RU2390519C2 - Compound capable of bonding with s1p receptor and pharmaceutical application thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

(I) capable of bonding with S1P receptor (specifically EDG-6, preferably EDG-1 and EDG-6), its non-toxic water-insoluble salts or its methyl or ethyl ester.

EFFECT: obtaining compounds which can be used in preventing and/or treating graft rejection, graft-versus-host diseases, autoimmune diseases and allergic diseases.

11 cl, 66 ex

Description

Technical field

The present invention relates to a compound having the ability to bind to a sphingosine-1-phosphate receptor (hereinafter referred to as S1P in some cases), which is useful as a medicine, and to a medicine containing such a compound as an active ingredient.

More specifically, the present invention relates to:

(1) a compound having the ability to bind to the S1P receptor (in particular, EDG-6, preferably EDG-1 and EDG-6);

(2) a medicament containing such a compound as an active ingredient;

(3) a compound represented by the following formula (I):

where all characters have the meanings indicated below;

its prodrug and its salts; and

(4) a medicament containing a compound represented by formula (I), a prodrug thereof, and a salt thereof as an active ingredient.

State of the art

Sphingosine-1-phosphate (S1P), having the structural formula represented by formula (A), is a lipid resulting from the intracellular metabolic metabolism of sphingolipids or the extracellular action of secretory sphingosine kinase. It should be noted that S1P acts both intercellular and intracellular messenger (Biochem. Pharm., 58 , 201 (1999)).

As receptors for S1P, EDG-1, which is a G-protein bound receptor, and the molecules that are its analogues, EDG-3, EDG-5, EDG-6 and EDG-8 (also called S1P ₁ , S1P, are known ₃ , S1P ₂ , S1P ₄ and S1P _5, respectively). They are called the EDG receptor family, along with EDG-2, EDG-4 and EDG-7, which are lysophosphatidic acid (LPA) receptors. S1P receptors bind to S1P and transmit signals to cells through the G protein associated with the receptors. Gs, Gi, Gq, and G _{12/13 are} known as G proteins with which the S1P receptor can bind, and it is believed that this receptor is associated with responses such as increased cell proliferation, inhibition of cell proliferation, induction of cell hemotaxis and inhibition of cell hemotaxis.

As the biological effect of S1P, in vitro experiments revealed inhibition of smooth muscle or cancer cell migration, platelet aggregation, induction of cell hemotaxis, inhibition of cell hemotaxis, etc., and as a result of in vivo experiments, S1P showed the effect of controlling blood pressure, promotion of angiogenesis, restoration of renal blood flow, inhibition of pulmonary fibrosis, promotion of homing of lymphocytes to the lymphatic organs, etc. It is believed that these various physiological effects are mediated by S1P receptors present on cell membranes. However, with the exception of some cases, it was not clear which subtypes of S1P receptors mediate such effects in practice.

Recently, studies of mice deficient in EDG-1 have clearly shown that S1P induced angiogenesis through EDG-1 (Yujing Liu, et al., J. Clin. Invest., 106 , 951 (2000)). Therefore, it has been proposed to use an EDG-1 agonist as an agent for treating a disease caused by angioplasia. For example, it is used as an agent for the prophylaxis and / or treatment of peripheral arterial disease, such as arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease, or diabetic neuropathy; varicose veins, such as hemorrhoids, anal fissures, anal fistula; exfoliating aortic aneurysm, sepsis, inflammatory disease such as angiitis, nephritis or pneumonia, various edematous diseases caused by ischemia of various organs or increased penetration of blood, such as myocardial infarction, cerebral infarction, angina pectoris, DIC (disseminated intravascular coagulation), pleurisy, insufficiency or multiple organ failure. In addition, it is used as a selectivity enhancer for treating wounds of the cornea, skin, digestive organs and the like, for example, for preventing and / or treating pressure sores, burns, chronic ulcerative colitis or Crohn’s disease. In addition, it is used as a preoperative, postoperative and / or prognostic activator of blood vessels during transplantation of various organs, for example, as an activator of adhesion of transplanted organs, for example, in heart transplantation, kidney transplantation, skin transplantation or liver transplantation.

On the other hand, unlike other EDG receptors, localization and strong expression of EDG-6 occurs in the cells of the lymphatic and hematopoietic systems, including the spleen, leukocytes, lymph glands, thymus, bone marrow, lungs, etc., which says possible close association with the effects of S1P during inflammation or in the immune system (Biochem. Biophys. Res. Commun., 268 , 583 (2000)).

Moreover, it is known that the EDG-6 polypeptide or its homolog is associated with immunomodulation, anti-inflammatory effect, etc., which makes such substances potentially suitable for the treatment of autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, etc. .p.), allergic diseases (such as atopic dermatitis, asthma, etc.), inflammation, infection, ulcers, lymphomas, malignant tumors, leukemia, arteriosclerosis, diseases associated with lymphocyte infiltration into the tissue, etc. .

Therefore, drugs acting against EDG-6 have proven to be useful as prophylactic and / or drugs for transplant rejection, organ transplant rejection, transplant versus host disease, autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis and etc.), allergic disease (atopic dermatitis, asthma, etc.), inflammation, infection, ulcer, lymphoma, malignant tumor, leukemia, arteriosclerosis, disease related to infiltration atsiey lymphocytes in the tissue, etc.

It is known that 2-amino-2- [2- (4-octylphenyl) ethyl] -1,3-propanediol hydrochloride (registration number CAS 162359-56-0, hereinafter referred to as "FTY720") containing sphingosine-like structure has an immunosuppressive action. However, its target molecule remained unknown for a long time. It has recently been found that FTY720 phosphorylates in vivo and phosphorylated FTY720 binds to the S1P receptor (see Science, 296 , 346 (2002); and J. Biol. Chem., 277 , 21453 (2002)). Extensive studies have found that phosphorylated FTY720 binds to various subtypes of S1P receptors, namely EDG-1, EDG-3, EDG-6 and EDG-8.

FTY720 is one of the compounds of 2-amino-1,3-propanediol represented by the formula (Y):

where R ^Y represents a linear or branched carbon chain, which may contain a substituent (s), aryl, which may contain a substituent (s), cycloalkyl, which may contain a substituent (s), etc .; and R ^2Y , R ^3Y , R ^4Y and R ^5Y are the same or different from each other, and each represents a hydrogen atom, alkyl, aralkyl, acyl or alkoxycarbonyl (only the necessary parts of the symbol definitions are selected). It is disclosed that these compounds are useful as immunosuppressants (see WO 94/008943).

As a result of recent clinical trials of the action of FTY720 in human kidney transplantation, it has been reported that FTY720 has the effect of significantly reducing the incidence of severe rejection. It was found that the main action that FTY720 exhibits is aimed at reducing the number of lymphocytes in the peripheral blood without suppressing proliferation or activation, memory function and the ability to recognize a foreign substance in a viral infection and lymphocytes. Thus, FTY720 has been shown to be useful in the treatment of a disease, such as transplant rejection.

However, it was also reported that FTY720 has a side effect, causing bradycardia after its administration (J. Am. Soc. Nephrol., 13 , 1073 (2002)). Therefore, when using it, you should be very careful. Therefore, there was a need for a highly safe drug with a high therapeutic effect and, at the same time, a mild side effect.

Recently, it has been reported that an EDG-1 agonist is useful as an immunosuppressant. However, it has never been indicated that an EDG-6 agonist or antagonist is useful as an immunosuppressant (see WO 03/061567).

