RU2433121C2 - Derivative of aminocarbon acid and application of said substances for medical purposes - Google Patents

Abstract

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 R^4-1 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

Description

FIELD OF THE INVENTION

The present invention relates to a compound capable of binding to a sphingosine-1-phosphate receptor (hereinafter referred to as “S1P”), which can be used as a medicine and a medicine containing said compound as an active ingredient.

In particular, an object of the present invention is:

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

where all characters have the meanings below; its salt, N-oxide, MES or prodrug;

(2) a medicament containing, as an active ingredient, a compound represented by the formula (I), a salt thereof, an N-oxide, a solvate or a prodrug.

State of the art

Sphingosine-1-phosphate (S1P), expressed by formula (A), is a lipid synthesized as a result of intracellular metabolic metabolism of sphingolipids or the intercellular action of secretory sphingosine kinase. It has been established that S1P acts as an intercellular and intracellular messenger (Biochem. Pharm., 58, 201 (1999)).

Known S1P receptors are EDG-1, which is a G-protein bound receptor, and similar molecules, EDG-3, EDG-5, EDG-6 and EDG-8 (also referred to as S1P ₁ , S1P ₃ , S1P ₂ , respectively , S1P ₄ and S1P ₅ ). These receptors belong to the EDG family together with the receptors EDG-2, EDG-4 and EDG-7, which are receptors of lysophosphatidic acid (LPA). S1P receptors bind to S1P and transmit signals to cells through the G protein associated with these receptors. Gs, Gi, Gq and G _12/13 , etc. are known as G-proteins with which the S1P receptor can bind, and it is believed that this receptor is involved in such reactions as enhancing cell proliferation, suppressing cell proliferation, inducing cell chemotaxis and inhibiting cell chemotaxis.

When performing in vitro experiments, it was found that the biological effect of S1P is expressed in the inhibition of smooth muscle or cancer cell migration, platelet aggregation, induction of cell chemotaxis, inhibition of cell chemotaxis and similar processes, and based on the results of in vitro experiments, it was found that S1P is capable of control blood pressure, stimulate the development of blood vessels, reduce blood flow in the kidneys, inhibit pulmonary fibrosis, stimulate the homing of lymphocytes in the lymphatic organ and so on. It is believed that the above physiological actions are mediated by S1P receptors present in the cell membrane. However, with the exception of individual cases, it is practically not known which subtypes of S1P receptors actually mediate these effects.

As a result of a study in which mice lacking EDG-1 were used, it has recently been established with a high degree of certainty that S1P induces the development of blood vessels through the EDG-1 receptor (J. Clin. Invest., 106, 951 (2000)) . Therefore, it can be assumed that the EDG-1 agonist can be used to treat diseases caused by the development of blood vessels. For example, such an agonist can be used as an agent for the prophylaxis and / or treatment of peripheral arterial diseases, such as arteriosclerosis obliterans, thromboangiitis obliterans, Burger's disease, or diabetic neuropathy; varicose veins, such as hemorrhoids, fissure, or anus; exfoliating aortic aneurysm, sepsis, inflammatory diseases such as vasculitis, nephritis or pneumonia, various edematous diseases resulting from ischemia of different organs and increased blood penetration, such as myocardial infarction, cerebral infarction, angina pectoris, disseminated intravascular coagulation (DIC), pleurisy congestive heart failure, multiple organ failure, shock due to blood incompatibility during blood transfusion and the like. In addition, the EDG-1 agonist can also be used as a means to accelerate wound healing on the cornea, skin, digestive organs, or the like, or, for example, as a means for the prevention and / or treatment of bedsores, burns, ulcerative colitis, disease Crohn or the like. An EDG-1 agonist can also be used as a preoperative, postoperative and / or prognostic vascular activator in transplantation of various organs, for example, as an activator of adhesion of transplanted organs, in particular, in heart transplantation, kidney transplantation, skin transplantation 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, which implies that EDG-6 is closely related to the effect exerted S1P during inflammation or in the immune system (Biochem. Biophys. Res. Commun., 268, 583 (2000)).

In addition, it is known that the EDG-6 polypeptide or its homolog mediates immunomodulation, anti-inflammatory reactions and similar processes similarly to EDG-1, which suggests the potential use of these substances in the treatment of autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, muscular dystrophy and the like), allergic diseases (such as atopic dermatitis, hay fever, food allergy and an allergy to chemicals (e.g. anesthetic, such as like lidocaine) and the like), asthma, inflammatory diseases, infections, ulcers, lymphomas, malignant tumors (such as cancer and the like), leukemia, arteriosclerosis, diseases caused by lymphocyte infiltration in the tissue, such as multiple organ failure and impaired reperfusion after ischemia, shock due to incompatibility of blood during a blood transfusion and the like.

It is known that EDG-8 is mainly expressed in nerve cells; therefore, EDG-8 can be used to treat various neurodegenerative diseases (such as Parkinson's disease, Parkinson's syndrome, Alzheimer's disease and amyotrophic lateral sclerosis).

Thus, it is believed that a drug acting on EDG-1, EDG-6 and / or EDG-8 can be used as a prophylactic and / or therapeutic agent in case of transplant rejection, destruction of the transplanted organ, transplant versus host reaction ”(For example, an acute graft versus host reaction during bone marrow transplantation and the like), autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis and muscular dystrophy), allergic diseases th (such as atopic dermatitis, hay fever, food allergies and allergies to chemicals (e.g. anesthetic such as lidocaine) and the like), asthma, inflammatory diseases, infections, ulcers, lymphomas, malignant tumors (e.g. cancer), leukemia arteriosclerosis, diseases caused by lymphocyte infiltration in the tissue, such as multiple organ failure and impaired reperfusion after ischemia, shock due to blood incompatibility during blood transfusion, neurodegenerative diseases (such as disease P rkinsona, Parkinsonian syndrome, Alzheimer's disease and amyotrophic lateral sclerosis) and the like.

In recent years, the scientific literature has noted that an EDG-1 agonist can be used as an immunosuppressant. However, there is no information that an EDG-6 agonist or antagonist can be used as an immunosuppressant (see Patent Document 1: WO 03/061567).

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

where Ar ^S is phenyl or naphthyl; A ^S means carboxy or a similar group; n ^S is 2, 3 or 4; R ^1S and R ^2S each independently means a hydrogen atom, a halogen atom, hydroxy, carboxy, C1-6 alkyl, which may be substituted by 1-3 halogen atoms, or phenyl, which may be substituted by 1-3 halogen atoms; R ^3S means a hydrogen atom or C1-4 alkyl, which may be substituted by 1-3 hydroxyl groups or halogen atoms; all R ^4S each independently means hydroxy, halogen atom, carboxy or the like group; C ^S is C 1-8 alkyl, C 1-8 alkoxy, phenyl or the like, or C ^S has no meaning; and B ^S is phenyl, C5-16 alkyl or a similar group (only the necessary parts of the definitions of the symbols are indicated);

its pharmaceutically acceptable salt and hydrate; and

the compound represented by formula (T):

where Ar ^T is phenyl or naphthyl; And ^T means carboxy or a similar group; m ^T is 0 or 1; n ^T is 0 or 1; R ^1T and R ^2T each independently means a hydrogen atom, a halogen atom, a hydroxy, carboxy, C 1-4 alkyl or phenyl, which may be substituted by a halogen atom or the like; R ^3T means a hydrogen atom or C1-4 alkyl, which may be substituted by a hydroxyl group or a halogen atom or the like; all R ^4T independently represent a halogen atom, C1-4 alkyl, C1-3 alkoxy or the like; C ^T is C1-8 alkyl, C1-8 alkoxy, phenyl or a similar group, or C ^T has no meaning; and B ^T means phenyl, C5-16 alkyl or a similar group (only the necessary parts of the definitions of the symbols are indicated);

its pharmaceutically acceptable salt and hydrate can be used as EDG-1 agonists (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):

означает простую или двойную связь; его пролекарство или нетоксичная соль являются агонистами EDG-1 (см. патентный документ 4: WO 02/092068).where R ^1Z means C1-8 alkyl, C1-8 alkoxy, halogen atom, nitro or trifluoromethyl; ring A ^Z means a C5-7 monocyclic carbocyclic ring or a 5- or 7-membered monocyclic heterocyclic ring containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom; E ^Z is —CH ₂ -, —O—, —S— or —NR ^6Z , where R ^6Z is a hydrogen atom or C1-8 alkyl; R ^2Z is C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl; R ^3Z means a hydrogen atom or C1-8 alkyl; R ^4Z means a hydrogen atom or C1-8 alkyl, or R ^2Z and R ^4Z taken together can form —CH ₂ CH ₂ - or —CH = CH—; G ^Z means —CONR ^7Z -, —NR ^7Z CO—, —SO ₂ NR ^7Z -, —NR ^7Z SO ₂ -, —CH ₂ NR ^7Z - or —NR ^7Z CH ₂ -, where R ^7Z represents a hydrogen atom, C1 -8 alkyl or a similar group; Q ^Z is C1-4 alkylene or a similar group: p ^Z is 0 or an integer from 1 to 5; q ^Z is an integer from 4 to 6; r ^Z means 0 or an integer from 1 to 4; and

means a single or double bond; its prodrug or non-toxic salt are EDG-1 agonists (see Patent Document 4: WO 02/092068).

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

where the ring A ^Y means a cyclic group; ring B ^Y means a cyclic group which may have one or more substituents; X ^Y means a bond or a spacer having a main chain containing 1-8 atoms, wherein one spacer atom together with a substituent in the ring B ^Y can form a ring group which may have one or more substituents; Y ^Y means a bond or a spacer having a main chain containing 1-10 atoms, wherein one spacer atom together with a substituent in the ring B ^Y can form a ring group which may have one or more substituents; Z ^Y means an acid group that can be protected; nY is 0 or 1, wherein when nY is 0, mY is 1 and R ^1Y is a hydrogen atom or substituent, and when nY is 1, mY is 0 or an integer from 1 to 7, and R ^1Y is a substituent, which, when mY is 2 or more, all R ^1Y have the same or different values; its salt, solvate or prodrug has the ability to bind to the S1P receptor (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

The tasks solved by the invention

Immunosuppressants are used to prevent and / or treat inflammatory diseases, autoimmune diseases, allergic diseases and / or transplant rejection. However, the currently used immunosuppressants and drugs for the treatment of autoimmune diseases 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 a drug for the treatment of autoimmune diseases, which is safe, does not affect the metabolic enzyme, has a rather long-lasting effect and less side effects.

Means for solving these problems

The authors of the present invention comprehensively investigated compounds that can bind to the sphingosine-1-phosphate receptor (S1P), with the aim of their use as a medicine. As a result of these studies, it was found that the compounds of the present invention have a strong agonistic effect on the S1P receptor, in particular EDG-1 and / or EDG-6. In addition, it was also found that part of the compounds of the present invention has an agonistic effect on the receptor EDG-8; these compounds of the present invention reduced the number of lymphocytes in peripheral blood and had an immunosuppressive effect; moreover, the immunosuppressive effect of the compounds of the present invention persisted even after 24 hours, which cannot be expected based on in vitro activity. It was very surprising that the compounds of the present invention had no side effects and were safe for many animal species.

The objects of the present invention are:

[1] the compound represented by formula (I)

where ring A means a cyclic group;

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

X is a bond or a spacer having a main chain containing 1-8 atoms, wherein one spacer atom together with a substituent in ring B can form a ring that can have one or more substituents;

Y is a bond or spacer having a main chain containing 1-10 atoms, wherein one spacer atom together with a substituent in ring B can form a ring that can have one or more substituents;

Z is an acid group that can be protected; and

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

its salt, N-oxide, MES or prodrug;

[2] the compound according to the above [1], a salt thereof, an N-oxide, a solvate or prodrug, where Z is (1) a carboxyl group that may be protected; (2) a hydroxyl group that can be protected, (3) a hydroxamic acid group that can be protected, (4) a sulfonic acid group that can be protected, (5) a boronic acid group that can be protected, (6) a carbamoyl group that can be protected, (7) a sulfamoyl group that can be protected, (8) a group -P (= O) (OR ² ) (OR ³ ), in which R ² and R ³ each independently represents a hydrogen atom and a C1-8 alkyl group, or R ² and R ³ taken together means a C2-4 alkylene group, or (9) a tetrazolyl group;

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

in which a carbon atom or a nitrogen atom can be substituted by an arbitrary number of substituents at arbitrary positions in which substituents are possible, and a right-facing arrow indicates a bond with Z;

[4] the compound of [1] above, a salt, N-oxide, solvate or prodrug thereof, wherein ring B is a benzene ring which may have one or more substituents, or a dihydronaphthalene ring which may have one or more substituents;

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

in which R ⁴ , R ^4-1 , R ⁵ , R ^5-1 and R ^5-2 each independently means a hydrogen atom, a halogen atom, trifluoromethyl, trifluoromethoxy, C1-8 alkoxy or C1-8 alkyl; p is 0 or an integer from 1 to 4, wherein when p is 2 or more, all R ⁴ may have the same or different values; and the arrow pointing to the right means communication with Z;

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

where all characters have the meanings indicated in the above paragraphs [1] and [5];

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

означает α-конфигурацию; символ

означает β-конфигурацию; и обращенная вправо стрелка означает связь с кольцом В;in which R ⁶ and R ⁷ each independently means a hydrogen atom, a halogen atom, a hydroxyl group that can be protected, an amino group that can be protected, C1-8 alkyl or C1-8 alkyl substituted with a hydroxyl group that can be protected; or R ⁶ and R ⁷ together with the carbon atom to which they are attached can form a ring which may have one or more substituents; symbol

means α-configuration; symbol

means β-configuration; and the arrow pointing to the right means a connection with ring B;

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

in which all characters have the meanings indicated in the above paragraph [7];

[9] the compound of [8] above, its salt, N-oxide, solvate or prodrug, where X is

in which all symbols have the meanings indicated in the above paragraph [7];

[10] the compound of [1] above, its salt, N-oxide, solvate or prodrug, wherein ring A is a benzene ring or a pyridine ring;

[11] the compound according to the above [1], a salt thereof, an N-oxide, a solvate or prodrug, wherein R ¹ is a halogen atom, C1-8 alkyl or C1-8 alkoxy;

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

where all characters have the meanings indicated in the above paragraphs [1] and [5];

[13] the compound of [12] above, a salt, N-oxide, solvate or prodrug thereof, wherein Z is a carboxyl that can be protected;

[14] the compound of [12] above, a salt, N-oxide, solvate or prodrug thereof, wherein X is

in which the arrow pointing to the right means a connection with the ring B, and all other symbols have the meanings indicated in the above paragraph [7];

[15] the compound of [12] above, a salt, N-oxide, solvate or prodrug thereof, wherein ring A is a benzene ring or a pyridine ring;

[16] the compound of [12] above, a salt, N-oxide, solvate or prodrug thereof, wherein R ¹ is a halogen atom, C1-8 alkyl, which may have one or more substituents, or C1-8 alkoxy, which may have one or more substituents;

[17] the compound according to the above [12], a salt thereof, an N-oxide, a solvate or prodrug represented by the formula (IC-2):

where all characters have the meanings indicated in the above paragraphs [1] and [5];

[18] the compound of [1] above, its salt, N-oxide, solvate or prodrug, which is 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3 , 4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({6 - [(4-isobutyl-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({6 - [(4-isobutyl-3-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({6 - [(2-ethoxy-4-isobutylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - [(6 - {[4- isopropoxy-2- (tr fluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1 - [(6 - {[2,4-bis- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1 - ({1-chloro-6 - [(2-methoxy-4-propylbenzyl) oxy] -3,4- dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({1-chloro-6 - [(4-isobutyl-2-methoxybenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) - 3-azetidinecarboxylic acid, 1 - [(1-chloro-6 - {[(2S) -3- (2,4-difluorophenyl) -2-methylpropyl] oxy} -3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1 - [(6 - {[4-ethoxy-2- (trifluoromethyl) benzyl] oxy} -1-m ethyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1 - ({6 - [(4-ethyl-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2 -naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1,5-dimethyl-3,4-dihydro-2-naphthalenyl} methyl) -3 -azetidinecarboxylic acid, 1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-chloro-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1- [ (6 - {[2- (difluoromethoxy) -4-propylbenzyl] oxy} -1,5-dimethyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1 - [(6 - {[ 4-ethoxy-3- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthal nyl) methyl] -3-azetidinecarboxylic acid or 1 - ({6 - [(2-methoxy-6-propyl-3-pyridinyl) methoxy] -1,5-dimethyl-3,4-dihydro-2-naphthalenyl} methyl ) -3-azetidinecarboxylic acid;

[19] the compound of [17] above, a salt, N-oxide, solvate or prodrug thereof, which is 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3 , 4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid or 1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2- naphthalenyl) methyl] -3-azetidinecarboxylic acid;

[20] a pharmaceutical composition comprising a compound represented by formula (I) according to the above [1], a salt thereof, an N-oxide, a solvate or prodrug thereof;

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

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

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

[24] the pharmaceutical composition according to the above [23], wherein the disease due to EDG-1, EDG-6 and / or EDG-8 is rejection during transplantation of an organ, tissue and / or cells, an autoimmune disease, an allergic disease, asthma, multiple organ failure, impaired reperfusion after ischemia, a malignant tumor and / or neurodegenerative disease;

[25] the pharmaceutical composition according to paragraph [24] above, wherein rejection during transplantation of an organ, tissue and / or cell is rejection during transplantation of a kidney, liver, heart, lung, skin graft, cornea, blood vessel, tendon, bone graft, bone cell brain, nerve cells and / or cells of the pancreatic islet; an autoimmune disease is collagenosis, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, autoimmune diabetes, lung fibrosis and / or liver fibrosis, and an allergic disease is atopic dermatitis, pollinosis and / or

[26] the pharmaceutical composition according to the above [20], which is an immunosuppressant and / or agent that causes lymphopenia;

[27] an agent comprising a compound represented by formula (I) according to the above [1], a salt thereof, an N-oxide, a solvate or a prodrug thereof in combination with one or at least two agents selected from the group consisting of an antimetabolite, an alkylating agent, a T-cell activation inhibitor, a calcineurin inhibitor, a proliferation signal inhibitor, a steroid, an immunosuppressant, an antibody used to suppress an immune response, a rejection treatment agent, an antibiotic, an antiviral agent and an antifungal agent;

[28] a method for preventing and / or treating a disease caused by EDG-1, EDG-6 and / or EDG-8 in a mammal, comprising administering to the mammal an effective amount of a compound expressed by formula (I) according to the above [1], salts, N-oxide, MES or prodrugs;

[29] a method for suppressing an immune response and / or inducing lymphopenia in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) according to [1] above, a salt thereof, an N-oxide, solvate or prodrug;

[30] the use of a compound expressed by formula (I) according to the above [1], a salt thereof, an N-oxide, a solvate or a prodrug to obtain an agent for the prophylaxis and / or treatment of a disease due to EDG-1, EDG-6, and / or EDG-8;

[31] the use of a compound expressed by formula (I) according to the above [1], a salt thereof, an N-oxide, a solvate or a prodrug to obtain an immunosuppressant and / or an agent causing lymphopenia;

[32] a method for producing a compound expressed by formula (I) according to the above [1], a salt thereof, an N-oxide, a solvate or a prodrug.

In the present specification, S1P means sphingosine-1-phosphate ((2S, 3R, 4E) -2-amino-3-hydroxyoctadec-4-enyl-1-phosphate). EDG means the endothelial differentiation gene, which is a general term for EDG-1 - EDG-8. Among the endothelial differentiation genes, EDG-1, EDG-3, EDG-5, EDG-6, and EDG-8 (referred to as S1P ₁ , S1P ₃ , S1P ₂ , S1P _4, and S1P _5, respectively) are considered S1P receptors.

In the present description of the invention, a compound having the ability to bind to a receptor is an agonist, antagonist and inverse agonist. An agonist can be a complete agonist and a partial agonist.

In the present invention, a preferred compound capable of binding to the S1P receptor is an EDG-1 agonist that may have an agonist activity against EDG-6 and / or an EDG-6 agonist that may have an agonist activity against EDG-1.

In the present description of the invention, examples of diseases caused by EDG-1 and / or EDG-6 include transplant rejection, destruction of the transplanted organ, graft versus host reaction (eg, acute graft versus host disease 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 diseases, infections, ulcers, lymphomas, malignant tumors (e.g. cancer), leukemia, arteriosclerosis, diseases caused by lymphocyte infiltration into the tissue, shock due to incompatibility blood transfusion, acute heart failure, angina pectoris, cerebral apoplexy, traumatic lesions, genetic diseases, diseases of the peripheral arteries, such as obliterating arteriosclerosis, obliterating t omboangiitis, Burger’s disease, diabetic neuropathy, sepsis, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous disease, varicose veins such as hemorrhoids, anus fissure or fistula, stratified aortic aneurysm, disseminated intravascular (vascular) D vascular , pleurisy, congestive heart failure, multiple organ failure, shock due to blood incompatibility during blood transfusion, pressure sores, burns, ulcerative colitis, Crohn’s disease, osteoporosis, f ibrosis (e.g., pulmonary fibrosis and liver fibrosis), interstitial pneumonia, chronic hepatitis, cirrhosis, chronic renal failure, and glomerular kidney sclerosis. In addition, EDG-1 is also a preoperative, postoperative and / or prognostic activator of blood vessels for transplantation of various organs, tissues and / or cells, for example, an activator of adhesion of transplanted organs, tissues and / or cells during heart transplantation, kidney transplantation, skin transplantation, or liver transplantation and the like.

In the present description of the invention, examples of diseases caused by EDG-8 include neurodegenerative diseases. Neurodegenerative diseases are all diseases caused by denaturation of the nerve, without limiting the causes of such diseases. The neurodegenerative diseases of the present invention also include a violation of the nervous system. Preferred examples of neurodegenerative diseases are diseases of the central nervous system, such as Parkinson's disease, Parkinson's syndrome, Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington's disease, cerebrospinal and cerebellar ataxia, dentanural olivopontocerebellar atrophy, corticobasal degeneration, familial dementia, frontotemporal dementia, starch dementia, diffuse somatic Levy disease, striatal degeneration, choreoathetosis, dystonia, Meigs syndrome, late atrophy of the cerebral cortex, familial spastic lower paraplegia, motor neuron disease, Machado-Joseph disease, Peak syndrome, neurological dysfunction after cerebral embolism intracerebral hemorrhage, such as hypertensive intracerebral hemorrhage, cerebral infarction, such as cerebral thrombosis and cerebral embolism, transient ischemic disorder cerebral circulation and subarachnoid hemorrhage), neurological dysfunction after spinal injury, demyelinating disease (e.g., multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, acute cerebralitis and transverse myelitis), for example, a brain tumor, and spinal cord infections (e.g., meningitis, brain abscess, CJD, and AIDS-related dementia) and a mental disorder (e.g., general upset syndrome CTBA, bipolar disorder, a disease of the nervous system, psychosomatic disorders and epilepsy). More preferred neurodegenerative diseases are, for example, Parkinson's disease, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis and the like. In addition, disorders of the nervous system include all diseases with nerve cell dysfunction. That is, these disorders usually include disorders diagnosed as symptoms of diseases. Examples of disorders in the case of Parkinson's disease or Parkinson's syndrome are tremors, muscle tension, slow movement, impaired position reflexes, autonomic disorders, rapid movements, gait disturbance and neurological disorders. Alzheimer's disease includes dementia. Amyotrophic lateral sclerosis and familial amyotrophic lateral sclerosis include muscle atrophy, muscle weakness, impaired upper limb function, impaired gait, dysarthria, dysphagia and respiratory failure.

In the present description of the invention, rejection includes acute rejection occurring within 3 months, chronic rejection that occurs later and the graft versus host reaction (for example, an acute graft versus host reaction during bone marrow transplantation and the like).

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

In the present description of the invention, the term “mediated by T cells” means that a T cell is involved in one of the processes of occurrence, exacerbation and development of a disease.

In the present description of the invention, an autoimmune disease includes collagenosis, systemic lupus erythematosus, Behcet's disease, rheumatoid arthritis, multiple sclerosis, nephrotic syndrome, lupus nephritis, Sjogren's syndrome, scleroderma, dermatomyositis, psoriasis, inflammatory bowel disease (for example, nonspecific ulcer disease and the like), complex connective tissue disease, primary myxedema, Addison's disease, hypolytic anemia, autoimmune hemolytic anemia, idiopathic thrombosis openicheskuyu purpura, autoimmune thrombopenia, autoimmune diabetes (e.g., type I diabetes), uveitis, antiretseptornoe disease, myasthenia gravis, muscular distrofitirotoksikoz, thyroiditis, Hashimoto's disease and the like.

In the present description of the invention, an 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 diseases are atopic dermatitis, hay fever and food allergy.

In the present description of the invention, an immunosuppressant means a drug that is mainly used for the prevention and / or treatment of transplant rejection. As such a medicine, for example, an antimetabolite, an alkylating agent, a T-cell activation inhibitor (i.e., a T-cell function suppressor), a calcineurin inhibitor, a proliferation signal inhibitor, a steroid, an antibody used to suppress the immune response, other anti rejection and the like. These drugs are used in clinical settings for the treatment of autoimmune diseases.

In the present description of the invention, a lymphopenia inducing agent means a medicament that reduces the number of lymphocytes in the peripheral blood, reduces the number of lymphocytes in the bloodstream, reduces the number of penetrating lymphocytes, stimulates the homing of lymphocytes into the secondary lymphatic tissue, suppresses the circulation of lymphocytes from lymph nodes into the blood and the like .

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

In the present description of the invention, stimulation of homing of lymphocytes into the secondary lymphatic tissue means stimulating the migration of lymphocytes into the secondary lymphatic tissue, enhancing the separation of lymphocytes in the secondary lymphatic tissue, prolonging the preservation of lymphocytes in the secondary lymphatic tissue and the like. Thanks to the above actions, it is possible to reduce the number of lymphocytes at the site of inflammation or rejection. In addition, lymphocytes in peripheral blood can be protected in a similar manner during cancer treatment. Protecting peripheral blood lymphocytes during cancer treatment means pre-homing the lymphocytes present in peripheral blood into the secondary lymphatic tissue before starting cancer treatment (in particular, chemotherapy, radiation therapy, etc.). This effect includes the protection of lymphocytes at the previous transplantation stage of the introduction of a large amount of anti-cancer agents. Serious side effects such as hypofunction of hematopoietic cells are known to treat cancer with chemotherapy or a similar method using an anti-cancer agent, resulting in the subject becoming exposed to infections. Such side effects can be mitigated by the above method.

The compound of the present invention can be used as an anti-rejection agent having an antibacterial effect, since a compound having a lymphopenic effect cannot maximally reduce the lymphocyte content in a living organism.

In the present description of the invention, a side effect resulting from the use of an immunosuppressant means impaired renal function, impaired liver function, infection, lymphoma, circulatory disorder such as bradycardia or hypertension, diarrhea, vomiting, alopecia, hirsutism, hyperlipidemia, respiratory failure, central nervous system disorder systems and changes in body mass.

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

In the present description of the invention, “carbocyclic ring” means, for example, “C3-15 carbocyclic ring”. A “C3-15 carbocyclic ring” is a C3-15 monocyclic ring or a polycyclic carbocyclic aryl ring, a partially or fully saturated carbocyclic ring, a polycyclic carbocyclic ring joined by a spiro bond, and a polycyclic carbocyclic ring joined by a transverse bond. Examples of such rings are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cycloheptene, cyclodecene, cyclodecene, cyclodecene, cyclodecene, cyclodecene, cyclodecene, cyclodecene, cyclodecene, cyclodecene, cyclodecene, cyclodecene, cyclodecene, cyclodecene, cyclodecene perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, 6,7-dihydro-5H-benzo [7] canceled, 5H-benzo [7] canceled, heptalene, perhydride heptalene, biphenylene, as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene, phenalen, phenanthrene, anthracene, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] undecane, bicyclo [2.2.1] heptane, bicyclo [2.2.1] hept-2-en, bicyclo- [3.1.1] heptane, bicyclo [3.1.1] hept-2-en, bicyclo [2.2.2] octane, bicyclo [2.2.2] oct-2 en, adamantane and noradamantane.

As used herein, “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 are cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononan, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, benzene, benzene cycloheptene, cyclooctene, cycloheptene, cycloheptene, cycloheptene, cycloheptene perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, 6,7-dihydro-5H-benzo [7] canceled, 5H-benzo [7] canceled, heptalene and perhydroheptalene.

As used herein, “C3-7 monocyclic carbocyclic ring” means a C3-7 monocyclic carbocyclic aryl ring or a ring resulting from partial or complete saturation of the ring. 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 “C3-7 monocyclic saturated carbocyclic ring” are cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.

In the present description of the invention, “heterocyclic ring” means “3-15 membered heterocyclic ring containing 1-5 heteroatoms, each of which is selected from an oxygen atom, a nitrogen atom and a sulfur atom”. A “3-15 membered heterocyclic ring containing 1-5 heteroatoms each selected from an oxygen atom, a nitrogen atom and a sulfur atom” is a 3-15 membered monocyclic ring or a polycyclic heterocyclic aryl ring containing 1-5 heteroatoms, each of which is selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and a ring obtained by partial or complete saturation of the ring, a polycyclic heterocyclic ring joined by a spiro bond, and a polycyclic heterocyclic ring, connecting My cross-linked. Examples of such rings are pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepin, oxazole, isoxazole, thiazole, oxazazole, isaziazide oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofiran, benzothiophene, isobenzothiopheninoline, pinoline, quinoline, quinoline quinoxaline, quinazoline, cinnoli m, benzoxazole, benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine, benzoxadiazepine, benzothiadiazepine, benzazepine, benzodiazepine, benzofurazan, benzothiadiazene, phenazene benzene, benzene triazobenzene benzene, benzene triazobenazene phenoxazine, phenoxathiine, thianthrene, phenanthridine, phenanthroline, perimidine, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazolin, triazolidine, tetrazoline, tetrazolidine, pyrazolidine, pyrazolidine, dihydropyridine pyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, digidroazepin, tetrahydroazepine, perhydroazepine, digidrodiazepin, tetragidrodiazepin, perhydrodiazepin, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, digidrooksepin, tetragidrooksepin, perhydrooxepine, thiran, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothia in, pergidrotiepin, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazolyl, tetrahydroisothiazole (isothiazolidine), digidrofurazan, tetragidrofurazan, digidrooksadiazol, tetragidrooksadizol (oxadiazolidine), digidrooksazin, morpholine, digidrooksadiazin, tetragidrooksadiazin , dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadia sol, tetragidrotiadiazol (thiadiazolidine), dihydrothiazinyl, tetrahydrothiazine, digidrotiadiazin, tetrahydrothiadiazine, digidrotiazepin, tetragidrotiazepin, pergidrotiazepin, digidrotiadiazepin, tetragidrotiadiazepin, pergidrotiadiazepin, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, pergidrobenzofuran, dihydroisobenzofuran, pergidroizobenzofuran, dihydrobenzothiophene, pergidrobenzotiofen, digidroizobenzotiofen , perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, per idrohinolin, dihydroisoquinoline, tetrahydroisoquinoline, perhydoisoquinoline, dihydrophthalazine, tetrahydrophthalazine, pergidroftalazin, dihydronaphthyridine, tetragidronaftiridin, pergidronaftiridin, dihydroquinoxaline, tetrahydroquinoxaline, pergidrohinoksalin, dihydroquinazoline, tetrahydroquinazoline, pergidrohinazolin, digidrotsinnolin, tetragidrotsinnolin, pergidrotsinnolin, benzoksaitin, digidrobenzoksazin, digidrobenzotiazin, pirazinomorfolin, dihydrobenzoxazol, pergidrobenzoksazol, dihydrobenzothiazole, perhydrobenzothiazole, dihydroben nzimidazol, pergidrobenzimidazol, digidrobenzazepin, tetrahydrobenzazepin, digidrobenzodiazepin, tetragidrobenzodiazepin, benzodioksepan, digidrobenzoksazepin, tetragidrobenzoksazepin, digidrokarbazol, tetrahydrocarbazole, pergidrokarbazol, dihydroacridin, tetrahydroacridine, pergidroakridin, digidrodibenzofuran, digidrodibenzotiofen, tetragidrodibenzofuran, tetragidrodibenzotiofen, pergidrodibenzofuran, pergidrodibenzotiofen, dioxolane, dioxane, dithiolane, dithiane, dioxindane, benzodioxan, chromene, chroman, benzodithiolane, benz dithian, azaspiro [4.4] nonane, oxazaspiro [4.4] nonane, dioxaspiro [4.4] nonane, azaspiro [4.5] decane, thiaspiro [4.5] decane, dithiaspiro [4.5] decane, dioxaspiro [4.5] decane, oxazaspiro [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, oxazaspiro [2.5] octane, 1,3,8-triazaspiro [4.5] decane, 2,7-diazaspiro [4.5] decane, 1,4,9- triazaspiro [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 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and a ring obtained by partial or complete saturation of the ring” means “5-12 a membered monocyclic ring or a polycyclic heterocyclic aryl ring containing 1-3 heteroatoms, each of which is selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and a ring obtained by partial or complete saturation of the ring a cyclic heterocyclic ring joined by a spiro bond; and a polycyclic heterocyclic ring joined by a transverse bond. ” Examples of such rings are pyrrole, imidazole, triazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepin, oxazole, isoxazole, thiazole, isothiazole oxazole, fraz oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dynianinoline, quinoline quinoline, isolinoline, quinoline quinoline, isolinoline, isolinoline, benzoxazole, benzothiazo l, benzimidazole, chromene, benzoxepine, dihydrobenzoxepine, benzoxazepine, benzoxadiazepine, benzothiadiazine, benzazepine, benzodiazepine, benzofurazan, benzothiadiazolidine, pyrrolidine, pyrrolidine, pyrrolidine piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydr oazepin, perhydroazepine, digidrodiazepin, tetragidrodiazepin, perhydrodiazepin, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, digidrooksepin, tetragidrooksepin, perhydrooxepine, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, digidrotiepin, tetragidrotiepin, pergidrotiepin, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine ), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetragidrofurazan, digidrooksadiazol, tetragidrooksadiazol (oxadiazolidine), digidrooksazin, morpholine, digidrooksadiazin, tetragidrooksadiazin, digidrooksazepin, tetragidrooksazepin, pergidrooksazepin, digidrooksadiazepin, tetragidrooksadiazepin, pergidrooksadiazepin, digidrotiadiazol, tetragidrotiadiazol (thiadiazolidine), dihydrothiazinyl, tetrahydrothiazine, digidrotiadiazin, tetrahydrothiadiazine, digidrotiazepin, tetragidrotiazepin, pergidrotiazepin, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morph Olin, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, pergidrobenzofuran, dihydroisobenzofuran, pergidroizobenzofuran, dihydrobenzothiophene, pergidrobenzotiofen, digidroizobenzotiofen, pergidroizobenzotiofen, digidroindazol, pergidroindazol, dihydroquinoline, tetrahydroquinoline, perhydroquinolino, dihydroisoquinoline, tetrahydroisoquinoline, perhydoisoquinoline, dihydrophthalazine, tetrahydrophthalazine, pergidroftalazin, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perg idrohinoksalin, dihydroquinazoline, tetrahydroquinazoline, pergidrohinazolin, digidrotsinnolin, tetragidrotsinnolin, pergidrotsinnolin, benzoxathian, digidrobenzoksazin, digidrobenzotiazin, pirazinomorfolin, dihydrobenzoxazol, pergidrobenzoksazol, dihydrobenzothiazole, pergidrobenzotiazol, dihydrobenzimidazol, pergidrobenzimidazol, digidrobenzazepin, tetrahydrobenzazepin, digidrobenzodiazepin, tetragidrobenzodiazepin, benzodioksepan, digidrobenzoksazepin, tetragidrobenzoksazepin, dioxolane, dioxane, dithiolan, dithian, dioxaindan, b benzodioxane, chromane, benzodithiolane, benzodithian, azaspiro [4.4] nonane, oxazaspiro [4.4] nonane, azaspiro [4.4] nonane, azaspiro [4.5] decane, thiaspiro [4.5] decane, diazaspiro [4.5] decane, dioxaspiro [ oxazaspiro [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, oxazaspiro [2.5] octane, 1,3,8-triazaspiro [4.5] decane, 2,7-diazaspiro [4.5] decane, 1,4,9-triazaspiro [5.5] undecane and azabicyclo [2.1.1] hexane.

