolidate the results (0-day). A similar procedure performed in the 0-day repeated on the 2nd, 4th, 6th, 8th, 10th, 12th, 14th and 16th day. The test compound was dissolved in the carrier and administered orally or applied on both surfaces of the right ear (20 μl) prior to the application of okalona. The control group was subjected to only media. Immediately after injection of the test compounds and 24 hours after application of okalona in mice was measured thickness of the auricle using a thickness gauge with a circular scale (OZAKI MFG. CO., LTD) was ispolzovali the result as an indicator of the effectiveness of treatment of dermatitis model dermatitis in mice caused by constant exposure to the hapten.

Biological example 5. The model of arthritis induced by adjuvant

Experimental method

The study was made using male or female Lewis rats aged 7 weeks. Rats were measured volume of the left hind paws, after which the pad of the right hind paws of each rat were subcutaneously injected with 500 μg of a suspension of dry cells of mycobacteria Mycobacterium butyricum (Difco), used as an adjuvant in liquid paraffin, thus creating a model of adjuvant-induced arthritis in rats. Comparing the experimental group to which oral was administered to test the connection with the control group, which did not enter the test compound was determined therapeutic or prophylactic effect.

Biological example 6. The model of experimental allergic encephalomyelitis (EAE)

(Case 1) Introducing the compound of the present invention from the day of sensitization

Experimental method

Killed mycobacteria Mycobacterium tuberculosis (M. tuberculosis H37 Ra, Difco, catalog No. 231141) suspended in distilled water for injection to dissolve MBP (myelin basic protein, SIGMA, catalog No. M-2295) (killed Mycobacterium Mycobacterium tuberculosis: 1000 µg/ml MBP: 60 µg/ml). The resulting solution was mixed with an equivalent quantity is ω FCA (full beta-blockers, CHEMICON, catalog No. AR001) with the formation of the emulsion. Female rats LEW/CrlCrlj (Charles River Laboratories, Japan, Inc., at the age of 6 weeks at the time of purchase, at the age of 7 weeks during sensitization) were actively senzibilizirani by a single subcutaneous injection (0.1 ml/rat) emulsion in the right paw pad under mild anesthesia simple ether inducyruya thus the symptoms of experimental allergic encephalomyelitis. Day sensitization was defined as the 0-th day.

Symptoms of EAE in rats was controlled every day from 8-day on the 20th day and was evaluated on the basis of the following criteria: relaxation of the tail: 1 point, partial hind limb paralysis: 1 point, complete hind limb paralysis: even 1 point, and incontinence: 1 point. The maximum score was 4 points. The death of the animal was estimated at 5 points.

As the carrier used a 0.5% solution MS (0.5/vol.% solution of methylcellulose 400 SP, Wako Pure Chemical Industries, Ltd., catalog No. 133-14255), tested the connection forcibly orally was administered in an amount of 5 ml/kg once a day starting on the day prior to sensitization, and until the 19th day. The control group forcibly orally was administered the same amount of 0.5% solution MS once a day for the same period of time. Body weight was measured every day, starting with the 0-th day, and the dose was determined on the basis of daily measuring what my body mass.

Results

The effectiveness of the test compounds was determined by comparing the results obtained in the experimental group, which oral was administered the test compound with the results obtained in the control group, which oral introduced only media. During this period the introduction of the compound obtained in example 37, almost completely inhibited the appearance of symptoms when taken orally injected a dose of 0.1 mg/kg, and completely inhibited the appearance of symptoms when taken orally injected dose, 0.3 mg/kg of the Compound obtained in example 37-5, almost completely inhibited the appearance of symptoms when taken orally injected dose, 0.3 mg/kg

(Case 2) Introducing the compound of the present invention immediately before the appearance of disease symptoms

Experimental method

Killed mycobacteria Mycobacterium tuberculosis (M. tuberculosis H37 Ra, Difco, catalog No. 231141) suspended in distilled water for injection to dissolve MBP (myelin basic protein, SIGMA, catalog No. M-2295) (killed Mycobacterium Mycobacterium tuberculosis: 1000 µg/ml MBP: 60 µg/ml). The resulting solution was mixed with an equivalent amount of FCA (full beta-blockers, CHEMICON, catalog No. AR001) with the formation of the emulsion. Female rats LEW/CrlCrlj (Charles River Laboratories, Japan, Inc., at the age of 6 weeks at the time of purchase, the age of 7 weeks during sensitization) were actively senzibilizirani by a single subcutaneous injection (0.1 ml/rat) emulsion in the right paw pad under mild anesthesia simple ether, inducyruya thus the symptoms of experimental allergic encephalomyelitis. Day sensitization was defined as the 0-th day.