Moreover, it is disclosed that the compound represented by formula (S):

where Ar ^S is phenyl or naphthyl; A ^S is carboxy, etc .; n ^S is 2, 3 or 4; R ^1S and R ^2S each independently represents 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 represents a hydrogen atom or C1-4 alkyl, which may be substituted by 1-3 hydroxy or halogen atoms; R ^4S , each independently, is hydroxy, a halogen atom, a carboxy, etc .; C ^S is C1-8 alkyl, C1-8 alkoxy, phenyl, etc. or C ^{S is} absent; and B ^S is phenyl, C5-16 alkyl, etc. (only the necessary parts of the symbol definitions are selected);

its pharmaceutically acceptable salt and its hydrate, and

the compound represented by formula (T):

where Ar ^T represents phenyl or naphthyl; A ^T is carboxy, etc .; m ^T has a value of 0 or 1; n ^T is 0 or 1; R ^1T and R ^2T , each independently, represents a hydrogen atom, a halogen atom, hydroxy, carboxy, C1-4 alkyl or phenyl, which may be substituted by a halogen atom, etc .; R ^3T represents a hydrogen atom, C1-4 alkyl, which may be substituted by a hydroxy or a halogen atom, etc .; R ^4T each independently represents a halogen atom, C1-4 alkyl, C1-3 alkoxy, etc .; C ^T is C1-8 alkyl, C1-8 alkoxy, phenyl, etc. or C ^{T is} absent; and B ^T represents phenyl, C5-16 alkyl, etc. (only the necessary parts of the symbol definitions are selected);

its pharmaceutically acceptable salt and its hydrate are useful as agonists of EDG-1 (see WO 03/062248 and WO 03/062252).

Also, as an agonist of EDG-1, a carboxylic acid derivative represented by the formula (Z) is known:

представляет собой простую связь или двойную связь, его пролекарство или его нетоксичная соль (WO 02/092068).where R ^1Z represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl; ring A ^Z represents a C5-7 monocyclic carbocyclic group or a 5-7-membered monocyclic heterocyclic group 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 represents a hydrogen atom or C1-8 alkyl; R ^2Z represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl; R ^3Z represents a hydrogen atom or C1-8 alkyl; R ^4Z represents a hydrogen atom or C 1-8 alkyl, or R ^2Z and R ^4Z may be bonded together to form —CH ₂ CH ₂ - or —CH = CH—; G ^Z represents —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 the like; Q ^Z represents C1-4 alkylene or the like; p ^Z represents 0 or an integer having a value from 1 to 5; q ^Z is an integer of 4 to 6; r ^Z represents 0 or an integer having a value from 1 to 4;

represents a single bond or double bond, its prodrug or its non-toxic salt (WO 02/092068).

Disclosure of the present invention

Immunosuppressants are useful for the prevention and / treatment of inflammatory diseases, allergic diseases and / or rejection during transplantation. However, it is known that many of the currently used immunosuppressants have strong side effects that occur quite often. In addition, the disadvantage of such funds is to reduce the effect of the action of these funds for a short period of time. There are concerns that FTY720, as described above, is also affected by the metabolic enzyme. Moreover, it has been reported that in clinical trials, FTY720 does show side effects, including bradycardia. Therefore, there was an urgent need to develop a drug that exhibits a long-lasting pharmacological effect, has minor side effects, shows high safety and cannot be affected by metabolic enzymes.

As a result of extensive studies conducted on sphigosin-1-phosphate (S1P) receptors useful as drugs, the inventors of the present invention unexpectedly found that the compounds of the present invention have significant binding ability to EDG-6. They also found that some of the compounds of the present invention have potent agonistic activity against EDG-1. In addition, they found that the compounds of the present invention having the ability to bind to EDG-6, in particular the compounds of the present invention having agonistic activity against EDG-1, have an additional effect on reducing the number of lymphocytes in the peripheral blood and immunosuppressive effect . In addition, it was surprisingly discovered that the pharmacological activity of these compounds of the present invention can be maintained for a long time, thus, the present invention was created.

The present invention relates to:

1. The compound represented by formula (I):

where ring A represents a cyclic group;

ring B represents a cyclic group, which may further comprise a substituent (s);

X represents a bond or spacer group containing from 1 to 8 atoms in its main chain, in which one atom in the spacer group, taken together with a substituent in ring B, can form a ring group, which may contain a substituent (s);

Y represents a bond or spacer group containing from 1 to 10 atoms in its main chain, in which one atom in the spacer group, taken together with a substituent in ring B, can form a ring group that may contain a substituent (s);

n is 0 or 1, wherein when n is 0, m is 1 and R ¹ is a hydrogen atom or a substituent, and when n is 1, m is 0 or is an integer of from 1 to 7, and R ¹ is a substituent, wherein when m is 2 or more, the substituents R ¹ are the same or different from each other,

its salt, its solvate or its prodrug.

2. The compound in accordance with the above p. 1, which is a compound represented by formula (I):

where all characters have the meanings indicated in paragraph 1 above, and

where the compound represented by formula (Ia) is excluded:

where R ^1a represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl;

ring A ^a represents a C5-7 monocyclic carbocyclic group or a 5-7-membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom;

E ^a represents —CH ₂ -, —O—, —S— or —NR ^6a -, where R ^6a represents a hydrogen atom or C1-8 alkyl;

R ^2a represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl;

R ^3a represents a hydrogen atom or C1-8 alkyl;

R ^4a represents a hydrogen atom or C1-8 alkyl, or

R ^2a and R ^4a may be coupled together to form —CH ₂ CH ₂ - or —CH = CH—;

G ^a is —CONR ^7a -, —NR ^7a CO—, —SO ₂ NR ^7a -, —NR ^7a SO ₂ -, —CH ₂ NR ^7a - or —NR ^7a CH ₂ -, where R ^7a represents a hydrogen atom C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1, and Cyc1 represents a C5-7 monocyclic carbocyclic group or a 5-7 membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom;

Q ^a represents C1-4 alkylene or

where J ¹ , J ² , J ³ and J ⁴ each independently represents a carbon atom or a nitrogen atom, where the number of nitrogen atoms is 2 or less; R ^5a represents (1) C1-8 alkyl, (2) halogen atom, (3) nitro, (4) cyano, (5) trifluoromethyl, (6) trifluoromethoxy, (7) phenyl, (8) tetrazolyl, (9 ) -OR ^9a , (10) -SR ^10a , (11) -COOR ^11a , (12) -NR ^12a R ^13a , (13) -CONR ^14a R ^15a , (14) -SO ₂ NR ^16a R ^17a , (15 ) -NR ^18a COR ^19a , (16) -NR ^20a SO ₂ R ^21a , (17) -SO ₂ R ^22a or (18) -OP (O) (OR ^23a ) ₂ , where R ^9a - R ^18a , R ^20a and R ^23a each independently represents a hydrogen atom, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted with Cyc2, or R ^12a and R ^13a , R ^14a and R ^15a or R ^16a and R ^17a , taken together with the atom the nitrogen to which they are attached form a 5-7 membered monocyclic heterocyclic group containing one or two nitrogen atoms, one n oxygen atom and / or one sulfur atom, wherein said heterocyclic group may be substituted with C1-8 alkyl, hydroxy or amino; R ^19a and R ^21a each independently represents C1-8 alkyl, Cyc2 or C1-8 alkyl substituted with Cyc2; R ^22a is hydroxy, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted with Cyc2; and Cyc2 represents a C5-7 monocyclic carbocyclic group or a 5-7-membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom;

p represents 0 or an integer having a value from 1 to 5;

q is an integer of 4 to 6;

r represents 0 or an integer having a value from 1 to 4;

s is 0 or an integer having a value from 1 to 4; and

представляет собой простую связь или двойную связь.

represents a single bond or double bond.