As used herein, a “5-7 membered monocyclic heterocyclic ring containing 1 to 2 nitrogen atoms, one oxygen atom and / or one sulfur atom” is a ring obtained by saturation of a 5-7 membered monocyclic heterocyclic aryl ring, containing 1-2 nitrogen atoms, one oxygen atom and / or one sulfur atom, or a ring obtained by partial or complete saturation of the ring. Examples of such rings are pyrrole, imidazole, pyrazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, digidroazepin, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, tetrahydrooxazole, tetrahydroisoxazole, tetrahydrothiazole, tetrahydroisothiazole, dihydroox adiazole, tetrahydrooxadiazole, dihydrothiodiazole, tetrahydrothiodiazole, tetrahydrooxadiazine, tetrahydrothiadiazine, tetrahydrooxadiazepine, perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiadiazine morphine, thihydrothiazin azin.

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

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

In the present description of the invention, “substituent” in the definition of “cyclic group which may have one or more substituents” does not have any restrictions if said group is a substituent. 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 alkynyl 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 alkenyloxy, which may be substituted, (10) C2-20 alkynyloxy which may be substituted, (11) hydroxy protected by a cyclic group which may be substituted, (12) C1-20 acyloxy which may be substituted, (13) thio o, (14) mercapto, (15) C1-20 alkylthio which may be substituted, (16) C2-20 alkenylthio which may be substituted, (17) C2-20 alkynylthio which may be substituted, (18) mercapto substituted by a cyclic group which may be substituted, (19) C1-20 alkylsulfinyl which may be substituted, (20) C2-20 alkenylsulfinyl which may be substituted, (21) C2-20 alkynylsulfinyl which may be substituted, ( 22) sulfinyl substituted with a cyclic group which may be substituted, (23) C1-20 alkylsulfonyl which may be substituted, (24) C2-20 alkenylsulfonyl which may may be substituted, (25) C2-20 alkynylsulfonyl which may be substituted, (26) sulfonyl substituted by a cyclic group which may be substituted, (27) sulfino which may be substituted, (28) sulfo which may be substituted , (29) sulfamoyl, which can be substituted (if there are two substituents, these substituents together with the nitrogen atom to which they are attached can form a 5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atoms, one oxygen atom and / or one sulfur atom (said heterocyclic ring o may be substituted with 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 ) carbamoyl, which can be substituted (if there are two substituents, these substituents together with the nitrogen atom to which they are attached can form a 5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atoms, one oxygen atom and / or one atom sulfur (said heterocyclic ring may be substituted with C1-8 alkyl, hydroxy or mino)), (34) cyano, (35) amidino, which can be substituted (if there are two substituents, these substituents together with the nitrogen atom to which they are attached can form a 5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atom, one oxygen atom and / or one sulfur atom (said heterocyclic ring may be substituted with C1-8 alkyl, hydroxy or amino)), (36) nitro, (37) nitroso, (38) imino, which may be substituted, (39) an amino which may be substituted (in the presence of two substituents, said substituents together with the nitrogen atom to which they are attached, they can form a 5-7-membered monocyclic heterocyclic ring containing 1-2 nitrogen atoms, one oxygen atom and / or one sulfur atom (this heterocyclic ring may be substituted with C1-8 alkyl, hydroxy or amino)), (40) trifluoromethyl, (41) trifluoromethoxy, (42) halogen atom and the like.

In the present description of the invention, the “substituent” in the above “C1-20 alkyl which may be substituted” or a similar group is, for example, (1) C1-20 alkyl, (2) C2-20 alkenyl, (3) C2-20 alkynyl, (4) C1-20 alkylidene, (5) cyclic group, (6) C1-20 alkyl substituted with cyclic group, (7) oxo, (8) hydroxy, (9) C1-20 alkyloxy, (10) C2 -20 alkenyloxy, (11) C2-20 alkynyloxy, (12) hydroxy, protected by a cyclic group, (13) C1-20 acylthio, (14) thioxo, (15) mercapto, (16) C1-20 alkylthio, (17) C2-20 alkenylthio, (18) C2-20 alkynylthio, (19) mercapto substituted with a cyclic group, (20) C1-20 alkylsulfinyl, (21) C2-20 alkenylsulfinyl, (22) C2-20 alkynylsulfinyl, (23) cyclic substituted sulfinyl, (24) C1-20 alkylsulfonyl, (25) C2-20 alkenylsulfonyl, (26) C2 -20 alkynylsulfonyl, (27) sulfonyl substituted with a cyclic group, (28) C1-20 alkylsulfonyl substituted with a cyclic group, (29) sulfino, (30) sulfo, (31) sulfamoyl, (32) carboxy, (33) C1- 20 acyl, (34) C1-20 acyl substituted by a cyclic group, (35) carbonyl substituted by a cyclic group, (36) carbamoyl, (37) cyano, (38) amidino, (39) nitro, (40) nitroso, ( 41) imino, (42) amino, (43) mono (C1-8 alkyl) amino, (44) d (C1-8 alkyl) amino, (45) trifluoromethyl, (46) trifluoromethoxy, (47) a halogen atom or the like. These substituents may be in any substitution position using any possible number of substituents.

As used herein, “C1-20 alkyl” means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonade and their isomers.

As used herein, “C1-8 alkyl” means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomers.

As used herein, “C2-20 alkenyl” means ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nondenecenyl isomers.

As used herein, “C2-20 alkynyl” means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptinyl, octynyl, noninyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecinyl, pentadecinyl, hexadecinyl, heptadecynyl, octadecynyl iquinicinone, nonadene isomers.

As used herein, “C1-20 alkylidene” means methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, decylidene, undecylidene, dodecylidene, tridecylidene, tetradecylidene, pentadecylidene, hedecadecylideneidene, hedecadecylideneidene, hedecidecylideneidene, hedecidecylideneidene, hedecidecylidene, lide and their isomers.

As used herein, “C1-20 alkyloxy” means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, hepta and their isomers.

As used herein, “C1-8 alkoxy” means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and their isomers.

In the present specification, the "C2-20 alkenyloxy" means ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, nonenyloxy, decenyloxy, undecenyloxy, dodetseniloksi, tridecenyloxy, tetradecenyloxy, pentadetseniloksi, geksadetseniloksi, geptadetseniloksi, octadecenyloxy, nonadecenyloxy, ikozeniloksi and isomers.

As used herein, “C2-20 alkynyloxy” means ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, nonynyloxy, decynyloxy, undecynyloxy, dodecynyloxy, tridecynyloxy, tetradecynoxy, idodecynodyloxy, hedecydecynoxy, hendecynodecynoxy, hexadecynoxy, hendecyninyl isomers.

In the present specification, the "C1-20 alkylthio" is methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio, undetsiltio, dodecylthio, tridetsiltio, tetradetsiltio, pentadetsiltio, geksadetsiltio, geptadetsiltio, oktadetsiltio, nonadetsiltio, ikoziltio and their isomers.

In the present description of the invention, “C2-20 alkenylthio” means ethenylthio, propenylthio, butenylthio, pentenylthio, hexenylthio, heptenylthio, octenylthio, nonenylthio, decenylthio, undecenylthio, dodecenylthioethioentioethioentioethioentioethioentioethioentioethioentioethioentioethioentioethioentioethylentiodenio isomers.

As used herein, “C2-20 alkynylthio” means ethynylthio, propynylthio, butynylthio, pentynylthio, hexynylthio, heptinylthio, octynylthio, undecynylthio, dodecyntinodecyntinodetinodeinylethinodinodecyntinodecyntindecyntinodecyntindecyntindeinodeinideindetindeinideindetindeinodecyntinideindeinodeinideindetindeinideindeinideindeinodeinideindeinodeinideindeinideindeinideindeinideindeinideindeinideindeinideindeinideindeinideindeinideindeinodeinodinodeinodinideinodinideinideinideinideinideinideinideinideinideinideinideinideinideinideinolines isomers.

In the present specification, the "C1-20 alkylsulfinyl" means methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl, geptilsulfinil, oktilsulfinil, nonilsulfinil, detsilsulfinil, undetsilsulfinil, dodetsilsulfinil, tridetsilsulfinil, tetradetsilsulfinil, pentadetsilsulfinil, geksadetsilsulfinil, geptadetsilsulfinil, oktadetsilsulfinil, nonadetsilsulfinil, ikozilsulfinil and their isomers.

In the present specification, the "C2-20 alkenylsulfinyl" means etenilsulfinil, propenilsulfinil, butenilsulfinil, pentenilsulfinil, geksenilsulfinil, geptenilsulfinil, oktenilsulfinil, nonenilsulfinil, detsenilsulfinil, undetsenilsulfinil, dodetsenilsulfinil, tridetsenilsulfinil, tetradetsenilsulfinil, pentadetsenilsulfinil, geksadetsenilsulfinil, geptadetsenilsulfinil, oktadetsenilsulfinil, nonadetsenilsulfinil, ikozenilsulfinil and isomers.

In the present specification, the "C2-20 alkinilsulfinil" means etinilsulfinil, propinilsulfinil, butinilsulfinil, pentinilsulfinil, geksinilsulfinil, geptinilsulfinil, oktinilsulfinil, noninilsulfinil, detsinilsulfinil, undetsinilsulfinil, dodetsinilsulfinil, tridetsinilsulfinil, tetradetsinilsulfinil, pentadetsinilsulfinil, geksadetsinilsulfinil, geptadetsinilsulfinil, oktadetsinilsulfinil, nonadetsinilsulfinil, ikozinilsulfinil and isomers.

In the present specification, the "C1-20 alkylsulfonyl" means methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, nonilsulfonil, detsilsulfonil, undetsilsulfonil, dodetsilsulfonil, tridetsilsulfonil, tetradetsilsulfonil, pentadetsilsulfonil, hexadecylsulfonio, geptadetsilsulfonil, oktadetsilsulfonil, nonadetsilsulfonil, ikozilsulfonil and their isomers.

In the present specification, the "C2-20 alkenylsulfonyl" means etenilsulfonil, propenilsulfonil, butenilsulfonil, pentenilsulfonil, geksenilsulfonil, geptenilsulfonil, oktenilsulfonil, nonenilsulfonil, detsenilsulfonil, undetsenilsulfonil, dodetsenilsulfonil, tridetsenilsulfonil, tetradetsenilsulfonil, pentadetsenilsulfonil, geksadetsenilsulfonil, geptadetsenilsulfonil, oktadetsenilsulfonil, nonadetsenilsulfonil, ikozenilsulfonil and isomers.

In the present specification, the "C2-20 alkynylsulfonyl" means etinilsulfonil, propinilsulfonil, butinilsulfonil, pentinilsulfonil, geksinilsulfonil, geptinilsulfonil, oktinilsulfonil, noninilsulfonil, detsinilsulfonil, undetsinilsulfonil, dodetsinilsulfonil, tridetsinilsulfonil, tetradetsinilsulfonil, pentadetsinilsulfonil, geksadetsinilsulfonil, geptadetsinilsulfonil, oktadetsinilsulfonil, nonadetsinilsulfonil, ikozinilsulfonil and isomers.

In present specification "C1-20 acyl group" means a methanoyl, ethanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, ikozanoil and their isomers.

In the present specification, the "C1-20 acyloxy" denotes metanoiloksi, ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, geptanoiloksi, oktanoiloksi, nonanoiloksi, decanoyloxy, undekanoiloksi, dodekanoiloksi, tridekanoiloksi, tetradecanoyloxy, pentadekanoiloksi, hexadecanoyloxy, geptadekanoiloksi, octadecanoyloxy, nonadekanoiloksi, ikozanoiloksi and their isomers.

As used herein, “mono (C1-8 alkyl) amino” means methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, octylamino and their isomers.

As used herein, “di (C1-8 alkyl) amino” means dimethylamino, diethylamino, dipropylamino, dibutylamino, methylethylamino, methylpropylamino, ethylpropylamino, and isomers thereof.

In the present description of the invention, “protective group” in the definitions of “acid group that can be protected”, “carboxyl group that can be protected”, “hydroxyl group that can be protected”, “hydroxamic acid group that can be protected” , “Sulfonic acid group that can be protected”, “boronic acid group that can be protected”, “carbamoyl group that can be protected”, “sulfamoyl group that can be protected” and “amino group that can Jet be protected "represents a group similar to the" substituent "in the above definition," which may be substituted (substituent) ".

As used herein, “halogen atom” means fluoro, chloro, bromo and iodo.

In the present description of the invention, “bond” means the direct binding 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 gap occupied by 1-10 atoms sequentially linked in the main chain. 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 1,2-cyclopentylene is considered equal to 2, and the number of atoms in 1,3-cyclopentylene is considered equal to 3. “A spacer having a main chain containing 1-10 atoms” is a divalent group with 1-10 atoms in the main chain, which consists of 1-4 combinations selected from the group consisting of C1-10 alkylene which may be substituted, C2-10 alkenylene which may be substituted, C2-10 alkynylene which may be substituted, nitrogen atom ( -NH-), which may be substituted, -CO-, -O-, -S-, -SO-, -SO ₂ -, - (carbocyclic ring which may be replaced EHO) -, - (heterocyclic ring which may be substituted) -, and the like.

As used herein, “C1-10 alkylene” means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and their isomers.

As used herein, “C2-4 alkylene” means ethylene, trimethylene, tetramethylene and their isomers.

As used herein, “C2-10 alkenylene” means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene, decenyl and their isomers.

As used herein, “C2-10 alkynylene” means ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptinylene, octynylene, nonynylene, decynylene and their isomers.

In the present description of the invention, “spacer having a main chain containing 1 to 9 atoms” means a gap occupied by 1 to 9 atoms sequentially linked in the main chain. 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 1,2-cyclopentylene is considered equal to 2, and the number of atoms in 1,3-cyclopentylene is considered equal to 3. “A spacer having a main chain containing 1-9 atoms” is a divalent group with 1-9 atoms in the main chain, which consists of 1-4 combinations selected from the group consisting of C1-9 alkylene which may be substituted, C2-9 alkenylene which may be substituted, C2-9 alkynylene which may be substituted, a nitrogen atom ( -NH-), which may be substituted, -CO-, -O-, -S-, -SO-, -SO ₂ -, - (carbocyclic ring, which may be substituted o) -, - (heterocyclic ring which may be substituted) -, and the like.

As used herein, “C1-9 alkylene” means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene and their isomers.

As used herein, “C2-9 alkenylene” means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene and their isomers.

As used herein, “C2-9 alkynylene” means ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptinylene, octynylene, nonynylene and their isomers.

In the present description of the invention, “spacer having a main chain containing 1-8 atoms” means the gap occupied by 1-8 atoms sequentially linked in the main chain. 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 1,2-cyclopentylene is considered equal to 2, and the number of atoms in 1,3-cyclopentylene is considered equal to 3. “A spacer having a main chain containing 1-8 atoms” is a divalent group with 1-8 atoms in the main chain, which consists of 1-4 combinations selected from the group consisting of C1-8 alkylene which may be substituted, C2-8 alkenylene which may be substituted, C2-8 alkynylene which may be substituted, a nitrogen atom ( -NH-), which may be substituted, -CO-, -O-, -S-, -SO-, -SO ₂ -, - (carbocyclic ring, which may be substituted o) -, - (heterocyclic ring which may be substituted) -, 1,2,4-oxadiazole, which may be substituted, and the like.

As used herein, “C1-8 alkylene” means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and their isomers.

As used herein, “C2-8 alkenylene” means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, and isomers thereof.

As used herein, “C2-8 alkynylene” means ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptinylene, octynylene and their isomers.

In the present description of the invention, “spacer having a main chain containing 1-7 atoms” means a gap occupied by 1-7 atoms sequentially linked in the main chain. 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 1,2-cyclopentylene is considered equal to 2, and the number of atoms in 1,3-cyclopentylene is considered equal to 3. “A spacer having a main chain containing 1-7 atoms” is a divalent group with 1-7 atoms in the main chain, which consists of 1-4 combinations selected from the group consisting of C1-7 alkylene which may be substituted, C2-7 alkenylene which may be substituted, C2-7 alkynylene which may be substituted, a nitrogen atom ( -NH-), which may be substituted, -CO-, -O-, -S-, -SO-, -SO ₂ -, - (carbocyclic ring, which may be substituted o) -, - (heterocyclic ring which may be substituted) -, 1,2,4-oxadiazole, which may be substituted, and the like.

As used herein, “C1-7 alkylene” means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and their isomers.

As used herein, “C2-7 alkenylene” means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene and their isomers.

As used herein, “C2-7 alkynylene” means ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptinylene and their isomers.

In the present description of the invention, examples of the acid group are the following groups that can be protected: (1) a carboxyl group, (2) a hydroxyl group forming an acid (e.g., a phenolic hydroxyl group), (3) a hydroxamic acid group, (4) a sulfonic group acids, (5) a boronic acid group, (6) a carbamoyl group, (7) a sulfamoyl group, (8) a group -P (= O) (OH) ₂ , (9) a group -P (= O) (OR ² ) (OR ³ ) (in this group, R ² and R ³ have the above meanings) and (10) a tetrazolyl group.

As used herein, a “ring that may have one or more substituents” containing one spacer atom denoted by X and a substituent in ring B is a “ring that may have one or more substituents” formed by one spacer atom, denoted by X, together with one substituent in ring B. “A ring that may have one or more substituents” is a ring similar to the above “cyclic group which may have one or more substitute her. "

In the present description of the invention, a “ring that may have one or more substituents” containing one spacer atom designated by Y and a substituent in ring B is a “ring that may have one or more substituents” formed by one spacer atom, denoted by Y, together with one substituent in ring B. An example of a “ring that may have one or more substituents” is a “nitrogen-containing heterocyclic ring that may have one or more substituents”. An example of a “nitrogen-containing heterocyclic ring” in the definition of “a nitrogen-containing heterocyclic ring that may have one or more substituents” is a “3-15 membered heterocyclic ring containing one nitrogen atom, which may further include 1-4 heteroatoms, each of which is selected from an oxygen atom, a nitrogen atom and a sulfur atom. ” “A 3-15 membered heterocyclic ring containing one nitrogen atom, which may further include 1-4 heteroatoms, each selected from an oxygen atom, nitrogen nitrogen and a sulfur atom”, is a 3-15 membered monocyclic ring or a polycyclic heterocyclic an aryl ring containing one nitrogen atom, which may additionally include 1-4 heteroatoms, each of which is selected from an oxygen atom, a nitrogen atom and a sulfur atom, and may be partially or fully saturated, a polycyclic heterocyclic ring, joined by a spiro bond, and a polycyclic heterocyclic ring joined by a transverse bond. Examples of such rings are pyrrole, imidazole, triazole, tetrazole, pyrazole, azepine, diazepine, indole, isoindole, indolizine, indazole, quinoline, isoquinoline, quinolizine, phthalazine, pteridine, naphthyridine, quinoxaline, benzinazole, quinazole, quinazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzofurazan, benzothiadiazole, benzotriazole, pyrrolopyridine, benzimidazole, benzazepine, benzodiazepine, benzotriazole, carbazole, β-carboline, acridine, phenazine, phenazine, phenazine, phenazine, phenazine, phenazine, phenazine, phenazine, phenazine, phenazine, phenazine, phenazine, phenazine, phenazine azoloizohinolin, pirazolonaftiridin, pirimidoindol, indolizinoindol, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazolin, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydroox sol, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazolyl, tetrahydroisothiazole (isothiazolidine), digidrofurazan, tetragidrofurazan, digidrooksadiazol, tetragidrooksadiazol (oxadiazolidine), digidrooksazin, morpholine, digidrooksadiazin, tetragidrooksadiazin, digidrooksazepin, tetragidrooksazepin , perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiad iazolidin), dihydrothiazinyl, tetrahydrothiazine, digidrotiadiazin, tetrahydrothiadiazine, digidrotiazepin, tetragidrotiazepin, pergidrotiazepin, digidrotiadiazepin, tetragidrotiadiazepin, pergidrotiadiazepin, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, digidroindazol, pergidroindazol, dihydroquinoline, tetrahydroquinoline, perhydroquinolino, dihydroisoquinoline, tetrahydroisoquinoline, perhydoisoquinoline, dihydrophthalazine , tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquino Sahlin, tetrahydroquinoxaline, pergidrohinoksalin, dihydroquinazoline, tetrahydroquinazoline, pergidrohinazolin, tetragidropirrolopiridin, digidrotsinnolin, tetragidrotsinnolin, pergidrotsinnolin, digidrobenzoksazin, digidrobenzotiazin, pirazinomorfolin, dihydrobenzoxazol, pergidrobenzoksazol, dihydrobenzothiazole, pergidrobenzotiazol, dihydrobenzimidazol, pergidrobenzimidazol, digidrobenzazepin, tetrahydrobenzazepin, digidrobenzodiazepin, tetragidrobenzodiazepin, digidrobenzoksazepin, tetragidrobenzoksazepin, dihydrocarbazole, those ragidrokarbazol, pergidrokarbazol, dihydroacridin, tetrahydroacridine, pergidroakridin, tetrapiridonaftiridin, dihydro-β-carboline, tetrahydro-β-carboline, digidrodigidroazepinoindol, geksagidroazepinoindol, tetragidropirazoloizohinolin, tetragidropirazolonaftiridin, digidroazepinoindazol, geksagidroazepinoindazol, digidropirazolopiridoazepin, geksagidropirazolopiridoazepin, tetragidropirimidoindol, digidrotiazinoindol, tetragidrotiazinoindol, digidrooksazinoindol, tetragidrooksazinoindol, hexahydroindolisinoindole, digi roindolobenzodiazepine, octahydroindoloquinolisine, hexahydroimidazopyridoindole, hexahydro-pyrrolothiazepinoindole, azaspiro [4.4] nonane, oxazaspiro [4.4] nonane, oxazaspiro [2.5] octane, azaspiro [4.5] decanazole 4,5, 2,7-triazane, 4,5-decanazole, 4,5-decanazole, 4,5-dianazole, 4,5-decane, 4,5-decane 4.5] decane, 1,4,9-triazaspiro [5.5] undecane, oxazaspiro [4.5] decane, azaspiro [5.5] undecane, azabicyclo [2.2.1] heptane, 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 1-4 heteroatoms, each of which is selected from an oxygen atom, a nitrogen atom and a sulfur atom”, represents “9-15- a member polycyclic heterocyclic ring containing one nitrogen atom, which may additionally include 1-4 heteroatoms, each of which is selected from an oxygen atom, a nitrogen atom and a sulfur atom, and may be partially or fully saturated. " Examples of such a ring are indole, isoindole, indolysin, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazine azinazazepiazinazazepiazinazazepiazinazazepiazazazepiazinazazole benzofurazan, benzothiadiazole, benzotriazole, carbazole, β-carboline, acridine, phenazine, phenothiazine, phenoxazine, phenanthridine, phenanthroline, perimidine, indoline, isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline ergidrohinolin, dihydroisoquinoline, tetrahydroisoquinoline, perhydoisoquinoline, dihydrophthalazine, tetrahydrophthalazine, pergidroftalazin, dihydronaphthyridine, tetragidronaftiridin, pergidronaftiridin, dihydroquinoxaline, tetrahydroquinoxaline, pergidrohinoksalin, dihydroquinazoline, tetrahydroquinazoline, pergidrohinazolin, digidrotsinnolin, tetragidrotsinnolin, pergidrotsinnolin, digidrobenzoksazin, digidrobenzotiazin, pirazinomorfolin, dihydrobenzoxazol, pergidrobenzoksazol, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazo , Pergidrobenzimidazol, digidrobenzazepin, tetrahydrobenzazepin, digidrobenzodiazepin, tetragidrobenzodiazepin, digidrobenzoksazepin, tetragidrobenzoksazepin, digidrokarbazol, tetrahydrocarbazole, pergidrokarbazol, dihydro-β-carboline, tetrahydro-β-carboline, dihydroacridin, tetrahydroacridine, pergidroakridin, azaspiro [4.4] nonane, oksazaspiro [4.4] nonane , azaspiro [4.5] decane, oxazaspiro [4.5] decane, azaspiro [5.5] undecane.

In the present description of the invention, “substituent”, denoted by the symbol R ¹ , has the same meanings as “substituent” in the above definition of “which may have one or more substituents”.

In the present description of the invention, R ⁴ and R ^4-1 have the same meanings as the “substituent” in the “cyclic group which may have one or more substituents”, ring B.

In the present description of the invention, R ⁵ , R ^5-1 and R ^5-2 have the same meanings as the “substituent” in the “spacer having a main chain containing 1-10 atoms, one atom of which can form a ring, which may have one or more substituents, together with a substituent in ring B, denoted by Y.

In the present description of the invention, “a ring which may have one or more substituents”, denoted by R ⁶ and R ⁷ , together with the carbon atom to which they are attached, have the same meanings as the above “cyclic group, which may further have one or more substituents. "

In the present invention, any ring, group and atom represented by ring A, ring B, X, Y, Z, R ¹ , R ² , R ³ , respectively

R ⁴ , R ^4-1 , R ⁵ , R ^5-1 , R ^5-2 , R ⁶ and R ⁷ . The following are preferred groups, rings and atoms. It should be noted that all symbols used in the present description of the invention have the same meanings as the above symbols.

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

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

In the present invention, a “ring” in the definition of “a ring which may have one or more substituents” formed by one spacer atom designated by Y, together with a substituent in ring B, is preferably a “3-15 membered heterocyclic ring containing one atom nitrogen, which may additionally include 1-4 heteroatoms, each of which is selected from an oxygen atom, a nitrogen atom and a sulfur atom, ”more preferably“ a 9-15 membered polycyclic heterocyclic ring containing one nitrogen atom, which yes further may include 1-4 heteroatoms selected from an oxygen atom, a nitrogen nitrogen atom and a sulfur atom, ”or particularly preferably a tetrahydroisoquinoline ring and a tetrahydro-β-carboline ring.

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

where all the symbols have the above meanings; even more preferred

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

where all characters have the above meanings.

In the present invention, Y preferably means a divalent group having a main chain containing 1-10 atoms, which consists of a combination of 1-4 groups selected from groups including a C1-10 alkylene group which may be substituted, a C2-10 alkenylene group, which may be substituted, a nitrogen atom (-NH-), which may be substituted, -CO-, -O-, -S-, - (aziridine, which may be substituted) -, - (azetidine, which may be substituted) -, - (pyrrolidine which may be substituted) -, - (piperidine which may be substituted) -, - (piperazine which may be substituted) substituted) - and - (tetrahydropyridine, which may be substituted) -, more preferably -CH ₂ -NH- (CH ₂ ) ₂ -, -CH ₂ - (azetidine) -, -CH ₂ - (piperidine) - (CH ₂ ) ₂ -, - (tetrahydropyridine) - (CH ₂ ) ₂ -, -CH = CH-CH ₂ -NH- (CH ₂ ) ₂ - and CR ^5-1 = CR ^5-2 -CH ₂ - (azetidine) - (in the groups R ^5-1 and R ^5-2 have the above meanings), most preferably —CH ₂ - (azetidine) -.

In the present invention, Z preferably means an acid group that can be protected, more preferably a carboxyl group that can be protected, a hydroxyl group that can be protected (e.g., —OR (= O) (OR ² ) (OR ³ ) (in groups R ² and R ³ have the above meanings), a hydroxamic acid group that can be protected, a sulfonic acid group that can be protected, a boronic acid group that can be protected, a carbamoyl group that can be protected, a sulfamoyl group, cat The wet one may be protected, —OR (= O) (OR ² ) (OR ³ ) (in the groups R ² and R ³ are as defined above) or a tetrazolyl group, particularly preferably a carboxyl group that can be protected.

In the present invention, a “protecting group” in the definition of “an acid group that can be protected (a protecting group)”, denoted by Z, is preferably a C1-20 alkyl group which may be substituted. In addition, the case where Z means an unprotected group is also preferred.

In the present invention, R ¹ preferably means a halogen atom, C1-8 alkyl which may be substituted, C1-8 alkoxy which may be substituted, and the like, and more preferably chlorine atom, fluorine atom, ethyl group, propyl group, isopropyl a group, an isobutyl group, a sec-butyl group, a trifluoromethyl group, a methoxyl group, a difluoromethoxyl group, an isopropoxy group or a sec-butoxy group and the like.

In the present invention, R ² preferably means a hydrogen atom or C1-8 alkyl which may be substituted, and the like, and more preferably a hydrogen atom or a methyl group and the like.

In the present invention, R ³ preferably means a 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, R ⁴ and R ^4-1 preferably mean a hydrogen atom, a halogen atom, C1-8 alkyl, C1-8 alkoxy, trifluoromethyl group, trifluoromethoxyl group and the like, and more preferably a hydrogen atom, chlorine atom, methyl group, methoxy a group, a trifluoromethyl group and the like.

In the present invention, R ⁵ , R ^5-1 and R ^5-2 preferably mean a hydrogen atom, a halogen atom, a C1-8 alkyl group, a trifluoromethyl group, a trifluoromethoxyl group and the like, and more preferably a hydrogen atom, a chlorine atom, a methyl group, trifluoromethyl group and the like.

In the present invention, R ⁶ preferably means a hydrogen atom, a halogen atom, C1-8 alkyl, a hydroxyl group that can be protected, an amino group that can be protected, C1-8 alkyl substituted with a hydroxyl group that can be protected, and more preferably a hydrogen atom, a methyl group, a methoxy group and the like.

In the present invention, R ⁷ preferably means a hydrogen atom, a halogen atom, C1-8 alkyl, a hydroxyl group that can be protected, an amino group that can be protected, C1-8 alkyl substituted with a hydroxyl group that can be protected, and more preferably a hydrogen atom, a methyl group, a methoxy group and the like.

In the present invention, a “ring which may have one or more substituents”, designated R ⁶ and R ⁷ , together with the carbon atom to which they are attached, is preferably a “C3-7 monocyclic carbocyclic ring”, more preferably “C3-7 monocyclic saturated carbocyclic ring ”or particularly preferably cyclopropane ring and cyclobutane ring.

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

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

In the present invention, p is preferably 0, 1 or 2.

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

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 the symbols have the above meanings;

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 characters have the above meanings.

Particularly preferred is a compound expressed by any of the following formulas, a salt, N-oxide, solvate or prodrug thereof:

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 formula (IB-6):

where all characters have the above meanings.

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 characters have the above meanings.

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

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 formula (ID-2-1):

where all characters have the above meanings.

In the above formulas (IC-1), (IC-2), (IC-1-1) and (IC-2-1), m is preferably 2, and all R ¹ have the same or different meanings. In addition, the substitution positions are preferably positions 2 and 4, positions 3 and 4, positions 3 and 5, particularly preferably positions 2 and 4.

In the present invention, all the compounds described in the examples, their salts, N-oxides, solvates and prodrugs are preferred compounds. Particularly preferred examples of these compounds are 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1- ( {6 - [(4-isobutyl-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({6 - [(4-isobutyl- 3-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({6 - [(2-ethoxy-4-isobutylbenzyl) oxy] -1- methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - [(6 - {[4-isopropoxy-2- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4- dihydro-2-naphtha alynyl) methyl] -3-azetidinecarboxylic acid, 1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3- azetidinecarboxylic acid, 1 - ({1-chloro-6 - [(2-methoxy-4-propylbenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({1- chloro-6 - [(4-isobutyl-2-methoxybenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - [(1-chloro-6 - {[(2S) -3- (2,4-difluorophenyl) -2-methylpropyl] oxy} -3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1 - [(6 - {[4-ethoxy-2- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidine boronic acid, 1 - ({6 - [(4-ethyl-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({6- [(2-methoxy-4-propylbenzyl) oxy] -1,5-dimethyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({6 - [(2-difluoromethoxy-4 -propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1 -chloro-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1 - [(6 - {[2- (difluoromethoxy) -4-propylbenzyl] oxy} -1,5-dimethyl-3, 4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1 - [(6 - {[4- toxi-3- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid and 1 - ({6 - [(2-methoxy-6-propyl- 3-pyridinyl) methoxy] -1,5-dimethyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, their salts, N-oxides, solvates and prodrugs. Even more preferred examples of these compounds are 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1- [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1 - ({1-chloro-6 - [(2-methoxy-4-propylbenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - ({1-chloro-6 - [(4-isobutyl-2- methoxybenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, 1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-chloro-3, 4-dihydro-2-naphthalenyl) methyl ] -3-azetidinecarboxylic acid, 1 - [(6 - {[2- (difluoromethoxy) -4-propylbenzyl] oxy} -1,5-dimethyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, 1 - [(6 - {[4-ethoxy-3- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid and 1 - ({ 6 - [(2-methoxy-6-propyl-3-pyridinyl) methoxy] -1,5-dimethyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid, their salts, N-oxides, solvates and prodrugs. The most preferred examples of these compounds are 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid and 1- [ (6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, their salts, N-oxides, solvates and prodrugs .

Isomers

Except where otherwise indicated, all isomers are included in the scope of the present invention. For example, alkyl, alkenyl, alkynyl, alkyloxy, alkoxy, alkenyloxy, alkynyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylene, alkenylene, alkynylene, acyl and acyloxy include straight and branched chain groups. In addition, the scope of the present invention includes all isomers in the presence of a double bond, a ring and a condensed ring (E-, Z-, cis and trans forms), isomers in the presence of an asymmetric carbon atom, or the like (R-, S-, α- and β-configurations, enantiomers and diastereomers), optically active substances with rotation of the plane of polarization of light (D-, L-, d- and l-forms), polar compounds obtained by chromatographic separation (more polar compounds and less polar compounds ), equilibrium compounds, rotamers, mixtures of these compounds in any proportion and a racemic mixture. All tautomers are also within the scope of the present invention.

означает α-конфигурацию, символ

означает β-конфигурацию, и символ

означает смесь α-конфигурации и β-конфигурации в произвольном соотношении. Следует отметить, что в настоящем изобретении соединение, имеющее все вышеуказанные конфигурации, не ограничивается лишь той конфигурацией, которая является по существу чистой и однородной, если такая конфигурация преобладает в данном соединении.As should be clear to a person skilled in the art, in the present invention, unless otherwise indicated, the symbol

means α-configuration, symbol

means β-configuration and the symbol

means a mixture of α-configuration and β-configuration in an arbitrary ratio. It should be noted that in the present invention, a compound having all of the above configurations is not limited to that configuration that is substantially pure and uniform if such a configuration prevails in the compound.