Symptoms of EAE in rats was controlled every day from the 7th day on the 20th day and was evaluated on the basis of the following criteria: relaxation of the tail: 1 point, partial hind limb paralysis: 1 point, complete hind limb paralysis: even 1 point, and incontinence: 1 point. The maximum score was 4 points. The death of the animal was estimated at 5 points.

As the carrier used a 0.5% solution MS (0.5/vol.% solution of methylcellulose 400 SP, Wako Pure Chemical Industries, Ltd., catalog No. 133-14255), tested the connection forcibly orally was administered in an amount of 5 ml/kg once a day, starting from the 9th day prior to sensitization, and until the 19th day. The control group forcibly orally was administered the same amount of 0.5% solution MS once a day for the same period of time. Body weight was measured every day, starting from 9-th day, and the dose was determined on the basis of daily measured weight.

Results

The effectiveness of the test compounds was determined by comparing the results obtained in the experimental group, which oral was administered the test compound with the results obtained in the control group, which oral introduced only media. In the course of the criminal code the data period of the introduction of the connection, obtained in example 37, almost completely inhibited the appearance of symptoms when taken orally injected dose, 0.3 mg/kg Was found that the compound obtained in example 37-5, inhibited the symptoms of oral injected dose, 0.3 mg/kg

(Case 3) Introducing the compound of the present invention after the onset of symptoms

Experimental method

Killed mycobacteria Mycobacterium tuberculosis (M. tuberculosis H37 Ra, Difco, catalog No. 231141) suspended in distilled water for injection to dissolve MBP (myelin basic protein, SIGMA, catalog No. M-2295) (killed Mycobacterium Mycobacterium tuberculosis: 1000 µg/ml MBP: 60 µg/ml). The resulting solution was mixed with an equivalent amount of FCA (full beta-blockers, CHEMICON, catalog No. AR001) with the formation of the emulsion. Female rats LEW/CrlCrlj (Charles River Laboratories, Japan, Inc., at the age of 6 weeks at the time of purchase, at the age of 7 weeks during sensitization) were actively senzibilizirani by a single subcutaneous injection (0.1 ml/rat) emulsion in the right paw pad under mild anesthesia simple ether inducyruya thus the symptoms of experimental allergic encephalomyelitis. Day sensitization was defined as the 0-th day.

Symptoms of EAE in rats was controlled every day 10-day 20-day and was evaluated on the basis of the following criteria: d who acacia tail: 1 point, incomplete paralysis of hind limbs: 1 point, complete hind limb paralysis: still 1 point and incontinence: 1 point. The maximum score was 4 points. The death of the animal was estimated at 5 points.

As the carrier used a 0.5% solution MS (0.5/vol.% solution of methylcellulose 400 SP, Wako Pure Chemical Industries, Ltd., catalog No. 133-14255), tested the connection forcibly orally was administered in an amount of 5 ml/kg once a day, starting from the 11th day or 12-day to the 19th day, after all rats appeared the symptoms of EAE. The control group forcibly orally was administered the same amount of 0.5% solution MS once a day for the same period of time. Body weight was measured every day, starting from the 10th day, and the dose was determined on the basis of daily measured weight.

Results

The effectiveness of the test compounds was determined by comparing the results obtained in the experimental group, which oral was administered the test compound with the results obtained in the control group, which oral introduced only media.

Biological example 7. The definition of cardiotoxicity (bradycardia)

Experimental method

In the jugular vein and the carotid artery or the femoral vein and femoral artery) mammals (for example, SD rats and rabbits) are injected with a catheter. The end of art is realnoe cannula was attached to a pressure transducer (DX-100, the company NIHON KONDEN CORP.) for measuring blood pressure using a tensiometer (AP-641G, the company NIHON KONDEN CORP.) and to measure heart rate using the device for instant measurement of heart rate (at-601G, the company NIHON KONDEN CORP.), respectively. Alternative heart rate was measured using an electrocardiogram. The test compound was administered intravenously or orally shot the animal or animals in psihostimuliruuschem state after activation. Then measured the change in blood pressure and heart rate.

Results

The compound of the present invention had less influence on the present. For example, when administered intravenously to rabbits compound obtained in example 37, in a dose of 0.01 mg/kg, heart rate in rabbits was decreased by 20% or less.