3. The compound in accordance with the above p. 2, which is represented by formula (IA):

where Y ¹ and Y ² each independently represents a bond or spacer group containing from 1 to 9 atoms in its main chain, where the total number of atoms of the main chains of Y ¹ and Y ² is 9 or less;

R ⁷ represents a hydrogen atom or a substituent or, taken together with one atom in the spacer group represented by Y ¹ and / or Y ² , forms a nitrogen-containing heterocyclic group which may contain a substituent (s); and

other symbols have the meanings indicated in paragraph 1 above.

4. The compound in accordance with the above p. 2, which is represented by formula (IB):

where the ring B ¹ represents a nitrogen-containing heterocyclic group which may contain a substituent (s), where the nitrogen atom in the spacer group represented by Y is combined with a substituent in the ring B and Y ¹ ; and

other symbols have the meanings indicated in paragraphs 1 and 3 above.

5. A compound according to the above 2, wherein ring A is a benzene, indane, indene or naphthalene ring.

6. The compound according to the above 2, wherein ring B is a C5-12 monocyclic or bicyclic carbocyclic group which may contain substituent (s).

7. The compound according to the above 6, wherein ring B is a benzene or naphthalene ring, which may contain substituent (s).

8. The compound according to the above 2, wherein ring B is a 5-12 membered monocyclic or bicyclic heterocyclic group which contains from 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and may be partially or fully saturated.

9. The compound according to the above 2, wherein ring B is dihydronaphthalene, indene, 6,7-dihydro-5H-benzo [7] annululene, pyridine, indole, chromene, benzofuran, benzothiophene, benzoxazole, dihydrobenzoxenoic, tetrahydroisoin , isoindoline or tetrahydrobenzazepine ring, which may contain substituent (s).

10. The compound according to the above 4, wherein the nitrogen-containing heterocyclic group represented by the B ¹ ring is a pyrrole, tetrahydropyridine, dihydropyrrole or tetrahydroazepine ring.

11. The compound according to the above 2, wherein X is a divalent group containing from 1 to 8 atoms in its main chain, which is from 1 to 4 combinations selected from the group consisting of C1-8 alkylene, which may be substituted, C2-8 alkenylene which may be substituted, a nitrogen atom that may be substituted, -CO-, -O-, C3-6 cycloalkylene which may be substituted, and phenylene which may be substituted.

12. The compound according to the above 11, wherein X is —CH ₂ -, - (CH ₂ ) ₂ -, - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ -, - (CH ₂ ) ₅ -, - (CH ₂ ) ₆ -, - (CH ₂ ) ₇ -, - (CH ₂ ) ₈ -, -CH ₂ -O-, - (CH ₂ ) ₂ -O-, - (CH ₂ ) ₃ -O-, - (CH ₂ ) ₄ -O-, - (CH ₂ ) ₅ -O-, -CH = CH-CH ₂ -O- or -cyclopropylene-CH ₂ -O-, each of which may be substituted where the right side of each group is associated with ring B.

13. The compound according to the above 2, wherein Y is a divalent group containing from 1 to 10 atoms in its main chain, which is from 1 to 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 that may be substituted, -CO-, -O-, -S-, phenylene which may be substituted , - (aziridine, which may be substituted) -, - (azetidine, which may be substituted) -, - (pyrrolidine, which may be ameschen) -, - (piperidine which may be substituted) -, - (piperazine which may be substituted) - and - (tetrahydropyridine which may be substituted) -.

14. The compound according to the above 13, wherein Y is - (CH ₂ ) ₃ —NHCH ₂ -, - (CH ₂ ) ₃ —NCH ₃ —CH ₂ -, - (CH ₂ ) ₃ —NH— (CH ₂ ) ₂ -, - (CH ₂ ) ₂ -NH- (CH ₂ ) ₂ -, - (CH ₂ ) ₂ -CONHCH ₂ -, - (CH ₂ ) ₂ -CONH- (m-phenylene) -, -CR ^Y1 = CH-CH ₂ -NH- (CH ₂ ) ₄ -, -CR ^Y1 = CH-CH ₂ -NH- (CH ₂ ) ₅ -, -CR ^Y1 = CH-CH ₂ -NH- (CH ₂ ) ₂ -, -CH = CR ^Y1 -CH ₂ -NH- (CH ₂ ) ₂ -, -CR ^Y1 = CH-CH ₂ -NH-CH ₂ -, -CH ₂ - (azetidine) -, - (CH ₂ ) ₂ - (azetidine) -, - (CH ₂ ) ₃ - (azetidine) -, -CR ^Y1 = CH-CH ₂ - (azetidine) -, -CH = CR ^Y1 -CH ₂ - (azetidine) -, - ( CH ₂ ) ₃ - (piperidine) - or -CR ^Y1 = CH-CH ₂ - (piperidine) -, each of which may be substituted, where R ^Y1 represents a hydrogen atom, a halogen atom or C1-4 alkyl, which may be substituted by 1-3 halogen atoms, and Right side of each group is connected to the ring B.

15. The compound in accordance with the above p. 3, where Y ¹ represents a divalent group containing from 1 to 4 atoms in its main chain, which represents from 1 to 4 combinations selected from the group comprising C1-3 alkylene and -CO-.

16. A compound according to the above 15, wherein Y ¹ is —CH ₂ -, - (CH ₂ ) ₂ -, - (CH ₂ ) ₂ —CO—, —CO— (CH ₂ ) ₂ -, or - (CH ₂ ) ₃ -, each of which may be substituted.

17. The compound in accordance with the above p. 3, where Y ² represents a divalent group containing from 1 to 5 atoms in its main chain, which represents from 1 to 4 combinations selected from the group comprising C1-3 alkylene, which may be substituted, and phenylene, which may be substituted.

18. The compound according to the above 17, wherein Y ² is —CH ₂ -, - (CH ₂ ) ₂ - or - (m-phenylene) -, each of which may be substituted.

19. The compound according to the above 2, wherein the substituent represented by R ¹ is a halogen atom, C1-20 alkyl which may be substituted, or C1-20 alkyloxy which may be substituted.

20. The compound according to the above p. 19, where the substituent represented by R ¹ is fluoro, chloro, bromo, methyl, trifluoromethyl or methoxy.

21. The compound in accordance with the above p. 3, where R ⁷ represents a hydrogen atom or C1-20 alkyl, which may be substituted.

22. A compound according to the above 2, which is a compound represented by the formula (I-S-3a):

where X ^S has the same meaning as indicated for X in claim 1 above, where X ^{S is} not - (CH ₂ ) _q -E ^a -; R ^S0 , R ^S1 , R ^S2 , R ^S3 , R ^S4 , R ^S5 , R ^S6 , R ^S7 , R ^S8 , R ^S9 , R ^S10 and R ^S11 each independently represents a hydrogen atom, a halogen atom or C1-4 alkyl, which may be substituted by 1-3 halogen atoms; E ^a , q and other symbols have the meanings indicated above in paragraphs 1 and 2, or

formula (I-S-7a):

where each of R ^S0 , R ^S1 , R ^S2 , R ^S3 , R ^S4 , R ^S5 and R ^S6 has the above meaning; R ^S12 , R ^S13 , R ^S14 and R ^S15 each independently represents a hydrogen atom, a halogen atom or C1-4 alkyl, which may be substituted by 1-3 halogen atoms; E ^a , q and other symbols have the meanings indicated in paragraphs 1 and 2 above.