Salt, N-oxide and MES

Salts of the compounds of the present invention expressed by formula (I) include all pharmaceutically acceptable salts. Said salts are preferably non-toxic and water soluble. Salts of a compound of the present invention expressed by formula (I) preferably include alkali metal salts (such as potassium, sodium and lithium), alkaline earth metal salts (such as calcium and magnesium), ammonium salts (such as tetramethylammonium salt and tetrabutylammonium salt), organic amine salts (such as triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine and N-methyl-D-glucamine), and acid addition salts (such to inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate), and organic acid salts (e.g., acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzene sulfonate , toluenesulfonate, isethionate, glucuronate and gluconate) or the like, Among the above salts, sodium salt, potassium salt, calcium salt or hydrochloride salt are preferred.

These salts further include a quaternary ammonium salt. The quaternary ammonium salt is a compound represented by the formula (I) in which the nitrogen atom is quaternized by the group R ⁰ . The group R ⁰ is C1-8 alkyl which may be substituted with phenyl.

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

Examples of a suitable solvate of the compound represented by formula (I) include solvates such as a hydrate and an alcoholate (such as methanolate and ethanolate). The solvates each are preferably non-toxic and water-soluble compounds and, for example, are preferably monohydrate. In addition, solvates of a compound of the present invention include solvates of alkali metal salts, alkaline earth metal salts, ammonium salts, organic amine salts, acid addition salts and N-oxides of the above compound of the present invention.

The compound represented by formula (I) can be converted to any of the above salts and solvates by standard methods.

Prodrugs

A prodrug of a compound expressed by formula (I), a salt thereof, an N-oxide or a solvate is a compound that is converted to a compound of formula (I) as a result of interaction with an enzyme, gastric acid or the like in a subject. For example, in the preparation of a prodrug of a compound expressed by formula (I), an amine-containing compound of formula (I) is acylated, alkylated or phosphorylated (for example, eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl- 2-oxo-1,3-dioxolen-4-yl) methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, acetoxymethyl or tert-butyl group); a compound of formula (I) containing a hydroxyl group is acylated, alkylated, phosphorylated or boronated (for example, an acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethyl carbonyl group is introduced into the hydroxyl group of the compound of formula (I)); a compound of formula (I) containing a carboxyl group is esterified or amidated (for example, a carboxyl group of a compound of formula (I) is converted to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester phthalidyl ether, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, cyclohexyloxycarbonylethyl ester or methylamide). These compounds can be obtained by standard methods. The prodrug of the compound expressed by formula (I) may be a hydrate or non-hydrate. A prodrug of a compound expressed by formula (I) may also be a compound that is converted to 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 labeled with a radioactive isotope (such as ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

The compounds of the present invention expressed by formula (I), their salts, N-oxides, solvates or prodrugs (hereinafter briefly referred to as “the compounds of the present invention”) perfectly dissolve and absorb when administered orally, are characterized by a prolonged pharmacological action (for example, stimulating activity in relation to homing of lymphocytes and immunosuppressive effects on lymphocytes), they are practically not exposed to enzymes that mediate the metabolism of the drug, and have neither Coy toxicity. These characteristics are the most important physical, chemical and pharmaceutical properties required when creating drugs. Satisfying the above requirements, the compounds of the present invention appear to be very valuable drugs (see The Merck Manual of Diagnosis and Therapy, 17 ^th Ed., Merck & Co.).

The fact that the compound of the present invention, which is readily soluble and absorbed upon oral administration, is characterized by a prolonged pharmacological effect, is safe and has a high safety index (SI), is suitable for use as a medicine, can be investigated by the methods described in the following experimental systems or biological examples, or modified methods. In addition, the presence of the compound of the present invention of such excellent characteristics as a long half-life from serum, stability in the gastrointestinal tract, absorption by oral administration, bioavailability and the like can be easily determined by known methods, for example, using the method described in “Yakubutsu bioavailability (Hyouka to kaizen no kagaku)”, July 6, 1998, Gendaiiryou-sha, or similar methods.

(I) Experiments performed to evaluate compound 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 a thermometer) is placed in a test tube. Then, a solvent is added (official solution I included in the Japanese Pharmacopoeia, official solution II included in the Japanese Pharmacopoeia, and official solution II with bovine bile acid in artificial bile (0.5% (w / w), SIGMA), buffer solution with a pH of 7.4 (obtained by 4-fold dilution of Mc Ilvine buffer), a buffer solution with a pH of 4.0 (obtained by 4-fold dilution of Mc Ilvine buffer), purified water and physiological saline, heated to 37 ° C in a water bath until concentrations of 1.5 mg / m are reached The mixture is stirred at a constant temperature of 37 ° C for 30 minutes, filtered through a filter (typically DISMIC-13cp, cellulose acetate, hydrophilic, 0.20 μm, Advantec). The filtrate is diluted 2 times immediately after filtration. in an organic solvent in which the test compound is well soluble (acetonitrile or methanol) and mixed.The solubility of the test compound can be determined by calculating its concentration by external standard method using HPLC.

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

[Experimental method]

For hungry adult short-legged hounds, pentagastrin (10 mcg / kg) is injected intramuscularly (im). After fifteen minutes, the test compound (100 mg / animal) with water (20 ml) was orally administered. After another fifteen minutes, pentagastrin (10 μg / kg) is injected intramuscularly (im). Then after 15 and 30 minutes and after 1, 2, 3, 4, 6, 8 and 10 hours after administration of the test compound, blood samples were taken from the animal and extracted with acetonitrile. The concentration of the compound in plasma is measured by high performance liquid chromatography (internal standard method). By measuring the plasma concentration thus obtained, it is possible to determine the area under the plasma concentration curve (AUC), μg / ml / min) and the maximum plasma concentration (C _max , ng / ml).

(II) An experimental system for determining the potency of a compound of the present invention

(pathological model)

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

Ectopic heart transplantation model for rats

[Experimental method]

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

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

Experimental Allergic Encephalomyelitis Model (EAE)

[Experimental method]

Experimental allergic encephalomyelitis is caused in Levy rats using various antigens, in particular the spinal cord or MOG (myelin oligodendrocyte glucoprotein). By comparing the group to which the test compound was orally administered with the control group, a therapeutic or prophylactic effect can be determined.

(III) Toxicity Experiments of a Compound of the Present Invention

Determination of the activity of the compounds of the present invention in relation to current I _Kr  hERG

[Experimental method]

As described in Zou, et al., Biophys. J., 74, 230-241 (1998), using HEK293 cells overexpressing the ether-a-go-go-related human gene (hERG), using the patch clamp, the maximum current I _Kr hERG induced in the tail induced can be measured and recorded impulse of depolarization and subsequent impulse of repolarization. The rate of change (inhibition ratio) is calculated by comparing the maximum current in the tail before administration of the test compound and 10 minutes after administration. The effect of the test compound on the current I _Kr hERG can be determined based on the inhibition ratio.

The name of the compound of the present invention was determined using the computer program ACD / NAME ™, created by Advanced Chemistry Development for the mechanical naming of IUPAC nomenclature. For example, the following compound is called 1 - {[1-chloro-6- (3-cyclohexylpropoxy) -3,4-dihydronaphthalen-2-yl] methyl} acetidine-2-carboxylic acid.

Methods for preparing a compound of the present invention

The compound of the present invention can be obtained by appropriately modifying a 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, 2 ^nd Ed. (by Richard C. Larock, John Wiley & Sons Inc. (1999)), by the following method and / or the method corresponding to the following method, and the method described in the example. It should be noted that in each of the methods discussed below, the starting compound can be used as a salt. As such a salt, a salt of the above-described compound of formula (I) is used.

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

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

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

(A-1) A compound represented by the formula (2):

where all the symbols have the above meanings;

and the compound represented by formula (3):

where all the symbols have the above meanings;

they undergo a Mitsunobu reaction and then, if necessary, the protective groups are removed, as a result of which a compound represented by the formula (I-1-A) is formed.

The Mitsunobu reaction known in the art is carried out, for example, in an organic solvent (such as dichloromethane, dimethyl ether, tetrahydrofuran, acetonitrile, benzene or toluene) in the presence of an azo compound (such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1,1 '- ( azodicarbonyl) dipiperidine or 1,1'-azobis (N, N-dimethylformamide)) and a phosphine compound (such as triphenylphosphine, tributylphosphine, trimethylphosphine or triphenylphosphine on a polymer carrier) at a temperature of from about 0 to 60 ° C. The deprotection reaction of the carboxyl group, hydroxyl group, hydroxamic acid, sulfonic acid, boronic acid, carbamoyl group, sulfamoyl group, phosphonic acid, phosphoric acid and tetrazolyl group can be carried out in a known manner, for example by the method described in WO 02/092068, corresponding him by the method and / or method described in Protective Groups in Organic Synthesis (TW Greene, John Wiley & Sons Inc. (1999)). The protective group does not have any restrictions if such a group can be easily and selectively removed.

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

where L is a leaving group such as a halogen atom, a methanesulfonyloxy group (OMs group), a toluenesulfonyloxy group (OTs group), a trifluoromethanesulfonyloxy group (OTf group), an alkylthio group, an alkyl sulfinyl group, an alkyl sulfonyl group and the hydroxy sulfonyl group are as defined above;

or a compound represented by formula (5):

where all the symbols have the above meanings;

and the compound represented by formula (3) is subjected to an esterification reaction and then, if necessary, the protective groups are removed, resulting in the formation of a compound represented by formula (I-1-A).

The esterification known in the art is carried out, for example, in an organic solvent (such as N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran or tert-butyl methyl ether) in the presence of an alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide or lithium hydroxide), an alkaline earth metal hydroxide (such as barium hydroxide or calcium hydroxide), a carbonate (such as sodium carbonate, potassium carbonate or cesium carbonate), aqueous solutions or mixtures thereof at a rate Aturi from about 0 to 100 ° C. Protecting groups can be removed as described above.

(B) The compound of the present invention, in which Y means

where Y ² and Y ³ each independently means a bond or spacer having a main chain containing 1-8 atoms (provided that the total number of atoms of the main chain in Y ² and Y ³ does not exceed 8), and R ¹⁰² means a hydrogen atom or a substituent or heterocyclic ring containing at least one nitrogen atom, which may have one or more substituents formed by the spacer atom designated Y ² , together with R ¹⁰² ,

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 characters have the above meanings,

and the compound represented by formula (7):

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

The reductive amination known in the art is carried out, for example, in an organic solvent (such as N, N-dimethylformamide, dichloromethane, methanol or a mixed solvent containing these solvents in any parts) in the presence or absence of a desiccant (such as trimethoxymethane or triethoxymethane) in the presence or absence of an organic acid (such as acetic acid), in the presence or absence of a base (such as triethylamine, sodium bicarbonate or sodium hydroxide) using reducing Itel (such as triacetoxy sodium borohydride, cyanosodium borohydride, tetrabutylammonium borohydride or sodium borohydride) at a temperature of from about 0 to 100 ° C. Protecting groups can be removed as described above.

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

where Y ¹ and Y ⁶ each independently means a bond or spacer having a main chain containing 1-9 atoms (provided that the total number of atoms of the main chain in Y ¹ and Y ⁶ does not exceed 9), and all symbols have the above meanings , 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 formula (8):

where all characters have the above meanings,

and the compound represented by formula (9):

where all characters have the above meanings,

or a compound represented by formula (10):

where all characters have the above meanings,

and the compound represented by formula (11):

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

Alkylation known in the art is performed, for example, in an organic solvent (such as N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran or tert-butyl methyl ether) in the presence of an alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide or lithium hydroxide), an alkaline earth metal hydroxide (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 ture of about 0 to 100 ° C. Protecting groups can be removed as described above.

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

where Y ⁴ means a bond or spacer having a main chain containing 1-7 atoms, R ¹⁰³ , R ¹⁰⁴ and R ¹⁰⁵ independently mean a hydrogen atom or a Deputy, and other symbols have the above meanings,

that is, the compound 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 characters have the above meanings, and

the compound represented by formula (13):

where all the symbols have the above meanings, they undergo an amine addition reaction and then deprotect if necessary.

The amine addition reaction known in the art is carried out, for example, in an organic solvent (such as methanol, ethanol, propanol, benzene, toluene, diethyl ether, tetrahydrofuran or dimethoxyethane) or without a solvent in the presence or absence of a base (such as diisopropylethylamine) when a temperature of from about -78 ° C to a boiling point under reflux. Protecting groups can be removed as described above.

(E) The compound of the present invention, in which Z is a hydroxyl group that can be protected, and Y is:

where Y ⁵ means a bond or spacer having a main chain containing 1 to 9 atoms, i.e. a compound represented by the formula (I-2-E):

where all characters have the above meanings,

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

where R ¹⁰¹ means a hydrogen atom or a protective group similar to a “protective group” in the definition of “carboxyl group which can be protected” represented by the Z group, and other symbols have the above meanings, reduction reactions followed by the introduction of a protective group if necessary.

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

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

where R ¹²¹ and R ¹²² each independently means a hydrogen atom or a protective group similar to the “protective group” in the definition of “hydroxamic acid group that can be protected” represented by the Z group, and other symbols have the above meanings, are obtained by exposing the compound, which can be obtained by the above method, where Z is a carboxyl group, i.e. a compound represented by the formula (I-1-1):

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

where all the symbols have the above meanings, amidation reactions followed by deprotection if necessary.

The amidation reaction is known in the art, and examples of a method for performing said reaction include (1) a method using an acid halide, (2) a method using mixed anhydride and (3) a method using a condensing agent. The following is a description of these methods. For example, (1) a method using an acid chloride is performed as follows: a carboxylic acid is reacted with a halogenating acid agent (such as oxalyl chloride or thionyl chloride) in an organic solvent (such as chloroform, dichloromethane, diethyl ether or tetrahydrofuran) or without solvent at a temperature of from about about -20 ° C to boiling temperature under reflux; the resulting acid halide is reacted with an 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. Alternatively, when performing this method, the resulting acid halide is reacted with an amine in an organic solvent (such as dioxane or tetrahydrofuran) using an aqueous alkali metal solution (such as sodium hydrogen carbonate solution or sodium hydroxide solution) at a temperature of from about 0 to 40 ° C. For example, (2) the mixed anhydride method is performed as follows: a carboxylic acid is reacted with a halide (such as pivaloyl chloride, tosyl chloride or mesyl chloride) or an acid derivative (such as ethyl chloroformate or isobutyl chloroformate) in an organic solvent (such as chloroform, dichloromethane, dichloromethane diethyl ether or tetrahydrofuran) or without solvent in the presence of a base (such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or diisopropylethylamine) ur from about 0 to 40 ° C; and the resulting mixed anhydride is reacted with an amine in an organic solvent (such as chloroform, dichloromethane, diethyl ether or tetrahydrofuran) at a temperature of from about 0 to 40 ° C. For example, (3) a process using a condensing agent is performed as follows: a carboxylic acid and an amine are reacted 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 solvent free 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- (dimethyl amino) propyl] carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine or cyclic anhydride of 1-propanephosphonic acid (PPA)) with and without 1-hydroxybenzotriazole (HOBt). All of these reactions (1), (2) and (3) are preferably carried out in an inert gas atmosphere (such as argon or nitrogen) under anhydrous conditions. Protecting groups can be removed as described above.

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

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

where all the symbols have the above meanings, the reaction of formation of a tetrazole ring.

The tetrazole ring formation reaction known in the art is carried out, for example, in an organic solvent (such as dimethylformamide, dioxane or tetrahydrofuran) in the presence of an azide compound (such as sodium azide, trimethylsilyl azide or tributyltin azide) at a temperature of from about −10 to 150 ° FROM.

(H) A compound of the present invention in which Z is —OP (= O) (OR ² ) (OR ³ ), where R ² and R ³ are as defined above, that is, a compound represented by formula (I-5-H ):

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

(H-1) The compound represented by formula (I-5-H), in which the elements R ² and R ³ each means a hydrogen atom, that is, the compound represented by formula (I-5-H-1):

where all the symbols have the above meanings, get by reacting a compound that can be obtained by the above method, where Z is a hydroxyl group, that is, a compound represented by formula (I-1-2):

and a dialkylphosphoramidite compound, after which the resulting compound is subjected to an oxidation reaction and then a reduction reaction.

The reaction between the alcohol compound and the dialkylphosphoramidite compound and the oxidation reaction is known in the art. The alcohol compound is reacted with a dialkylphosphoramidite compound (such as dibenzylphosphoramidite or N, N-diethyl-1,5-dihydro-2,4,3-benzodioxaphosphepin-3-amine) in an organic solvent (such as methylene chloride, toluene or tetrahydrofuran) tetrazole. An oxidation reaction is then carried out using an oxidizing agent (such as m-chloroperbenzoic acid, iodine or hydrogen peroxide). The reduction reaction, also known in the art, is carried out in a solvent [such as an ether (such as tetrahydrofuran, dioxane, dimethoxyethane or diethyl ether), alcohol (such as methanol or ethanol), benzene (such as benzene or toluene), ketone ( such as acetone or methyl ethyl ketone), nitrile (such as acetonitrile), amide (such as dimethylformamide), water, ethyl acetate, acetic acid or a mixed solvent containing these two or more types] in the presence of a hydrogenation catalyst (such as palladium coal, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum coal, nickel, Raney nickel, ruthenium chloride or ASCA-2 catalyst (NE CHEMCAT CORPORATION, catalyst from 4.5% palladium and 0.5% platinum on activated coal, see Fine Chemical, Oct. 1, 2002, pp. 5 to 14)) in the presence or absence of an acid (such as hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid , oxalic acid, trifluoroacetic acid or formic acid) in tmosfere hydrogen under normal or elevated pressure in the presence of ammonium formate or hydrazine at a temperature of about 0 to 200 ° C. In addition to the above method, all reactions between the alcohol compound and the dialkylphosphoramidite compound, in particular the oxidation reaction and the reduction reaction, can also be carried out by the method described in “Guide to Organic Chemistry Experiment 3-Synthesis Reaction [I]” (edited by Toshio Goto, Tetsuo Shiba , and Teruo Matsuura, Kagaku-dojin Publishing Company, INC, 1990).

(H-2) The compound represented by formula (I-5-H), in which R ² and R ³ each is not a hydrogen atom, that is, the compound represented by formula (I-5-H-2):

where R ^2H-2 and R ^3H-2 have the same meanings as R ² and R ³ , provided that none of these elements is a hydrogen atom, can be obtained by reacting a compound represented by the formula (I-1 -2), and the compound represented by formula (16):

where all characters have the above meanings.

This reaction, known in the art, is carried out in an organic solvent (e.g. tetrahydrofuran or methylene chloride) in the presence of a base (such as pyridine, triethylamine or butyl lithium) at a temperature of from about -78 ° C to 40 ° C.

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

For each reaction described herein, a solid phase reagent on a polymer carrier (such as polystyrene, polyacrylamide, polypropylene or polyethylene glycol) can be used.

With each reaction described herein, the products obtained can be purified by standard purification methods. For example, purification can be carried out by distillation at atmospheric or reduced pressure, using high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, acceptor resin, column chromatography by washing or recrystallization. Purification can be carried out after each reaction or after several reactions.

As is well known to specialists in this field, the reaction with heating, discussed in the present description of the invention, can be performed in a water bath, oil bath, sand bath or when heated by microwave radiation.

Toxicity

The compounds of the present invention have a sufficiently low toxicity, and therefore, they are considered safe enough for use as medicines.

The use of pharmaceuticals

The compound of the present invention has the ability to bind to the S1P receptor (in particular, EDG-1, EDG-6 and / or EDG-8, preferably EDG-1 and / or EDG-6). Therefore, this compound is suitable for use as a prophylactic and / or therapeutic agent in the treatment of mammals (for example, humans and animals other than humans, such as monkeys, sheep, cows, horses, dogs, cats, rabbits, rats and mice) in such cases such as transplant rejection, destruction of the transplanted organ, the graft versus host reaction (for example, the acute graft versus host reaction during bone marrow transplantation, etc.), autoimmune diseases (e.g. measures, 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 (dermatitis), allergic diseases, diseases , food allergies, psoriasis and drug allergies (e.g., an anesthetic, such as lidocaine), inflammatory diseases (e.g., varicose veins, such as morra, fissure or fistula of the anus, stratified aortic aneurysm or sepsis, vasculitis, nephritis, pneumonia and chronic active hepatitis), respiratory diseases (e.g. lung fibrosis, asthma and interstitial pneumonia), metabolic diseases and endocrine disease (e.g. diabetes type I), circulatory system diseases (for example, impaired reperfusion after ischemia, arteriosclerosis, arteriosclerosis obliterans, thromboangiitis obliterans, diabetic neuropathy, acute heart failure and angina pectoris diarrhea), various edematous disorders caused by increased blood penetrating ability (for example, myocardial infarction, cerebral infarction, DIC, pleurisy, congestive heart failure and multiple organ failure), traumatic lesions (e.g. bedsores and burns), osteoporosis, chronic hepatitis, fibrosis, such as liver fibrosis, chronic renal failure, glomerulosclerosis of the kidney, infection, ulcer, lymphoma, malignant tumor (e.g. cancer), leukemia, cerebral embolism, ischemic pathology of various organ , Shock due to incompatibility during blood transfusion, genetic diseases, neurodegenerative diseases (e.g., Parkinson's disease, Parkinsonian 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 preparation containing the compound of the present invention and another medicament used to achieve the above objective is usually administered systemically or topically, orally or parenterally. The doses administered are determined depending on age, body weight, disease symptoms, desired therapeutic effect, route of administration, and duration of treatment. Dosages intended for administration to an adult usually range from 1 ng to 100 mg when administered orally from one to several times a day, from 0.1 ng to 10 ng when administered parenterally from one to several times a day or continuously injected into a vein within 1-24 hours a day. As described above, the doses administered depend on different conditions. Therefore, there may be cases where the dose will be less than or greater than the above range.

The compound of the present invention or a combination preparation containing the compound of the present invention and another drug is used in solid form for oral administration, in liquid form for oral administration, injection, liquid ointments, suppositories, eye drops, inhalation dosage form or the like for parenteral administration.

Solid forms for oral administration include tablets, pills, capsules, powder and granules. Capsules include hard and soft capsules. Tablets include sublingual tablets, slow dissolving tablets, rapidly disintegrating tablets for oral administration, and the like. In addition, such oral solid forms may contain one or more active substances in pure form or in admixture with a carrier (such as lactose, mannitol, glucose, microcrystalline cellulose or starch), a binder (such as hydroxypropyl cellulose, polyvinylpyrrolidone or metasilicate aluminate magnesium), a disintegrant (such as cellulose calcium glycolate), lubricants (such as magnesium stearate), a stabilizing agent and a solubilizing agent (such as glutamic acid or asp araginic acid) and can be obtained by methods well known in the art. Solid forms can optionally be coated with a coating agent (such as sucrose, gelatin, hydroxypropyl cellulose or hydroxypropyl methylcellulose phthalate) or a coating of two or more layers. In addition, the coating can be applied to capsules made of absorbable substances, such as gelatin.

Sublingual tablets are prepared by a known method. For example, one or more active substances in the form of a pharmaceutical preparation prepared by methods well known in the art are mixed with a carrier (such as lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica or starch), a binder (such as hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium aluminum metasilicate), a disintegrant (such as starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium or cellulose calcium glycolate), a lubricant (such as magnesium stearate), a swelling agent (such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carbopol, carboxymethyl cellulose, polyvinyl alcohol, xanthan gum or guar gum), an excipient that causes swelling (such as glucose, fructose, fructose maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid or arginine), a stabilizing agent, a solubilizing agent (such as polyethylene glycol, propylene glycol, glutamic acid or aspara gynic acid), a flavoring agent (such as orange, strawberry, mint, lemon or vanilla) and the like. In addition, if necessary, a coating agent (such as sucrose, gelatin, hydroxypropyl cellulose or hydroxypropyl methyl cellulose phthalate) or a coating of two or more layers may be applied to said tablets. In addition, if necessary, commonly used additional substances can be added to these tablets, such as an antiseptic, antioxidant, coloring agent and sweetener. Slow absorption tablets are prepared or prepared by a known method. For example, one or more active substances in the form of a pharmaceutical preparation prepared by methods well known in the art are mixed with a carrier (such as lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica or starch), a binder (such as hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium aluminum metasilicate), a disintegrant (such as starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium or cellulose calcium glycolate), a lubricant (t akim as magnesium stearate), an adhesive agent (such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carbopol, carboxymethyl cellulose, polyvinyl alcohol, xanthan gum or guar gum), an auxiliary adhesive substance (such as glucose, fructose, malten, mannitol, mannitol , citrate, silicate, glycine, glutamic acid or arginine), a stabilizing agent, a solubilizing agent (such as polyethylene glycol, propylene glycol, glutamic acid or aspartic acid), aromatic congestion (such as orange, strawberry, mint, lemon or vanilla) and the like. In addition, if necessary, a coating agent (such as sucrose, gelatin, hydroxypropyl cellulose or hydroxypropyl methyl cellulose phthalate) or a coating of two or more layers may be applied to said tablets. In addition, if necessary, commonly used additional substances can be added to these tablets, such as an antiseptic, antioxidant, coloring agent and sweetener. Rapidly disintegrating tablets for oral administration are prepared by a 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 art by applying to the particles of a powdered or granular substance an appropriate coating agent (such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or a copolymer of acrylate and methacrylate) and a plasticizer (such as polyethylene glycol or triethyl citrate) are mixed with a carrier (such as lactose, mannitol, glucose, microcrystalline c cellulose, colloidal silica or starch), a binder (such as hydroxypropylcellulose, polyvinylpyrrolidone or magnesium aluminum metasilicate), a disintegrant (such as starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, sodium croscarmellose, or magnesium carboxymethyl cellulose) with an auxiliary dispersing agent (such as glucose, fructose, mannitol, xylitol, ethyrtrite, maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid or arginine), stabilizes conductive agent, a solubilizing agent (such as polyethylene glycol, propylene glycol, glutamic acid or aspartic acid), flavors (such as orange, strawberry, mint, lemon, or vanilla) and the like. In addition, if necessary, a coating agent (such as sucrose, gelatin, hydroxypropyl cellulose or hydroxypropyl methyl cellulose phthalate) or a coating of two or more layers may be applied to said tablets. In addition, if necessary, commonly used additional substances, such as a preservative, antioxidant, coloring agent and sweetener, may be added to said tablets.

Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs. In liquid forms, one or more active substances can be dissolved, suspended or emulsified in a diluent commonly used in the art (such as purified water, ethanol, or a mixture thereof). In addition, liquid forms may also contain wetting agents, suspending agents, emulsifiers, sweeteners, flavorings, a fragrance, a preservative or a buffering agent.

The agent for parenteral administration may be in the form of an ointment, gel, cream, wet compress, paste, liquid ointment, aerosol, inhalation dosage form, spray solution, eye drops, nasal solution or the like. These funds containing one or more active substances are obtained by known methods or in accordance with the commonly used technology for the preparation of medicines.

The ointment is obtained by known or commonly used methods. For example, to obtain such an ointment, one or more active substances are ground or dissolved in the base. The ointment base is selected from known or commonly used substances. For example, alone or as a combination of two or more substances, substances such as higher aliphatic acids or esters of higher aliphatic acids (such as myristic acid, palmitic acid, stearic acid, oleic acid, myristic acid ester, palmitic acid ester can be used) stearic acid ester and oleic acid ester), wax (e.g. beeswax, whale wax and ceresin), a surfactant (e.g. polyoxyethylene ester lalkoxyphosphoric acid), higher alcohols (e.g. cetanol, stearyl alcohol and setostearyl alcohol), silicone oil (e.g. dimethyl polysiloxane), hydrocarbons (e.g. hydrophilic petrolatum, white petrolatum, purified lanolin and liquid paraffin), glycol glycol (e.g. , propylene glycol, polyethylene glycol and macrogol), vegetable oils (e.g. castor oil, olive oil, sesame oil and turpentine oil), animal oils (e.g. mink oil, yolk oil, squalane oil and squalene e oil), water, absorption accelerator or antiallergic agent. The base may further include a humectant, preservative, stabilizer, antioxidant, perfume, or the like.

The gel is prepared by known or commonly used methods. For example, to obtain such a gel, one or more active substances are dissolved in the base. The gel base is selected from known or commonly used substances. For example, alone or as a combination of two or more substances, substances such as lower alcohols (e.g. ethanol, isopropyl alcohol), a gelling agent (e.g. carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and ethyl cellulose), a neutralizing agent (e.g. triethanolamine and diisopropanol can be used) ), a surfactant (e.g., polyethylene glycol monostearate), gum, water, an absorption accelerator, or anti-allergic agent. The gel base may further include a preservative, antioxidant, perfume, or the like.

The cream is obtained by known or commonly used methods. For example, to obtain such a cream, one or more active substances are dissolved or emulsified in the base. The cream base is selected from known or commonly used substances. For example, alone or as a combination of two or more substances, substances such as a higher aliphatic acid ester, lower alcohol, hydrocarbons, polyhydric alcohols (e.g. propylene glycol and 1,3-butylene glycol), higher alcohols (e.g. 2-hexyldecanol) can be used. and cetanol), emulsifiers (e.g., polyoxyethylene alkyl ether and aliphatic acid ester), water, an absorption accelerator, or an anti-allergic agent. The cream base may further include a preservative, antioxidant, perfume, or the like.

A wet compress is obtained by known or commonly used methods. For example, to obtain such a wet compress, one or more active substances are dissolved in the base, after which the mixed mixture is applied to the substrate. The base for the wet compress is selected from known or commonly used substances. For example, separately or as a combination of two or more substances, you can use substances such as a thickener (e.g. polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin and methyl cellulose), a wetting agent (e.g. urea, glycerin and propylene glycol), a filler ( for example, kaolin, zinc oxide, talc, calcium and magnesium), water, a solubilizing agent, a tackifier, and an anti-allergic agent. The wet compress base may further include a preservative, antioxidant, perfume, or the like.

A pasting agent is prepared by known or commonly used methods. For example, to obtain such a pasting agent, one or more active substances are dissolved in a base and then applied to a substrate. The basis for the paste means is selected from known or commonly used substances. For example, alone or as a combination of two or more substances, substances such as a polymer base, fat and oil, a higher aliphatic acid, a tackifier or an anti-allergic agent can be used. The basis for the pasting agent may further include a preservative, antioxidant, perfume or the like.

Liquid ointment is obtained by known or commonly used methods. For example, to obtain such a liquid ointment, one or more active substances are dissolved, suspended or emulsified in one substance or in a combination of two or more substances selected from water, alcohol (e.g. ethanol and polyethylene glycol), higher aliphatic acid, glycerin, soap, emulsifier , a suspending agent and the like. The liquid ointment may further include a preservative, antioxidant, perfume, or the like.

The aerosol, inhalation dosage form and nebulized solution may contain a stabilizer, such as sodium hydrosulfite, and a buffer that makes the solution isotonic, such as an isotonic agent (e.g., sodium chloride, sodium citrate and citric acid).

An injection preparation for parenteral administration may be in the form of a solution, suspension, emulsion or solid injection preparation to be dissolved or suspended in a solvent immediately before use. An injection preparation is prepared by dissolving, suspending or emulsifying one or more active substances in a solvent. As such a solvent, distilled water for injection, physiological saline, vegetable oil, alcohols such as propylene glycol, polyethylene glycol and ethanol, or the like, and combinations thereof can be used. The injection preparation may further include a stabilizer, a solubilizing agent (e.g., glutamic acid, aspartic acid, polysolvate 80 (trade name)), suspending agent, emulsifier, emollient, buffer, antiseptic or the like. The injection preparation is sterilized at the final stage or obtained under aseptic conditions. Alternatively, an aseptic solid agent, such as a lyophilized product, which is made aseptic or dissolved in aseptic distilled water for injection or another solvent before use, can be used.

Eye drops for parenteral administration may be a liquid, suspension, emulsion or oil, or may be dissolved in a solvent immediately before use. Said eye drops are prepared by known methods. For example, one or more active substances are dissolved, suspended or emulsified in a solvent. As a solvent for eye drops, sterilized purified water, saline and other aqueous or non-aqueous solvents for an injectable preparation (eg, vegetable oil) and combinations thereof can be used. Eye drops may include an isotonic agent (e.g., sodium chloride and concentrated glycerin), a buffering agent (e.g., sodium phosphate and sodium acetate), a surfactant (e.g., polysolvate 80 (trade name), polyoxyl stearate 40, castor oil, cured with polyoxyethylene ), a stabilizer (e.g. sodium citrate and sodium edetate), an antiseptic (e.g. benzalkonium chloride and paraben), or the like, which should be selected accordingly if necessary. Eye drops are sterilized or obtained under aseptic conditions at the final stage. Alternatively, an aseptic solid agent, such as a lyophilized product, which is made aseptic or dissolved in aseptic distilled water for injection or another solvent before use, can be used.

A dosage form for inhalation intended for parenteral administration may be an aerosol, powder for inhalation, or liquid for inhalation. The inhalation fluid may be dissolved or suspended in water and another suitable medium immediately before use. These inhalation dosage forms are prepared by a known method. For example, an inhalation liquid is obtained from substances that, if necessary, are suitably selected from antiseptics (e.g., benzalkonium chloride and paraben), colorants, buffers (e.g., sodium phosphate and sodium acetate), isotonic agents (e.g., sodium chloride and concentrated glycerin ), thickeners (e.g., carboxyvinyl polymer), absorption accelerators, and the like.

Powder for inhalation is obtained from substances that, if necessary, are suitably selected from lubricants (e.g., stearic acid and its salts), binders (e.g., starch and dextrin), carriers (e.g., lactose and cellulose), colorants, antiseptics (e.g. , benzalkonium chloride and paraben), absorption accelerators or the like.

A nebulizing device (e.g., aerosol inhaler and nebulizer) is usually used to administer the inhalation fluid. An inhaler is usually used to administer the powder for inhalation.

Other examples of compositions include suppositories for rectal administration and vaginal suppositories for administration to the vagina, obtained by the usual method and containing one or more active substances.

The compound of the present invention can be administered in the form of a combined preparation in combination with other drugs to achieve the following objectives:

1) addition and / or enhancement of the prophylactic and / or therapeutic effect of this compound;

2) improving the pharmacokinetics and absorption and reducing doses of the administered compound; and / or

3) reduction of side effects of this compound.

A combination preparation containing a compound of the present invention can be administered together with other pharmaceuticals in the form of a complex preparation in which both components are mixed in one preparation, or as separate preparations. The introduction in the form of separate preparations involves the simultaneous administration and administration at regular intervals. When administered at regular intervals, the compound of the present invention and then another pharmaceutical agent are first administered, or another pharmaceutical agent and then the compound of the present invention are first administered. Such drugs can be administered in the same or different ways.

Combination preparations containing other pharmaceutical agents that complement and / or enhance the prophylactic and / or therapeutic effect of the compounds of the present invention are not limited to the preparations given as examples in the present description of the invention. In addition, combination preparations containing other pharmaceuticals that complement and / or enhance the prophylactic and / or therapeutic effect of the compounds of the present invention include not only compounds discovered to date, but also compounds that will be discovered in the future based on mechanisms described in the present description of the invention.