Measuring the values of the ED5024 hours after administration of the test compounds in a dose set by the method described in biological example 2, as With mg/kg, and determining the dose determined by the method described in this biological example in which the heart rate decreased by 20%, in the form of DAmg/kg, the ratio (DA/C) can be represented in the form of an index security (A) (SIA: the index without the provisions And connections.

Biological example 8. The definition of security compounds of the present invention

Experimental method

The compound of the present invention forcibly orally injected through a tube into the stomach of rats SD (Crj:CD (SD) IGS, male, aged 6 weeks) once a day for a period of time from 4 days to 14 days. Rats were opened the next day after stopping the introduction of the compounds of the present invention and measured the mass of different organs, performed the histopathological examination, hematological examination and biochemical analysis of blood.

Results

It was found that the compound of the present invention is quite safe.

Measuring the values of the ED5024 hours after administration of the test compounds in a dose set by the method described in biological example 2, as With mg/kg, and determining the dose determined by the method described in this biological sample, in which there is a significant increase in the mass of the liver, in the form of DBmg/kg, the ratio (DB/C) can be represented in the form of a security index (IN) (SIB: index security In the connection.

Examples of the preparation of drugs

Below are examples of the preparation of drugs of the present invention.

Examples the preparation of medicines 1

1-{[1-Chloro-6-(3-cyclohexylpropionic)-3,4-dihydronaphthalene-2-yl]methyl}azetidin-3-carboxylic acid (100 g), calcium carboxymethylcellulose (disintegrant, 20,0 g), magnesium stearate (lubricating agent, 10.0 g) and microcrystalline cellulose (870 g) were mixed with the standard method and stamped tablets, while receiving 10,000 tablets, each of which contained 10 mg of the active ingredient.

Example preparation of the medicinal product 2

1-{[1-Chloro-6-(3-cyclohexylpropionic)-3,4-dihydronaphthalene-2-yl]methyl}azetidin-3-carboxylic acid (100 g), mannitol (2 kg) and distilled water (50 l) was mixed with the standard method. Then the solution was filtered through a dust filter, and then 5 ml aliquots were injected into the vials, which were sterilized in the autoclave, while receiving 10,000 ampoules each containing 10 mg of active ingredient.

Industrial applicability

The connection according to the present invention can be used in the following farmacevticheskih drugs.

The compound of the present invention has the ability to contact the S1P receptor (in particular, EDG-1, EDG-6 and/or EDG-8). Therefore, the compound of the present invention can be used as a prophylactic and/or therapeutic agent in the treatment of mammals (such as humans or animals, other than man, such as monkeys, sheep, cows, horses, dogs, cats, rabbits, rats and mice), such as graft rejection, destruction of the transplanted organ, graft-versus-host (e.g., acute graft-versus-host during bone marrow transplantation, and the like), autoimmune diseases (e.g. systemic lupus erythematosus, Behcet's disease, scleroderma, nephrotic syndrome, rheumatoid arthritis, ulcerative colitis, Crohn's disease, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, myasthenia gravis, muscular dystrophy and multiple sclerosis), allergic diseases (such as atopic dermatitis, hay fever, food Allergy, psoriasis and allergies to medications (e.g., anesthetic, such as lidocaine)), inflammatory diseases (e.g., varicose veins, such as hemorrhoids, fissure or fistula of the anus, dissecting aortic aneurysm, or sepsis, vasculitis, nephritis, pneumonia and chronic active hepatitis), diseases of the respiratory tract (e.g., lung fibrosis, asthma, and interstitial pneumonia), metabolic diseases and endocrine diseases (such as diabetes type I), diseases of the circulatory system (for example, violation of reperfusion after ischemia, arteriosclero is, obliterative arteriosclerosis, obliterating thromboangiitis, diabetic neuropathy, acute heart failure and angina), various edematous disorders caused by increased penetration of the blood (e.g., myocardial infarction, heart attack, brain, DIC (disseminated intravascular coagulation), pleuritis, congestive heart failure, multiple failure of the authorities), traumatic lesions (eg, pressure ulcers and burns), osteoporosis, chronic hepatitis, fibrosis, such as liver fibrosis, chronic renal failure, glomerulosclerosis kidney, infection, ulcer, lymphoma, malignant tumor (e.g., cancer), leukemia, cerebral embolism, ischemic pathology of different organs, the shock due to the incompatibility of blood during blood transfusion, genetic diseases, neurodegenerative diseases (such as Parkinson's disease, parkinsonovy syndrome, Alzheimer's disease and amyotrophic lateral sclerosis), and the like.