23. The compound in accordance with the above p. 2, which is a compound of formula (I-T):

where R ^S16 , R ^S17 , R ^S18 , R ^S19 and R ^S20 each independently represents a hydrogen atom, a halogen atom or C1-4 alkyl, which may be substituted by 1-3 halogen atoms; and other symbols have the meanings indicated above in paragraphs 1, 2 and 22.

24. The compound in accordance with the above p. 2, which is a compound of formula (I-U):

where R ^S21 , R ^S22 , R ^S23 , R ^S24 , R ^S25 and R ^S26 each independently represents a hydrogen atom, a halogen atom or C1-4 alkyl, which may be substituted by 1-3 halogen atoms; and other symbols have the meanings indicated above in paragraphs 1, 2 and 22.

25. The compound in accordance with the above p. 2, which is a

(1) N - {(2E) -3- [4- (3-phenylpropoxy) phenyl] prop-2-enyl} -β-alanine,

(2) N - {[6- (3-phenylpropoxy) -2-naphthyl] methyl} -β-alanine,

(3) 1 - {[6- (3-phenylpropoxy) -2-naphthyl] methyl} azetidine-3-carboxylic acid,

(4) 1 - {[6- (3-phenylpropoxy) -2-naphthyl] methyl} piperidine-4-carboxylic acid,

(5) N - {(2E) -3- [2-methyl-4- (3-phenylpropoxy) phenyl] prop-2-enyl} -β-alanine,

(6) 1 - {(2E) -3- [4- (3-phenylpropoxy) phenyl] -2-propenyl} piperidine-4-carboxylic acid,

(7) 1 - {(2E) -3- [4- (3-phenylpropoxy) phenyl] -2-propenyl} azetidine-3-carboxylic acid,

(8) N- {3- [4- (3-phenylpropoxy) phenyl] propyl} -β-alanine,

(9) 3 - ({((2E) -3- [4- (3-phenylpropyl) phenyl] -2-butenyl} amino) propanoic acid,

(10) 3 - ({(2E) -3- [4- (3-cyclohexylpropoxy) -2-methylphenyl] -2-propenyl} amino) propanoic acid,

(11) 1 - {[1-methyl-6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid,

(12) N - {[1- (5-phenylpentyl) -1H-indol-5-yl] methyl} -β-alanine,

(13) 3- [4- [4- (3-phenylpropoxy) phenyl] -3,6-dihydropyridin-1 (2H) -yl] propanoic acid,

(14) 1- (6- [3- (4-chlorophenyl) propoxy] -1-methyl-3,4-dihydro-2-naphthalenylmethyl) -3-azetidinecarboxylic acid or

(15) 1- (6- [3- (4-fluorophenyl) propoxy] -1-methyl-3,4-dihydro-2-naphthalenylmethyl) -3-azetidinecarboxylic acid.

26. The compound according to the above 1, which is

(1) N - ((2E) -3- {2-methyl-4 - [(5-phenylpentyl) oxy] phenyl} prop-2-enyl) -β-alanine,

(2) N - ((2E) -3- {4 - [(5-phenylpentyl) oxy] phenyl} -2-propenyl) -β-alanine or

(3) 3 - ({[1-methyl-6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} amino) propanoic acid.

27. A pharmaceutical composition that comprises a compound represented by formula (I) in claim 1 above, a salt thereof, a solvate thereof, or a prodrug thereof.

28. The pharmaceutical composition in accordance with the above p. 27, which is an agent that binds to the S1P receptor.

29. The pharmaceutical composition in accordance with the above p, which is an agent that binds to the EDG-6 receptor, which may be capable of binding to EDG-1.

30. The pharmaceutical composition according to paragraph 29 above, wherein the EDG-6 binding agent, which may have the ability to bind to EDG-1, is an EDG-6 agonist that may have agonistic activity against EDG-1 .

31. The pharmaceutical composition in accordance with the above p. 27, which is an agent for the prevention and / or treatment of a disease associated with EDG-1 and / or EDG-6.

32. The pharmaceutical composition according to the above p, where the disease associated with EDG-1 and / or EDG-6 is rejection during transplantation, an autoimmune disease and / or allergic disease.

33. The pharmaceutical composition in accordance with paragraph 31 above, wherein the disease associated with EDG-1 and / or EDG-6 is rejection during transplantation of a kidney, liver, heart, lung, skin graft, cornea, bone, bone cell brain and / or cells of pancreatic islets, collagen disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, Crohn's disease, autoimmune diabetes, pulmonary fibrosis, atopic dermatitis and / or asthma.

34. The pharmaceutical composition in accordance with the above p. 27, which is an immunosuppressant.

35. The pharmaceutical composition in accordance with the above p. 27, which is an agent that causes lymphopenia.

36. The pharmaceutical composition in accordance with the above paragraphs 28, 31, 34 and 35, which includes

(1) 2- [3- (4- (5-phenylpentyloxy) phenyl) propanoylamino] acetic acid,

(2) 3- [3- (4- (5-phenylpentyloxy) phenyl) propylamino] propanoic acid,

(3) 3- [2- (4- (5-phenylpentyloxy) phenyl) ethylamino] propanoic acid,

(4) 2- [3- (4- (5-phenylpentyloxy) phenyl) propylamino] acetic acid,

(5) 2- [N-methyl-3- (4- (5-phenylpentyloxy) phenyl) propylamino] acetic acid,

(6) N - ((2E) -3- {2-methyl-4 - [(5-phenylpentyl) oxy] phenyl} prop-2-enyl) -β-alanine,

(7) N - ((2E) -3- {4 - [(5-phenylpentyl) oxy] phenyl} -2-propenyl) -β-alanine,

(8) 3 - ({[1-methyl-6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} amino) propanoic acid,

(9) 3-carboxyl-5- [3- (4- (5-phenylpentyloxy) phenyl) propanoylamino] benzoic acid or

(10) 2-chloro-5- [3- (2-fluoro-4- (5-phenylpentyloxy) phenyl) propanoylamino] benzoic acid,

their salts, their solvates or their prodrugs.

37. A drug comprising a compound represented by formula (I) according to the above 1, a salt thereof, a solvate thereof or a prodrug thereof in combination with one or at least two agents selected from the group consisting of an antimetabolite, an alkylating agent , T cell activation inhibitor, calcineurin inhibitor, proliferation signal inhibitor, steroid, immunosuppressive agent, antibody used for immunosuppression, rejection treatment agent, antibiotic, antiviral agent and antifungal howling means.

38. An immunosuppressant and / or agent that causes lymphopenia, which includes a compound having the ability to bind to EDG-6 and which may have the ability to bind to EDG-1.

39. The immunosuppressant and / or agent that causes lymphopenia, according to the above p, which is a means for the prevention and / or treatment of rejection during transplantation, autoimmune disease and / or allergic disease.

40. A method for the prevention and / or treatment of a disease associated with EDG-1 and / or EDG-6 in a mammal, which comprises administering to the mammal an effective amount of a compound represented by formula (I) according to the above 1, a salt thereof, a solvate thereof or its prodrugs.

41. A method for suppressing immunity and / or inducing lymphopenia in a mammal, which method comprises administering to the mammal an effective amount of a compound represented by formula (I) according to the above 1, a salt thereof, a solvate thereof or a prodrug thereof.