Diseases in respect of which the above combined drugs have a prophylactic and / or therapeutic effect, do not have any restrictions. In particular, such diseases include diseases in the treatment of which the prophylactic and / or therapeutic effect of the compounds of the present invention can be supplemented and / or enhanced. For example, other immunosuppressants, antibiotics, or the like may be used to supplement and / or enhance the prophylactic and / or therapeutic effect in case of transplant rejection due to EDG-1 and / or EDG-6. To complement and / or enhance the prophylactic and / or therapeutic effect in the treatment of autoimmune diseases, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), anti-rheumatic drugs that change the course of the disease (DMARD, slow-acting anti-rheumatic drugs), other immunosuppressants, T-cell inhibitors can be used anti-inflammatory enzyme preparations that protect cartilage, prostaglandins, prostaglandin synthase inhibitors, IL-1 inhibitors, IL-6 inhibitors (including protein s drugs such as anti-IL-6 receptor), TNF-α inhibitors (including protein preparations such as an antibody against TNF-α), γ-interferon agonists, phosphodiesterase inhibitors, metalloproteinase inhibitors and the like. Examples of drugs used to supplement and / or enhance the prophylactic and / or therapeutic effect in the treatment of allergic diseases, for example atopic dermatitis, include immunosuppressants, steroids, non-steroidal anti-inflammatory drugs, prostaglandins, anti-allergic drugs, mediator release inhibitors, antihistamines, drugs forskolin, phosphodiesterase inhibitors and cannabinoid-2 receptor stimulants.

Examples of immunosuppressants include azathioprine (trade name: IMULAN and AZANIN), misoribine (trade name: BREDININ), methotrexate (trade name: METOTREXAT, REVMATREX), mycophenolate mofetil (trade name: SELCEPT), cyclophosphamide (cyclofosphamide) A (trade name: NEORAL, SANDIMMUN), tacrolimus (FK506, trade name: PROGRAPH), sirolimus (RAPAMICIN), everolimus (trade name: CERTICAN), prednisolone (trade name: PREDONIN), methylprednisolone (trade name: MEDLOL, OKT3 ( trade name: MUROMONAB CD3), anti-human lymphocyte globulin (ALG, trade name: ALBULIN), deoxyspergualin (DSG, husperimus hydrochloride and trade name: SPANIDIN).

Examples of antibiotics include cefuroxime sodium, meropenem trihydrate, netilmicin sulfate, sisomycin sulfate, ceftibutene, RA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromycin sulfate, or cefetametpivoxyl hydrochloride. Examples of antibiotics used as dosage forms for inhalation include PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromycin sulfate or cefetametpivoxyl hydrochloride.

Examples of steroids used in topical preparations include clobetasol propionate, diflorazone diacetate, fluocinonide, mometasone furancarboxylate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difleuprednate, budezenide, valexone diacetone, diacetone valone diacetone, valonexone diacetone, valonexone diacetone; dexamethasone, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate-propionate, deprodone propionate, prednisone valerate acetate, and etonid fluocinolone, beclomethasone propionate, triamcinolone acetonide, flumethasone pivalate, alclometasone dipropionate, clobetasone butyrate, prednisolone, beclomethasone propionate and fludroksikortid. Examples of drugs for internal use and injection include cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butyl acetate, prednisolone sodium phosphate, halogenpred predolone acetate, halogenpred predolone acetate, methyl halopred predolzone, methyl halopred predolzone, methyl halopredzone, methyl acetate sodium methylprednisolone, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexameth sodium phosphate azone, dexamethasone palmitate, parametasone acetate and betamethasone. Examples of dosage forms for inhalation include beclomethasone propionate, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, cyclesenide, dexamethasone palmitate, mometasone furancarbonate, prasterone sulfonate, deflazacort, methylprednisolone and methylprednisolone sodium suleptanate.

Examples of nonsteroidal anti-inflammatory drugs (NSAID) include sasapirin, sodium salicylate, aspirin, composition aspirin dialyuminata, diflunisal, indomethacin, suprofen, ufenamate, dimetilizopropilazulen, bufexamac, felbinac, diclofenac, tolmetin sodium, Clinoril, fenbufen, nabumetone, proglumetacin, indometatsinfarnezil, acemetacin , proglumetacin maleate, amfenac sodium, mofesolac, etodolac, ibuprofen, ibuprofenpiconol, naproxen, flurbiprofen, flurbiprofenaxetil, ketoprofen, phenoprofen-calcium, thiaprofenene, oxaprozin, pranoprofen oprofen-sodium, aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate, tolfenamic acid, flotaphenin, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam, anpiroxinol hydrochloride, epiridinolidiridinolidiridinolidiridinolidiridinolidiridinolina, tiridinofridinol, tiryridinol Cedes G, amipilo N, sorbon, antipyretics of the pyrine system, acetaminophen, phenacetin, dimethothiazine mesylate, composition of simetrid and antipyretics of the antipyrine system.

Examples of anti-rheumatic drugs that alter the course of the disease (DMARD, slow-acting anti-rheumatic drugs) include aurothioglucose, sodium aurothiomalate, auranofin, actarite, D-penicillamine preparations, disodium lobenzarite, butylamine, hydroxychloroquine, salidosefilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilofisulosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilosulfosilofosilosulfofylsulfide lisulfosulfidelosulfosulfidelosulfosulfidelosulfosulfidelosulfosulfidelosulfosulfoform

Examples of anti-inflammatory enzyme preparations include lysozyme chloride, bromelain, pronase, serrapeptase, or streptokinase-streptodornase composition.

Examples of cartilage protecting agents include sodium hyaluronate, glucosamine, chondroitin sulfate and glucosaminoglycan polysulfate.

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

Examples of the prostaglandin synthase inhibitor include salazosulfapyridine, mesalazine, olsalazine, 4-aminosalicylic acid, JTE-522, auranofin, carprofen, difenpiramid, flunoksaprofen, flurbiprofen, indomethacin, ketoprofen, lornoxicam, loxoprofen, meloxicam, oxaprozin, parsalmid, piproksen, piroxicam, piroksikambetadeks , cinnamate piroxicam, indomethacinate tropine, zaltoprofen and pranoprofen.

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

Examples of IL-6 inhibitors (including protein preparations such as anti-IL-6 receptor antibodies) include MRA.

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

Examples of a phosphodiesterase inhibitor include rolipram, cilomilast (trade name: ariflo), Bay 19-8004, NIK-616, roflumilast (BY-217), tsipamfillin (BGL-61063), atisolam (CP-80633), SCH-351591, YM- 976, V-11294A, PD-168787, D-4396, IC-485 or ONO-6126 as a PDE-4 inhibitor.

Examples of mediator release inhibitors include tranylast, cromolyn sodium, anlexanox, repirinast, ibudilast, tazanolast and pemilolast potassium.

Examples of antihistamines include ketotifen fumarate, mechitazine, azelastine hydrochloride, oxatomide, terfenadine, emedastine fumarate, epinastine hydrochloride, astemizole, ebastine, cetirizine hydrochloride, bepastastine, fexofenadine, Loladadine CR-60, desoladadine-7, desoladin-7-decoladin, Desoladin-20, desoladin-60, desoladin -530, mometasone furoate, misolastine, BP-294, andolast, auranofin and acrivastin.

Effect of the invention

The compound of the present invention has the ability to bind to the S1P receptor (in particular, EDG-1, EDG-6 and / or EDG-8). Therefore, this compound is suitable for use as a prophylactic and / or therapeutic agent in the treatment of mammals (for example, humans and animals other than humans, such as monkeys, sheep, cows, horses, dogs, cats, rabbits, rats and mice) in such cases such as transplant rejection, destruction of the transplanted organ, the graft versus host reaction (for example, the acute graft versus host reaction during bone marrow transplantation, etc.), autoimmune diseases (e.g. measures, 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 (dermatitis), allergic diseases, diseases , food allergies, psoriasis and drug allergies (e.g., an anesthetic, such as lidocaine), inflammatory diseases (e.g., varicose veins, such as morra, fissure or fistula of the anus, stratified aortic aneurysm or sepsis, vasculitis, nephritis, pneumonia and chronic active hepatitis), respiratory diseases (e.g. lung fibrosis, asthma and interstitial pneumonia), metabolic diseases and endocrine diseases (e.g. diabetes type I), circulatory system diseases (for example, impaired reperfusion after ischemia, arteriosclerosis, arteriosclerosis obliterans, thromboangiitis obliterans, diabetic neuropathy, acute heart failure and stenosis rdia), various edematous disorders caused by increased blood penetrating ability (for example, myocardial infarction, cerebral infarction, disseminated intravascular coagulation (DIC), pleurisy, congestive heart failure, multiple organ failure), traumatic lesions (e.g. bedsores and burns), osteoporosis, chronic hepatitis, fibrosis, such as liver fibrosis, chronic renal failure, glomerulosclerosis of the kidney, infection, ulcer, lymphoma, malignant tumor (e.g. cancer), leukemia, cerebral embolism, ischemic pathology of different organs, shock due to blood incompatibility during blood transfusion, genetic diseases, neurodegenerative diseases (e.g. Parkinson's disease, Parkinson's syndrome, Alzheimer's disease and amyotrophic lateral sclerosis) and the like.

The best embodiment of 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 corresponds to the eluting or developing solvent used, and the ratio is expressed as volume. The aqueous ammonia solution used is a commercially available 28% aqueous ammonia solution.

For the measurement, the solvent indicated in the brackets of the NMR data was used.

A powder X-ray diffraction pattern was obtained under the following conditions: device: BRUKER D8 DISCOVER with GADDS from BRUKER axs; target: Cu; filter: none; voltage: 40 kV; electric current: 40 mA; exposure time: 5 min.

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

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

Example 1: 6- (benzyloxy) -3,4-dihydronaphthalen-1 (2H) -one

To a solution of 6-hydroxy-3,4-dihydronaphthalen-1 (2H) -one (24.3 g) in acetone (160 ml) was added benzyl bromide (29.4 ml) and potassium carbonate (31.1 g) at room temperature and stirred at 40 ° C for 3.5 hours. Insoluble materials were filtered off, the filtrate was concentrated, and the reaction product was washed with a mixed solvent of tert-butyl methyl ether and hexane (1: 4), to thereby give the title compound (34.5 g) having the following physical properties.

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

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

To a solution of the compound (34.5 g) obtained in Example 1 in tetrahydrofuran (300 ml) was added methylmagnesium bromide (3 mol / L solution in diethyl ether, 55 ml) at 0 ° C and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C. and poured into an ice-saturated aqueous solution of ammonium chloride. Then, 2 mol / L hydrochloric acid was added, and the mixture was stirred at room temperature for 3 hours. The reaction product was extracted with ethyl acetate, the organic layer was washed successively with water and brine, dried and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), to thereby give the title compound (24.8 g) having the following physical properties.

TLC: Rf 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., N, N-dimethylformamide (60 ml) was added dropwise and stirred for 20 minutes. Then, a solution of the compound (24.8 g) obtained in Example 2 in methylene chloride (60 ml) was slowly added dropwise and stirred at room temperature for 90 minutes. The reaction mixture was cooled to 0 ° C, poured onto ice and allowed to stand for some time. Then, the reaction product was extracted with a mixed solvent of hexane and ethyl acetate (1: 2). The organic layer was washed successively with water and brine, dried and concentrated. The resulting solid was washed with tert-butyl methyl ether to give the title compound (19.9 g) having the following physical properties.

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

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

Trifluoroacetic acid (140 ml) was added to thioanisole (35 ml) at 0 ° C. Then, the compound (9.17 g) obtained in Example 3 was added portionwise and stirred at room temperature for 4 hours. The reaction mixture was poured onto ice and 5 mol / L aqueous sodium hydroxide solution was added. The mixture was washed with tert-butyl methyl ether, 1 mol / L hydrochloric acid was added to the aqueous layer, and extracted with ethyl acetate. The organic layer was dried and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 2: 1), to thereby give the title compound (6.03 g) having the following physical properties.

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

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

The method of Example 1 was carried out using the compound obtained in Example 4 instead of 6-hydroxy-3,4-dihydronaphthalen-1 (2H) -one and 1-bromo-3- (4-fluorophenyl) propane instead of benzyl bromide, resulting in the title compound was obtained having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 10.32 (s, 1H), 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 (d, J = 2 , 50 Hz, 1H), 3.99 (t, J = 6.00 Hz, 2H), 2.79 (t, J = 7.50 Hz, 2H), 2.69-2.75 (m, 2H ), 2.47-2.56 (m, 5H), 2.04-2.14 (m, 2H).

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

To a solution of the compound (5.04 g) obtained in Example 5 in tetrahydrofuran (50 ml), triethylamine (4.33 ml), methylazetidine-3-carboxylate hydrochloride (4.71 g, which was obtained in the following example) were successively added. 38) and triacetoxy disodium borohydride (9.88 g) under ice cooling. The reaction mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture under ice-cooling. The resulting mixture was concentrated, and the resulting solution was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate, water and brine. The reaction product was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1 and 1: 6), to thereby give the title compound (6.12 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): 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), 3.50-3.58 (m, 2H), 3.23-3.40 (m, 5H), 2.78 (t, J = 7.50 Hz, 2H), 2.62-2.72 (m, 2H), 2.22-2.31 (m, 2H), 2.09 (s, 3H) 2.00-2.13 (m, 2H).

Examples 6-1 to 6-10

The method of Example 6 was carried out using the corresponding aldehyde instead of the compound obtained in Example 5. Thus, compounds having the following physical properties were obtained.

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

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

¹ H-NMR (CDCl ₃ ): δ 7.09-7.28 (m, 5H), 6.62-6.75 (m, 2H), 3.94 (t, J = 6.13 Hz, 2H ), 3.71 (s, 3H), 3.50-3.60 (m, 2H), 3.24-3.41 (m, 5H), 2.78 (t, J = 7.55 Hz, 2H), 2.63-2.72 (m, 2H), 2.22-2.32 (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-azetidinecarboxylate

TLC: Rf 0.89 (chloroform: methanol = 9: 1).

¹ H-NMR (CDCl ₃ ): δ 7.12-7.24 (m, 5H), 6.63-6.76 (m, 2H), 4.04-4.12 (m, 1H), 3 91 (t, J = 9.00 Hz, 1H), 3.70 (s, 3H), 3.48-3.61 (m, 2H), 3.09-3.43 (m, 6H), 2.82-2.94 (m, 1H), 2.66 (t, J = 9.00 Hz, 2H), 2.17-2.30 (m, 2H), 2.08 (s, 3H) 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-fluorophenyl) -2-methylpropyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.06-7.23 (m, 3H), 6.89-7.02 (m, 2H), 6.63-6.75 (m, 2H), 3 76 (d, J = 5.9 Hz, 2H), 3.71 (s, 2H), 3.51-3.59 (m, 2H), 3.22-3.41 (m, 6H), 2.84 (dd, J = 13.5, 6.4 Hz, 1H), 2.67 (t, J = 7.3 Hz, 2H), 2.52 (dd, J = 13.5, 7, 9 Hz, 1H), 2.12-2.31 (m, 3H), 2.09 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H).

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

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

¹ H-NMR (CDCl ₃ ): δ 7.18 (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), 3.23-3.41 (m, 5H), 2.84 (dd, J = 13.45, 6.50 Hz, 1H), 2.61-2.75 (m, 2H), 2 52 (dd, J = 13.45, 7.68 Hz, 1H), 2.12-2.33 (m, 3H), 2.09 (s, 3H), 1.00 (d, J = 6 7 Hz, 3H).

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

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

¹ H-NMR (CDCl ₃ ): δ 7.51 (d, J = 8.60 Hz, 1H), 7.11-7.19 (m, 2H), 6.91-7.02 (m, 2H ), 6.73 (dd, J = 8.60, 2.56 Hz, 1H), 6.66 (d, J = 2.56 Hz, 1H), 3.95 (t, J = 6.22 Hz) , 2H), 3.71 (s, 3H), 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), 1.99-2.13 (m, 2H).

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

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

Example 6-7: methyl-1 - {[6- [3- (4-fluorophenyl) propoxy] -3- (trifluoromethyl) -1-benzothien-2-yl] methyl} -3-azetidinecarboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.70-7.80 (m, 1H), 7.11-7.29 (m, 3H), 6.92-7.09 (m, 3H), 3 95-4.07 (m, 4H), 3.66-3.77 (m, 5H), 3.34-3.51 (m, 3H), 2.81 (t, J = 7.5 Hz , 2H); 2.04-2.19 (m, 2H).

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

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

¹ H-NMR (CDCl ₃ ): δ 7.18 (d, J = 8.50 Hz, 1H), 7.08-7.16 (m, 1H), 6.74-6.82 (m, 2H ), 6.66-6.72 (m, 2H), 3.78 (d, J = 6.00 Hz, 2H), 3.71 (s, 3H), 3.50-3.58 (m, 2H), 3.25-3.37 (m, 5H), 2.85 (dd, J = 14.00, 6.50 Hz, 1H), 2.64-2.71 (m, 2H), 2 57 (dd, J = 14.00, 7.50 Hz, 1H), 2.17-2.31 (m, 3H), 2.08 (s, 3H), 1.01 (d, J = 6 , 50 Hz, 3H).

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

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

¹ H-NMR (CDCl ₃ ): δ 7.18 (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), 3.51-3.58 (m, 2H), 3.24-3.40 (m, 5H), 2.85 (dd, J = 14.00, 6.50 Hz, 1H), 2.64-2.71 (m, 2H), 2.58 (dd, J = 14.00, 8, 00 Hz, 1H), 2.19-2.31 (m, 3H), 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-azetidinecarboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.23 (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), 3.75 (d, J = 5.9 Hz, 2H), 3.70 (s, 2H), 3.50- 3.59 (m, 2H), 3.23-3.41 (m, 6H), 2.85 (dd, J = 13.5, 6.5 Hz, 1H), 2.67 (t, J = 7.1 Hz, 2H), 2.52 (dd, J = 13.5, 7.8 Hz, 1H), 2.13-2.32 (m, 3H), 2.09 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H).

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

To a solution of the 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 ice-cooling. The reaction mixture was stirred for 3 hours under ice cooling. To the resulting mixture was added 1 mol / L hydrochloric acid (40 ml). The resulting insoluble matter was filtered, washed with water and dried. The resulting solid was recrystallized from water-tetrahydrofuran, to thereby give the title compound (5.55 g) having the following physical properties.

Melting point: 154.0-155.3 ° C.

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

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.60 Hz, 1H), 7.15-7.25 (m, 2H), 6.92-7.02 (m, 2H), 6.75 (dd, J = 8.60, 2.56 Hz, 1H), 6.71 (d, J = 2.56 Hz, 1H), 4.10-4.26 (m, 4H ), 4.07 (s, 2H), 3.95 (t, J = 6.13 Hz, 2H), 3.34-3.48 (m, 1H), 2.66-2.82 (m, 4H), 2.20-2.28 (m, 2H), 2.20 (s, 3H), 1.98-2.10 (m, 2H).

Examples 7-1 to 7-10

The method of Example 7 was carried out using the compounds obtained in Examples 6-1 to 6-10, instead of the compound obtained in Example 6. If necessary, the reaction product was converted to the corresponding salt to obtain the title compounds having the following physical properties.

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

Melting point: 165.4-166.9 ° C.

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

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.60 Hz, 1H), 7.16-7.28 (m, 4H), 6.75 (dd, J = 8, 60, 2.74 Hz, 1H), 6.70 (d, J = 2.74 Hz, 1H), 4.09-4.24 (m, 4H), 4.07 (s, 2H), 3, 96 (t, J = 6.22 Hz, 2H), 3.34-3.47 (m, 1H), 2.67-2.82 (m, 4H), 2.17-2.28 (m, 5H), 1.99-2.11 (m, 2H).

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

TLC: Rf 0.11 (1-butanol: acetic acid: water = 20: 4: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.60 Hz, 1H), 7.12-7.23 (m, 4H), 6.75 (dd, J = 8, 60, 2.65 Hz, 1H), 6.70 (d, J = 2.65 Hz, 1H), 4.20-4.41 (m, 4H), 4.15 (s, 2H), 4, 07 (dd, J = 9.30, 6.30 Hz, 1H), 3.98 (dd, J = 9.30, 7.50 Hz, 1H), 3.60-3.76 (m, 1H) , 3.10-3.20 (m, 1H), 2.79-2.92 (m, 1H), 2.67-2.76 (m, 2H), 2.21 (s, 3H), 2 17-2.27 (m, 2H), 1.36 (d, J = 6.95 Hz, 3H), 1.23 (d, J = 6.95 Hz, 6H).

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

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

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.42 Hz, 1H), 7.09-7.23 (m, 2H), 6.87-7.03 (m, 2H), 6.74 (dd, J = 8.42, 2.56 Hz, 1H), 6.69 (d, J = 2.56 Hz, 1H), 4.12-4.27 (m, 4H ), 4.09 (s, 2H), 3.78 (d, J = 6.04 Hz, 2H), 3.35-3.47 (m, 1H), 2.83 (dd, J = 13, 45, 6.50 Hz, 1H), 2.67-2.75 (m, 2H), 2.54 (dd, J = 13.45, 7.78 Hz, 1H), 2.20 (s, 3H ), 2.09-2.29 (m, 3H), 0.99 (d, J = 6.77 Hz, 3H).

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

Melting point: 142.5-143.6 ° C.

TLC: Rf 0.24 (chloroform: methanol: aqueous ammonia = 5: 1: 0.1).

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.42 Hz, 1H), 7.09-7.23 (m, 2H), 6.87-7.03 (m, 2H), 6.74 (dd, J = 8.42, 2.56 Hz, 1H), 6.69 (d, J = 2.56 Hz, 1H), 4.12-4.27 (m, 4H ), 4.09 (s, 2H), 3.78 (d, J = 6.04 Hz, 2H), 3.35-3.47 (m, 1H), 2.83 (dd, J = 13, 45, 6.50 Hz, 1H), 2.67-2.75 (m, 2H), 2.54 (dd, J = 13.45, 7.78 Hz, 1H), 2.20 (s, 3H ), 2.09-2.29 (m, 3H), 0.99 (d, J = 6.77 Hz, 3H).

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

TLC: Rf 0.12 (chloroform: methanol: aqueous ammonia = 5: 1: 0.1).

¹ H-NMR (CD ₃ OD): δ 7.55 (d, J = 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), 3.36-3.49 (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-fluorobenzyl) cyclopropyl] methoxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.14 (chloroform: methanol: aqueous ammonia = 5: 1: 0.1).

¹ H-NMR (CD ₃ OD): δ 7.29 (d, J = 8.60 Hz, 1H), 7.13-7.22 (m, 2H), 6.88-6.98 (m, 2H), 6.65-6.73 (m, 2H), 4.10-4.26 (m, 4H), 4.07 (s, 2H), 3.61 (s, 2H), 3.36 -3.47 (m, 1H), 2.78 (s, 2H), 2.66-2.75 (m, 2H), 2.14-2.28 (m, 5H), 0.52-0 68 (m, 4H).

Example 7-7: 1 - {[6- [3- (4-fluorophenyl) propoxy] -3- (trifluoromethyl) -1-benzothien-2-yl] methyl} -3-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): 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, 5.3 Hz, 2H), 7.05 (dd, J = 9.0, 2.4 Hz, 1H), 6.98 (t, J = 8.8 Hz, 2H), 4.09 (d, J = 2.0 Hz, 2H), 4.02 (t, J = 6.2 Hz, 2H), 3.72 (t, J = 8.2 Hz, 2H) 3.50 (t, J = 8.2 Hz, 2H), 3.23-3.35 (m, 1H), 2.81 (t, J = 7.3 Hz, 2H), 2.01- 2.15 (m, 2H).

Example 7-8: 1 - [(6 - {[(2S) -3- (2,4-difluorophenyl) -2-methylpropyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

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

[α] _D ²⁵ : + 30.6 ° (c 0.10; chloroform-ethanol, 1: 1).

¹ H-NMR (CDCl ₃ + CD ₃ OD): δ 7.26 (d, J = 8.50 Hz, 1H), 7.09-7.18 (m, 1H), 6.75-6.83 (m, 2H), 6.73 (dd, J = 8.50, 2.50 Hz, 1H), 6.68 (d, J = 2.50 Hz, 1H), 4.31 (dd, J = 10.00, 5.00 Hz, 2H), 4.00 (t, J = 10.00 Hz, 2H), 3.94 (s, 2H), 3.80 (d, J = 6.00 Hz, 2H), 3.20-3.32 (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), 2.20-2.35 (m, 3H), 2.18 (s, 3H), 1.02 (d, J = 6 , 50 Hz, 3H).

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

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

[α] _D ²⁵ : + 64.1 ° (c 0.10; chloroform-ethanol, 1: 1).

¹ H-NMR (CDCl ₃ + CD ₃ OD): δ 7.26 (d, J = 8.50 Hz, 1H), 7.03-7.15 (m, 3H), 6.72 (dd, J = 8.50, 2.50 Hz, 1H), 6.67 (d, J = 2.50 Hz, 1H), 4.25-4.35 (m, 2H), 3.99 (t, J = 10.00 Hz, 2H), 3.93 (s, 2H), 3.80 (d, J = 6.00 Hz, 2H), 3.22-3.32 (m, 1H), 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 21-2.36 (m, 3H), 2.18 (s, 3H), 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 -azetidine carboxylic acid

Melting point: 148.6-148.9 ° C.

[α] _D ²⁵ : + 43.2 ° (c 0.50, ethanol).

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

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.66-6.78 (m, 2H), 4.12-4.28 (m, 4H), 4.10 (s, 2H), 3.78 (d, J = 5.9 Hz, 2H), 3.33-3.50 (m, 1H), 2.84 (dd, J = 13.5, 6.5 Hz, 1H), 2.65-2.77 (m, 2H), 2.55 (dd, J = 13.5, 7.8 Hz, 1H), 2.12-2.31 (m, 6H), 1.00 (d, J = 6.8 Hz, 3H).

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

Azetidine-3-carboxylic acid (46 mg) and sodium hydroxide (18 mg) were dissolved in methanol (4 ml). Trimethoxymethane (0.050 ml) and a mixed solution of 6- [3- (4-chlorophenyl) propoxy] -3,4-dihydronaphthalene-2-carboaldehyde (100 mg) in tetrahydrofuran (1 ml) and methanol (1 ml) were successively added to the resulting solution. ) upon cooling with ice. The reaction mixture was stirred for 3.5 hours under ice cooling. Sodium borohydride (17 mg) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred under ice cooling for 20 minutes. Then, 4 mol / L hydrochloride / ethyl acetate solution was added to the reaction mixture until neutral and concentrated. The resulting residue was purified by flash column chromatography on silica gel (chloroform: methanol: aqueous ammonia = 80: 10: 1 to 80: 20: 4), to thereby give the title compound (79 mg) having the following physical properties.

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

¹ H-NMR (CD ₃ OD): δ 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), 4.11-4.25 (m, 4H), 3.94 (t, J = 6.00 Hz, 2H), 3.89 (s, 2H), 3.35-3.48 (m, 1H), 2.73-2.86 (m, 4H), 2.22-2 30 (m, 2H); 1.98-2.10 (m, 2H).

Examples 8-1 to 8-5

The method of Example 8 was performed using the appropriate aldehyde instead of 6- [3- (4-chlorophenyl) propoxy] -1-methyl-3,4-dihydronaphthalene-2-carboaldehyde. If necessary, the reaction product was converted to the corresponding salt, to thereby give the title compounds having the following physical properties.

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

(free form)

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

¹ H-NMR (CD ₃ OD): 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), 4.09-4 22 (m, 4H), 4.06 (s, 2H), 3.95-4.02 (m, 2H), 3.34-3.45 (m, 1H), 2.63-2.76 (m, 4H), 2.18-2.28 (m, 5H), 1.74-1.81 (m, 4H).

(hydrochloride)

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

¹ H-NMR (CD ₃ OD): δ 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 (dd, J = 8.50, 2.50 Hz, 1H), 6.71 (d, J = 2.50 Hz, 1H), 4.19-4 45 (m, 4H), 4.16 (s, 2H), 3.95-4.02 (m, 2H), 3.64-3.78 (m, 1H), 2.62-2.76 (m, 4H), 2.19-2.28 (m, 5H), 1.74-1.81 (m, 4H).

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

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

¹ H-NMR (CD ₃ OD): δ 7.35 (d, J = 8.42 Hz, 1H), 7.16-7.22 (m, 2H), 7.07-7.11 (m, 2H), 6.74-6.82 (m, 2H), 4.19-4.49 (m, 4H), 4.17 (s, 2H), 3.63-3.79 (m, 1H) 3.53 (s, 2H), 2.71 (s, 2H), 2.68-2.79 (m, 2H), 2.23 (s, 3H), 2.18-2.31 (m , 2H); 1.01 (s, 6H).

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

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

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.60 Hz, 1H), 7.14-7.24 (m, 4H), 6.71 (dd, J = 8, 60, 2.40 Hz, 1H), 6.67 (d, J = 2.40 Hz, 1H), 4.18-4.43 (m, 4H), 4.16 (s, 2H), 3, 66-3.78 (m, 1H), 3.61 (s, 2H), 2.78 (s, 2H), 2.67-2.76 (m, 2H), 2.21 (s, 3H) 2.17-2.30 (m, 2H); 0.54-0.69 (m, 4H).

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

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

¹ H-NMR (CD ₃ OD): 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), 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), 4.16 (s, 2H), 3.65-3.78 (m, 1H), 2.72-2.78 (m, 2H), 2.21-2.29 (m, 5H).

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

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

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.50 Hz, 1H), 7.19 (dd, J = 8.50, 5.50 Hz, 2H), 6.96 (t, J = 8.50 Hz, 2H), 6.75 (dd, J = 8.50, 2.50 Hz, 1H), 6.71 (d, J = 2.50 Hz, 1H), 4 , 20-4.45 (m, 4H), 4.15 (s, 2H), 3.95-4.02 (m, 2H), 3.63-3.78 (m, 1H), 2.62 -2.77 (m, 4H), 2.18-2.30 (m, 5H), 1.72-1.82 (m, 4H).

Example 9: tert-butyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-1 (2H) -pyridinecarboxylate

Using tert-butyl-4-oxopiperidin-1-carboxylate, 1,1,1-trifluoro-N-phenyl-N - [(trifluoromethyl) sulfonyl] methanesulfonamide and 4.4,4 ', 4', 5.5.5 ', 5'-octamethyl-2,2'-bi-1,3,2-dioxaborane, a similar procedure was performed as described in Tetrahedron Letters, 2000, 41, 3705-3708, whereby the title compound was obtained having following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 6.25-6.70 (m, 1H), 3.86-4.02 (m, 2H), 3.44 (t, J = 5.58 Hz, 2H ), 2.12-2.34 (m, 2H), 1.42-1.49 (m, 9H), 1.26 (s, 12H).

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

To a solution of 1-bromo-2-methyl-4- (3-phenylpropoxy) benzene (641 mg) in anhydrous N, N-dimethylformamide (10 ml) was sequentially added the 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. A saturated aqueous solution of ammonium chloride (20 ml) and tert-butyl methyl ether (30 ml) were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography (hexane: ethyl acetate = 20: 1 to 1: 1), to thereby give the title compound (180 mg) having the following physical properties.

TLC: Rf 0.50 (hexane: ethyl acetate = 5: 1).

¹ H-NMR (CDCl ₃ ): δ 7.24-7.38 (m, 2H), 7.15-7.25 (m, 3H), 6.98 (d, J = 8.23 Hz, 1H ), 6.72 (d, J = 2.56 Hz, 1H), 6.68 (dd, J = 8.23, 2.56 Hz, 1H), 5.41-5.60 (m, 1H) 3.98-4.06 (m, 2H), 3.95 (t, J = 6.31 Hz, 2H), 3.60 (t, J = 5.67 Hz, 2H), 2.74- 2.87 (m, 2H), 2.27-2.39 (m, 2H), 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-tetrahydropyridining hydrochloride

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

TLC: Rf 0.28 (chloroform: methanol: aqueous ammonia = 8: 1: 0.1).

¹ H-NMR (CD ₃ OD): δ 7.08-7.32 (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 = 6.31 Hz, 2H), 3.72-3.84 (m, 2H), 3.34-3.49 (m, 2H), 2.73-2.83 (m, 2H), 2.46-2, 64 (m, 2H), 2.27 (s, 3H), 1.96-2.13 (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), tert-butyl acrylate (0.13 ml) and N, N-diisopropylethylamine (0.105 ml) were successively added at room temperature. The reaction mixture was stirred at room temperature for 20 hours. The mixture was concentrated. The resulting residue was purified by flash column chromatography (hexane: ethyl acetate: triethylamine = 20: 1: 0 to 67: 33: 1) to give the title compound (116 mg) having the following physical properties.

TLC: Rf 0.78 (hexane: ethyl acetate: triethylamine = 1: 1: 0.5).

¹ H-NMR (CDCl ₃ ): δ 7.24-7.34 (m, 2H), 7.13-7.24 (m, 3H), 7.00 (d, J = 8.23 Hz, 1H ), 6.69-6.73 (m, 1H), 6.63-6.69 (m, 1H), 5.44-5.54 (m, 1H), 3.94 (t, J = 6 , 31 Hz, 2H), 3.08-3.17 (m, 2H), 2.74-2.85 (m, 4H), 2.69 (t, J = 5.58 Hz, 2H), 2 50 (t, J = 7.50 Hz, 2H), 2.29-2.41 (m, 2H), 2.26 (s, 3H), 2.04-2.15 (m, 2H), 1.46 (s, 9H).

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

Trifluoroacetic 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 freeze dried to give the title compound (100 mg) having the following physical properties.

TLC: Rf 0.44 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4).

¹ H-NMR (d ₆ -DMSO): δ 7.11-7.36 (m, 5H), 7.01 (d, J = 8.23 Hz, 1H), 6.75-6.78 (m , 1H), 6.70-6.75 (m, 1H), 5.48-5.56 (m, 1H), 3.98 (t, J = 6.31 Hz, 2H), 3.81- 3.90 (m, 2H), 3.40-3.52 (m, 4H), 2.82 (t, J = 7.32 Hz, 2H), 2.71-2.78 (m, 2H) 2.52-2.63 (m, 2H); 2.25 (s, 3H); 1.95-2.11 (m, 2H).

Examples 13-1 to 13-4

The method of Examples 12-13 was performed using the corresponding amine compound instead of the compound obtained in Example 11. Thus, a compound having the following physical properties was obtained.

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

TLC: Rf 0.44 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4).

¹ H-NMR (d ₆ -DMSO): δ 7.11-7.35 (m, 6H), 7.00-7.08 (m, 1H), 6.95-6.99 (m, 1H) 6.83-6.93 (m, 1H), 6.07-6.17 (m, 1H), 4.03 (t, J = 6.40 Hz, 2H), 3.84-3.95 (m, 2H), 3.36-3.53 (m, 4H), 2.69-2.87 (m, 6H), 1.98-2.13 (m, 2H).

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

TLC: Rf 0.44 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4).

¹ H-NMR (d ₆ -DMSO): δ 8.24 (d, J = 2.56 Hz, 1H), 7.80 (dd, J = 8.69, 2.56 Hz, 1H), 7, 11-7.34 (m, 5H), 6.80 (d, J = 8.69 Hz, 1H), 6.04-6.15 (m, 1H), 4.31 (t, J = 6, 59 Hz, 2H), 3.87-3.98 (m, 2H), 3.47-3.54 (m, 2H), 3.44 (t, J = 7.32 Hz, 2H), 2, 61-2.88 (m, 6H); 1.98-2.13 (m, 2H).

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

TLC: Rf 0.44 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4).

¹ H-NMR (d ₆ -DMSO): δ 7.79 (s, 1H), 7.59 (s, 1H), 7.20-7.32 (m, 2H), 7.08-7.20 (m, 3H), 5.83-5.94 (m, 1H), 4.10 (t, J = 6.86 Hz, 2H), 3.78-3.89 (m, 2H), 3, 36-3.54 (m, 4H), 2.79 (t, J = 7.32 Hz, 2H), 2.54-2.70 (m, 4H), 1.72-1.89 (m, 2H), 1.50-1.66 (m, 2H).