Brief description of drawings

Figure 1 shows the diffraction pattern of the powder x-ray diffraction of the compound obtained in example 48.

Figure 2 shows the chart of differential scanning calorimetry (DSC) of the compound obtained in example 48.

Figure 3 shows the powder diffraction pattern diffracts and x-ray connection obtained in example 48(1).

Figure 4 shows a chart of differential scanning calorimetry (DSC) of the compound obtained in example 48(1).

Figure 5 shows the diffraction pattern of the powder x-ray diffraction of compound (crystalline substance type a)obtained in example 49.

Figure 6 shows a chart of differential scanning calorimetry (DSC) of the compound (crystalline substance type a)obtained in example 49.

7 shows the diffraction pattern of the powder x-ray diffraction of compound (crystalline substance type)obtained in example 49.

On Fig shows a chart of differential scanning calorimetry (DSC) of the compound (crystalline substance type)obtained in example 49.

Figure 9 shows the diffraction pattern of the powder x-ray diffraction of the compound obtained in example 49(1).

Figure 10 shows a graph of differential scanning calorimetry (DSC) of the compound obtained in example 49(1).

1. The compound expressed by the formula (IC-2):

where Z means carbamoyl group which may be substituted by C1-4 alkyl or hydroxy;
R1means C1-8 alkyl or C1-8 alkoxy;
R4and R4-1each independently means a hydrogen atom or C1-8 alkyl;
m means an integer from 1 to 5, when pravno 2 or more, all R1can have the same or different values;
its pharmaceutically acceptable salt, N-oxide or MES.

2. A compound selected from
1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
1-({6-[(4-isobutyl-3-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
1-({6-[(2-ethoxy-4-isobutylbenzene)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
1-[(6-{[4-isopropoxy-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
1-({1-chloro-6-[(2-methoxy-4-propylbenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
1-({1-chloro-6-[(4-isobutyl-2-methoxybenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
1-[(1-chloro-6-{[(2S)-3-(2,4-differenl)-2-methylpropyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
1-[(6-{[4-ethoxy-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
1-({6-[(4-ethyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone KIS is the notes,
1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-chloro-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
1-[(6-{[2-(deformedarse)-4-propylbenzyl] oxy}-1,5-dimethyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
1-[(6-{[4-ethoxy-3-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
1-({6-[(2-methoxy-6-propyl-3-pyridinyl)methoxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
1-[(6-{[(2S)-3-(4-forfinal)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
1-[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
N-[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-yl)methyl]-β-alanine,
1-[(6-{[2-deformedarse-4-propylbenzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid, and
1-[(6-{[2-methoxy~4-propylbenzyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
its pharmaceutically acceptable salt, N-oxide or MES.

3. The compound according to claim 2, selected from
monohydrate 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
monohydrate 1-[(6-{[2,4-bis(triform the Teal)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
hydrochloride of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
hydrochloride of 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone acid,
1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone sodium
1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone potassium,
geekalicious salt of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid,
1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone sodium
1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinone potassium.

4. The connection, which is 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid.

5. Pharmaceutical composition having agonistic activity against EDG-1, EDG-6 and/or EDG-8, containing the compound according to claim 2, its pharmaceutically acceptable salt, N-oxide or MES, as an active ingredient, and a carrier.

6. The pharmaceutical composition according to claim 5, which is an agonist of EDG-1.

7. The pharmaceutical composition according to claim 5, which is an agent for the prophylaxis and/and the and treatment of multiple sclerosis.

8. The pharmaceutical composition according to claim 5, which is an immunosuppressant and/or means for causing lymphopenia.

9. The method of prevention and/or treatment of diseases caused EDG-1, EDG-6 and/or EDG-8 in a mammal, comprising administration to the mammal of an effective amount of a compound according to claim 2, its pharmaceutically acceptable salt, N-oxide or MES.

10. The method of prevention and/or treatment of multiple sclerosis in a mammal, comprising administration to the mammal of an effective amount of a compound according to claim 2, its pharmaceutically acceptable salt, N-oxide or MES.

11. The method of suppressing the immune response and/or the induction of lymphopenia in a mammal, comprising administration to the mammal of an effective amount of a compound according to claim 2, its pharmaceutically acceptable salt, N-oxide or MES.