42. The use of the compound represented by formula (I) according to the above 1, its salt, solvate or prodrug thereof for the manufacture of a medicament for the prevention and / or treatment of a disease associated with EDG-1 and / or EDG-6.

43. The use of the compound represented by formula (I) according to the above 1, its salt, its solvate or its prodrug to obtain an immunosuppressant and / or agent that causes lymphopenia.

44. A drug comprising a compound having the ability to bind to the S1P receptor.

45. The drug according to the above item 44, which is an immunosuppressant and / or agent that causes lymphopenia.

46. The drug according to the above p, where the S1P receptor is EDG-1 and EDG-6.

47. The drug according to the above p, where the S1P receptor is EDG-6.

48. The drug according to the above p, where the compound having the ability to bind to EDG-1 and EDG-6, is an agonist of EDG-1 and an agonist of EDG-6.

49. The drug according to the above p, where the compound having the ability to bind to EDG-6, is an agonist of EDG-6.

50. The drug according to the above item 45, which is an agent for the prevention and / or suppression of rejection.

51. The drug according to the above p. 50, where rejection is transplant rejection, T-cell-mediated rejection, acute rejection and / or chronic rejection.

52. The drug according to the above p, where the graft is a transplant of an organ, tissue and / or cells.

53. The drug according to the above p, where the organ is a kidney, liver, heart and / or lung, the tissue is a skin graft, cornea and / or bone, and the cells are bone marrow cells and / or cells of pancreatic islets.

54. The drug according to the above p, which is an agent for the prevention and / or treatment of an autoimmune disease and / or allergic disease.

55. The drug according to the above p. 54, where the allergic disease is atopic dermatitis.

56. The drug of claim 45, wherein the lymphopenia causing agent is an agent for activating homing of lymphocytes into the secondary lymphatic tissue, an agent for suppressing lymphocyte recirculation from lymph nodes into the blood, or an agent for protecting lymphocytes in peripheral blood in the treatment of cancer .

57. A drug comprising a compound having the ability to bind to the S1P receptor, in combination with one or at least two agents selected from the group consisting of antimetabolite, alkylating agent, T-cell activation inhibitor, calcineurin inhibitor, signal inhibitor proliferations, steroid, immunosuppressant, antibody used in immune suppression, rejection medication, antibiotic, antiviral agent and antifungal agent.

58. A method for producing a compound represented by formula (I), a salt thereof, a solvate thereof, or a prodrug thereof; etc.

As used herein, S1P means sphingosine-1-phosphate ((2S, 3R, 4E) -2-amino-3-hydroxyoctadec-4-enyl-1-phosphate). EDG means the gene for endothelial differentiation and is a generic term that includes the genes EDG-1 - EDG-8. Of these EDGs, the genes EDG-1, EDG-3, EDG-5, EDG-6, and EDG-8 (each individually named S1P ₁ , S1P ₃ , S1P ₂ , S1P _4, and S1P _5, respectively) are considered S1P receptors.

As used herein, a “receptor-binding compound” includes agonists, antagonists, and inverse agonists.

In the present description, an agonist includes full agonists and partial agonists.

As used herein, a disease associated with EDG-6 includes, for example, transplant rejection, organ transplant rejection, transplant versus host disease, autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, etc.), allergic diseases ( atopic dermatitis, asthma, etc.), inflammation, infection, ulcers, lymphomas, malignant tumors, leukemia, arteriosclerosis, diseases associated with lymphocyte infiltration into tissue, etc.

In the present description, an EDG-1 related disease includes, for example, acute heart failure, angina pectoris, stroke, traumatic injuries, genetic diseases, peripheral arterial diseases such as arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease or diabetic neuropathy, sepsis, angiitis , nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous diseases, varicose veins, such as hemorrhoids, anal fissures, anal fistula; stratified aortic aneurysm, DIC (disseminated intravascular coagulation), pleurisy, congestive heart failure or multiple organ failure, bedsores, burns, chronic ulcerative colitis, Crohn’s disease, osteoporosis, pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, cirrhosis, cirrhosis, cirrhosis, cirrhosis, cirrhosis, cirrhosis, cirrhosis, cirrhosis, cirrhosis, cirrhosis, cirrhosis etc. EDG-1 is also involved in the preoperative, postoperative and / or prognostic activation of blood vessels accompanying transplantation of various organs, for example, in activating the adhesion of transplanted organs, for example, in heart transplantation, kidney transplantation, skin transplantation or liver transplantation.

In the present description, rejection during transplantation means acute rejection that occurs within 3 months after transplantation, chronic rejection that occurs after a specified period, and the disease transplant against the host.

As used herein, graft means a transplanted organ (e.g., kidney, liver, heart, lung, small intestine, etc.), transplanted tissue (e.g., skin graft (e.g., full-thickness graft, epidermal graft, derma graft, graft) Davis, etc.), cornea, bone, germinal tissue, etc.) or transplanted cells (e.g., bone marrow cells, hematopoietic stem cells, peripheral blood stem cells, spinal cord blood stem cells, cells of pancreatic islets, Langerhans cells that are part of pancreatic islet cells, hepatocytes, nerve cells, intestinal epithelial cells, etc.). Preferred organs include kidney, liver, heart, and lung. As preferred tissues, skin graft and cornea can be mentioned. As preferred cells, bone marrow cells and pancreatic islet cells can be mentioned.

As used herein, T-cell-mediated means that T-cells are involved at any stage in the onset, exacerbation or duration of the disease.

In the present description, an autoimmune disease includes, for example, collagen disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, nephrotic syndrome, lupus nephritis, Sjogren's syndrome, scleroderma, multiple myositis, psoriasis, inflammatory bowel disease, Crohn's disease, mixed tissue disease primary myxedema, Addison’s disease, hypolastic anemia, autoimmune hemolytic anemia, autoimmune thrombopenia, autoimmune diabetes (type I diabetes), uveitis, antireceptor th disease, myasthenia gravis, thyrotoxicosis, thyroiditis, Hashimoto's disease, etc.

As used herein, an allergic disease includes, for example, atopic dermatitis, asthma, rhinitis, conjunctivitis, hay fever, and the like. Atopic dermatitis may be mentioned as a preferred allergic disease.

As used herein, an immunosuppressant means a medicament for use in the prophylaxis and / or treatment of transplant rejection, autoimmune disease, various malignant tumors, cancer, allergic diseases, etc. As such a medicine, an antimetabolite, an alkylating agent, a T-cell activation inhibitor (T-cell suppressor), a calcineurin inhibitor, a proliferation signal inhibitor, a steroid, an antibody used in immune suppression, other drugs for treating rejection, etc. can be used. P.

As used herein, an agent causing lymphopenia means a drug having the effect of decreasing the number of lymphocytes in the peripheral blood, decreasing the circulation of lymphocytes, decreasing the number of penetrating lymphocytes, activating the homing of lymphocytes into the secondary lymphatic tissue, inhibiting the recirculation of lymphocytes from the lymph nodes into the blood, inhibiting the enzyme in ways of nucleic acid synthesis of lymphocytes (pyrimidine metabolism system and purine metabolism system), etc.

In the present description, secondary lymphatic tissue includes, for example, lymph nodes, Peyer's patches (intestinal lymphatic tissue), spleen, and the like.