Example 13-4: 3- [6- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -3,4-dihydro-2 (1H) -isoquinolinyl] propanoic acid trifluoroacetate

TLC: Rf 0.19 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4).

¹ H-NMR (CD ₃ OD): δ 8.12 (d, J = 8.23 Hz, 2H), 8.00-8.10 (m, 2H), 7.35-7.50 (m, 3H), 4.58 (s, 2H), 3.65-3.77 (m, 2H), 3.60 (t, J = 6.86 Hz, 2H), 3.29-3.39 (m , 2H), 2.94 (t, J = 6.86 Hz, 2H), 2.61 (d, J = 6.95 Hz, 2H), 1.84-2.06 (m, 1H), 0 95 (d, J = 6.59 Hz, 6H).

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

A 37% aqueous formalin solution (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 ice-cooling. The reaction solution was stirred for 2 hours and phosphate buffer (pH 6.8) (1.0 ml) was added. 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, receiving the title compound (300 mg) having the following properties.

TLC: Rf 0.64 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4).

¹ H-NMR (d ₆ -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), 6.67 (dd, J = 8.42, 2.38 Hz, 1H), 5.08 (s, 2H), 3.66 (s, 2H), 3.33-3.40 (m, 1H), 2.79-2.93 (m, 2H); 2.57-2.70 (m, 2H).

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

The method of Example 12 was carried out using the compound obtained in Example 14 instead of the compound obtained in Example 11. The obtained compound was protected using di-tert-butyl dicarbonate, to thereby give the title compound having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.80-7.86 (m, 1H), 7.43-7.50 (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), 2.64-2.74 (m, 2H), 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-9H-β-carboline-9-carboxylate

ASCA-II catalyst (4.5% palladium-0.5% platinum on charcoal) (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. The above atmosphere was replaced by an atmosphere of gaseous argon. The mixture was filtered through celite (trade name) and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), to thereby give the title compound (203 mg) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.54-7.68 (m, 1H), 7.20 (d, J = 8.42 Hz, 1H), 6.76 (dd, J = 8.42 , 2.29 Hz, 1H), 4.54-5.36 (m, 1H), 3.90 (s, 2H), 2.87-3.03 (m, 2H), 2.77-2, 88 (m, 2H), 2.60-2.77 (m, 2H), 2.45-2.58 (m, 2H), 1.66 (s, 9H), 1.45 (s, 9H) .

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

To a solution of the compound (112 mg) obtained in Example 16 in anhydrous tetrahydrofuran (2.0 ml), 3-phenylpropan-1-ol (0.074 ml), 1,1'-azobis (N, N'-dimethylformamide) was successively added. (93 mg) and triphenylphosphine (141 mg) in an atmosphere of gaseous argon. The reaction solution was stirred at room temperature for 48 hours. Tert-butyl methyl ether (3 ml) was added to the reaction solution, the resulting insoluble matter was filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), to thereby give the title compound (84 mg) having the following physical properties.

TLC: Rf 0.71 (hexane: ethyl acetate = 1: 1).

¹ H-NMR (CDCl ₃ ): δ 7.66-7.76 (m, 1H), 7.15-7.35 (m, 6H), 6.86 (dd, J = 8.42, 2, 20 Hz, 1H), 4.02 (t, J = 6.31 Hz, 2H), 3.91 (s, 2H), 2.93 (t, J = 7.50 Hz, 2H), 2.78 -2.89 (m, 4H), 2.64-2.75 (m, 2H), 2.54 (t, J = 7.50 Hz, 2H), 2.05-2.20 (m, 2H) ), 1.65 (s, 9H), 1.45 (s, 9H).

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

The method of Example 13 was performed using the compound obtained in Example 17 instead of the compound obtained in Example 12. Thus, a compound having the following physical properties was obtained.

TLC: Rf 0.12 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4).

¹ H-NMR (CD ₃ OD): δ 7.34 (d, J = 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 (s, 2H), 3.97 (t, J = 6.22 Hz, 2H) 3.67-3.78 (m, 2H), 3.63 (t, J = 6.95 Hz, 2H), 3.03-3.19 (m, 2H), 2.94 (t, J = 6.95 Hz, 2H), 2.75-2.87 (m, 2H), 2.00-2.16 (m, 2H).

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

The method of Examples 17 and 18 was performed using 3- (4-chlorophenyl) propan-1-ol instead of 3-phenylpropan-1-ol. If necessary, the reaction products were converted to hydrochloride, thereby obtaining the title compound having the following physical properties.

(trifluoroacetate)

TAC: Rf 0.11 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4).

¹ H-NMR (CD ₃ OD): δ 7.35 (d, J = 8.60 Hz, 1H), 7.25 (d, J = 8.79 Hz, 2H), 7.19 (d, J = 8.79 Hz, 2H), 6.85 (d, J = 2.01 Hz, 1H), 6.74 (dd, J = 8.60, 2.01 Hz, 1H), 4.53 (s , 2H), 3.96 (t, J = 6.13 Hz, 2H), 3.67-3.80 (m, 2H), 3.63 (t, J = 6.95 Hz, 2H), 3 02-3.16 (m, 2H), 2.94 (t, J = 6.95 Hz, 2H), 2.74-2.86 (m, 2H), 1.98-2.19 (m , 2H).

(hydrochloride)

TLC: Rf 0.11 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4).

¹ H-NMR (CD ₃ OD): 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 (dd, J = 8.78, 2.20 Hz, 1H), 4.40-4 65 (m, 2H), 3.96 (t, J = 6.13 Hz, 2H), 3.57-3.78 (m, 4H), 3.05-3.16 (m, 2H), 2.94 (t, J = 7.04 Hz, 2H); 2.75-2.86 (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

The method of Examples 14, 12 and 13 was performed using {2- [5- (3-phenylpropoxy) -1H-indol-3-yl] ethyl} amine instead of {2- [6- (benzyloxy) -1H-indol-3 -yl] ethyl} amine. The reaction product was purified by silica gel chromatography, to thereby give the title compound having the following physical properties.

TLC: Rf 0.16 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4).

¹ H-NMR (CD ₃ OD): δ 6.99-7.28 (m, 6H), 6.83 (d, J = 2.29 Hz, 1H), 6.72 (dd, J = 8, 69, 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 (t, J = 6.04 Hz, 2H), 2.67-2.77 (m, 2H), 2.57 ( t, J = 6.77 Hz, 2H), 1.90-2.06 (m, 2H).

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

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, to thereby give the title compound having the following physical properties. The resulting compound was used in the following reaction without further purification.

TLC: Rf 0.21 (chloroform: methanol: aqueous ammonia = 8: 1: 0.1).

¹ H-NMR (CDCl ₃ ): δ 7.61 (d, J = 8.10 Hz, 2H), 7.37 (d, J = 8.10 Hz, 2H), 4.61 (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 was added 4-isobutylbenzoic acid (6.7 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (7.28 g) and 1-hydroxybenzotriazole monohydrate (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. Water (50 ml) was added to the reaction mixture and extracted with a solution from a mixture of ethyl acetate and hexane (10: 1). The extract was washed successively with 0.5 mol / L hydrochloric acid, saturated sodium bicarbonate and water. The reaction product was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane - hexane: ethyl acetate = 1: 1), to thereby give the title compound (4.14 g) having the following physical properties.

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

¹ H-NMR (CD ₃ OD): δ 8.13 (d, J = 8.60 Hz, 2H), 8.11 (d, J = 8.42 Hz, 2H), 7.53 (d, J = 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 oxalyl chloride (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 the compound (2.14 g) obtained in Example 21 and N, N-diisopropylethylamine (14.6 ml) were added at -78 ° C. The reaction 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 washed successively with a 0.5 mol / L potassium hydrogen sulfate solution, 1 mol / L hydrochloric acid, saturated sodium bicarbonate solution and water. The reaction product was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), to thereby give the title compound (1.4 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 10.11 (s, 1H), 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 = 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 sodium triacetoxyborohydride (138 mg). The reaction mixture was stirred for 18 hours. The mixture was concentrated. The resulting residue was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate and water. The reaction product was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 160: 10: 1), to thereby give the title compound (75 mg) having the following physical properties.

TLC: Rf 0.48 (chloroform: methanol: aqueous ammonia = 8: 1: 0.1).

¹ H-NMR (CD ₃ OD): δ 8.12-8.16 (m, 4H), 7.58 (d, J = 8.23 Hz, 2H), 7.41 (d, J = 8, 23 Hz, 2H), 4.02 (s, 2H), 3.73 (t, J = 5.50 Hz, 2H), 2.88 (t, J = 5.50 Hz, 2H), 2.60 (d, J = 7.32 Hz, 2H), 1.91-2.04 (m, 1H), 0.94 (d, J = 6.59 Hz, 6H).

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

The method of Examples 12-22 was performed using piperidin-3-ol instead of the compound obtained in Example 11. Thus, a compound having the following physical properties was obtained.

TLC: Rf 0.71 (chloroform: methanol: aqueous ammonia = 8: 1: 0.1).

¹ H-NMR (CDCl ₃ ): δ 3.02 (s, 2H), 2.73 (t, J = 7.14 Hz, 2H), 2.64-2.70 (m, 2H), 2, 40 (t, J = 7.14 Hz, 2H), 2.35 (t, J = 6.77 Hz, 2H), 1.87-2.01 (m, 2H), 1.44 (s, 9H )

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

Sodium hydride (60% dispersion in oil, 800 mg) was added at room temperature to dimethyl sulfoxide (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. Of the total solution obtained, 1.3 ml was added at room temperature to a solution of triphenyl [4- (4-phenylbutyl) benzyl] phosphonium bromide salt (830 mg) in dimethyl sulfoxide (2.0 ml). The reaction mixture was stirred at room temperature for 30 minutes, and a solution of the compound (830 mg) obtained in Example 24 in dimethyl sulfoxide (2.0 ml) was added. The reaction mixture was stirred at 50 ° C for 18 hours. Water (10 ml) was added to the resulting mixture, and extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), to thereby give the title compound (112 mg) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.16-7.35 (m, 5H), 7.04-7.16 (m, 2H), 6.84 (d, J = 7.87 Hz, 2H ), 6.24-6.34 (m, 1H), 3.89-4.03 (m, 2H), 2.98-3.21 (m, 2H), 2.76-2.89 (m , 2H), 2.60-2.75 (m, 2H), 2.51-2.62 (m, 2H), 2.44-2.52 (m, 1H), 2.31-2.44 (m, 2H), 2.20-2.31 (m, 1H), 2.03-2.16 (m, 2H), 1.66-1.82 (m, 1H), 1.51-1 67 (m, 1H); 1.36-1.49 (m, 9H).

Examples 26-1 to 26-16

The method of Example 6 was carried out using the corresponding aldehyde instead of the compound obtained in Example 5. Thus, a compound having the following physical properties was obtained.

Example 26-1: methyl-1 - [(6 - {[(2E) -3- (4-fluorophenyl) -2-methylpropan-2-enyl] oxy} -1-methyl-3,4-dihydronaphthalene-2- il) methyl] azetidine-3-carboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.17-7.30 (m, 3H), 6.98-7.07 (m, 2H), 6.74-6.82 (m, 2H), 6 58 (s, 1H), 4.55 (s, 2H), 3.71 (s, 3H), 3.50-3.61 (m, 2H), 3.25-3.41 (m, 5H ), 2.64-2.74 (m, 2H), 2.22-2.32 (m, 2H), 2.09 (s, 3H), 1.94 (d, J = 1.46 Hz, 3H).

Example 26-2: methyl-1 - [(6 - {[(2S) -2- (4-fluorobenzyl) butyl] oxy} -1-methyl-3,4-dihydronaphthalen-2-yl) methyl] azetidin-3 carboxylate

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

¹ H-NMR (CDCl ₃ ): 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), 3.88-4.05 (m, 2H), 3.78 (d, J = 4.94 Hz, 2H), 3.74 (s, 3H), 3.52-3.62 (m, 5H), 2.64 - 2.80 (m, 4H), 2.26-2.36 (m, 2H), 2.13 (s, 3H) 1.89-2.01 (m, 1H); 1.39-1.56 (m, 2H); 0.97 (t, J = 7.20 Hz, 3H).

Example 26-3: methyl-1 - [(6 - {[(2R) -2- (4-fluorobenzyl) -3-methylbutyl] oxy} -1-methyl-3,4-dihydronaphthalen-2-yl) methyl] azetidine 3-carboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.07-7.21 (m, 3H), 6.80-7.02 (m, 2H), 6.49-6.72 (m, 2H), 3 80 (d, J = 5.12 Hz, 2H), 3.71 (s, 3H), 3.58-3.68 (m, 2H), 3.22-3.49 (m, 5H), 2.57-2.83 (m, 4H), 2.18-2.34 (m, 2H), 2.08 (s, 3H), 1.79-1.99 (m, 2H), 0, 97-1.03 (m, 6H).

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

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

¹ H-NMR (CDCl ₃ ): δ 10.33 (s, 1H), 7.79 (d, J = 8.78 Hz, 1H), 7.06-7.17 (m, 2H), 6, 89-7.04 (m, 2H), 6.80 (dd, J = 8.78, 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), 2.47-2.68 (m, 3H), 2.10-2.32 (m, 1H ), 1.03 (d, J = 6.77 Hz, 3H).

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

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

¹ H-NMR (CDCl ₃ ): δ 7.08-7.18 (m, 2H), 6.89-7.02 (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 (s, 2H), 3.56 (t, J = 6.2 Hz, 2H), 3.23-3.43 (m, 3H), 3.13 (s, 2H), 2.86 (dd, J = 13.4, 6.0 Hz, 1H), 2.52 (dd, J = 13.4, 7.7 Hz, 1H), 2.07-2.26 (m, 4H), 1.22 (s, 6H), 1.00 (d, J = 6.8 Hz, 3H).

Example 26-6: methyl-1 - ({6- [3- (4-fluorophenyl) propoxy] -1-benzothien-2-yl} methyl) azetidine-3-carboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.56 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.16 (dd, J = 8.6, 5.5 Hz, 2H), 6.88-7.06 (m, 4H), 3.99 (t, J = 6.2 Hz, 2H), 3.83 (s, 2H), 3.71 (s, 3H), 3.55-3.67 (m, 2H), 3.29-3.45 (m, 3H), 2.80 (t, J = 7.3 Hz, 2H) 2.02-2.18 (m, 2H).

Example 26-7: methyl-1 - {[1-chloro-6- (3-cyclohexylpropoxy) -3,4-dihydronaphthalen-2-yl] methyl} azetidine-3-carboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.51 (d, J = 8.6 Hz, 1H), 6.74 (dd, J = 8.6, 2.7 Hz, 1H), 6.67 ( d, J = 2.7 Hz, 1H), 3.95 (t, J = 6.7 Hz, 2H), 3.71 (s, 3H), 3.57 (t, J = 7.0 Hz, 2H), 3.27-3.49 (m, 5H), 2.76 (t, J = 7.1 Hz, 2H), 2.43 (t, J = 7.1 Hz, 2H), 1, 60-1.88 (m, 7H), 1.09-1.39 (m, 6H), 0.82-1.01 (m, 2H).

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

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

¹ H-NMR (CDCl ₃ ): 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 (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), 3.56 (t, J = 6.5 Hz, 2H), 3.28-3.47 (m, 5H), 2, 70-2.83 (m, 4H), 2.43 (t, J = 8.4 Hz, 2H), 2.00-2.13 (m, 2H).

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

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

¹ H-NMR (CDCl ₃ ): δ 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), 3.57 (t, J = 7.2 Hz, 2H), 3.28-3.49 (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), 2.13-2.28 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H).

Example 26-10: methyl-1 - ({6- [2- (4-fluorophenoxy) ethoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylate

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

¹ H-NMR (CDCl ₃ ): 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), 3.25-3.40 (m, 5H), 2.62-2.73 (m, 2H); 2.22-2.31 (m, 2H); 2.09 (s, 3H).

Example 26-11: methyl-1 - ({6- [2- (4-fluorophenoxy) propoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.19 (d, J = 8.42 Hz, 1H), 6.87-7.01 (m, 4H), 6.67-6.75 (m, 2H ), 4.56-4.69 (m, 1H), 4.14 (dd, J = 9.79, 5.67 Hz, 1H), 3.99 (dd, J = 9.79, 5.03 Hz, 1H), 3.70 (s, 3H), 3.49-3.59 (m, 2H), 3.24-3.40 (m, 5H), 2.62-2.72 (m, 2H), 2.21-2.31 (m, 2H), 2.08 (s, 3H), 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-dihydronaphthalen-2-yl} methyl) azetidine- 3-carboxylate

TLC: Rf 0.12 (hexane: ethyl acetate = 1: 2).

¹ H-NMR (CDCl ₃ ): 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- 3.57 (m, 2H), 3.25-3.37 (m, 5H), 2.64 -2.71 (m, 2H), 2.39 (dd, J = 7.00, 1.00 Hz, 2H), 2.22-2.30 (m, 2H), 2.08 (s, 3H), 1.91-2.03 (m, 1H), 0.93 (d, J = 6, 50 Hz, 6H).

Example 26-13: methyl-1 - ({6- [3- (4-methoxyphenyl) propoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.18 (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), 3.50-3.58 (m, 2H), 3.22-3.40 (m, 6H), 2.75 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.3 Hz, 2H), 2.26 (t, J = 7.5 Hz, 2H), 1.99-2.13 (m, 5H).

Example 26-14: methyl-1 - ({6- [3- (4-fluorophenoxy) propoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.19 (d, J = 8.42 Hz, 1H), 6.91-7.00 (m, 2H), 6.80-6.87 (m, 2H ), 6.73 (dd, J = 8.42, 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), 3.24-3.41 (m, 5H), 2.62-2.71 (m, 2H), 2 18-2.31 (m, 4H); 2.08 (s, 3H).

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

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

¹ H-NMR (CDCl ₃ ): δ 7.08-7.19 (m, 3H), 6.89-6.98 (m, 2H), 6.61-6.71 (m, 2H), 3 87 (dd, J = 5.67, 2.20 Hz, 2H), 3.70 (s, 3H), 3.59-3.68 (m, 2H), 3.50-3.58 (m , 2H), 3.27 (s, 5H), 2.73 (d, J = 7.68 Hz, 2H), 2.62-2.70 (m, 2H), 2.11-2.30 ( m, 3H), 2.08 (s, 3H), 0.89 (s, 9H), 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 0.18 (hexane: ethyl acetate = 1: 3).

¹ H-NMR (CDCl ₃ ): 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), 6.82 (d, J = 9.00 Hz, 2H), 5.63 (tq, J = 7.00, 1.00 Hz, 1H), 3.75 (d, J = 6.00 Hz, 2H), 3.72 (s, 3H), 3.54 -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) 2.15-2.26 (m, 1H); 2.04 (d, J = 1.00 Hz, 3H); 1.00 (d, J = 7.00 Hz; 3H).

Examples 27-1 to 27-16

The method of Example 7 was performed using the compounds obtained in Examples 26-1 to 26-16, instead of the compound obtained in Example 6. Thus, compounds having the following physical properties were obtained.

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

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

¹ H-NMR (CDCl ₃ ): δ 7.13-7.24 (m, 3H), 6.88-6.98 (m, 2H), 6.74 (dd, J = 8.40, 2, 54 Hz, 1H), 6.68 (d, J = 2.54 Hz, 1H), 6.50 (s, 1H), 4.49 (s, 2H), 4.10-4.21 (m, 2 H), 3.95-4.07 (m, 2H), 3.92 (s, 2H), 3.16-3.30 (m, 1H), 2.62-2.71 (m, 2H ), 2.15-2.25 (m, 2H), 2.12 (s, 3H), 1.86 (d, J = 1.10 Hz, 3H).

Example 27-2: 1 - [(6 - {[(2S) -2- (4-fluorobenzyl) butyl] oxyl} -1-methyl-3,4-dihydronaphthalen-2-yl) methyl] azetidine-3-carboxylic acid

TLC: Rf 0.13 (1-butanol: acetic acid: water = 20: 4: 1).

¹ H-NMR (CD ₃ OD): δ 7.29 (d, J = 8.60 Hz, 1H), 7.10-7.19 (m, 2H), 6.90-7.01 (m, 2H), 6.72 (dd, J = 8.60, 2.56 Hz, 1H), 6.67 (d, J = 2.56 Hz, 1H), 4.09-4.25 (m, 4H ), 4.06 (s, 2H), 3.80 (d, J = 5.12 Hz, 2H), 3.34-3.48 (m, 1H), 2.64-2.78 (m, 4H), 2.20 (s, 3H), 2.15-2.32 (m, 2H), 1.83-2.03 (m, 1H), 1.37-1.58 (m, 2H) 0.98 (t, J = 7.50 Hz, 3H).

Example 27-3: 1 - [(6 - {[(2R) -2- (4-fluorobenzyl) -3-methylbutyl] oxy} -1-methyl-3,4-dihydronaphthalen-2-yl) methyl] azetidine- 3-carboxylic acid

TLC: Rf 0.13 (1-butanol: acetic acid: water = 20: 4: 1).

¹ H-NMR (CD ₃ OD): δ 7.28 (d, J = 8.42 Hz, 1H), 7.11-7.22 (m, 2H), 6.88-7.03 (m, 2H), 6.68 (dd, J = 8.42, 2.56 Hz, 1H), 6.62 (d, J = 2.56 Hz, 1H), 4.08-4.23 (m, 4H ), 4.06 (s, 2H), 3.78-3.89 (m, 2H), 3.30-3.48 (m, 1H), 2.61-2.83 (m, 4H), 2.19 (s, 3H), 2.16-2.27 (m, 2H), 1.80-1.97 (m, 2H), 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-fluorophenyl) -2-methylpropyl] oxy} -3,4-dihydronaphthalen-2-yl) methyl] azetidine- 3-carboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.55 (d, J = 8.60 Hz, 1H), 7.10-7.25 (m, 2H), 6.90-7.03 (m, 2H), 6.80 (dd, J = 8.60, 2.38 Hz, 1H), 6.75 (d, J = 2.38 Hz, 1H), 4.19-4.27 (m, 4H ), 4.17 (s, 2H), 3.75-3.86 (m, 2H), 3.36-3.49 (m, 1H), 2.77-2.90 (m, 3H), 2.55 (dd, J = 13.36, 7.68 Hz, 1H), 2.40-2.50 (m, 2H), 2.09-2.27 (m, 1H), 1.01 ( d, J = 6.77 Hz, 3H).

Example 27-5: 1 - [(6 - {[(2S) -3- (4-fluorophenyl) -2-methylpropyl] oxy} -4,4-dimethyl-3,4-dihydronaphthalen-2-yl) methyl] azetidine-3-carboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.17 (dd, J = 8.4, 5.5 Hz, 2H), 7.05 (d, J = 8.2 Hz, 1H), 6.97 (t, J = 8.4 Hz, 2H), 6.84 (d, J = 2.2 Hz, 1H), 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- 3.50 (m, 1H), 2.84 (dd, J = 13.5, 6.6 Hz, 1H), 2.55 (dd, J = 13.5, 7.8 Hz, 1H), 2 08-2.27 (m, 3H), 1.23 (s, 6H), 1.00 (d, J = 6.8 Hz, 3H).

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

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

¹ H-NMR (CD ₃ OD): δ 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), 4.01 (t, J = 6.2 Hz, 2H), 3.32-3.47 (m, 1H), 2.80 (t, J = 7.5 Hz, 2H ), 2.01-2.15 (m, 2H).

Example 27-7: 1 - {[1-chloro-6- (3-cyclohexylpropoxy) -3,4-dihydronaphthalen-2-yl] methyl} azetidine-3-carboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.55 (d, J = 8.4 Hz, 1H), 6.73-6.84 (m, 2H), 4.24 (d, J = 8, 1 Hz, 4H), 4.18 (s, 2H), 3.97 (t, J = 6.5 Hz, 2H), 3.34-3.53 (m, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.45 (t, J = 7.5 Hz, 2H), 1.60-1.84 (m, 7H), 1.13-1.41 (m, 6H ), 0.83-1.02 (m, 2H).

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

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

¹ H-NMR (CD ₃ OD): δ 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 (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 72-2.88 (m, 4H); 2.40-2.51 (m, 2H); 1.96-2.17 (m, 2H).

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

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

¹ H-NMR (CD ₃ OD): δ 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, 2.6 Hz, 1H), 6.74 (d, J = 2.6 Hz, 1H), 4.17-4 23 (m, 4H), 4.14 (s, 2H), 3.81 (d, J = 5.9 Hz, 2H), 3.34-3.49 (m, 1H), 2.77- 2.89 (m, 3H), 2.55 (dd, J = 13.4, 7.9 Hz, 1H), 2.40-2.50 (m, 2H), 2.12-2.28 ( m, 1H), 1.01 (d, J = 6.8 Hz, 3H).

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

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

¹ H-NMR (CD ₃ OD): δ 7.34 (d, J = 8.60 Hz, 1H), 6.90-7.05 (m, 4H), 6.83 (dd, J = 8, 60, 2.74 Hz, 1H), 6.79 (d, J = 2.74 Hz, 1H), 4.13-4.37 (m, 8H), 4.10 (s, 2H), 3, 34-3.49 (m, 1H), 2.68-2.80 (m, 2H), 2.21 (s, 3H), 2.19-2.30 (m, 2H).

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

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

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.60 Hz, 1H), 6.91-7.03 (m, 4H), 6.78 (d, J = 8, 60, 2.74 Hz, 1H), 6.73 (d, J = 2.74 Hz, 1H), 4.61-4.75 (m, 1H), 4.00-4.30 (m, 8H ), 3.34-3.49 (m, 1H), 2.65-2.78 (m, 2H), 2.18-2.30 (m, 2H), 2.20 (s, 3H), 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-dihydronaphthalen-2-yl} methyl) azetidin-3- carboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 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), 6.82 (d, J = 2.50 Hz, 1H), 5.12 (s, 2H), 4.09-4.23 (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), 2.18-2.29 (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-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 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), 4.04-4 21 (m, 4H), 4.02 (s, 2 H), 3.94 (t, J = 6.3 Hz, 2H), 3.74 (s, 3H), 3.32-3.47 (m, 1H), 2.65-2.78 (m, 4H), 2.20-2.28 (m, 2H), 2.19 (s, 3 H), 1.95-2.08 ( m, 2H).

Example 27-14: 1 - ({6- [3- (4-fluorophenoxy) propoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.60 Hz, 1H), 6.85-7.02 (m, 4H), 6.79 (dd, J = 8, 60, 2.56 Hz, 1H), 6.74 (d, J = 2.56 Hz, 1H), 4.06-4.27 (m, 10H), 3.34-3.48 (m, 1H ), 2.65-2.76 (m, 2H), 2.20 (s, 3H), 2.14-2.29 (m, 4H).

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

TLC: Rf 0.17 (1-butanol: acetic acid: water = 20: 4: 1).

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.60 Hz, 1H), 7.15-7.24 (m, 2H), 6.91-7.04 (m, 2H), 6.74 (dd, J = 8.60, 2.38 Hz, 1H), 6.70 (d, J = 2.38 Hz, 1H), 4.09-4.26 (m, 4H ), 4.07 (s, 2H), 3.91 (d, J = 5.31 Hz, 2H), 3.63 (d, J = 5.85 Hz, 2H), 3.34-3.52 (m, 1H), 2.65-2.79 (m, 4H), 2.20 (s, 3H), 2.13-2.28 (m, 3H).

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

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

¹ H-NMR (CD ₃ OD): 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 (d, J = 8.50 Hz, 2H), 5.64 (tq, J = 7.50, 1.50 Hz, 1H), 4.10-4 26 (m, 4H), 3.98 (d, J = 7.50 Hz, 2H), 3.79 (d, J = 6.00 Hz, 2H), 3.35-3.43 (m, 1H), 2.85 (dd, J = 13.50, 6.50 Hz, 1H), 2.55 (dd, J = 13.50, 7.50 Hz, 1H), 2.13-2.25 (m, 4H), 1.01 (d, J = 7.00 Hz, 3H).

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

The method of Example 8 was performed using the appropriate aldehyde instead of 6- [3- (4-chlorophenyl) propoxy] -1-methyl-3,4-dihydronaphthalene-2-carboaldehyde. Thus, the title compound was obtained having the following physical properties.

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

¹ H-NMR (CDCl ₃ + CD ₃ OD): 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 (d, J = 9.00 Hz, 2H), 5.60-5.67 (m, 1H), 4.23 (dd, J = 10 , 00, 6.00 Hz, 2H), 4.05 (t, J = 10.00 Hz, 2H), 3.96 (t, J = 6.00 Hz, 2H), 3.85-3.91 (m, 2H), 3.24-3.33 (m, 1H), 2.79 (t, J = 7.50 Hz, 2H), 2.15 (d, J = 1.00 Hz, 3H) 2.04-2.14 (m, 2H).

Examples 29-1 to 29-5

The method of Examples 12 and 13 was performed using the corresponding amine compound instead of the compound obtained in Example 11. Thus, compounds having the following physical properties were obtained.

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

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

¹ H-NMR (CD ₃ OD): δ 7.40 (d, J = 8.97 Hz, 2H), 7.25 (d, J = 8.60 Hz, 2H), 7.19 (d, J = 8.60 Hz, 2H), 6.90 (d, J = 8.97 Hz, 2H), 5.97-6.08 (m, 1H), 3.90-4.01 (m, 4H) 3.55-3.63 (m, 2H), 3.51 (t, J = 6.59 Hz, 2H), 2.82-2.93 (m, 4H), 2.74-2.83 (m, 2H); 1.95-2.15 (m, 2H).

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

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

¹ H-NMR (CD ₃ OD): δ 7.40 (d, J = 8.97 Hz, 2H), 7.24 (d, J = 8.41 Hz, 2H), 7.15 (d, J = 8.41 Hz, 2H), 6.89 (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), 3.45-3.64 (m, 4H), 2.79-2.93 (m, 5H), 2.44-2.66 (m, 1H), 2.10-2.33 (m, 1H), 1.01 (d, J = 6.77 Hz, 3H).

Example 29-3: 3- {7 - [(5-phenylpentyl) oxy] -1,3,4,5-tetrahydro-2H-2-benzoazepin-2-yl} propanoic acid trifluoroacetate

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

¹ H-NMR (CD ₃ OD): 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, 2.56 Hz, 1H), 4.42-4.52 (m, 2H ), 3.97 (t, J = 6.40 Hz, 2H), 3.41-3.69 (m, 2H), 3.14-3.39 (m, 2H), 2.93-3, 06 (m, 2H), 2.82 (t, J = 6.95 Hz, 2H), 2.55-2.70 (m, 2H), 1.86-2.19 (m, 2H), 1 74-1.85 (m, 2H); 1.61-1.73 (m, 2H); 1.42-1.57 (m, 2H).

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

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

¹ H-NMR (CD ₃ OD): 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 (d, J = 2.01 Hz, 1H), 6.76 (dd, J = 8.42, 2.01 Hz, 1H), 4.55-4 69 (m, 2H), 4.01 (t, J = 6.13 Hz, 2H), 3.62 (s, 3H), 3.57-3.76 (m, 4H), 3.06- 3.17 (m, 2H), 2.98 (t, J = 7.14 Hz, 2H), 2.77-2.89 (m, 2H), 2.00-2.17 (m, 2H) .

Example 29-5: 3- {5 - [(5-phenylpentyl) oxy] -1,3-dihydro-2H-isoindol-2-yl} propanoic acid trifluoroacetate

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

¹ H-NMR (CD ₃ OD): 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), 3.97 (t, J = 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), 1.74-1.88 (m, 2H), 1.60-1.74 (m, 2H), 1.42-1.57 (m, 2H).

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

The method of Example 6 was carried out using 6 - {[(2S) -3- (4-chlorophenyl) -2-methylpropyl] oxy} -1-methyl-3,4-dihydronaphthalene-2-carbaldehyde instead of the compound obtained in Example 5 and methyl β-alaninate instead of methylazetidine-3-carboxylate hydrochloride. Thus, the title compound was obtained having the following physical properties.

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

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

The method of Example 7 was performed using the compound obtained in Example 30 instead of the compound obtained in Example 6. Thus, a compound having the following physical properties was obtained.

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

¹ H-NMR (CD ₃ OD): 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 (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) , 2.11-2.25 (m, 4H), 1.00 (d, J = 6.8 Hz, 3H).

Example 32: 2- (methoxymethoxy) -3-propylbenzene

Methoxymethyl chloride (8.4 ml) and potassium carbonate (30 g) were added to a solution of 3-propylphenol (10 g) in N, N-dimethylformamide (150 ml) at room temperature and stirred at 50 ° C for one day. The reaction solution was poured into a mixture of water and ice. The insoluble matter was filtered off and extracted with a mixed solvent of hexane and ethyl acetate (1: 1). The organic layer was washed successively with water and brine. The reaction product was dried over magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (from one hexane to hexane: ethyl acetate = 10: 1), to thereby give the title compound (8.0 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.18 (dd, J = 8.50, 7.50 Hz, 1H), 6.80-6.88 (m, 3H), 5.16 (s, 2H ), 3.48 (s, 3H), 2.56 (t, J = 7.50 Hz, 2H), 1.56-1.71 (m, 2H), 0.94 (t, J = 7, 50 Hz, 3H).

Example 33: 2- (methoxymethoxy) -4-propylbenzaldehyde

Tert-butyllithium (1.56 mol / ml solution in pentane, 33.9 ml) was added to a solution of the compound (7.95 g) obtained in Example 32 in hexane (100 ml) at 0 ° C and stirred for 30 minutes. Then, N, N-dimethylformamide (5.12 ml) was added dropwise. A saturated solution of ammonium chloride was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 14: 1 to 10: 1), to thereby give the title compound (4.94 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): 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), 5.30 (s, 2H), 3.53 (s, 3H), 2.62 (t, J = 7.5 Hz, 2H), 1.58-1, 75 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H).

Example 34: 2-hydroxy-4-propylbenzaldehyde

A 4 mol / L hydrochloride / 1,4-dioxane solution (50 ml) was added to a solution of the compound (4.50 g) obtained in Example 33 in 1,4-dioxane (10 ml) and stirred at room temperature for 1 hours. The reaction solution was concentrated, to thereby give the title compound (3.48 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): 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), 6.81 (s, 1H), 2.61 (t, J = 7.5 Hz, 2H), 1.58-1.74 (m, 2H), 0, 95 (t, J = 7.3 Hz, 3H).

Example 35: 2-methoxy-4-propylbenzaldehyde

Potassium carbonate (3.79 g) and methyl iodide (1.71 ml) were added to a solution of the compound (3.00 g) obtained in Example 34 in N, N-dimethylformamide (40 ml) at room temperature and stirred at 40 ° C for 2 hours. Water was added to the reaction solution and extracted with a mixed solvent of hexane and ethyl acetate (3: 1). The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the title compound (8.0 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 10.41 (s, 1H), 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 (t, J = 7.5 Hz, 2H), 1.59-1.77 (m, 2H), 0, 97 (t, J = 7.3 Hz, 3H).

Example 36: 1- (hydroxymethyl) -2-methoxy-4-propylbenzene

Sodium borohydride (958 mg) was added to a solution of the 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, water was added and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1 to 3: 1), to thereby give the title compound (2.87 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.16 (d, J = 7.5 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.71 (s, 1H) 4.65 (s, 2H), 3.87 (s, 3H), 2.58 (t, J = 7.5 Hz, 2H), 1.57-1.72 (m, 2H), 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-azetidinecarboxylic acid

The method of Examples 5, 6, and 7 was performed using 1- (bromomethyl) -2-methoxy-4-propylbenzene (which was obtained by adding phosphorus tribromide to the compound obtained in Example 36 in diethyl ether at 0 ° C. and reacting mixture at room temperature for 1 hour) instead of 1-bromo-3- (4-fluorophenyl) propane, to thereby give the title compound having the following physical properties.