12. The use of compounds according to claim 2, its pharmaceutically acceptable salt, N-oxide or MES to obtain funds for the prevention and/or treatment of diseases caused EDG-1, EDG-6 and/or EDG-8.

13. The use of compounds according to claim 2, its pharmaceutically acceptable salt, N-oxide or MES to obtain funds for the prevention and/or treatment of multiple sclerosis.

14. The use of compounds according to claim 2, its pharmaceutically acceptable salt, N-oxide or MES for receiving immunosuppressant and/or means is a, calling lymphopenia.

15. Crystalline form of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid having a diffraction angle 2θ at 8,427, 9,312, 10,428, 11,834, 12,651, 15,129, 16,792, 17,772, 18,286, 18,771, 19,267, 19,912, 21,157, 21,525, 22,224, 22,716, 23,432, 23,915, 25,355, 26,417 and 27,048 in the spectrum of the powder x-ray diffraction and/or an infrared absorption spectrum with characteristic absorption bands at 3418, 2957, 2931, 2820, 1605, 1500, 1382, 1250, 993 and 489 cm-1.

16. The crystalline form of the monohydrate of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid having a diffraction angle 2θ at 8,854, 11,144, 11,511, 12,133, 13,281, 13,986, 14,490, 15,264, 17,413, 18,584, 18,730, 19,285, 19,875, 20,963, 22,223, 22,440, 23,840, 23,988, 24,900 and 25,113 in the spectrum of the powder x-ray diffraction.

17. The crystalline form of the monohydrate of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinone acid having a diffraction angle 2θ at 9,076, 11,233, 11,660, 12,936, 13,619, 14,317, 15,794, 16,902, 17,366, 18,081, 18,788, 20,022, 21,444, 21,635, 22,391, 22,738, 23,425, 23,934, 24,553, 25,356 and 29,218 in the spectrum of the powder x-ray diffraction.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention describes novel bicyclic derivatives of general formula (I)

(values of radicals are given in the description) and a pharmaceutical composition containing said derivatives, as well as use of said novel compounds to treat or inhibit symptomatic diseases where CEPT is involved, and a method of treating said diseases.

EFFECT: high efficiency of using compounds when treating diseases.

14 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in free form or in form of a pharmaceutically acceptable salt, where A is independently selected from CH and at least one nitrogen atom; D denotes CR3; R1 and R2 denote H, R3 denotes C1-C8-alkyl, R5 denotes , R5j and R5k are independently selected from H, C1-C8-alkyl and C3-C15-carbocyclic group, or R5j and R5k together with the nitrogen atom to which they are bonded form an optionally substituted 4-14-member heterocyclic group; R6 denotes H; W denotes a C6-C15-aromatic carbocyclic group; X denotes -CH2-; n assumes values from 0 to 3, a pharmaceutical composition based on said compounds and having CRTh2 receptor modulating activity, as well as a method for synthesis of compounds of formula I.

EFFECT: novel compounds which can be used as anti-inflammatory agents are obtained and described.

9 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: in general formula I R1 denotes hydrogen atom, a halogen atom, hydroxy, lower alkyl, benzyloxy or -O-(CH2)-(CO)-(5-member heteroaryl with 2 heteroatoms selected from N, O), substituted with phenyl or lower alkyl; R2 denotes a hydrogen atom, a halogen atom, lower alkyl, lower alkynyl, amino, -NHC(O)Ra or -(CO)-Ra; R3 denotes a hydrogen atom, a halogen atom, cyano, lower alkyl, lower alkynyl, amino, -NHC(O)-Ra, -(CO)-Ra, 4- or 5-member heterocycloalkyl substituted with a =O group or a 5-member heteroaryl with 1-2 heteroatoms selected from N; R4 denotes a hydrogen atom or a 5-member heteroaryl with 2 heteroatoms selected from N; R5 denotes lower alkyl or C3-C7cycloalkyl; Ra denotes lower alkoxy, -(CH2)n-(6-member heteroaryl with 1 heteroatom selected from N), phenyl C3-C7-cycloalkyl or NR'R", where each of R' and R" independently denotes a hydrogen atom, lower alkyl, substituted hydroxy, lower alkynyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-member heterocycloalkyl with 1-2 heteroatoms selected from O, N) or -(CH2)n-(5- or 6-member heteroaryl with 1 heteroatom selected from N, O); n assumes values from 0 to 3. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare the medicinal agent.

EFFECT: high activity and selectivity towards GABA A receptor subunit α5.