In the present description, the effect of activating homing of lymphocytes into the secondary lymphatic tissue means activation of the migration of lymphocytes into the secondary lymphatic tissue, enhancing the separation of lymphocytes in the secondary lymphatic tissue, prolonging the retention of lymphocytes in the secondary lymphatic tissue, and the like. Thanks to such effects, the number of lymphocytes can be reduced in the area of inflammation or rejection, etc.

In the present description, the effect of protecting lymphocytes in peripheral blood during a course of cancer therapy means the effect of preliminary homing of lymphocytes in peripheral blood into the secondary lymphatic tissue before cancer therapy (in particular, chemotherapy, radiotherapy, etc.), thus ensuring the protection of lymphocytes . Such an effect includes the protection of lymphocytes at the pre-transplant stage of administration of a large amount of an anti-cancer agent. It is known that treatment of cancer with chemotherapy, etc. using an anti-cancer agent is accompanied by serious side effects, such as decreased hematopoietic cell function, which makes the patient susceptible to infections. Such side effects can be reduced by activating the function described above.

As used herein, a cyclic group is, for example, a carbocyclic group or a heterocyclic group.

As used herein, a carbocyclic group is, for example, a C3-15 carbocyclic group. A C3-15 carbocyclic group includes a C3-15 mono-, bi- or tricyclic carbocyclic aryl, a partially or fully saturated carbocyclic group, a bicyclic carbocyclic group containing a spiro bond and a bridged bicyclic carbocyclic group. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, tsiklononanovoe, tsiklodekanovoe, tsikloundekanovoe, cyclododecane, tsiklotridodekanovoe, tsiklotetradekanovoe, tsiklopentadekanovoe, cyclopentene, cyclohexene, tsiklogeptenovoe, tsiklooktenovoe, cyclopentadiene, cyclohexadiene, tsiklogeptadienovoe, tsiklooktadienovoe, benzene, pentalene, pergidropentalenovoe, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, di hydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, 6,7-dihydro-5H-benzo [7] annulled, 5H-benzo [7] annulled, heptalene, perhydroheptalene, biphenylene, az-indacene, sec-indacene, acenaphthalene, acenaphthene, phenanthrene, anthracene, spiro [4,4] nonanoic, spiro [4,5] decanoic, spiro [5,5] undecano, bicyclo [2,2,1] heptane, bicyclo [2,2,1] hept-2- hen, bicyclo [3,1,1] heptane, bicyclo [3,1,1] hept-2-ene, bicyclo [2,2,2] octane, bicyclo [2,2,2] oct-2-ene, adamantane and noradamantane rings, etc.

As used herein, a C5-12 monocyclic or bicyclic carbocyclic group is, for example, a C5-12 monocyclic or bicyclic carbocyclic aryl that is partially or fully saturated. Examples include cyclopentane, cyclohexane, cycloheptane, cyclooctane, tsiklononanovoe, tsiklodekanovoe, tsikloundekanovoe, cyclododecane, tsiklotridodekanovoe, tsiklotetradekanovoe, tsiklopentadekanovoe, cyclopentene, cyclohexene, tsiklogeptenovoe, tsiklooktenovoe, cyclopentadiene, cyclohexadiene, tsiklogeptadienovoe, tsiklooktadienovoe, benzene, pentalene, pergidropentalenovoe, azulene, pergidroazulenovoe, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaph talin, perhydronaphthalene, 6,7-dihydro-5H-benzo [7] annululene, 5H-benzo [7] annululene, heptalene and perhydroheptalene ring, etc.

As used herein, a C5-7 monocyclic carbocyclic group is, for example, C5-7 a monocyclic carbocyclic aryl, which may be partially or fully saturated. Examples include cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene and benzene rings and the like.

In the present description, a heterocyclic group is, for example, a 3-15 membered heterocyclic group containing from 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. A 3-15 membered heterocyclic group containing from 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom includes, for example, a 3-15 membered monocyclic, bicyclic or tricyclic heterocyclic aryl, a bicyclic heterocyclic group containing a spiro a bond, and a bicyclic heterocyclic group containing a bridging bond, each of which contains from 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and may be partially or fully saturated. Examples include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiazole, azazole, azazole, azazole, isazazole, isazazole, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzene iofenovoe, izobenzotiofenovoe, ditianaftalinovoe, indazole, quinoline, isoquinoline, hinolizinovoe, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzoksepinovoe, benzoksazepinovoe, benzoksadiazepinovoe, benzotiepinovoe, benzothiazepine, benzotiadiazepinovoe, benzazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, β-carboline, acridine, phenazine, dibenzofuran, xanthene, dibenzotiofenovoe, phenothiazine, fenoksazinovoe, fenoksatiinovoe, tiantrenovoe, fenantridinovoe, phenanthroline, pyrimidine, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazolinovoe, triazolidinovoe, tetrazolinovoe, tetrazolidinovoe, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrim ins digidropiridazinovoe, tetragidropiridazinovoe, pergidropiridazinovoe, digidroazepinovoe, tetragidroazepinovoe, perhydroazepin, digidrodiazepinovoe, tetragidrodiazepinovoe, pergidrodiazepinovoe, oxirane, oxetane, digidrofuranovoe, tetrahydrofuran, digidropiranovoe, tetrahydropyran, digidrooksepinovoe, tetragidrooksepinovoe, pergidrooksepinovoe, tiiranovoe, tietanovoe, digidrotiofenovoe, tetrahydrothiophene, digidrotiopiranovoe, tetragidrotiopiranovoe, dihydrothiopine, tetrahydrothiopine, p rgidrotiepinovoe, digidrooksazolnoe, tetragidrooksazolnoe (oxazolidine), digidroizoksazolnoe, tetragidroizoksazolnoe (izoksazolidinovoe) digidrotiazolnoe, tetragidrotiazolnoe (thiazolidine) digidroizotiazolnoe, tetragidroizotiazolnoe (izotiazolidinovoe) digidrofurazanovoe, tetragidrofurazanovoe, digidrooksadiazolnoe, tetragidrooksadiazolnoe (oksadiazolidinovoe) digidrooksazinovoe, tetragidrooksazinovoe, digidrooksadiazinovoe, tetragidrooksadiazinovoe, digidrooksazepinovoe tetrahydrooxazepine, per gidrooksazepinovoe, digidrooksadiazepinovoe, tetragidrooksadiazepinovoe, pergidrooksadiazepinovoe, digidrotiadiazolnoe, tetragidrotiadiazolnoe (tiadiazolidinovoe) digidrotiazinovoe, tetrahydrothiazine, digidrotiadiazinovoe, tetragidrotiadiazinovoe, digidrotiazepinovoe, tetragidrotiazepinovoe, pergidrotiazepinovoe, digidrotiadiazepinovoe, tetragidrotiadiazepinovoe, pergidrotiadiazepinovoe, morpholine, thiomorpholine, oksatianovoe, indoline, isoindoline, dihydrobenzofuran, pergidrobenzofuranovoe, dihydro izobenzofuranovoe, pergidroizobenzofuranovoe, digidrobenzotiofenovoe, pergidrobenzotiofenovoe, digidroizobenzotiofenovoe, pergidroizobenzotiofenovoe, digidroindazolnoe, pergidroindazolnoe, digidrohinolinovoe, tetrahydroquinoline, pergidrohinolinovoe, digidroizohinolinovoe, tetrahydroisoquinoline, pergidroizohinolinovoe, digidroftalazinovoe, tetragidroftalazinovoe, pergidroftalazinovoe, digidronaftiridinovoe, tetragidronaftiridinovoe, pergidronaftiridinovoe, digidrohinoksalinovoe, tetragidrohinoksalinovoe, Perge drohinoksalinovoe, digidrohinazolinovoe, tetragidrohinazolinovoe, pergidrohinazolinovoe, digidrotsinnolinovoe, tetragidrotsinnolinovoe, pergidrotsinnolinovoe, benzooksatianovoe, digidrobenzooksazinovoe, digidrobenzotiazinovoe, pirazinomorfolinovoe, digidrobenzoksazolnoe, pergidrobenzoksazolnoe, digidrobenzotiazolnoe, pergidrobenzotiazolnoe, digidrobenzimidazolnoe, pergidrobenzimidazolnoe, digidrobenzazepinovoe, tetragidrobenzazepinovoe, digidrobenzodiazepinovoe, tetragidrobenzodiazepinovoe, benzodioksepanovoe, dig idrobenzoksazepinovoe, tetragidrobenzoksazepinovoe, digidrokarbazolnoe, tetragidrokarbazolnoe, pergidrokarbazolnoe, digidroakridinovoe, tetragidroakridinovoe, pergidroakridinovoe, digidrodibenzofuranovoe, digidrodibenzotiofenovoe, tetragidrodibenzofuranovoe, tetragidrodibenzotiofenovoe, pergidrodibenzofuranovoe, pergidrodibenzotiofenovoe, dioxolane, dioxane, dithiolan, dithiane, dioksaindanovoe, benzodioksanovoe, chromene, chromane, benzoditiolanovoe and benzoditianovoe ring, etc. .P.