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 6.73-6.86 (m, 4H), 5.04 (s, 2H), 4.12-4.29 (m, 4H), 4.10 (s, 2H), 3.84 (s, 3H), 3.34- 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); 1.57-1.74 (m, 2H); 0.94 (t, J = 7.4 Hz, 3H);

amorphous substance.

Examples 37-1 to 37-16

The method of Example 37 was carried out using the corresponding phenol compound instead of the compound obtained in Example 4 and the corresponding alcohol compound instead of the compound obtained in Example 36, whereby the title compound having the following physical properties was obtained.

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

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

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.60 Hz, 1H), 7.26 (d, J = 7.68 Hz, 1H), 6.83 (dd, J = 8.60, 2.74 Hz, 1H), 6.77-6.80 (m, 2H), 6.71-6.75 (m, 1H), 5.04 (s, 2H), 4, 11-4.27 (m, 4H), 4.09 (s, 2H), 3.84 (s, 3H), 3.34-3.48 (m, 1H), 2.67-2.77 ( m, 2H), 2.48 (d, J = 7.32 Hz, 2H), 2.20 (s, 3H), 2.18-2.28 (m, 2H), 1.81-1.95 (m, 1H), 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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 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 (dd, J = 7.50, 1.50 Hz, 1H), 6.85 (dd, J = 8.50, 2.50 Hz, 1H), 6 81 (d, J = 2.50 Hz, 1H), 5.04 (s, 2H), 4.12-4.26 (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 -2.29 (m, 5H), 1.81-1.95 (m, 1H), 0.86 (d, J = 7.00 Hz, 6H).

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

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

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 6.68-6.88 (m, 4H), 5.06 (s, 2H), 4.12-4.30 (m, 4H), 4.03-4.14 (m, 4H), 3.36-3.50 (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 78-1.96 (m, 1H), 1.38 (t, J = 7.0 Hz, 3H), 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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): 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), 6.81 (dd, J = 8.50, 2.50 Hz, 1H), 6 78 (d, J = 2.50 Hz, 1H), 5.14 (s, 2H), 4.62-4.73 (m, 1H), 4.08-4.24 (m, 4H), 4.06 (s, 2H), 3.35-3.47 (m, 1H), 2.70-2.77 (m, 2H), 2.19-2.28 (m, 5H), 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-azetidinecarboxylic acid

¹ H-NMR (CD ₃ OD): δ 7.96-8.03 (m, 3H), 7.36 (d, J = 8.50 Hz, 1H), 6.82-6.88 (m, 2H), 5.35 (s, 2H), 4.12-4.27 (m, 4H), 4.09 (s, 2H), 3.37-3.49 (m, 1H), 2.70 -2.79 (m, 2H); 2.19-2.30 (m, 5H);

amorphous substance.

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

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

¹ H-NMR (CD ₃ OD): δ 7.55 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.86 (dd, J = 8.6, 2.6 Hz, 1H), 6.80-6.84 (m, 2H), 6.76 (d, J = 7.7 Hz, 1H), 5.06 (s, 2H) 4.23 (d, J = 8.2 Hz, 4H), 4.18 (s, 2H), 3.84 (s, 3H), 3.35-3.51 (m, 1H), 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- 1.74 (m, 2H); 0.94 (t, J = 7.3 Hz, 3H);

crystalline substance.

Melting point 157.9-158.0 ° C.

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

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

¹ H-NMR (CD ₃ OD): δ 7.56 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 6.88 (dd, J = 8.6, 2.6 Hz, 1H), 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), 3 84 (s, 3H), 3.37-3.50 (m, 1H), 2.84 (t, J = 7.7 Hz, 2H), 2.41-2.52 (m, 4H), 1.80-1.97 (m, 1H); 0.91 (d, J = 6.8 Hz, 6H);

amorphous substance.

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

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

¹ H-NMR (CD ₃ OD): δ 7.53 (d, J = 8.6 Hz, 1H), 7.15-7.31 (m, 1H), 6.81-6.94 (m, 2H), 6.71-6.81 (m, 2H), 3.97-4.18 (m, 6H), 3.83 (d, J = 5.9 Hz, 2H), 3.31-3 46 (m, 1H), 2.76-2.92 (m, 3H), 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) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.59 (d, J = 8.80 Hz, 1H) 7.34 (d, J = 8.60 Hz, 1H) 7.21 (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) 4.11-4 31 (m, 4H) 4.02-4.15 (m, 4H) 3.34-3.50 (m, 1H) 2.73 (t, J = 6.80 Hz, 2H) 2.14- 2.32 (m, 5H) 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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): 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- 3.46 (m, 1H), 2.60-2.76 (m, 4H), 2.18-2.28 (m, 5H), 1.24 (t, J = 7.50 Hz, 3H) .

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

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

¹ H-NMR (CD ₃ OD): 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), 5.05 (s, 2H), 4.10-4.25 (m, 4H), 4, 07 (s, 2H), 3.85 (s, 3H), 3.35-3.46 (m, 1H), 2.70-2.77 (m, 2H), 2.56-2.63 ( m, 2H), 2.17-2.27 (m, 8H), 1.59-1.72 (m, 2H), 0.95 (t, J = 7.50 Hz, 3H).

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

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

¹ H-NMR (CD ₃ OD): δ 7.42 (d, J = 7.50 Hz, 1H), 7.33 (d, J = 8.50 Hz, 1H), 7.01-7.11 (m, 2H), 6.82 (t, J = 74.00 Hz, 1H), 6.79-6.86 (m, 2H), 5.08 (s, 2H), 4.10-4, 25 (m, 4H), 4.08 (s, 2H), 3.35-3.49 (m, 1H), 2.69-2.77 (m, 2H), 2.61 (t, J = 7.50 Hz, 2H), 2.19-2.28 (m, 5H), 1.58-1.72 (m, 2H), 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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.92-8.08 (m, 3H), 7.61 (d, J = 8.60 Hz, 1H), 6.86-6.96 (m, 2H), 5.37 (s, 2H), 4.07-4.25 (m, 6H), 3.36-3.49 (m, 1H), 2.79-2.92 (m, 2H) 2.40-2.52 (m, 2H);

crystalline substance.

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

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

¹ H-NMR (CD ₃ OD): δ 7.43 (d, J = 7.50 Hz, 1H), 7.23 (d, J = 8.50 Hz, 1H), 7.08 (d, J = 7.50 Hz, 1H), 7.02 (s, 1H), 6.85 (d, J = 8.50 Hz, 1H), 6.82 (t, J = 74.00 Hz, 1H), 5.09 (s, 2H), 4.10-4.25 (m, 4H), 4.08 (s, 2H), 3.34-3.47 (m, 1H), 2.70-2, 77 (m, 2H), 2.58-2.66 (m, 2H), 2.17-2.28 (m, 8H), 1.59-1.72 (m, 2H), 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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.58-7.64 (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), 6.81 (d, J = 2.50 Hz, 1H), 5.05 (s, 2H) 4.11-4.25 (m, 6H), 4.08 (s, 2H), 3.35-3.48 (m, 1H), 2.69-2.77 (m, 2H), 2 18-2.27 (m, 5H); 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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.62 (d, J = 7.32 Hz, 1H), 7.22 (d, J = 8.78 Hz, 1H), 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), 4.05 (s, 2H), 3.96 (s, 3H), 3.34-3.48 (m, 1H), 2.69-2.77 (m, 2H), 2.61-2.69 (m , 2H), 2.14-2.29 (m, 8H), 1.64-1.85 (m, 2H), 0.95 (t, J = 7.41 Hz, 3H);

crystalline substance.

Example 38: methylazetidine-3-carboxylate hydrochloride

Methanol (70 ml) was added dropwise to thionyl chloride (23.4 ml), stirring at 0 ° C, then azetidine-3-carboxylic acid (CAS No. 36476-78-5, 25 g) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated, to thereby give the title compound (36 g) having the following physical properties.

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

¹ H-NMR (CD ₃ OD): δ 4.18-4.33 (m, 4H), 3.72-3.81 (m, 4H).

Example 38-1: Ethylazetidine-3-carboxylate hydrochloride

The method of Example 38 was performed using ethanol instead of methanol. Thus, the title compound was obtained having the following physical properties.

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

¹ H-NMR (DMSO-d ₆ ): δ 9.19-9.59 (m, 1H), 9.01-9.26 (m, 1H), 4.13 (q, J = 7.1 Hz , 2H), 3.95-4.15 (m, 4H), 3.60-3.76 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H).

Example 39: ethyl 1-benzylazetidine-3-carboxylate

Tetraethylammonium acetate tetrahydrate (9.42 g) was added to a solution of diethyl 1-benzylazetidine-3,3-dicarboxylate (7.00 g, which was obtained by the method described in Synthetic Communications, Volume 33, No. 19, p. 3347, 2003) in 1,3 dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU, 40 ml) and stirred at 130 ° C. for 12 hours. Water was added to the reaction solution and extracted with a mixed solvent of acetate and hexane (1: 1). The organic layer was washed with water, hexane was added, and 0.5 mol / L hydrochloric acid was extracted. The aqueous layer was washed with tert-butyl methyl ether, the pH was adjusted to 8 using 5 mol / L aqueous sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the title compound (3.21 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.11-7.41 (m, 5H), 4.15 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 3, 46-3.58 (m, 2H), 3.23-3.41 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H).

Example 40: Ethylazetidine-3-carboxylate hydrochloride

A 4 N hydrochloride / dioxane solution (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. Ethanol (30 ml) and 20% palladium hydroxide on charcoal (approximately 50% humidity, 200 mg) were added to the reaction product and stirred at 70 ° C. for 7 hours in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated, to thereby give 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-propylphenol

Palladium on charcoal (5 wt.%, 54 mg) was added to a solution of eugenol (No. CAS 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, to thereby give the title compound (447 mg) having the following physical properties.

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

Example 42: 2-methoxy-4-propylphenyl trifluoromethanesulfonate

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 of −4 ° C., trifluoromethanesulfonic acid anhydride (108.6 ml) was slowly added dropwise and stirred at an internal temperature of about 0 to 10 ° C. for about 30 minutes. 0.5 mol / L hydrochloric acid (400 ml) was added to the reaction solution and extracted with toluene. The organic layer was washed successively with water and brine, dried and concentrated to give the title compound (178.7 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): 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), 2.59 (t, J = 7.60 Hz, 2H), 1.59-1.73 (m, 2H), 0.96 (t, J = 7.20 Hz, 3H).

Example 43: methyl 2-methoxy-4-propyl benzoate

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 were intensively stirred at an internal temperature of about 70 ° C in an atmosphere of carbon monoxide for about 2.5 hours. The reaction solution was cooled, diluted with tert-butyl methyl ether (20 ml), 3.5% aqueous sodium bicarbonate solution (67.5 ml), thiocyanuric acid (201 mg) and activated carbon (500 mg) were added and stirred vigorously at room temperature for about 30 minutes. The precipitate was filtered. The organic layer was washed successively with water and brine, dried and concentrated to give the title compound (3.10 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.73 (d, J = 8.00 Hz, 1H), 6.77-6.82 (m, 2H), 3.90 (s, 3H), 3, 87 (s, 3H), 2.61 (t, J = 7.50 Hz, 2H), 1.59-1.73 (m, 2H), 0.95 (t, J = 7.50 Hz, 3H )

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

A solution of aluminum red in toluene (content 66.5%, 2.05 g) was slowly added to a solution of the 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. Methanol (0.5 ml) was added to the reaction solution at an internal temperature of 9 ° C to terminate the reaction. The reaction solution was poured into a 50% aqueous solution of potassium and sodium tartrate tetrahydrate and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried and concentrated to give the title compound (0.91 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.16 (d, J = 7.50 Hz, 1H), 6.76 (dd, J = 7.50, 1.50 Hz, 1H), 6.71 ( d, J = 1.50 Hz, 1H), 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), 0.95 (t, J = 7.50 Hz, 3H).

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

Pyridine (79 ml) was added to a solution of the compound (160 g) obtained in Example 44 in dimethoxyethane (640 ml). Then, thionyl chloride (71.3 ml) was slowly added dropwise with stirring, and the mixture was stirred for 30 minutes. The reaction solution was cooled, a mixture of water and ice was added and extracted with tert-butyl methyl ether. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and brine, dried and concentrated, to thereby give the title compound (169 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.24 (d, J = 7.50 Hz, 1H), 6.76 (dd, J = 7.50, 1.50 Hz, 1H), 6.71 ( d, J = 1.50 Hz, 1H), 4.64 (s, 2H), 3.87 (s, 3H), 2.53-2.64 (m, 2H), 1.57-1.72 (m, 2H), 0.95 (t, J = 7.50 Hz, 3H).

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

Potassium phosphate (189 g) was added to a solution of the 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 water was added. The precipitate was filtered and dried. The resulting crude material (263 g) was recrystallized from a mixed solvent of ethyl acetate (520 ml) and heptane (2600 ml), to thereby give the title compound (213 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 10.30 (s, 1H), 7.46 (d, J = 8.50 Hz, 1H), 7.31 (d, J = 7.50 Hz, 1H) 6.89 (dd, J = 8.50, 2.50 Hz, 1H), 6.84 (d, J = 2.50 Hz, 1H), 6.79 (dd, J = 7.50, 1 , 50 Hz, 1H), 6.73 (d, J = 1.50 Hz, 1H), 5.10 (s, 2H), 3.86 (s, 3H), 2.68-2.76 (m , 2H), 2.56-2.63 (m, 2H), 2.47-2.54 (m, 5H), 1.58-1.73 (m, 2H), 0.96 (t, J = 7.50 Hz, 3H).

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

The method of Example 46 was performed using 2,4-bis (trifluoromethyl) benzyl chloride (CAS No. 195136-46-0) instead of the compound obtained in Example 45. Thus, the title compound was obtained having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 10.33 (s, 1H), 7.96 (s, 1H), 7.92 (d, J = 9.00 Hz, 1H), 7.85 (d, J = 9.00 Hz, 1H), 7.50 (d, J = 8.50 Hz, 1H), 6.82-6.88 (m, 2H), 5.36 (s, 2H), 2, 71-2.78 (m, 2H); 2.48-2.55 (m, 5H).

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

Triethylamine (95.5 ml) and sodium triacetoxyborohydride (145 g) were added at 0 ° C. to a solution of the compound (200 g) obtained in Example 46 in tetrahydrofuran (800 ml) and stirred for 10 minutes. To the resulting mixture was added dropwise a solution of the compound (113 g) obtained in Example 38-1 in acetonitrile (400 ml) and stirred at a temperature of 30 to 40 ° C. for 1.5 hours. An aqueous solution of sodium carbonate was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium carbonate, dried and concentrated, to thereby give the title compound (281 g) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): 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), 5.06 (s, 2H), 4.16 (q, J = 7.00 Hz, 2H), 3.85 (s, 3H), 3, 52-3.60 (m, 2H), 3.25-3.38 (m, 5H), 2.64-2.72 (m, 2H), 2.55-2.63 (m, 2H), 2.22-2.30 (m, 2H), 2.09 (s, 3H), 1.58-1.72 (m, 2H), 1.26 (t, J = 7.00 Hz, 3H) 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-azetidinecarboxylate

The method of Example 47 was performed using the compound obtained in Example 46-1 instead of the compound obtained in Example 46. Thus, the title compound was obtained having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.91-7.97 (m, 2H), 7.83 (d, J = 8.00 Hz, 1H), 7.20 (d, J = 8.50 Hz, 1H), 6.73-6.79 (m, 2H), 5.32 (s, 2H), 4.16 (q, J = 7.00 Hz, 2H), 3.51-3.61 (m, 2H), 3.23-3.37 (m, 5H), 2.65-2.73 (m, 2H), 2.22-2.33 (m, 2H), 2.09 (s , 3H), 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-azetidinecarboxylic acid

An aqueous (135 ml) sodium hydroxide solution (28 g) was added to a solution of the compound (262 g) obtained in Example 47 in methanol (1320 ml) and stirred at 40 ° C. for 2 hours. 5 mol / L hydrochloric acid (135 ml) and water (1050 ml) were added to the reaction solution, and the precipitate was filtered. The resulting precipitate was washed with a mixed solvent (470 ml) consisting of methanol and water, and dried. The resulting powder was suspended in acetone (2.0 L) and stirred at 60 ° C. for 2 hours. The reaction solution was cooled. The precipitate was filtered and washed with acetone (390 ml), to thereby give the title compound (191 g) having the following physical properties.

Melting point 158-163 ° C.

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

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.50 Hz, 1H), 7.25 (d, J = 7.50 Hz, 1H), 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 = 8.06 Hz, 2H), 2.59 (t, J = 7.50 Hz, 2H), 2.23 (m, 5H), 1.65 (m, 2H); 0.94 (t, J = 7.50 Hz, 3H);

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

X-ray powder diffraction spectrum: the measurement results are shown in table 1 and the diagram is shown in figure 1.

Table 1 The value of d (Å) Diffraction angle (2θ, °) Relative intensity (%) d = 10,48375 8,427 67.8 d = 9,48985 9,312 24.9 d = 8.47631 10,428 19.9 d = 7.47227 11,834 48.0 d = 6,99142 12,651 76,4 d = 5.85132 15,129 10.1 d = 5,27542 16,792 65.6 d = 4.98672 17,772 49.7 d = 4.84775 18,286 100.0 d = 4.72367 18,771 34.0 d = 4.60305 19,267 19.1 d = 4,45544 19,912 37.8 d = 4,19597 21,157 74.6 d = 4,12497 21,525 34.5 d = 3,99689 22,224 34.2 d = 3,91138 22,716 27,2 d = 3.79347 23,432 65.7 d = 3,71787 23,915 42.7 d = 3,50995 25,355 28,2 d = 3.37123 26,417 16,4 d = 3.29393 27,048 22.0

Differential Scanning Calorimetry (DSC, heating rate: 5 ° C / min): the presence of an endothermic peak at a temperature of about 170 ° C was confirmed. The diagram is shown in figure 2.

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

The method of Example 48 was performed using the compound obtained in Example 47-1 instead of the compound obtained in Example 47. Thus, the title compound was obtained having the following physical properties.

Melting point: 155-165 ° C.

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

¹ H-NMR (CD ₃ OD): 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), 4.13-4.29 (m, 4H), 4.09 (s, 2H), 3.33-3.49 (m, 1H), 2.68 -2.79 (m, 2H); 2.17-2.33 (m, 5H);

X-ray powder diffraction spectrum: the measurement results are shown in table 2 and the diagram is shown in figure 3.

table 2 The value of d (Å) Diffraction angle (2θ, °) Relative intensity (%) 10,47991 8,430 13.7 8.42050 10,497 11.1 7,36612 12,005 22.3 6,68490 13,233 17,2 5.68958 15,562 13.7 5,41787 16,347 64.1 5.25255 16,866 13.6 5,02870 17,622 31.6 4,83075 18,350 100.0 4,75633 18,640 43,4 4,56545 19,427 44.9 4.49335 19,742 29.9 4,37825 20,266 27.6 4,21626 21,053 29.1 4,16364 21,322 20.9 4,01449 22,124 44.6 3,93543 22,575 17.4 3,83216 23,191 34.6 3.77205 23,566 46.3 3,69712 24,051 31,4 3,58866 24,789 35.6

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

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

A mixed solvent 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 completely dissolved. Water (210 ml) was added to the resulting solution and allowed to stand at 0 ° C for 1 hour. The precipitate was filtered. The resulting precipitate was washed with a mixed solvent of methanol and water (2: 3) and dried, thereby obtaining the title compound (crystalline substance A) (2.89 g) having the following physical properties.

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

¹ H-NMR (CD ₃ OD): 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), 4.12-4.28 (m, 4H), 4.09 (s, 2H), 3.84 (s, 3H), 3.34- 3.50 (m, 1H), 2.72 (t, J = 6.8 Hz, 2H), 2.59 (t, J = 7.3 Hz, 2H), 2.16-2.30 (m 5H), 1.57-1.74 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

X-ray powder diffraction spectrum: the measurement results are shown in table 3 and the diagram is shown in figure 5.

Table 3 The value of d (Å) Diffraction angle (2θ, °) Relative intensity (%) d = 9.97990 8,854 100.0 d = 7.93331 11,144 18.9 d = 7.68139 11,511 24.0 d = 7,28869 12,133 13,4 d = 6.66106 13,281 64.6 d = 6.32713 13,986 28.7 d = 6,10808 14,490 12.0 d = 5,80013 15,264 6.1 d = 5,08879 17,413 61.6 d = 4.77069 18,584 22.7 d = 4.73380 18,730 19.6 d = 4,59884 19,285 14.2 d = 4,46361 19,875 21.8 d = 4,23432 20,963 19,2 d = 3,99706 22,223 52.3 d = 3.95885 22,440 42.5 d = 3,72944 23,840 22.2 d = 3,70683 23,988 24.2 d = 3,57303 24,900 24.0 d = 3,54316 25,113 29.1

Differential Scanning Calorimetry (DSC, heating rate: 5 ° C / min): the presence of endothermic peaks was confirmed at a temperature of about 123 ° C and about 168 ° C. The diagram is shown in Fig.6.

To the title compound (Type A crystalline substance) (500 mg) obtained in this example, a mixed solution (3.75 ml) consisting of methyl ethyl ketone and water (10: 1) was added. After the mixture was completely dissolved, the resulting solution was first left to stand at room temperature overnight and then at a low temperature (about 5 ° C) for 2 days. The resulting solid was collected by filtration, dried at 40 ° C. under reduced pressure (about 6 mm Hg) for 4 hours, to thereby give the title compound (crystalline type B) (305 mg) as a white solid, having the following physical properties.

X-ray powder diffraction spectrum: the measurement results are shown in table 4 and the diagram is shown in Fig.7.

Table 4 The value of d (Å) Diffraction angle (2θ, °) Relative intensity (%) d = 9.73547 9,076 77.1 d = 7.87100 11,233 31.7 d = 7.58344 11,660 29.3 d = 6.83790 12,936 71.2 d = 6.49668 13,619 59,4 d = 6.18156 14,317 13.9 d = 5,60660 15,794 20.6 d = 5.24141 16,902 71.3 d = 5.10255 17,366 86.8 d = 4,90216 18,081 49.1 d = 4.71929 18,788 27.4 d = 4.43114 20,022 87.8 d = 4,14036 21,444 30.5 d = 4.10430 21,635 30,2 d = 3,96738 22,391 100.0 d = 3,90770 22,738 61.3 d = 3.79457 23,425 32,7 d = 3.71500 23,934 41.6 d = 3,62279 24,553 31,4 d = 3,50981 25,356 28.3 d = 3,05410 29,218 28.8

Differential scanning calorimetry (DSC, heating rate: 5 ° C / min): the presence of endothermic peaks was confirmed at a temperature of about 115 ° C and about 167 ° C. The diagram is shown in FIG.

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

The method of Example 49 was performed using the compound obtained in Example 48-1 instead of the compound obtained in Example 48. Thus, the title compound was obtained having the following physical properties.

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

¹ H-NMR (CD ₃ OD): δ 7.91-8.03 (m, 3H), 7.35 (d, J = 8.60 Hz, 1H), 6.79-6.88 (m, 2H), 5.34 (s, 2H), 4.13-4.29 (m, 4H), 4.10 (s, 2H), 3.33-3.49 (m, 1H), 2.68 -2.78 (m, 2H); 2.17-2.33 (m, 5H);

X-ray powder diffraction spectrum: the measurement results are shown in table 5 and the diagram is shown in Fig.9.

Table 5 The value of d (Å) Diffraction angle (2θ, °) Relative intensity (%) 11,56944 7,635 76,2 7,75051 11,407 38,0 7.43156 11,899 59.1 6.95904 12,710 49.7 6,69471 13,214 20.1 6,49820 13,615 38.1 6,04854 14,633 14.3 5,80619 15,247 25.5 5.28185 16,771 36.8 5,13914 17,241 50.6 4,89009 18,126 20.7 4,66002 19,029 100.0 4.44685 19,950 75.8 4,37032 20,303 36.3 4,26592 20,805 96.7 4,17962 21,240 18.8 4,05539 21,899 13.6 3,87521 22,930 64.0 3,78047 23,513 85.5 3,64590 24,394 23.1

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

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

0.1 mol / L hydrochloric acid (5.54 ml) was gradually added in an ice bath to a mixed solution of the compound (201 mg) obtained in Example 48 in methanol (8 ml) and water (2 ml). The solution was freeze dried to give the title compound (218 mg) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.17-7.48 (m, 2H), 6.63-6.92 (m, 4H), 5.05 (s, 2H), 3.23-4 71 (m, 12H), 2.65-2.82 (m, 2H), 2.57 (t, J = 7.41 Hz, 2H), 2.31-2.45 (m, 2H), 2.18 (s, 3H), 1.50-1.79 (m, 2H), 0.95 (t, J = 7.32 Hz, 3H).

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

The method of Example 50 was performed using the compound obtained in Example 48-1, instead of the compound obtained in Example 48. Thus, a compound having the following physical properties was obtained.

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

¹ H-NMR (CD ₃ OD): δ 7.87-8.09 (m, 3H), 7.37 (d, J = 8.05 Hz, 1H), 6.76-6.95 (m, 2H), 5.35 (s, 2H), 4.21-4.50 (m, 4H), 4.16 (s, 2H), 3.57-3.82 (m, 1H), 2.58 -2.83 (m, 2H); 2.15-2.38 (m, 5H).

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

To the compound (200 mg) obtained in Example 48, 0.1 mol / L aqueous sodium hydroxide solution (4.56 ml) was added, and the resulting solution was freeze dried. The resulting residue was dissolved in water and freeze dried again to give the title compound (209 mg) having the following physical properties.

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

¹ H-NMR (CDCl ₃ ): δ 7.21-7.30 (m, 2H), 6.99-7.15 (m, 1H), 6.59-6.78 (m, 3H), 4 95 (s, 2H), 3.74 (s, 3H), 3.33-3.49 (m, 2H), 3.07-3.30 (m, 5H), 2.45-2.70 (m, 4H), 2.06-2.20 (m, 2H), 1.95 (s, 3H), 1.51-1.68 (m, 2H), 0.92 (t, J = 7 , 23 Hz, 3H).

Examples 51-2 to 51-5

The method of Example 51 was performed 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, resulting in the corresponding compounds having the following physical properties.

Example 51-2: 1 - (Potassium (3-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylate potassium

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

¹ H-NMR (CDCl ₃ ): δ 7.21-7.37 (m, 2H), 7.06 (d, J = 9.15 Hz, 1H), 6.50-6.87 (m, 3H ), 4.94 (s, 2H), 3.73 (s, 3H), 3.30-3.47 (m, 2H), 3.03-3.26 (m, 4H), 2.82- 2.99 (m, 1H), 2.41-2.68 (m, 4H), 2.06-2.20 (m, 2H), 1.95 (s, 3H), 1.46-1, 71 (m, 2H), 0.91 (t, J = 7.32 Hz, 3H).

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

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

¹ H-NMR (CDCl ₃ ): δ 7.17-7.40 (m, 2H), 6.67-6.90 (m, 4H), 5.05 (s, 2H), 3.94-4 42 (m, 4H), 3.90 (s, 2H), 3.83 (s, 3H), 3.27-3.56 (m, 1H), 2.69 (t, J = 7.3 Hz, 2H), 2.52-2.62 (m, 2H), 2.28-2.41 (m, 2H), 2.16 (s, 3H), 1.54-1.72 (m, 2H), 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-azetidinecarboxylate sodium

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

¹ H-NMR (CD ₃ OD): δ 7.89-8.10 (m, 3H), 7.18-7.36 (m, 1H), 6.73-6.85 (m, 2H), 5.33 (s, 2H), 3.51-3.73 (m, 2H), 3.35-3.48 (m, 4H), 3.17-3.26 (m, 1H), 2, 56-2.78 (m, 2H), 2.17-2.34 (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-potassium azetidinecarboxylate

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

¹ H-NMR (CD ₃ OD): δ 7.84-8.12 (m, 3H), 7.16-7.38 (m, 1H), 6.65-6.87 (m, 2H), 5.33 (s, 2H), 3.55-3.70 (m, 2H), 3.35-3.50 (m, 4H), 3.13-3.27 (m, 1H), 2, 62-2.77 (m, 2H), 2.18-2.30 (m, 2H), 2.10 (s, 3H).

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

M-chloroperbenzoic acid (57.3 mg) was added in an ice bath to a solution of the compound (100 mg) obtained in Example 47 in dichloromethane (2 ml) and stirred for 30 minutes. A saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and dichloromethane were added to the reaction solution. The organic layer was washed with brine, dried and concentrated. The resulting amorphous substance (128 mg) was purified by silica gel column chromatography (from ethyl acetate: methanol = 4: 1 to dichloromethane: methanol = 10: 1), separately isolating the title compounds having the following physical properties.

Less polar connection

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

¹ H-NMR (CDCl ₃ ): δ 7.24-7.38 (m, 2H), 6.65-6.92 (m, 4H), 5.08 (s, 2H), 4.42-4 69 (m, 2H), 4.27-4.40 (m, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.48 ( s, 2H), 3.18-3.34 (m, 1H), 2.51-2.85 (m, 6H), 2.20 (s, 3H), 1.58-1.74 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H).

More polar connection

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

¹ H-NMR (CDCl ₃ ): δ 7.19-7.39 (m, 2H), 6.60-6.98 (m, 4H), 5.08 (s, 2H), 4.49-4 67 (m, 2H), 4.03-4.26 (m, 6H), 3.81-3.98 (m, 4H), 2.47-2.95 (m, 6H), 2.18 (s, 3H), 1.55-1.74 (m, 2H), 1.26 (t, J = 7.4 Hz, 3H), 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-azetidinecarboxylic acid

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

Less polar connection

TLC: Rf 0.32 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CDCl ₃ ): δ 7.20-7.37 (m, 2H), 6.65-6.92 (m, 4H), 5.05 (s, 2H), 4.82-5 00 (m, 2H), 4.40-4.59 (m, 2H), 4.27 (s, 2H), 3.83 (s, 3H), 3.27-3.42 (m, 1H ), 2.63-2.78 (m, 2H), 2.53-2.63 (m, 2H), 2.36-2.53 (m, 2H), 2.17 (s, 3H), 1.53-1.75 (m, 2H); 0.90-0.99 (m, 3H).

The compound (more polar compound) obtained in Example 52 was subjected to the above-described reaction, to thereby give the title compound having the following physical properties.

More polar connection

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CDCl ₃ ): δ 7.21-7.35 (m, 2H), 6.66-6.90 (m, 4H), 5.04 (s, 2H), 4.49-4 77 (m, 6H), 3.82 (s, 3H), 3.52-3.69 (m, 1H), 2.37-2.77 (m, 6H), 2.22 (s, 3H) ), 1.52-1.75 (m, 2H), 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-azetidinecarboxylic acid (cis isomer, RS configuration not yet determined)

10% palladium-carbon (wet, 10 mg) was added to a solution (8.0 ml) of the compound (100 mg) obtained in Example 48 in 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 silica gel column chromatography (chloroform: methanol: aqueous ammonia = 80: 10: 1 to 20: 5: 1), to thereby give the title compound (45 mg) having the following physical properties.

TLC: Rf 0.43 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.24 (d, J = 7.68 Hz, 1H), 7.00 (d, J = 8.60 Hz, 1H), 6.80 (s, 1H ), 6.69-6.78 (m, 2H), 6.63-6.69 (m, 1H), 4.98 (s, 2H), 4.12-4.30 (m, 4H), 3.83 (s, 3H), 3.33-3.50 (m, 1H), 3.23-3.29 (m, 1H), 3.16 (dd, J = 12.81, 8.23 Hz, 1H), 2.75-2.96 (m, 3H), 2.51-2.63 (m, 2H), 1.95-2.18 (m, 1H), 1.55-1, 81 (m, 4H), 1.09 (d, J = 7.14 Hz, 3H), 0.94 (t, J = 7.32 Hz, 3H).

Example 55: 1 - {[6-hydroxy-7- (2-methoxy-4-propylbenzyl) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid (compound 55 (a) ) and 1 - {[6-hydroxy-5- (2-methoxy-4-propylbenzyl) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid (compound 55 (b))

To the compound (200 mg) obtained in Example 48, a first liquid (200 ml) was added, as indicated in the description of the disintegration test given in the 14th edition of the Japanese Pharmacopoeia, and was stirred at 37 ° C for one day. The reaction solution was cooled to 0 ° C, and the pH was adjusted to 4-5 using an aqueous solution of sodium hydroxide. The precipitate was filtered. The resulting precipitate was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 80: 10: 1 to 20: 5: 1), to thereby give the title compound 55 (a) (60 mg) and the title compound 55 (b) (9 mg) having the following physical properties.

Compound 55 (a)

TLC: Rf 0.22 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 6.98 (s, 1H), 6.90 (d, J = 7.50 Hz, 1H), 6.75 (d, J = 1.46 Hz, 1H ), 6.64 (dd, J = 7.50, 1.46 Hz, 1H), 6.57 (s, 1H), 4.08-4.24 (m, 4H), 4.02 (s, 2H), 3.82 (s, 2H), 3.80 (s, 3H), 3.32-3.45 (m, 1H), 2.59-2.69 (m, 2H), 2.49 -2.59 (m, 2H), 2.15-2.24 (m, 2H), 2.05 (s, 3H), 1.55-1.69 (m, 2H), 0.92 (t , J = 7.32 Hz, 3H).

Compound 55 (b)

TLC: Rf 0.22 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.20 (d, J = 8.45 Hz, 1H), 6.72-6.75 (m, 1H), 6.73 (d, J = 8, 45 Hz, 1H), 6.48-6.56 (m, 2H), 4.04-4.24 (m, 4H), 4.03 (s, 2H), 3.92 (s, 2H), 3.87 (s, 3H), 3.30-3.45 (m, 1H), 2.42-2.57 (m, 4H), 2.19 (s, 3H), 2.00-2, 13 (m, 2H), 1.52-1.68 (m, 2H), 0.91 (t, J = 7.41 Hz, 3H).

Examples 56-1 to 56-9

The methods of Examples 5 and 6 were performed and, if necessary, the method of Example 7 using the corresponding benzyl bromide compound instead of 1-bromo-3- (4-fluorophenyl) propane and the corresponding azetidine compound instead of methylazetidine-3-carboxylate hydrochloride, resulting in the title compounds were obtained having the following physical properties.

Example 56-1: 1 - ({6 - [(4-isobutyl-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxamide

TLC: Rf 0.38 (chloroform: methanol: aqueous ammonia = 280: 30: 1).

¹ H-NMR (CD ₃ OD): δ 7.25 (d, J = 7.50 Hz, 1H), 7.19 (d, J = 8.42 Hz, 1H), 6.68-6.81 (m, 4H), 5.02 (s, 2H), 3.84 (s, 3H), 3.48-3.58 (m, 2H), 3.31-3.41 (m, 5H), 2.58-2.72 (m, 2H), 2.48 (d, J = 7.14 Hz, 2H), 2.16-2.30 (m, 2H), 2.10 (s, 3H) 1.78-1.98 (m, 1H); 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-azetidinecarboxamide

TLC: Rf 0.47 (chloroform: methanol: aqueous ammonia = 280: 30: 1).