18 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 2,8-dimethyl-5-[2-(6-methyl-pyridyl-3)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole salts of general formula (1) exhibiting antidepressive and antihypoxic activity where n=1, 2 Y = (CH2COOH)2, HOOCCH(OH)CH2COOH, (HOOCCH2)2C(OH)COOH. Besides, the invention concerns a pharmaceutical agent.

EFFECT: ensured production of new biologically active compounds exhibiting antidepressive and antihypoxic activity.

6 cl, 5 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I ; or to its pharmaceutically acceptable salts where n represents 0, 1 or 2; Y1 represents a bond or a group C(O); Y2, represents a bond, the groups C(O) or S(O)2; R1 represents hydrogen, halogen, cyano, C1-2alkyl; R2 represents hydrogen, halogen, cyano, C1-4alkyl, C1-3alkoxy, halogen-substituted-C1-3alkyl, halogen-substituted-C1-3alkoxyl, C6aryl-C0alkyl, tetrazolyl, C3-6cycloalkyl-C0alkyl, C6-7heterocycloalkyl-C0-4alkyl where 1 or 2 carbon atoms in the ring are substituted by the groups selected from -O-, -NH-, -S(O) and -SO2-; and phenoxy groups; where said aryl and heterocycloalkyl groups R2 can be substituted by 1 or 2 radicals independently selected from C1-6alkyl; R3 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group and a group -NR6aR6b where R6a and R6b are independently selected from hydrogen and C1-4alkyl; R4 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group; R5 represents hydrogen or C1-3alkyl group; L represents a bivalent radical selected from ; ; ; ; ; ; ; ; ; ; ; ; and ; where asterisks the junctions of Y2 and R2; where any bivalent radical L can be substituted by 1 or 2 radicals independently selected from halogen, hydroxy, cyano, C1-4alkyl, C1-4alkyl carbonylamino, C1-4alkoxy, C1-4alkoxycarbonyl, halogen-substituted - C1-4alkyl, C1-3alkylsulfonyl, C1-3alkylsulfonyl-amino, cyano-substituted - C1-4alkyl and halogen-substituted -C1-4alkoxy radicals. Also, the invention refers to a method of Hedgehog path inhibition in a cell and to a method of undesired cell proliferation inhibition which involves the interaction of the compound of formula I and the cell.

EFFECT: new substituted imidazole derivatives which can be effective in treatment of some types of cancer are prepared.

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a condensed cyclic aromatic compound having the formula [2] given below: , where each R1 R2, R3, R5-R8, R10-R13, R15-R18, R20 denotes a hydrogen atom, R4, R9, R14, R19 denote phenyl, optionally substituted with two substitutes selected from tertbutyl. The invention also relates to use of said compound as an organic light-emitting layer in an organic light-emitting device.

EFFECT: obtaining a substance which can be used to make a light-emitting device which is durable and has high radiation efficiency.

2 cl, 6 ex, 2 tbl, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to new amino acid derivatives of formula (I), , in which R-groups have the following value: -R1 is -H;-R2 is -C(O)R15 or -SO2R15; -R3 is -H;-R4 is -H or -(1-4C)alkyl; -R6 is -H; -R7 is -H; -R8 is -H, cyanogroup, halogen, nitrogroup; -(1-6C)alkyl optionally substituted by amino group, hydroxyl or halogen; -heteroaryl representing a 5 or 6-members aromatic ring containing one or more heteroatoms N optionally substituted by -(1-4C) alkyl; -C(R16)NOR16, -C(O)N(R17)2, -C(O)R18 or -C(O)OR19; -R9 is -H; -R10 is -H or -(1-4C)alkyl; -R11 is -H; -R12 is -H; -R13 is -H; -R14 is -H; -R15 is -H; -(1-6C)alkyl, -(2-6C)alkynyl, -O(2-6C)alkyl) all optionally substituted by one or more, halogen, cyanogroup or 5-members heteroaryl where 5-members heteroaryl represents an aromatic ring containing one or more heteroatoms selected from a group including N, O or S; -(hetero)aryl representing 5 or 6-members aromatic ring system containing one or more heteroatoms selected from group including N, O or S, optionally substituted by -(1-4C)alkyl, halogen or NH2; -NH2, -(di)(1-4C)alkylamihogroup, -(1-4C)alkylamihogroup or -NR16OR16; R16 is -H or -(1-4C)alkyl; -R17 is -H or -(1-6C)alkyl optionally substituted by halogen, or 5 or 6-members heteroaryl or aryl optionally substituted by halogen, -(1-4C)alkyl or -(1-4C)alkoxygroup where heteroaryl represents an aromatic ring containing one or more heteroatoms selected from the group including N, O or S; -R18 is -H or -(1-4C)alkyl; -R19 is -H or -(1-6C)alkyl.