In the present description, a 5-12 membered, monocyclic or bicyclic heterocyclic aryl, which contains from 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and may be partially or fully saturated, is, for example, 5-12 a membered monocyclic or bicyclic heterocyclic aryl, a bicyclic heterocyclic group containing a spiro bond, or a bridging group containing a bicyclic heterocyclic group, each of which contains from 1 to 3 heteroatoms selected from oxygens, nitrogen atom and sulfur atom and may be partially or fully saturated. Examples include pyrrole, imidazole, triazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepino, oxazole, isoxazinoazole, thiazinazole, thiazinazole, thiazinazole, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolysine, benzofuran, isobenzofuran, benzothiophene, iso benzothiophene, ditianaftalinovoe, indazole, quinoline, isoquinoline, hinolizinovoe, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzoksepinovoe, digidrobenzoksepinovoe, benzoksazepinovoe, benzoksadiazepinovoe, benzotiepinovoe, benzothiazepine, benzotiadiazepinovoe, benzazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, tria zolinovoe, triazolidinovoe, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, digidropirazinovoe, tetragidropirazinovoe, piperazine, digidropirimidinovoe, tetrahydropyrimidine, pergidropirimidinovoe, digidropiridazinovoe, tetragidropiridazinovoe, pergidropiridazinovoe, digidroazepinovoe, tetragidroazepinovoe, perhydroazepin, digidrodiazepinovoe, tetragidrodiazepinovoe, pergidrodiazepinovoe, digidrofuranovoe, tetrahydrofuran, digidropiranovoe, tetrahydropyranic, digi drooksepinovoe, tetragidrooksepinovoe, pergidrooksepinovoe, digidrotiofenovoe, tetrahydrothiophene, digidrotiopiranovoe, tetragidrotiopiranovoe, digidrotiepinovoe, tetragidrotiepinovoe, pergidrotiepinovoe, digidrooksazolnoe, tetragidrooksazolnoe (oxazolidine), digidroizoksazolnoe, tetragidroizoksazolnoe (izoksazolidinovoe) digidrotiazolnoe, tetragidrotiazolnoe (thiazolidine) digidroizotiazolnoe, tetragidroizotiazolnoe (izotiazolidinovoe) digidrofurazanovoe, tetrahydrofurazan, dihydrooxadiazole, t etragidrooksadiazolnoe (oksadiazolidinovoe) digidrooksazinovoe, tetragidrooksazinovoe, digidrooksadiazinovoe, tetragidrooksadiazinovoe, digidrooksazepinovoe, tetragidrooksazepinovoe, pergidrooksazepinovoe, digidrooksadiazepinovoe, tetragidrooksadiazepinovoe, pergidrooksadiazepinovoe, digidrotiadiazolnoe, tetragidrotiadiazolnoe (tiadiazolidinovoe) digidrotiazinovoe, tetrahydrothiazine, digidrotiadiazinovoe, tetragidrotiadiazinovoe, digidrotiazepinovoe, tetragidrotiazepinovoe, pergidrotiazepinovoe, digidrotiadiaz epinovoe, tetragidrotiadiazepinovoe, pergidrotiadiazepinovoe, morpholine, thiomorpholine, oksatianovoe, indoline, isoindoline, dihydrobenzofuran, pergidrobenzofuranovoe, digidroizobenzofuranovoe, pergidroizobenzofuranovoe, digidrobenzotiofenovoe, pergidrobenzotiofenovoe, digidroizobenzotiofenovoe, pergidroizobenzotiofenovoe, digidroindazolnoe, pergidroindazolnoe, digidrohinolinovoe, tetrahydroquinoline, pergidrohinolinovoe, digidroizohinolinovoe, tetrahydroisoquinoline, pergidroizohinolinovoe, dihydro oftalazinovoe, tetragidroftalazinovoe, pergidroftalazinovoe, digidronaftiridinovoe, tetragidronaftiridinovoe, pergidronaftiridinovoe, digidrohinoksalinovoe, tetragidrohinoksalinovoe, pergidrohinoksalinovoe, digidrohinazolinovoe, tetragidrohinazolinovoe, pergidrohinazolinovoe, digidrotsinnolinovoe, tetragidrotsinnolinovoe, pergidrotsinnolinovoe, benzooksatianovoe, digidrobenzooksazinovoe, digidrobenzotiazinovoe, pirazinomorfolinovoe, digidrobenzoksazolnoe, pergidrobenzoksazolnoe, digidrobenzotiazolnoe, pergidrobenzoti ash, digidrobenzimidazolnoe, pergidrobenzimidazolnoe, digidrobenzazepinovoe, tetragidrobenzazepinovoe, digidrobenzodiazepinovoe, tetragidrobenzodiazepinovoe, benzodioksepanovoe, digidrobenzoksazepinovoe, tetragidrobenzoksazepinovoe, dioxolane, dioxane, dithiolan, dithiane, dioksaindanovoe, benzodioksanovoe, chromane, benzoditiolanovoe and benzoditianovoe ring, etc.

In the present description, a 5-7 membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom, is, for example, a 5-7 membered monocyclic heterocyclic aryl containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom, which may be partially or fully saturated. Examples include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiaine (thiopyran), thiepin, oxazole, isoxazazole, oxazazazole, oxazazazole, oxazazazole, , oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, igidropiridinovoe, tetrahydropyridine, piperidine, digidropirazinovoe, tetragidropirazinovoe, piperazine, digidropirimidinovoe, tetrahydropyrimidine, pergidropirimidinovoe, digidropiridazinovoe, tetragidropiridazinovoe, pergidropiridazinovoe, digidroazepinovoe, tetragidroazepinovoe, perhydroazepin, digidrodiazepinovoe, tetragidrodiazepinovoe, pergidrodiazepinovoe, digidrofuranovoe, tetrahydrofuran, digidropiranovoe, tetrahydropyran, digidrotiofenovoe, tetrahydrothiophene, digidrotiainovoe ( digi rotiopiranovoe) tetragidrotiainovoe (tetragidrotiopiranovoe) digidrooksazolnoe, tetragidrooksazolnoe, digidroizoksazolnoe, tetragidroizoksazolnoe, digidrotiazolnoe, tetragidrotiazolnoe, digidroizotiazolnoe, tetragidroizotiazolnoe, digidrooksadiazolnoe, tetragidrooksadiazolnoe, digidrotiodiazolnoe, tetragidrotiodiazolnoe, tetragidrooksadiazinovoe, tetragidrotiadiazinovoe, tetragidrooksazepinovoe, tetragidrooksadiazepinovoe, pergidrooksazepinovoe, pergidrooksadiazepinovoe, tetragidrotiazepinovoe, tetragid otiadiazepinovoe, pergidrotiazepinovoe, pergidrotiadiazepinovoe, morpholine and thiomorpholine ring, etc.