¹ H-NMR (CD ₃ OD): δ 7.26 (d, J = 7.68 Hz, 1H), 7.20 (d, J = 8.23 Hz, 1H), 6.68-6.82 (m, 4H), 5.02 (s, 2H), 3.84 (s, 3H), 3.46-3.60 (m, 2H), 3.19-3.41 (m, 5H), 2.72 (s, 3H), 2.60-2.70 (m, 2H), 2.48 (d, J = 7.32 Hz, 2H), 2.15-2.30 (m, 2H) 2.11 (s, 3H); 1.81-1.96 (m, 1H); 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-azetidinecarboxamide

TLC: Rf 0.20 (chloroform: methanol: aqueous ammonia = 80: 10: 1).

¹ H-NMR (CD ₃ OD): δ 7.26 (d, J = 7.68 Hz, 1H), 7.20 (d, J = 8.42 Hz, 1H), 6.66-6.83 (m, 4H), 5.02 (s, 2H), 3.84 (s, 3H), 3.46-3.57 (m, 2H), 3.34-3.44 (m, 4H), 3.10-3.26 (m, 1H), 2.59-2.71 (m, 2H), 2.47 (d, J = 7.32 Hz, 2H), 2.14-2.30 ( m, 2H), 2.10 (s, 3H), 1.80-1.96 (m, 1H), 0.91 (d, J = 6.59 Hz, 6H).

Example 56-4: 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-2-naphthyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.21 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD: CDCl ₃ = 3.6: 1): δ 8.03 (d, J = 10.06 Hz, 1H), 7.66 (d, J = 8.60 Hz, 1H ), 7.24-7.39 (m, 4H), 6.73-6.82 (m, 2H), 5.17 (s, 2H), 4.56 (s, 2H), 4.11- 4.25 (m, 4H), 3.87 (s, 3H), 3.31-3.46 (m, 1H), 2.72 (s, 3H), 2.58 (t, J = 7, 70 Hz, 2H), 1.58-1.72 (m, 2H), 0.94 (t, J = 7.32 Hz, 3H).

Example 56-5: 1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-methyl-2-naphthyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.31 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 8.14 (d, J = 9.15 Hz, 1H), 7.96-8.10 (m, 3H), 7.72 (d, J = 8, 60 Hz, 1H), 7.43 (d, J = 8.60 Hz, 1H), 7.31-7.39 (m, 2H), 5.48 (s, 2H), 4.60 (s, 2H), 4.14-4.25 (m, 4H), 3.33-3.48 (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-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.50 Hz, 1H), 7.28 (d, J = 7.50 Hz, 1H), 6.87 (d, J = 1.50 Hz, 1H), 6.77-6.85 (m, 3H), 5.05 (s, 2H), 4.13-4.25 (m, 4H), 4.09 (s, 2H), 3.91-4.01 (m, 1H), 3.86 (s, 3H), 3.36-3.47 (m, 1H), 2.63-2.82 (m, 4H) 2.18-2.28 (m, 5H); 1.15 (d, J = 6.00 Hz, 3H).

Example 56-7: 1 - [(6 - {[4- (1hydroxypropyl) -2-methoxybenzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.14 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.26-7.35 (m, 2H), 7.00 (d, J = 1.28 Hz, 1H), 6.89 (dd, J = 7, 78, 1.28 Hz, 1H), 6.82 (dd, J = 8.41, 2.74 Hz, 1H), 6.78 (d, J = 2.74 Hz, 1H), 5.06 ( s, 2H), 4.52 (t, J = 6.50 Hz, 1H), 4.09-4.26 (m, 4H), 4.06 (s, 2H), 3.87 (s, 3H ), 3.33-3.49 (m, 1H), 2.65-2.76 (m, 2H), 2.16-2.29 (m, 5H), 1.64-1.83 (m , 2H), 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-azetidinecarboxylic acid

TLC: Rf 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-azetidinecarboxylic acid

Examples 57-1 to 57-87

The methods of Examples 5, 6 and 7 were performed using the corresponding halide instead of 1-bromo-3- (4-fluorophenyl) propane, whereby the title compounds having the following physical properties were obtained.

Example 57-1: 1 - {[6- (2-hydroxy-3-phenylpropoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid

TLC: Rf 0.13 (butanol: acetic acid: water = 20: 4: 1).

¹ H-NMR (CD ₃ OD): 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), 2.67-2.75 (m , 2H), 2.20 (s, 3H), 2.17-2.28 (m, 2H).

Example 57-2: 1 - ({6- [3- (4-fluorophenyl) -2-methoxypropoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.15 (butanol: acetic acid: water = 20: 4: 1).

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.60 Hz, 1H), 7.19-7.29 (m, 2H), 6.92-7.05 (m, 2H), 6.76 (dd, J = 8.60, 2.56 Hz, 1H), 6.71 (d, J = 2.56 Hz, 1H), 4.12-4.27 (m, 4H ), 4.10 (s, 2H), 3.99 (dd, J = 9.90, 3.90 Hz, 1H), 3.89 (dd, J = 9.90, 5.10 Hz, 1H) 3.67-3.79 (m, 1H), 3.40 (s, 3H), 3.37-3.48 (m, 1H), 2.83-3.00 (m, 2H), 2 65-2.76 (m, 2H); 2.20 (s, 3H); 2.14-2.28 (m, 2H).

Example 57-3: 1 - ({1-chloro-6 - [(4-isobutylbenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.24 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 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 (dd, J = 8.4, 2.6 Hz, 1H), 6.86 (d, J = 2.6 Hz, 1H), 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), 2.41-2.51 (m, 4H), 1.77-1.94 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H).

Example 57-4: 1 - [(2Z) -3-chloro-3- (4 - {[(2S) -3- (4-fluorophenyl) -2-methylpropyl] oxy} phenyl) -2-propenyl] -3 -azetidine carboxylic acid

TLC: Rf 0.22 (butanol: acetic acid: water = 20: 4: 1).

¹ H-NMR (CDCl ₃ ): δ 7.54 (d, J = 9.00 Hz, 2H), 7.04-7.15 (m, 2H), 6.95 (t, J = 8.69 Hz, 2H), 6.85 (d, J = 9.00 Hz, 2H), 6.15 (t, J = 6.86 Hz, 1H), 4.16-4.32 (m, 2H), 3.89-4.05 (m, 4H), 3.78 (d, J = 5.85 Hz, 2H), 3.18-3.35 (m, 1H), 2.82 (dd, J = 13.50, 6.60 Hz, 1H), 2.54 (dd, J = 13.50, 7.80 Hz, 1H), 2.08-2.30 (m, 1H), 1.01 (d , J = 6.77 Hz, 3H).

Example 57-5: 1 - ({6- [2- (4-fluorobenzyl) -3-methoxypropoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.15 (butanol: acetic acid: water = 20: 4: 1).

¹ H-NMR (CD ₃ OD): δ 7.26 (d, J = 8.42 Hz, 1H), 7.14-7.22 (m, 2H), 6.91-7.04 (m, 2H), 6.72 (dd, J = 8.42, 2.56 Hz, 1H), 6.67 (d, J = 2.56 Hz, 1H), 3.75-4.02 (m, 7H ), 3.41 (d, J = 5.85 Hz, 2H), 3.25-3.38 (m, 5H), 2.76 (d, J = 7.68 Hz, 2H), 2.63 -2.72 (m, 2H), 2.18-2.31 (m, 3H), 2.16 (s, 3H).

Example 57-6: 1 - ({6 - [(3-isobutylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.29 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.60 Hz, 1H), 7.18-7.30 (m, 3H), 7.06-7.11 (m, 1H), 6.84 (dd, J = 8.60, 2.74 Hz, 1H), 6.79 (d, J = 2.74 Hz, 1H), 5.05 (s, 2H), 4, 12-4.27 (m, 4H), 4.09 (s, 2H), 3.34-3.47 (m, 1H), 2.66-2.76 (m, 2H), 2.47 ( d, J = 7.32 Hz, 2H), 2.18-2.28 (m, 5H), 1.77-1.92 (m, 1H), 0.88 (d, J = 6.59 Hz , 6H).

Example 57-7: 1 - [(2E) -3- (4 - {[((2S) -3- (4-chlorophenyl) -2-methylpropyl] oxy} -2-methylphenyl) -2-butenyl] -3- azetidine carboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.25 (d, J = 8.50 Hz, 2H), 7.15 (d, J = 8.50 Hz, 2H), 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 (m, 4H) 3.97 (d, J = 7.00 Hz, 2H), 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), 2.23 (s, 3H), 2.13-2 22 (m, 1H), 2.06 (s, 3H), 1.00 (d, J = 7.00 Hz, 3H).

Example 57-8: 1 - [(1-chloro-6 - {[(2S) -3- (4-chloro-2-fluorophenyl) -2-methylpropyl] oxy} -3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.24 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.51 (d, J = 8.60 Hz, 1H), 7.21 (t, J = 8.20 Hz, 1H), 7.06-7.17 (m, 2H), 6.76 (dd, J = 8.60, 2.70 Hz, 1H), 6.71 (d, J = 2.70 Hz, 1H), 3.87-3.97 ( m, 2H), 3.75-3.87 (m, 6H), 3.24-3.41 (m, 1H), 2.87 (dd, J = 12.40, 5.30 Hz, 1H) 2.79 (t, J = 7.10 Hz, 2H), 2.60 (dd, J = 12.40, 8.00 Hz, 1H), 2.43 (t, J = 7.10 Hz, 2H), 2.16-2.30 (m, 1H), 1.01 (d, J = 6.80 Hz, 3H).

Example 57-9: 1 - ({6- [3- (4-chlorophenyl) -3-hydroxypropoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.26-7.39 (m, 5H), 6.75 (dd, J = 8.50, 2.70 Hz, 1H), 6.70 (d, J = 2.70 Hz, 1H), 4.83-4.92 (m, 1H), 4.07-4.25 (m, 5H), 4.04 (s, 2H), 3.89-4 01 (m, 1H), 3.33-3.47 (m, 1H), 2.71 (t, J = 7.00 Hz, 2H), 2.00-2.29 (m, 7H).

Example 57-10: 1 - [(2Z) -3-chloro-3- (4 - {[(2S) -3- (4-fluorophenyl) -2-methylpropyl] oxy} -2-methylphenyl) -2-propenyl ] -3-azetidinecarboxylic acid

TLC: Rf 0.24 (butanol: acetic acid: water = 20: 4: 1).

¹ H-NMR (CD ₃ OD): δ 7.12-7.21 (m, 3H), 6.89-7.03 (m, 2H), 6.67-6.78 (m, 2H), 5.79 (t, J = 6.90 Hz, 1H), 4.16-4.32 (m, 4H), 4.09 (d, J = 6.90 Hz, 2H), 3.70-3 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, 7.68 Hz, 1H), 2.33 (s, 3H), 2.10-2.25 (m, 1H), 1.00 (d, J = 6.77 Hz, 3H).

Example 57-11: 1 - ({6- [3- (4-chlorophenyl) -3-methoxypropoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.22 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.24-7.41 (m, 5H), 6.74 (dd, J = 8.6, 2.6 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 4.42 (dd, J = 7.9, 5.3 Hz, 1H), 4.06-4.23 (m, 5H), 4.03 (s, 2H ), 3.85-3.96 (m, 1H), 3.35-3.46 (m, 1H), 3.19 (s, 3H), 2.71 (t, J = 7.3 Hz, 2H), 2.10-2.29 (m, 5H), 1.92-2.07 (m, 2H).

Example 57-12: 1 - ({1-chloro-6 - [(3-isobutylbenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.22 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.56 (d, J = 8.6 Hz, 1H), 7.18-7.31 (m, 3H), 7.07-7.13 (m, 1H), 6.83-6.92 (m, 2H), 5.08 (s, 2H), 4.21 (d, J = 7.7 Hz, 4H), 4.16 (s, 2H), 3.35-3.50 (m, 1H), 2.83 (t, J = 7.0 Hz, 2H), 2.41-2.52 (m, 4H), 1.78-1.93 ( m, 1H), 0.88 (d, J = 6.6 Hz, 6H).

Example 57-13: 1 - ({6- [3- (4,4-difluorocyclohexyl) propoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.28 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.29 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 8.4, 2.8 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 4.03-4.22 (m, 4H), 4.00 (s, 2H), 3.96 (t, J = 6.4 Hz, 2H) , 3.32-3.46 (m, 1H), 2.71 (t, J = 7.1 Hz, 2H), 2.23 (t, J = 7.1 Hz, 2H), 2.18 ( s, 3H), 1.91-2.09 (m, 2H), 1.58-1.88 (m, 7H), 1.33-1.49 (m, 2H), 1.14-1, 31 (m, 2H).

Example 57-14: 1 - ({6 - [(6-isobutyl-3-pyridinyl) methoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylate sodium

TLC: Rf 0.15 (butanol: acetic acid: water = 20: 4: 1).

¹ H-NMR (CD ₃ OD): 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 = 7.59 Hz, 2H), 3.14-3.39 (m, 3H), 2.55-2.73 (m, 5H), 2.17-2.29 (m, 2H), 2.09 (s, 3H), 1.96-2.15 (m, 2H), 0.93 (d, J = 6.59 Hz, 6H).

Example 57-15: 1 - ({6 - [(2-fluoro-4-isobutylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.31 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31-7.42 (m, 2H), 6.90-7.01 (m, 2H), 6.86 (dd, J = 8.50, 2 , 50 Hz, 1H), 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 (d, J = 7.00 Hz, 2H), 2.19- 2.28 (m, 5H), 1.79-1.94 (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-azetidinecarboxylic acid

TLC: Rf 0.19 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): 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 (d, J = 8.50 Hz, 1H), 6.82 (dd, J = 8.50, 2.50 Hz, 1H), 6 78 (d, J = 2.50 Hz, 1H), 5.07 (s, 2H), 4.11-4.23 (m, 4H), 4.06 (s, 2H), 3.84 ( s, 3H), 3.36-3.45 (m, 1H), 2.66-2.76 (m, 2H), 2.39 (d, J = 7.00 Hz, 2H), 2.18 -2.28 (m, 5H), 1.70-1.84 (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-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.4, 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 (s, 2H), 3.83 ( s, 3H), 3.79 (s, 3H), 3.34-3.48 (m, 1H), 2.72 (t, J = 6.0 Hz, 2H), 2.17-2.30 (m, 5H).

Example 57-18: 1 - [(6 - {[4- (benzyloxy) -2-methoxybenzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.23-7.48 (m, 7H), 6.82 (dd, J = 8.4, 2.9 Hz, 1H), 6.77 (d, J = 2.9 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.58 (dd, J = 8.3, 2.0 Hz, 1H), 5.09 ( s, 2H), 5.00 (s, 2H), 4.10-4.29 (m, 4H), 4.09 (s, 2H), 3.82 (s, 3H), 3.33-3 50 (m, 1H), 2.72 (t, J = 5.7 Hz, 2H), 2.17-2.29 (m, 5H).

Example 57-19: 1 - ({6 - [(3-isobutyl-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.21 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 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 (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), 3.34-3.48 (m, 1H), 2.68-2.76 (m, 2H), 2.54 (d, J = 7.00 Hz, 2H) 2.19-2.28 (m, 5H); 1.87-2.02 (m, 1H); 0.91 (d, J = 6.50 Hz, 6H).

Example 57-20: 1 - ({6 - [(4-isobutyl-2-methylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.21 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): 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), 3.99 (s, 2H), 3.34-3.45 (m, 1H), 2, 69-2.77 (m, 2H), 2.44 (d, J = 7.00 Hz, 2H), 2.33 (s, 3H), 2.18-2.29 (m, 5H), 1 77-1.93 (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-azetidinecarboxylic acid

TLC: Rf 0.36 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): 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), 4.12-4.29 (m, 4H), 4.10 (s, 2H), 3.84 (s, 3H), 3.34- 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), 1.54-1.67 (m, 2H), 1.30-1.44 (m, 2H), 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-azetidinecarboxylic acid

TLC: Rf 0.36 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 6.68-6.88 (m, 4H), 5.05 (s, 2H), 4.12-4.28 (m, 4H), 4.10 (s, 2H), 3.84 (s, 3H), 3.33- 3.51 (m, 1H), 2.68-2.78 (m, 2H), 2.51 (s, 2H), 2.16-2.30 (m, 5H), 0.92 (s, 9H).

Example 57-23: 1 - ({6 - [(4-isopropoxy-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.36 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 8.6, 2.7 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.48 (dd , J = 8.4, 2.4 Hz, 1H), 4.98 (s, 2H), 4.53-4.66 (m, 1H), 4.12-4.29 (m, 4H), 4.10 (s, 2H), 3.81 (s, 3H), 3.34-3.50 (m, 1H), 2.72 (t, J = 7.0 Hz, 2H), 2.16 -2.30 (m, 5H); 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-azetidinecarboxylic acid

TLC: Rf 0.32 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 6.73-6.88 (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), 2.40-2.62 (m, 1H), 2.15-2.30 (m, 5H) 1.69-1.93 (m, 5H); 1.22-1.56 (m, 5H).

Example 57-25: 1 - ({6 - [(4-isobutyl-2-isopropoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.32 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 6.67-6.88 (m, 4H), 5.03 (s, 2H), 4.57-4.70 (m, 1H), 4.12-4.29 (m, 4H), 4.10 (s, 2H), 3.35-3.50 (m, 1H), 2.72 (t, J = 6.8 Hz, 2H), 2.45 (d, J = 7.3 Hz, 2H), 2.16-2 30 (m, 5H), 1.77-1.95 (m, 1H), 1.31 (d, J = 5.9 Hz, 6H), 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-azetidinecarboxylic acid

TLC: Rf 0.17 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 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), 5.21 (s, 2H), 4.11-4.25 (m, 4H), 4.09 (s, 2H), 3.35-3.49 (m, 1H), 2.69-2.77 (m, 2H), 2.57 (d, J = 7.00 Hz , 2H), 2.19-2.27 (m, 5H), 1.84-1.97 (m, 1H), 0.91 (d, J = 6.50 Hz, 6H).

Example 57-27: 1 - ({6 - [(2-chloro-4-isobutylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.23 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.43 (d, J = 8.00 Hz, 1H), 7.34 (d, J = 8.50 Hz, 1H), 7.23 (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), 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), 2.19-2.28 (m, 5H) 1.81-1.92 (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-azetidinecarboxylic acid

TLC: Rf 0.32 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 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 (dd , J = 8.6, 2.2 Hz, 1H), 4.99 (s, 2H), 4.29-4.45 (m, 1H), 4.11-4.28 (m, 4H), 4.09 (s, 2H), 3.82 (s, 3H), 3.33-3.51 (m, 1H), 2.72 (t, J = 6.8 Hz, 2H), 2.16 -2.29 (m, 5H), 1.54-1.79 (m, 2H), 1.26 (d, J = 6.0 Hz, 3H), 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-azetidinecarboxylic acid

TLC: Rf 0.32 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 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 (dd , J = 8.6, 2.2 Hz, 1H), 4.99 (s, 2H), 4.29-4.45 (m, 1H), 4.11-4.28 (m, 4H), 4.09 (s, 2H), 3.82 (s, 3H), 3.33-3.51 (m, 1H), 2.72 (t, J = 6.8 Hz, 2H), 2.16 -2.29 (m, 5H), 1.54-1.79 (m, 2H), 1.26 (d, J = 6.0 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H).

Example 57-30: 1 - ({6 - [(3-isobutyl-5-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.50 Hz, 1H), 6.78-6.86 (m, 4H), 6.62-6.66 (m, 1H), 5.03 (s, 2H), 4.10-4.26 (m, 4H), 4.07 (s, 2H), 3.77 (s, 3H), 3.36-3.47 (m, 1H), 2.68-2.76 (m, 2H), 2.44 (d, J = 7.00 Hz, 2H), 2.18-2.27 (m, 5H), 1, 79-1.91 (m, 1H), 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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): 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), 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), 4.98 (s, 2H), 4.07-4.22 (m, 4H), 4.05 (s, 2H), 3.80 ( s, 3H), 3.35-3.46 (m, 1H), 2.66-2.76 (m, 2H), 2.46 (d, J = 7.00 Hz, 2H), 2.18 -2.27 (m, 5H), 1.81-1.96 (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-azetidinecarboxylic acid

TLC: Rf 0.33 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.60 (d, J = 8.80 Hz, 1H), 7.34 (d, J = 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) 4.12-4.29 (m, 4H), 4.10 (s, 2H), 3.99 (t, J = 6.50 Hz, 2H), 3.34-3.49 (m, 1H ), 2.73 (t, J = 7.00 Hz, 2H), 2.16-2.30 (m, 5H), 1.74-1.89 (m, 2H), 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-azetidinecarboxylic acid

TLC: Rf 0.33 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.59 (d, J = 8.60 Hz, 1H), 7.34 (d, J = 8.60 Hz, 1H), 7.21 (d, J = 2.60 Hz, 1H), 7.15 (dd, J = 8.60, 2.60 Hz, 1H), 6.75-6.86 (m, 2H), 5.14 (s, 2H) , 4.12-4.29 (m, 4H), 4.11 (s, 2H), 4.04 (t, J = 6.40 Hz, 2H), 3.36-3.50 (m, 1H ), 2.73 (t, J = 7.00 Hz, 2H), 2.16-2.31 (m, 5H), 1.70-1.85 (m, 2H), 1.44-1, 60 (m, 2H), 0.99 (t, J = 7.40 Hz, 3H).

Example 57-34: 1 - [(6 - {[4- (cyclobutyloxy) -2- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.33 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): 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) 4.68-4.81 (m, 1H); 4.11-4.31 (m, 4H); 4.11 (s, 2H); 3.33-3.51 (m, 1H); 2 73 (t, J = 7.10 Hz, 2H), 2.39-2.57 (m, 2H), 2.04-2.32 (m, 7H), 1.65-1.97 (m , 2H).

Example 57-35: 1 - [(6 - {[4- (cyclopentyloxy) -3- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.33 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.58 (d, J = 8.40 Hz, 1H), 7.34 (d, J = 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) 4.80-4.94 (m, 1H), 4.12-4.30 (m, 4H), 4.11 (s, 2H), 3.35-3.50 (m, 1H), 2, 73 (t, J = 7.30 Hz, 2H), 2.16-2.32 (m, 5H), 1.56-2.07 (m, 8H).

Example 57-36: 1 - [(6 - {[4-isobutoxy-2- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.33 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): 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), 6.73-6.88 (m, 2H), 5.14 (s, 2H) 4.10-4.30 (m, 4H), 4.10 (s, 2H), 3.80 (d, J = 6.40 Hz, 2H), 3.33-3.50 (m, 1H ), 2.73 (t, J = 7.30 Hz, 2H), 2.16-2.32 (m, 5H), 1.99-2.16 (m, 1H), 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-azetidinecarboxylic acid

TLC: Rf 0.15 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 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), 6 81 (d, J = 2.50 Hz, 1H), 5.13 (s, 2H), 4.11-4.26 (m, 4H), 4.08 (s, 2H), 3.36- 3.50 (m, 1H), 2.69-2.78 (m, 2H), 2.59 (t, J = 7.50 Hz, 2H), 2.18-2.28 (m, 5H) 1.56-1.74 (m, 2H); 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-azetidinecarboxylic acid

TLC: Rf 0.14 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.66 (d, J = 8.50 Hz, 2H), 7.64 (d, J = 8.50 Hz, 2H), 7.32 (d, J = 8.50 Hz, 1H), 6.82-6.89 (m, 2H), 5.19 (s, 2H), 4.10-4.25 (m, 4H), 4.07 (s, 2H), 3.35-3.47 (m, 1H), 2.69-2.78 (m, 2H), 2.18-2.28 (m, 5H).

Example 57-39: 1 - ({6 - [(2,4-dimethylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.15 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.50 Hz, 1H), 7.23 (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), 4.12-4.25 (m, 4H), 4.08 (s, 2H), 3.36-3.47 (m, 1H), 2, 70-2.78 (m, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 2.19-2.28 (m, 5H).

Example 57-40: 1 - [(6 - {[2-fluoro-4- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.15 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.74 (dd, J = 7.50, 7.50 Hz, 1H), 7.46-7.55 (m, 2H), 7.35 (d, J = 8.50 Hz, 1H), 6.88 (dd, J = 8.50, 2.50 Hz, 1H), 6.84 (d, J = 2.50 Hz, 1H), 5.22 ( s, 2H), 4.11-4.25 (m, 4H), 4.08 (s, 2H), 3.36-3.48 (m, 1H), 2.71-2.78 (m, 2H), 2.19-2.30 (m, 5H).

Example 57-41: 1 - ({6 - [(2-isobutyl-6-methoxy-4-pyridinyl) methoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.24 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.50 Hz, 1H), 6.78-6.85 (m, 3H), 6.63 (s, 1H), 5 07 (s, 2H), 4.10-4.25 (m, 4H), 4.07 (s, 2H), 3.87 (s, 3H), 3.35-3.48 (m, 1H ), 2.67-2.77 (m, 2H), 2.53 (d, J = 7.00 Hz, 2H), 2.18-2.28 (m, 5H), 2.03-2, 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-azetidinecarboxylic acid

TLC: Rf 0.24 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 8.46 (d, J = 2.00 Hz, 1H), 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), 4.11-4.25 (m, 4H), 4.08 (s, 2H), 3.37-3.46 (m, 1H), 2.83 (d, J = 7.50 Hz, 2H), 2.71-2.78 (m, 2H), 2.11-2 29 (m, 6H); 0.95 (d, J = 6.50 Hz, 6H).

Example 57-43: 1 - ({6 - [(2-fluoro-4-isopropoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.28 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): 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), 4.53-4.67 (m, 1H), 4.11-4 , 27 (m, 4H), 4.09 (s, 2H), 3.33-3.50 (m, 1H), 2.73 (t, J = 7.0 Hz, 2H), 2.16- 2.30 (m, 5H); 1.30 (d, J = 6.0 Hz, 6H).

Example 57-44: 1 - ({6 - [(4-isopropyl-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.23-7.33 (m, 2H), 6.74-6.88 (m, 4H), 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), 2.13-2.32 (m, 5H), 1.25 (d, J = 6.95 Hz, 6H).

Example 57-45: 1 - ({6 - [(2-cyano-4-isopropoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.21 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 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 (dd, J = 8.6, 2.6 Hz, 1H), 6 83 (d, J = 2.6 Hz, 1H), 5.14 (s, 2H), 4.58-4.74 (m, 1H), 4.09-4.26 (m, 4H), 4.08 (s, 2H), 3.33-3.48 (m, 1H), 2.74 (t, J = 7.0 Hz, 2H), 2.17-2.31 (m, 5H) 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-azetidinecarboxylic acid

TLC: Rf 0.19 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.18-7.26 (m, 3H), 7.15 (d, J = 8.50 Hz, 2H), 6.70 (d, J = 8, 50 Hz, 1H), 4.10-4.25 (m, 4H), 4.08 (s, 2H), 3.79 (d, J = 5.50 Hz, 2H), 3.35-3, 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), 2.18-2.28 (m, 9H), 1.05 (d, J = 7.00 Hz, 3H).

Example 57-47: 1 - [(6 - {[4-isobutyl-2- (methylsulfonyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.87 (d, J = 1.80 Hz, 1H), 7.66 (d, J = 7.90 Hz, 1H), 7.52 (dd, J = 7.90, 1.80 Hz, 1H), 7.36 (d, J = 8.40 Hz, 1H), 6.81-6.94 (m, 2H), 5.48 (s, 2H) 4.11-4.27 (m, 4H), 4.09 (s, 2H), 3.34-3.50 (m, 1H), 3.20 (s, 3H), 2.75 (t , J = 7.10 Hz, 2H), 2.61 (d, J = 7.10 Hz, 2H), 2.17-2.31 (m, 5H), 1.84-1.99 (m, 1H), 0.93 (d, J = 6.60 Hz, 6H).

Example 57-48: 1 - [(6 - {[4-isopropoxy-2- (methylsulfonyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.62 (d, J = 8.40 Hz, 1H), 7.56 (d, J = 2.60 Hz, 1H), 7.36 (d, J = 8.40 Hz, 1H), 7.23 (dd, J = 8.40, 2.60 Hz, 1H), 6.88 (dd, J = 8.40, 2.40 Hz, 1H), 6 84 (d, J = 2.40 Hz, 1H), 5.41 (s, 2H), 4.64-4.78 (m, 1H), 4.09-4.26 (m, 4H), 4.07 (s, 2H), 3.33-3.49 (m, 1H), 3.20 (s, 3H), 2.74 (t, J = 8.20 Hz, 2H), 2.17 -2.30 (m, 5H); 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-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.60 (s, 1H), 7.49 (d, J = 9.70 Hz, 1H), 7.30-7.43 (m, 2H), 6 80-6.93 (m, 2H), 5.19 (s, 2H), 4.10-4.26 (m, 4H), 4.09 (s, 2H), 3.33-3.49 (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-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.71-7.83 (m, 1H), 7.52 (dd, J = 9.20, 2.70 Hz, 1H), 7.30-7, 46 (m, 2H), 6.76-6.88 (m, 2H), 5.22 (s, 2H), 4.09-4.26 (m, 4H), 4.08 (s, 2H) 3.33-3.48 (m, 1H); 2.74 (t, J = 6.60 Hz, 2H); 2.15-2.30 (m, 5H).

Example 57-51: 1 - ({6 - [(3-fluoro-4-isopropoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.19 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 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), 4.50-4.64 (m, 1H), 4.09-4.27 (m , 4H), 4.07 (s, 2H), 3.33-3.49 (m, 1H), 2.67-2.78 (m, 2H), 2.19-2.28 (m, 2H ), 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-azetidinecarboxylic acid

TLC: Rf 0.21 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.53-7.66 (m, 2H), 7.32 (d, J = 8.60 Hz, 1H), 7.17 (d, J = 8, 60 Hz, 1H), 6.78-6.88 (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), 2.66-2.79 (m, 2H), 2.20 (s, 3H), 2, 18-2.29 (m, 2H); 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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.28 (d, J = 7.50 Hz, 1H), 7.18 (s, 1H), 6.82 (d, J = 1.50 Hz, 1H ), 6.75-6.79 (m, 2H), 5.06 (s, 2H), 4.10-4.25 (m, 4H), 4.07 (s, 2H), 3.85 ( s, 3H), 3.35-3.47 (m, 1H), 2.66-2.73 (m, 2H), 2.59 (t, J = 7.50 Hz, 2H), 2.18 -2.26 (m, 8H), 1.59-1.72 (m, 2H), 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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.25 (d, J = 8.00 Hz, 2H), 7.14-7.18 (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), 2.64-2.72 (m, 2H), 2.59 (dd, J = 13.50, 7.50 Hz, 1H), 2.18- 2.26 (m, 9H); 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-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 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), 4.12-4.29 (m, 4H), 4.11 (s, 2H), 3.70 -3.89 (m, 5H), 3.34-3.51 (m, 1H), 2.90 (dd, J = 14.3, 6.6 Hz, 1H), 2.72-2.84 (m, 2H), 2.58 (dd, J = 14.3, 7.5 Hz, 1H), 2.12-2.30 (m, 6H), 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-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.24 (d, J = 8.60 Hz, 2H), 7.17 (d, J = 8.60 Hz, 2H), 7.00 (s, 1H ), 6.69 (s, 1H), 4.12-4.28 (m, 4H), 4.10 (s, 2H), 3.85 (s, 3H), 3.81 (d, J = 5.90 Hz, 2H), 3.34-3.50 (m, 1H), 2.87 (dd, J = 13.40, 6.80 Hz, 1H), 2.60-2.70 (m , 2H), 2.55 (dd, J = 13.40, 7.70 Hz, 1H), 2.14-2.29 (m, 6H), 1.01 (d, J = 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-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 7.70 Hz, 1H), 7.13 (d, J = 8.60 Hz, 1H), 6.92 (d, J = 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), 4.13-4.28 (m, 4H), 4.10 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 3.34-3, 49 (m, 1H), 2.72-2.85 (m, 2H), 2.59 (t, J = 7.30 Hz, 2H), 2.11-2.27 (m, 5H), 1 57-1.74 (m, 2H); 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-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): 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), 5.08 (s, 2H), 4.06-4.23 (m, 4H), 4.04 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.33-3.45 (m, 1H), 2.53-2.70 (m, 4H), 2.15-2, 26 (m, 5H), 1.59-1.71 (m, 2H), 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-azetidinecarboxylic acid

TLC: Rf 0.24 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.22-7.35 (m, 2H), 6.72-6.87 (m, 4H), 5.04 (s, 2H), 4.10- 4.25 (m, 4H), 4.07 (s, 2H), 3.85 (s, 3H), 3.35-3.47 (m, 1H), 2.66-2.78 (m, 2H), 2.54-2.64 (m, 1H), 2.14-2.31 (m, 5H), 1.53-1.69 (m, 2H), 1.23 (d, J = 6.95 Hz, 3H); 0.82 (t, J = 7.32 Hz, 3H).

Example 57-60: 1 - ({1-chloro-6 - [(4-ethyl-2-methoxybenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.55 (d, J = 8.60 Hz, 1H), 7.25 (d, J = 7.70 Hz, 1H), 6.81-6.90 (m, 3H), 6.78 (dd, J = 7.70, 1.60 Hz, 1H), 5.06 (s, 2H), 4.23 (d, J = 8.20 Hz, 4H) 4.17 (s, 2H), 3.85 (s, 3H), 3.36-3.50 (m, 1H), 2.83 (t, J = 7.50 Hz, 2H), 2, 64 (q, 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-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.59 (d, J = 8.60 Hz, 1H), 7.58 (d, J = 8.60 Hz, 1H), 7.22 (d, J = 2.60 Hz, 1H), 7.16 (dd, J = 8.60, 2.60 Hz, 1H), 6.87 (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 ( q, J = 7.00 Hz, 2H), 3.36-3.50 (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-azetidinecarboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.52-7.64 (m, 2H), 7.19 (d, J = 2.6 Hz, 1H), 7.15 (dd, J = 8, 6, 2.6 Hz, 1H), 6.88 (dd, J = 8.2, 2.6 Hz, 1H), 6.82-6.85 (m, 1H), 5.16 (s, 2H ), 4.61-4.75 (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-azetidinecarboxylic acid

TLC: Rf 0.19 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.42 Hz, 1H), 7.23 (d, J = 7.50 Hz, 1H), 6.69-6.88 (m, 4H), 5.03 (s, 2H), 4.10-4.26 (m, 4H), 4.07 (s, 2H), 3.84 (s, 3H), 3.33- 3.49 (m, 1H); 2.64-2.79 (m, 2H); 2.33 (s, 3H); 2.15-2.29 (m, 5H).