EFFECT: compounds of this invention are high-specific to glucocorticoid receptor and can be used for treating inflammatory diseases.

6 cl, 58 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: chemistry.

SUBSTANCE: described are novel benzofuroxanes of general formula

, where R is phenylamino-, N-[4-methoxyphenyl]amino-, N-piperidyl-, which have fungicidal and bactericidal activity and which can be used in veterinary, medicine and agriculture.

EFFECT: high efficiency of the compositions.

2 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,4-dihydrobenzoxazine compounds of general formula [1] (where X denotes a nitrogen atom or CR3; R1 denotes a hydrogen atom or a halogen atom; R2 denotes a C1-6alkoxy group which can be substituted with 1-5 identical or different substitutes selected from a halogen atom and a hydroxyl group; and R3 denotes a halogen atom. However, R1 denotes a halogen atom when X denotes CR3). Said compounds are effective when treating diseases where activity of vanilloid receptors subtype 1 (VR1) is involved, e.g. pain.

EFFECT: more efficient use of pharmaceutical compositions based on said compounds, more effective treatment or pain killing.

19 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof , where D denotes phenyl; n equals 0; A, B and Q denote hydrogen; Z is selected from a group comprising a bond, straight C1-3alkylene; R1 is selected from a group comprising hydrogen, C1-10alkyl, C3-8cycloalkyl, benzyl, a 6-member monocyclic, 9-10-member bicyclic aromatic carbon-containing ring system and a spiro-ring system of formula (V): where X1 and X3 denote O; and where the said alkyl, cycloalkyl or benzyl from the R1 group is optionally substituted with 1-3 substitutes selected from a group comprising C1-3alkyl, cyano, phenyl, wherein the said phenyl is optionally substituted with 1-3 substitutes selected from halogen. The invention also relates to compounds of formulae .

Values of radicals of the said compounds are given in the claim. The invention also relates to a pharmaceutical composition having ORL1 receptor or µ opioid receptor inhibiting properties, containing an effective amount of the disclosed compound, a method of curing pain and a method of modulating pharmacological response from the opioid receptor, including the ORL1 or µ opioid receptor.

EFFECT: improved method.

41 cl, 5 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula as well as separate enantiomers, diastereomers, racemic mixures and pharmaceutically acceptable salts thereof, having mitotic kinesin KSP inhibiting activity, as well as inhibitory action on tumour cells, use thereof in preparing a medicinal agent and a pharmaceutical composition based on said compounds. In said formula, R denotes Z-NR2R3, Z-OH, Ar1 and Ar2 independently denote a phenyl which, if needed, is substituted with one or more groups independently selected from: F, CI, Br, I, OH, Z denotes an alkylene having 1-6 carbon atoms which, if needed, is substituted with C1-6alkyl, and R1 assumes values given in the claim.

EFFECT: improved method.

16 cl, 3 dwg, 124 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl-isoxazole-4-yl-imidazole derivatives of formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit GABA A α5 receptor binding site activity and selectivity. In general formula I

each of R1-R3 independently represents hydrogen atom or halogen atom; R4 represents hydrogen atom, lower alkyl, C3-C7cycloalkyl, -(CH2)n-O-lower alkyl or hydroxy substituted lowest alkyl; R5 represents -(CH2)m-phenyl or -(CH2)m-(5-6-members heteroaryl with 1-2 heteroatoms independently seected from N, O) which optionally substituted by one or more substitutes selected from a group consisting of halogen atom, cyano, nitro, lower alkyl, lower alkoxy, lower alkylsulphanyl, lower alkyl substituted by halogen atom, -C(O)-lower alkyl, -C(O)-O-lower alkyl, -NH-C(O)-O-lower alkyl or -C(O)-NH-R' where R' represents the lower alkynyl or hydroxy substituted lower alkyl, or represents -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-members heterocyclyl with 1-2 heteroatoms selected from N, O), -(CH2)n-(5-6-members heteroaryl with 1-2 heteroatoms selected from N, O) or -(CH2)n-phenyl optionally substituted by halogen atom; R6 represents hydrogen atom, -C(O)H, -(CH2)n-O-lower alkyl, -C(O)O-lower alkyl, lower alkyl substituted by hydroxy or halogen atom, or represents C3-C7-cycloalkyl, phenyl, or represents -(CH2)n-O-CH2-phenyl optionally substituted by halogen atom or lower alkyl, or represents -(CH2)n-O-CH2-(6-members heteroaryl with 1 heteroatom selected from N) optionally substituted by lower alkyl or lower alkyl substituted by halogen atoms, or represents -(CH2)n-NH-(CH2)o-(6-members heterocyclyl with 2 heteroatoms selected from N; n means 0, 1, 2 or 3; m means 0 or 1; o means 1, 2 or 3.