Example 57-64: 1 - ({6 - [(4-chloro-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.19 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): 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), 5.05 (s, 2H), 4.09-4.24 (m, 4H), 4.06 (s , 2H), 3.87 (s, 3H), 3.35-3.49 (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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.21-7.43 (m, 3H), 6.97-7.03 (m, 1H), 6.88-6.96 (m, 1H), 6.77-6.88 (m, 2H), 5.09 (s, 2H), 4.08-4.26 (m, 4H), 4.05 (s, 2H), 3.86 (s, 3H), 3.35-3.49 (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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.22-7.46 (m, 6H), 6.85 (dd, J = 8.72, 2.74 Hz, 1H), 6.81 (d, J = 2.74 Hz, 1H), 5.08 (s, 2H), 4.12-4.30 (m, 4H), 4.09 (s, 2H), 3.33-3.51 (m , 1H); 2.66-2.80 (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-azetidinecarboxylic acid

TLC: Rf 0.19 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.61 (d, J = 7.50 Hz, 1H), 7.32 (d, J = 8.60 Hz, 1H), 6.73-6.87 (m, 3H), 5.01 (s, 2H), 4.10-4.29 (m, 4H), 4.08 (s, 2H), 3.96 (s, 3H), 3.34- 3.49 (m, 1H), 2.57-2.81 (m, 4H), 2.15-2.31 (m, 5H), 1.67-1.82 (m, 2H), 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-azetidinecarboxylic acid

TLC: Rf 0.21 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 8.80 (s, 1H), 7.60 (s, 1H), 7.37 (d, J = 8.42 Hz, 1H), 6.81-6 91 (m, 2H), 5.26 (s, 2H), 4.14-4.29 (m, 4H), 4.11 (s, 2H), 3.34-3.51 (m, 1H ), 2.77 (d, J = 7.32 Hz, 2H), 2.71-2.80 (m, 2H), 2.22 (s, 3H), 2.19-2.30 (m, 2H), 2.04-2.18 (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-azetidinecarboxylic acid

TLC: Rf 0.21 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 8.55 (s, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.42 Hz, 1H), 6.89 (dd , J = 8.42, 2.56 Hz, 1H), 6.85 (d, J = 2.56 Hz, 1H), 5.20 (s, 2H), 4.12-4.28 (m, 4H), 4.10 (s, 2H), 3.33-3.50 (m, 1H), 2.70-2.79 (m, 2H), 2.66 (d, J = 7.32 Hz , 2H), 2.21 (s, 3H), 2.18-2.30 (m, 2H), 2.00-2.13 (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-azetidinecarboxylic acid

TLC: Rf 0.11 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.58 (d, J = 7.50 Hz, 1H), 7.33 (d, J = 8.23 Hz, 1H), 7.19-7.28 (m, 2H), 6.76-6.90 (m, 2H), 5.15 (s, 2H), 4.12-4.27 (m, 4H), 4.09 (s, 2H), 3.94 (s, 3H), 3.35-3.50 (m, 1H), 2.67-2.79 (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-azetidinecarboxylic acid

TLC: Rf 0.13 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.29-7.38 (m, 2H), 7.26 (dd, J = 8.78, 2.74 Hz, 1H), 6.98 (d, J = 8.78 Hz, 1H), 6.78-6.86 (m, 2H), 5.07 (s, 2H), 4.13-4.29 (m, 4H), 4.10 (s , 2H), 3.87 (s, 3H), 3.36-3.52 (m, 1H), 2.66-2.81 (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-azetidinecarboxylic acid

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.24 (d, J = 7.70 Hz, 1H), 7.02 (d, J = 9.00 Hz, 1H), 6.69-6.82 (m, 4H), 6.59 (s, 1H), 5.03 (s, 2H), 4.10-4.27 (m, 4H), 3.89 (s, 2H), 3.84 ( s, 3H), 3.33-3.49 (m, 1H), 2.81 (t, J = 8.10 Hz, 2H), 2.48 (d, J = 7.10 Hz, 2H), 2.26 (t, J = 8.10 Hz, 2H), 1.79-1.97 (m, 1H), 0.91 (d, J = 6.80 Hz, 6H).

Example 57-73: 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.24 (d, J = 7.50 Hz, 1H), 7.01 (d, J = 9.00 Hz, 1H), 6.71-6.85 (m, 4H), 6.59 (s, 1H), 5.02 (s, 2H), 4.10-4.27 (m, 4H), 3.89 (s, 2H), 3.84 ( s, 3H), 3.33-3.50 (m, 1H), 2.81 (t, J = 8.10 Hz, 2H), 2.59 (t, J = 7.10 Hz, 2H), 2.26 (t, J = 8.10 Hz, 2H), 1.56-1.74 (m, 2H), 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-azetidinecarboxylic acid

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): 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 (dd, J = 7.50, 1.50 Hz, 1H), 5.05 (s , 2H), 4.10-4.25 (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), 2.17-2.27 (m, 8H), 1.81-1.95 (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-azetidinecarboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.58-7.65 (m, 2H), 7.24 (d, J = 8.50 Hz, 1H), 7.18 (d, J = 9, 00 Hz, 1H), 6.87 (d, J = 8.50 Hz, 1H), 5.06 (s, 2H), 4.68-4.81 (m, 1H), 4.11-4, 24 (m, 4H), 4.09 (s, 2H), 3.36-3.47 (m, 1H), 2.68-2.78 (m, 2H), 2.17-2.27 ( m, 8H), 1.34 (d, J = 6.00 Hz, 6H).

Example 57-76: 1 - [(1-methyl-6 - {[4- (2,2,2-trifluoroethoxy) -3- (trifluoromethyl) benzyl] oxy} -3,4-dihydro-2-naphthalenyl) methyl ] -3-azetidinecarboxylic acid

TLC: Rf 0.35 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.62-7.74 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8, 8 Hz, 1H), 6.79-6.90 (m, 2H), 5.09 (s, 2H), 4.66 (q, J = 8.2 Hz, 2H), 4.13-4, 29 (m, 4H), 4.10 (s, 2H), 3.35-3.51 (m, 1H), 2.74 (t, J = 6.6 Hz, 2H), 2.15-2 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-azetidinecarboxylic acid

TLC: Rf 0.35 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.53-7.64 (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), 4.12-4.29 (m , 4H), 4.10 (s, 2H), 3.34-3.50 (m, 1H), 2.73 (t, J = 8.1 Hz, 2H), 2.17-2.30 ( m, 5H), 1.61-1.81 (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-azetidinecarboxylic acid

TLC: Rf 0.24 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 8.39 (s, 1H), 7.35 (d, J = 8.60 Hz, 1H), 7.01 (s, 1H), 6.85 (dd , J = 8.60, 2.56 Hz, 1H), 6.80 (d, J = 2.56 Hz, 1H), 5.28-5.42 (m, 1H), 5.13 (s, 2H), 4.13-4.29 (m, 4H), 4.10 (s, 2H), 3.34-3.50 (m, 1H), 2.70-2.80 (m, 2H) , 2.20-2.30 (m, 2H), 2.22 (s, 3H), 1.35 (d, J = 6.22 Hz, 6H).

Example 57-79: 1 - ({6 - [(4-chloro-6-isopropoxy-3-pyridinyl) methoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.24 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 8.20 (s, 1H), 7.33 (d, J = 8.42 Hz, 1H), 7.13 (s, 1H), 6.84 (dd , J = 8.42, 2.56 Hz, 1H), 6.80 (d, J = 2.56 Hz, 1H), 5.04 (s, 2H), 4.78-4.87 (m, 1H), 4.09-4.26 (m, 4H), 4.07 (s, 2H), 3.34-3.48 (m, 1H), 2.69-2.78 (m, 2H) , 2.20 (s, 3H), 2.18-2.30 (m, 2H), 1.37 (d, J = 6.04 Hz, 6H).

Example 57-80: 1 - [(6 - {[4- (2-hydroxy-2-methylpropyl) -2-methoxybenzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3 -azetidine carboxylic acid

TLC: Rf 0.25 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.50 Hz, 1H), 7.27 (d, J = 7.50 Hz, 1H), 6.89 (d, J = 1.50 Hz, 1H), 6.77-6.85 (m, 3H), 5.06 (s, 2H), 4.11-4.25 (m, 4H), 4.08 (s, 2H), 3.86 (s, 3H), 3.35-3.46 (m, 1H), 2.68-2.77 (m, 4H), 2.19-2.28 (m, 5H) 1.18 (s, 6H).

Example 57-81: 1 - ({1-tert-butyl-6 - [(2-methoxy-4-propylbenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.27 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.35 (d, J = 8.50 Hz, 1H), 7.26 (d, J = 7.50 Hz, 1H), 6.82 (d, J = 1.50 Hz, 1H), 6.73-6.79 (m, 3H), 5.03 (s, 2H), 4.29 (s, 2H), 4.03-4.23 (m, 4H), 3.85 (s, 3H), 3.33-3.43 (m, 1H), 2.55-2.63 (m, 2H), 2.46-2.53 (m, 2H) , 1.89-1.96 (m, 2H), 1.58-1.73 (m, 2H), 1.45 (s, 9H), 0.94 (t, J = 7.50 Hz, 3H )

Example 57-82: 1 - [(1-methyl-6 - {[4- (2,2,2-trifluoroethoxy) -2- (trifluoromethyl) benzyl] oxy} -3,4-dihydro-2-naphthalenyl) methyl ] -3-azetidinecarboxylic acid

TLC: Rf 0.24 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.69 (d, J = 8.60 Hz, 1H), 7.32-7.38 (m, 2H), 7.28 (dd, J = 8, 42, 2.74 Hz, 1H), 6.82 (dd, J = 8.60, 2.54 Hz, 1H), 6.79 (d, J = 2.54 Hz, 1H), 5.19 ( s, 2H), 4.64 (q, J = 8.29 Hz, 2H), 4.10-4.27 (m, 4H), 4.10 (s, 2H), 3.34-3.50 (m, 1H), 2.68-2.79 (m, 2H), 2.19-2.29 (m, 2H), 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-azetidinecarboxylic acid

TLC: Rf 0.27 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 8.28 (s, 1H), 7.33 (d, J = 8.60 Hz, 1H), 6.96 (s, 1H), 6.77-6 88 (m, 2H), 5.06 (s, 2H), 4.09-4.28 (m, 4H), 4.07 (s, 2H), 3.94 (s, 3H), 3, 34-3.48 (m, 1H), 2.67-2.78 (m, 4H), 2.15-2.32 (m, 5H), 1.65-1.83 (m, 2H), 0.97 (t, J = 7.32 Hz, 3H).

Example 57-84: 1 - ({5-iodo-6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid

TLC: Rf 0.38 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.44 (d, J = 7.50 Hz, 1H), 7.37 (d, J = 8.60 Hz, 1H), 6.86 (d, J = 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), 3.36-3.49 (m, 1H), 2.87-2.99 (m, 2H), 2.53-2.65 (m, 2H) 2.13-2.33 (m, 5H); 1.55-1.73 (m, 2H); 0.95 (t, J = 7.41 Hz, 3H).

Example 57-85: 1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -5-iodo-1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid

TLC: Rf 0.28 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 8.24-8.30 (m, 1H), 8.00-8.06 (m, 2H), 7.44 (d, J = 8.60 Hz, 1H), 6.88 (d, J = 8.60 Hz, 1H), 5.44 (s, 2H), 4.15-4.32 (m, 4H), 4.14 (s, 2H), 3.36-3.50 (m, 1H), 2.90-3.01 (m, 2H), 2.23-2.33 (m, 2H), 2.22 (s, 3H).

Example 57-86: 1 - {[1-ethyl-6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid

TLC: Rf 0.29 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 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), 4.09-4.26 (m, 4H), 4.05 (s, 2H), 3, 92-4.01 (m, 2H), 3.34-3.47 (m, 1H), 2.60-2.77 (m, 6H), 2.15-2.24 (m, 2H), 1.72-1.81 (m, 4H); 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-azetidinecarboxylic acid

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 20: 5: 1).

¹ H-NMR (CD ₃ OD): δ 7.29 (d, J = 8.60 Hz, 1H), 7.19-7.26 (m, 2H), 7.13-7.19 (m, 2H), 6.73 (dd, J = 8.60, 2.70 Hz, 1H), 6.69 (d, J = 2.70 Hz, 1H), 4.07-4.24 (m, 4H ), 4.02 (s, 2H), 3.93 (t, J = 6.13 Hz, 2H), 3.33-3.46 (m, 1H), 2.63-2.79 (m, 6H), 2.15-2.26 (m, 2H), 1.95-2.08 (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 fundamental methods of genetic engineering. In addition, the measurement methods used in the present invention to evaluate the compounds of the present invention have been improved with respect to the accuracy and / or sensitivity of the measurement. Below is a detailed description of the studies performed. Histological preparations were also obtained by standard methods using the fundamental methods of genetic engineering, modified accordingly.

Biological example 1. Measurement of the inhibitory activity of the compounds of the present invention in relation to binding [ ³ H] -PhS1P with EDG-6

Experimental method

The interaction was carried out on a 96-well assay plate using a Chinese Hamster Ovary (CHO) cell membrane fraction overexpressing EDG-6 and 1 mg protein / ml membrane fraction. 80 μl of a carrier solution (DMSO) diluted with a double volume of binding buffer (100 mmol / L Tris buffer, pH 7.5, 200 mM NaCl, 30 mM NaF, 1% BSA), or a ligand solution in double concentration was injected into each well. and 40 μl of 10 nmol / L [ ³ H] -PhS1P (phytosphingosine-1-phosphate 5,5,6,6-tetratritium obtained by the following image). Compound (anti-7: tert-butyl- (4S) -4 - [(1S, 2R) -1- (benzyloxy) -2-hydroxyhexadec-3-yn-1-yl] -2,2-dimethyl-1, 3-oxazolysin-3-carboxylate) obtained by the method described in Tetrahedron Lett., 38 (34), 6027-6030 (1997) was reacted with benzyl bromide in tetrahydrofuran in the presence of potassium hexamethyldisilylamide to protect the hydroxyl group. Then the specified compound was treated with a solution of hydrogen chloride / methanol to unlock the acetonide group. The compound thus obtained was reacted with N, N-diethyl-1,5-dihydro-2,4,3-benzodioxaphosphepin-3-amine in methylene chloride in the presence of tetrazole and then oxidized with m-chloroperbenzoic acid. The resulting compound was reacted in the presence of an ASCA-2 catalyst (NE CHEMCAT CORPORATION, catalyst containing 4.5% palladium - 0.5% platinum on activated carbon, see Fine Chemical, October 1, 2002, p. 5-14) in methanol in tritium atmosphere. The resulting compound was treated with 4 N. a solution of hydrogen chloride / 1,4-dioxane in methylene chloride, thereby obtaining the desired compound. Then, 40 μl of the membrane fraction solution was added and reacted at room temperature for 60 minutes. After completion of the reaction, the reaction mixture was suction filtered through a UNIFILTER filter for a 96-well plate, washed three times with 50 ml of washing buffer (50 mmol / L Tris buffer, pH 7.5, 0.5% BSA) and dried at 60 ° C for 45 minutes. Then, 50 μl / well of MicroScint 20 was added and the TopSeal-P plate was closed. Radioactivity was measured using a TopCount device (Perkin Elmer Inc.).

results

The compounds of the present invention were characterized by the presence of inhibitory activity against the binding of [ ³ H] -PhS1P to EDG-6.

Biological example 2. Counting the number of lymphocytes in the blood

Experimental method

Test compounds were orally administered to male BALB / c mice or male Sprague-Dawley rats (Charles River Laboratories, Japan, Inc., 6 weeks old during the study). 4-72 hours after administration, animals were bled from the abdominal aorta with ether anesthesia. The total number of leukocytes, lymphocytes, neutrophils, erythrocytes and platelets in the blood and the hematocrit were measured using a multi-purpose automatic blood element counter (SF-3000, Sysmex Corporation). When performing the measurement, the average number of blood elements in the group of animals to which the vehicle was introduced (control group) was set equal to 100% and the percentage value of the average number of blood elements in each group of animals to which the test compound was calculated was calculated compared to the control group. Based on the doses of the test compound and the percentages obtained upon administration of the vehicle and the test compounds, the dose of the compound necessary to reduce the number of blood elements by 50% was calculated as ED ₅₀ .

results

The 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 ED ₅₀ values 24 hours after the administration of the compounds obtained in Example 27-7 and Example 37 were 1.6 mg / kg and 0.029 mg / kg, respectively.

Biological example 3. Evaluation of the agonistic activity of the compounds of the present invention against EDG by determining changes in the intracellular concentration of calcium ions [Ca ²⁺ ]

Experimental method

CHO cells overexpressing the human EDG-1, EDG-3, EDG-5, or EDG-8 gene were cultured in Ham F12 medium (GibcoBRL company) containing 10% FBS (fetal bovine serum), penicillin / streptomycin and blasticidin (5 μg / ml). Cultured cells were incubated in a 5 μM Fura2-AM solution (Ham F12 medium containing 10% FBS, 20 mM HEPES buffer (pH 7.4) and 2.5 mM probenecid) at 37 ° C for 60 minutes. The cells were washed once with a Hanks solution containing 20 mM HEPES buffer (pH 7.4) and 2.5 mM probenecid, after which the plate was immersed in the same solution. The plate was then placed in a fluorescent drug screening system (FDSS 6000; Hamamatsu Photonics K.K.) and the intracellular concentration of calcium ions was measured without stimulation for 30 seconds. The test compound was added (final concentration: 1 nM to 10 μM, dimethyl sulfoxide (DMSO) solution) and after 5 minutes S1P (final concentration: 100 nM) was added. The increase in the intracellular concentration of calcium ions was measured before and after the addition of S1P at intervals of 3 seconds (excitation wavelength: 340 nm and 380 nm, fluorescence wavelength: 500 nm).

The agonistic activity of the compound against each EDG receptor was determined using the maximum value obtained by S1P stimulation in a well containing DMSO instead of the test compound as a control value (A), for which the value obtained before adding the test compound was compared with an increased value (B) in relation to the fluorescence intensity after addition, the ratio of the increase (%) of the intracellular concentration of calcium ions [Ca ²⁺ ] _{i was} calculated as the ratio of the increase (%) = (B / A) × 100. Determination whether the ratio of increase caused by the compound in different concentrations, and calculated the value of the EU ₅₀ .

results

It was found that the compounds of the present invention have agonistic activity against EDG-1. For example, the EC ₅₀ values of the compounds obtained in examples 18, 13-4, 29-1, 27-7, 37, and 37-6 were respectively 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 of dermatitis in mice caused by constant exposure to hapten

Experimental method

A 1% (w / v) solution of 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (hereinafter abbreviated as “oxalon”) (20 μl) was applied to the auricle (right ear, both surfaces) of mice ( BALB / c males) for primary sensitization. Seven days after sensitization, a 1% (w / v) oxalone solution (20 μl) was applied to the auricle to fix the result (day 0). A procedure similar to that performed on day 0 was repeated on the 2nd, 4th, 6th, 8th, 10th, 12th, 14th and 16th day. The test compound was dissolved in the vehicle and administered orally or applied to both surfaces of the right ear (20 μl) before applying oxalone. The control group was exposed only to the carrier. Immediately after administration of the test compound and 24 hours after the application of oxalone in mice, the thickness of the auricle was measured using a dial gauge (OZAKI MFG. CO., LTD) and the result was used as an indicator of the effectiveness of the treatment of dermatitis in the mouse model of dermatitis constant exposure to hapten.

Biological Example 5. Adjuvant Induced Arthritis Model

Experimental method

The study was performed using male or female Lewis rats at the age of 7 weeks. The volume of the left hind paw was measured in rats, after which 500 μg of Mycobacterium butyricum (Difco) mycobacterium suspension of dry cell suspension, used as an adjuvant in liquid paraffin, was subcutaneously injected into the paw of the right hind paw of each rat, thereby creating a model of adjuvant-induced arthritis in rats. By comparing the experimental group to which the test compound was orally administered, to the control group to which the test compound was not administered, the therapeutic or prophylactic effect was determined.

Biological example 6. Model experimental allergic encephalomyelitis (EAE)

(Case 1) Administration of the compound of the present invention from the day of sensitization

Experimental method

Killed Mycobacterium tuberculosis mycobacteria (M. tuberculosis H37 Ra, Difco, catalog No. 231141) were suspended in distilled water for injection to dissolve MBP (basic myelin protein, SIGMA, M-2295 catalog number) (killed Mycobacterium tuberculosis mycobacteria: 1000 μg ml, MVR: 60 μg / ml). The resulting solution was mixed with an equivalent amount of FCA (Freund's complete adjuvant, CHEMICON, catalog number AR001) to form an emulsion. Female LEW / CrlCrlj rats (Charles River Laboratories, Japan, Inc., aged 6 weeks during acquisition, 7 weeks during sensitization) were actively sensitized by single subcutaneous injection (0.1 ml / rat) of the emulsion into the paw of the right paw with mild anesthesia with ether, thus inducing the symptoms of experimental allergic encephalomyelitis. Sensitization day was defined as day 0.

Symptoms of EAE in rats were monitored every day from day 8 to day 20 and evaluated based on the following criteria: tail relaxation: 1 point, incomplete hind limb paralysis: 1 point, complete hind limb paralysis: 1 more point, and incontinence: 1 point The maximum score was 4 points. The death of the animal was evaluated at 5 points.

A 0.5% MS solution (0.5 wt./about. 400 cP methylcellulose solution, Wako Pure Chemical Industries, Ltd., catalog No. 133-14255) was used as a carrier, the test compound was forcibly administered orally in an amount of 5 ml / kg once a day, starting from the day preceding sensitization, and until the 19th day. The control group was forcibly orally administered the same amount of a 0.5% MS solution once a day for the same period of time. Body weight was measured every day, starting from day 0, and the dose was determined based on daily measured body weight.

results

The effectiveness of the test compound was determined by comparing the results obtained in the experimental group, which was orally administered the test compound, with the results obtained in the control group, which was orally administered only the carrier. During the indicated administration period, the compound obtained in Example 37 almost completely inhibited the onset of symptoms at an oral dose of 0.1 mg / kg, and completely inhibited the onset of symptoms at an oral dose of 0.3 mg / kg. The compound obtained in Example 37-5 almost completely inhibited the onset of symptoms at an orally administered dose of 0.3 mg / kg.

(Case 2) Administration of the compound of the present invention immediately before the onset of symptoms of the disease

Experimental method

Killed mycobacterium Mycobacterium tuberculosis (M. tuberculosis H37 Ra, Difco, catalog No. 231141) was suspended in distilled water for injection to dissolve MBP (basic myelin protein, SIGMA, catalog No. M-2295) (killed mycobacterium Mycobacterium tuberculosis: 1000 μg ml, MVR: 60 μg / ml). The resulting solution was mixed with an equivalent amount of FCA (Freund's complete adjuvant, CHEMICON, catalog number AR001) to form an emulsion. Female LEW / CrlCrlj rats (Charles River Laboratories, Japan, Inc., aged 6 weeks during acquisition, 7 weeks during sensitization) were actively sensitized by single subcutaneous injection (0.1 ml / rat) of the emulsion into the paw of the right paw with mild anesthesia with ether, thus inducing the symptoms of experimental allergic encephalomyelitis. Sensitization day was defined as day 0.

Symptoms of EAE in rats were monitored every day from day 7 to day 20 and evaluated based on the following criteria: tail relaxation: 1 point, incomplete hind limb paralysis: 1 point, complete hind limb paralysis: 1 more point, and incontinence: 1 point The maximum score was 4 points. The death of the animal was evaluated at 5 points.

A 0.5% MS solution (0.5 wt./about. 400 cP methylcellulose solution, Wako Pure Chemical Industries, Ltd., catalog No. 133-14255) was used as a carrier, the test compound was forcibly administered orally in an amount of 5 ml / kg once a day, starting from the 9th day preceding sensitization, and until the 19th day. The control group was forcibly orally administered the same amount of a 0.5% MS solution once a day for the same period of time. Body weight was measured every day, starting on the 9th day, and the dose was determined based on daily measured body weight.

results

The effectiveness of the test compound was determined by comparing the results obtained in the experimental group, which was orally administered the test compound, with the results obtained in the control group, which was orally administered only the carrier. During the indicated administration period, the compound obtained in Example 37 almost completely inhibited the onset of symptoms at an orally administered dose of 0.3 mg / kg. It was found that the compound obtained in example 37-5, inhibited the onset of symptoms with an orally administered dose of 0.3 mg / kg

(Case 3) Administration of the Compound of the Present Invention after the onset of Symptoms of a Disease

Experimental method

Killed Mycobacterium tuberculosis mycobacteria (M. tuberculosis H37 Ra, Difco, catalog No. 231141) were suspended in distilled water for injection to dissolve MBP (basic myelin protein, SIGMA, M-2295 catalog number) (killed Mycobacterium tuberculosis mycobacteria: 1000 μg ml, MVR: 60 μg / ml). The resulting solution was mixed with an equivalent amount of FCA (Freund's complete adjuvant, CHEMICON, catalog number AR001) to form an emulsion. Female LEW / CrlCrlj rats (Charles River Laboratories, Japan, Inc., aged 6 weeks during acquisition, 7 weeks during sensitization) were actively sensitized by single subcutaneous injection (0.1 ml / rat) of the emulsion into the paw of the right paw with mild anesthesia with ether, thus inducing the symptoms of experimental allergic encephalomyelitis. Sensitization day was defined as day 0.

Symptoms of EAE in rats were monitored every day from day 10 to day 20 and evaluated based on the following criteria: tail relaxation: 1 point, incomplete hind limb paralysis: 1 point, complete hind limb paralysis: 1 more point and incontinence: 1 point The maximum score was 4 points. The death of the animal was evaluated at 5 points.

A 0.5% MS solution (0.5 wt./about. 400 cP methylcellulose solution, Wako Pure Chemical Industries, Ltd., catalog No. 133-14255) was used as a carrier, the test compound was forcibly administered orally in an amount of 5 ml / kg once a day, starting from the 11th day or the 12th day to the 19th day after all rats had symptoms of EAE. The control group was forcibly orally administered the same amount of a 0.5% MS solution 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 based on daily measured body weight.

results

The effectiveness of the test compound was determined by comparing the results obtained in the experimental group, which was orally administered the test compound, with the results obtained in the control group, which was orally administered only the carrier.

Biological example 7. Determination of cardiotoxicity (bradycardia)

Experimental method

A catheter was inserted into the jugular vein and carotid artery (or femoral vein and femoral artery) of mammals (e.g., SD rats and rabbits). The end of the arterial cannula was connected to a pressure transducer (DX-100, NIHON KONDEN CORP.) To measure blood pressure using a tensiometer (AP-641G, NIHON KONDEN CORP.) And to measure heart rate using a device for instant frequency measurement heart rate (AT-601G, NIHON KONDEN CORP.), respectively. Alternatively, the heart rate was measured using an electrocardiogram. The test compound was administered intravenously or orally to anesthetized animals or animals in a psychostimulated state after activation. Then measured the change in blood pressure and heart rate.

results

The compound of the present invention had little effect on cardiotoxicity. For example, when rabbits were intravenously administered the compound obtained in Example 37 at a dose of 0.01 mg / kg, the heart rate in rabbits decreased by 20% or less.

By measuring the ED ₅₀ values 24 hours after administration of the test compound at a dose determined by the method described in biological example 2 as C mg / kg, and determining the dose established by the method described in this biological example, at which the heart rate decreased by 20%, as D _A mg / kg, the ratio (D _A / C) can be represented as a safety index (A) (SI _A : safety index A) of the compound.

Biological example 8. Determination of the safety of the compounds of the present invention

Experimental method

The compound of the present invention was forcibly administered orally through a tube into the stomach of SD rats (Crj: CD (SD) IGS, males, 6 weeks old) once a day for a period of time from 4 days to 14 days. Rats were opened the day after the administration of the compound of the present invention was stopped and the mass of different organs was measured, histopathological examination, hematological examination and biochemical blood analysis were performed.

results

It was found that the compound of the present invention is quite safe.

By measuring the ED ₅₀ values 24 hours after administration of the test compound at a dose determined by the method described in biological example 2 as C mg / kg, and determining the dose established by the method described in this biological example, at which a significant increase in liver mass occurs , in the form of D _B mg / kg, the ratio (D _B / C) can be represented as a safety index (B) (SI _B : safety index B) of the compound.

Examples of the preparation of medicines

The following are examples of the preparation of drugs of the present invention.

An example of the preparation of a medicinal product 1

1 - {[1-Chloro-6- (3-cyclohexylpropoxy) -3,4-dihydronaphthalen-2-yl] methyl} azetidine-3-carboxylic acid (100 g), calcium carboxymethyl cellulose (disintegrant, 20.0 g) , magnesium stearate (lubricant, 10.0 g) and microcrystalline cellulose (870 g) were mixed according to the standard method and tablets were pressed to obtain 10,000 tablets, each of which contained 10 mg of active ingredient.

An example of the preparation of a medicinal product 2

1 - {[1-Chloro-6- (3-cyclohexylpropoxy) -3,4-dihydronaphthalen-2-yl] methyl} azetidine-3-carboxylic acid (100 g), mannitol (2 kg) and distilled water (50 l ) were mixed by the standard method. Then, the solution was filtered through a dustproof filter, after which 5 ml aliquots were introduced into ampoules, which were sterilized in an autoclave, while obtaining 10,000 ampoules, each of which contained 10 mg of the active ingredient.

Industrial applicability

The compound of the present invention can be used in the following pharmaceutical preparations.

The compound of the present invention has the ability to bind to 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 (for example, humans or animals other than humans, such as monkeys, sheep, cows, horses, dogs, cats, rabbits, rats and mice) , in cases such as transplant rejection, destruction of the transplanted organ, the transplant versus host reaction (for example, the acute transplant versus host reaction during bone marrow transplantation and the like), autoimmune diseases malformations (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 allergic sclerosis, e.g. , pollinosis, food allergies, psoriasis and drug allergies (e.g., an anesthetic such as lidocaine)), inflammatory diseases (e.g., varicose veins veins such as hemorrhoids, fissure or fistula of the anus, exfoliating an aortic aneurysm or sepsis, vasculitis, nephritis, pneumonia and chronic active hepatitis), respiratory diseases (e.g. lung fibrosis, asthma and interstitial pneumonia), metabolic diseases and endocrine diseases (e.g. type I diabetes), circulatory system diseases (e.g., reperfusion disorders after ischemia, arteriosclerosis, arteriosclerosis obliterans, thromboangiitis obliterans, diabetic neuropathy, acute heart failure awe and angina pectoris), various edematous disorders caused by increased blood penetrating power (for example, myocardial infarction, cerebral infarction, DIC (disseminated intravascular coagulation), pleurisy, congestive heart failure, multiple organ failure), traumatic lesions (for example, pressure sores and burns ), osteoporosis, chronic hepatitis, fibrosis, such as liver fibrosis, chronic renal failure, glomerulosclerosis of the kidney, infection, ulcer, lymphoma, malignant tumor (e.g. cancer), l ykoz, cerebral embolism, ischemic abnormality of various organs, shock due to incompatibility during blood transfusion, genetic diseases, neurodegenerative diseases (e.g., Parkinson's disease, Parkinsonian syndrome, Alzheimer's disease and amyotrophic lateral sclerosis) and the like.

Brief Description of the Drawings

Figure 1 shows the x-ray powder diffraction pattern of the compound obtained in example 48.

2 is a differential scanning calorimetry (DSC) diagram of the compound obtained in Example 48.

Figure 3 shows the x-ray powder diffraction pattern of the compound obtained in example 48 (1).

4 is a differential scanning calorimetry (DSC) diagram of the compound obtained in Example 48 (1).

Figure 5 shows the x-ray powder diffraction pattern of the compound (type A crystalline substance) obtained in Example 49.

Figure 6 shows a diagram of differential scanning calorimetry (DSC) of the compound (crystalline substance type A) obtained in example 49.

7 shows a powder X-ray diffraction pattern of the compound (type B crystalline substance) obtained in Example 49.

On Fig shows a diagram of differential scanning calorimetry (DSC) of the compound (crystalline substance type B) obtained in example 49.

Figure 9 shows the x-ray powder diffraction pattern of the compound obtained in example 49 (1).

10 is a differential scanning calorimetry (DSC) diagram of the compound obtained in Example 49 (1).

Claims (17)

1. The compound expressed by formula (IC-2):

where Z is a carbamoyl group which may be substituted with C1-4 alkyl or hydroxy;
R ¹ means C1-8 alkyl or C1-8 alkoxy;
R ⁴ and R ^4-1 each independently means a hydrogen atom or C1-8 alkyl;
m is an integer from 1 to 5, when m is 2 or more, all R ¹ may 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-azetidinecarboxylic acid,
1 - ({6 - [(4-isobutyl-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid,
1 - ({6 - [(4-isobutyl-3-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid,
1 - ({6 - [(2-ethoxy-4-isobutylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid,
1 - [(6 - {[4-isopropoxy-2- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid,
1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid,
1 - ({1-chloro-6 - [(2-methoxy-4-propylbenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid,
1 - ({1-chloro-6 - [(4-isobutyl-2-methoxybenzyl) oxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid,
1 - [(1-chloro-6 - {[((2S) -3- (2,4-difluorophenyl) -2-methylpropyl] oxy} -3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid ,
1 - [(6 - {[4-ethoxy-2- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid,
1 - ({6 - [(4-ethyl-2-methoxybenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid,
1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1,5-dimethyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid,
1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-chloro-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid,
1 - [(6 - {[2- (difluoromethoxy) -4-propylbenzyl] oxy} -1,5-dimethyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid,
1 - [(6 - {[4-ethoxy-3- (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid,
1 - ({6 - [(2-methoxy-6-propyl-3-pyridinyl) methoxy] -1,5-dimethyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid,
1 - [(6 - {[(2S) -3- (4-fluorophenyl) -2-methylpropyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid,
1 - [(6 - {[(2S) -3- (4-chlorophenyl) -2-methylpropyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid,
N - [(6 - {[(2S) -3- (4-chlorophenyl) -2-methylpropyl] oxy} -1-methyl-3,4-dihydronaphthalen-2-yl) methyl] -β-alanine,
1 - [(6 - {[2-difluoromethoxy-4-propylbenzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid, and
1 - [(6 - {[2-methoxy ~ 4-propylbenzyl] oxy} -3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid,
its pharmaceutically acceptable salt, N-oxide or MES. 3. The compound according to claim 2, selected from
1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid monohydrate,
1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid monohydrate,
1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid hydrochloride,
1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid hydrochloride,
1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidine carbonate,
1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarbonate potassium,
hemicalcium salt of 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid,
1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidine carbonate,
1 - [(6 - {[2,4-bis (trifluoromethyl) benzyl] oxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidine carbonate. 4. A compound which is 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid. 5. A pharmaceutical composition having agonist 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 component, 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 a means for the prevention and / or treatment of multiple sclerosis. 8. The pharmaceutical composition according to claim 5, which is an immunosuppressant and / or agent that causes lymphopenia. 9. A method for the prevention and / or treatment of a disease due to EDG-1, EDG-6 and / or EDG-8 in a mammal, comprising administering to the mammal an effective amount of a compound of claim 2, a pharmaceutically acceptable salt, N-oxide or solvate thereof. 10. A method for the prevention and / or treatment of multiple sclerosis in a mammal, comprising administering to the mammal an effective amount of a compound of claim 2, a pharmaceutically acceptable salt, N-oxide or solvate thereof. 11. A method of suppressing an immune response and / or inducing lymphopenia in a mammal, comprising administering to the mammal an effective amount of a compound of claim 2, a pharmaceutically acceptable salt, N-oxide or solvate thereof. 12. The use of the compound according to claim 2, its pharmaceutically acceptable salt, N-oxide or MES to obtain funds for the prevention and / or treatment of diseases caused by EDG-1, EDG-6 and / or EDG-8. 13. The use of the compound 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 the compound according to claim 2, its pharmaceutically acceptable salt, N-oxide or MES to obtain an immunosuppressant and / or agent that causes lymphopenia. 15. The crystalline form of 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid having a diffraction angle of 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 powder X-ray or X-ray diffraction 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 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid monohydrate having a diffraction angle of 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 powder x-ray diffraction. 17. The crystalline form of 1 - ({6 - [(2-methoxy-4-propylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid monohydrate having a diffraction angle of 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 powder x-ray diffraction.

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