EFFECT: presented preparation of a drug containing one or more compound of formula I and application of the compounds for preparing the drug.

31 cl, 168 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxazole derivatives of general formula I. The disclosed compounds have affinity to the µ-opioid receptor. In general formula I

, n equals 0, 1 or 2, R1 denotes a phenyl residue bonded through a C1-C3alkyl chain, R2 denotes phenyl or thienyl, each of which is unsubstituted or mono-substituted with F or Cl, R3 and R4 independently denote a saturated, branched or straight C1-C6alkyl, phenyl or a phenyl residue bonded through a C1-C3akyl chain, or R3 and R4 together form an unsubstituted five-, six- or seven-member saturated ring which can optionally contain an extra heteroatom selected from a group comprising O or NR9, where R9 denotes phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which is unsubstituted or mono-substituted with a substitute selected from a group comprising F, Cl, Br, I and O-C1-C6alkyl, where the ring can be optionally condensed with a phenyl ring, R5 and R6 independently denote a saturated, branched or straight C1-C6alkyl, R7 and R8 independently denote a saturated, branched or straight unsubstituted C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, or R7 and R8 together form an unsubstituted or mono- or disubstituted five-, six- or seven-member saturated ring, where the substitutes are selected from a group comprising C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, where the ring can optionally contain an extra heteroatom selected from a group comprising S, O and NR10, where R10 denotes a phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which can be unsubstituted or mono-substituted with O-C1-C6alkyl. The invention also relates to methods of producing the disclosed compounds, a medicinal agent containing at least one substituted oxazole derivative of formula I, use of the compounds to prepare a medicinal agent.

EFFECT: improved properties.

13 cl, 1 tbl, 150 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2,6-substituted-4-monosubstituted aminopyrimidines of formula (I) or pharmaceutically acceptable salts thereof, which have prostaglandin D2 receptor antagonist properties. In formula R1 is 2,4-dichlorophenyl or 4-trifluoromethoxyphenyl, and when R1 is 2,4-dichlorophenyl, R2 is 3-carboxypyrrolidinyl, 3,5-di-(1-hydroxy-1-methylethyl)phenyl, 3-aminopiperdin-1-yl, 4-aminopiperidin-1-yl, 4-acetamidepiperidin-1-yl, 1-methyl-2-carboxy-2,3-dihydro-1H-indol-5-yl, 3-(1-tert-butylsulphonylaminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminosulphonylaminocarbonyl-1-methylethyl)phenyl, 3-(1-thiomorpholin-4-ylcarbonyl-1-methylethyl)phenyl, 3-(1-aminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminocarbonyl-1-methylethyl)phenyl, 3-carboxymethylpiperidin-1-yl, 3-methylsulphonylaminocarbonylpiperidin-1-yl, 3-ethylsulphonylaminocarbonylpiperidin-1-yl, 3-tert-butylsulphonylaminocarbonylpiperidin-1-yl, 3-trifluoromethylsulphonylaminocarbonylpiperidin-1-yl, 3-[(1H-tetrazol-5-yl)aminocarbonyl]piperidin-1-yl, 3-aminocarbonylpiperidin-1-yl, 3-dimethylaminocarbonylpiperidin-1-yl, 3-dimethylaminosulphonylaminocarbonylpiperidin-1-yl or 2-carboxy-2,3-dihydrobenzofuran-5-yl, and when R1 is 4-trifluoromethoxyphenyl, R2 is 3-(1-methyl-1-carboxyethyl)piperidinyl, 3-carboxypiperidinyl, 3-methylsulphonylaminocarbonylpiperidin-1-yl, 5-carboxythiophen-2-yl. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: high efficiency of using said compounds.

3 cl, 1 tbl, 13 ex

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