In the present description, a 5-7-membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom formed by substituents and the nitrogen atom associated with them is, for example, a 5-7-membered monocyclic heterocyclic aryl containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom, which may be partially or fully saturated. Examples include pyrrole, imidazole, pyrazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, digidropirazinovoe, tetragidropirazinovoe, piperazine, digidropirimidinovoe, tetrahydropyrimidine, pergidropirimidinovoe, digidropiridazinovoe, tetragidropiridazinovoe, pergidropiridazinovoe, digidroazepinovoe, tetragidroazepinovoe, perhydroazepin, dihydrodiazepine, tetrahydrodiazepine, perhydrodiasis pin, tetragidrooksazolnoe, tetragidroizoksazolnoe, tetragidrotiazolnoe, tetragidroizotiazolnoe, digidrooksadiazolnoe, tetragidrooksadiazolnoe, digidrotiodiazolnoe, tetragidrotiodiazolnoe, tetragidrooksadiazinovoe, tetragidrotiadiazinovoe, tetragidrooksadiazepinovoe, pergidrooksazepinovoe, pergidrooksadiazepinovoe, tetragidrotiadiazepinovoe, pergidrotiazepinovoe, pergidrotiadiazepinovoe, morpholine and thiomorpholine ring, etc.

In the present description, a cyclic group in a cyclic group, which may additionally contain substituent (s), a cyclic group that can be substituted, and in the “substituted by a cyclic group” has the same meanings as the cyclic group described above.

In the present description, the substituent in “which may contain substituent (s)” is not specifically limited, provided that it is a substituent. Examples include C1-20 alkyl which may be substituted, C2-20 alkenyl which may be substituted, C2- 20 alkynyl which may be substituted, C1-20 alkylidene which may be substituted, a cyclic group which may be substituted, oxo, hydroxy, C1-20 alkyloxy which may be substituted, C2-20 alkenyloxy which may be substituted, C2-20 alkynyloxy, which may be substituted, hydroxy, which m can be protected by a cyclic group which may be substituted, C1-20 acyloxy which may be substituted, thioxo, mercapto, C1-20 alkylthio which may be substituted, C2-20 alkenylthio which may be substituted, C2-20 alkynylthio, which may be substituted, mercapto substituted by a cyclic group which may be substituted, C1-20 alkylsulfinyl which may be substituted, C2-20 alkenylsulfinyl which may be substituted, C2-20 alkynylsulfinyl which may be substituted, sulfinyl substituted by cyclic a group which may be substituted, C1 -20 alkylsulfonyl which may be substituted, C2-20 alkenylsulfonyl which may be substituted, C2-20 alkynylsulfonyl which may be substituted, sulfonyl substituted by a cyclic group which may be substituted, sulfino which may be substituted, sulfo which may be substituted, sulfamoyl, which may be substituted (when two substituents are present, these substituents taken together with the nitrogen atom to which they are attached form a 5-7 membered monocyclic heterocyclic group containing one or two nitrogen atoms, one atom oxygen and / or one sulfur atom (such a heterocyclic group may be substituted with C1-8 alkyl, hydroxy or amino)), carbonyl which may be substituted, carboxy which may be substituted, C1-20 acyl which may be substituted, carbamoyl which can be substituted (when two substituents are present, these substituents taken together with the nitrogen atom to which they are attached form a 5-7 membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and / or one atom sulfur (such a heterocyclic group can be substituted with C1-8 alkyl, hydroxy or amino)), cyano, amidino, which can be substituted (when two substituents are present, these substituents taken together with the nitrogen atom to which they are attached form a 5-7 membered monocyclic heterocyclic a group containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom (such a heterocyclic group may be substituted with C1-8 alkyl, hydroxy or amino)), nitro, nitroso, imino, which may be substituted, amino, which may be substituted (when two substituents are present, these substituents, taken together with the nitrogen atom to which they are bonded, form a 5-7-membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom (such a heterocyclic group may be substituted by C1-8 alkyl, hydroxy or amino)), a halogen atom, and the like.

In the present description, the substituent represented by R ¹ , R ⁷ , R ²⁷ , R ²⁹ , R ³⁰ and R ³¹ has the same meaning as the substituent in the cyclic group, which may further comprise substituent (s) as described above.

In the present description, the substituent in “which may be substituted” is, for example, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1-20 alkylidene, cyclic group, C1-20 alkyl substituted with cyclic group, oxo, hydroxy, C1-20 alkyloxy, C2-20 alkenyloxy, C2-20 alkynyloxy, hydroxy, which may be protected by a cyclic group, C1-20 acylthio, thioxo, mercapto, C1-20 alkylthio, C2-20 alkenylthio, C2-20 alkynylthio, mercapto substituted with a cyclic group, C1-20 alkylsulfinyl, C2-20 alkenylsulfinyl, C2-20 alkynylsulfinyl, sulfinyl substituted with cyclic oh, C1-20 alkylsulfonyl, C2-20 alkenylsulfonyl, C2-20 alkynylsulfonyl, sulfonyl substituted with a cyclic group, C1-20 alkylsulfonyl substituted with a cyclic group, sulfino, sulfo, sulfamoyl, carboxy, C1-20 acyl, C1-20 acyl, substituted by a cyclic group, carbonyl substituted by a cyclic group, carbamoyl, cyano, amidino, nitro, nitroso, imino, amino, halogen atom or the like. They are substituted at any position which may be substituted by any possible number of substituents.

In the present specification, C1-20 alkyl includes, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and their isomers.

In the present specification, C1-8 alkyl includes, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomers.

In the present specification, C2-20 alkenyl includes, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nenedenyl, isomers.

In the present specification, C2-20 alkynyl includes, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptinyl, octynyl, noninyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecinyl, hexadecinyl, heptadecynyl, octadecinyl, nonade isomers.

In the present specification, C1-20 alkylidene includes, for example, methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, decylidene, undecylidene, dodecylidene, tridecylidene, tetradecylidene, pentadecylidene, hedecadecylideneideneidene, heptidecylideneidene, heptidecylideneidene, heptidecylideneidene, heptidecylidene, heptidecylidene, heptidecylidene, heptidecylidene, heptidecylidene, heptidecylidene, heidecidelicideneidene, heidecidelicideneidene, heli and their isomers.

As used herein includes C1-20 alkyloxy, e.g., methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, aykoziloksi and their isomers.

In the present specification, C1-8 alkoxy includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and their isomers.

As used herein includes C2-20 alkenyloxy, such as ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, nonenyloxy, decenyloxy, undecenyloxy, dodetseniloksi, tridecenyloxy, tetradecenyloxy, pentadetseniloksi, geksadetseniloksi, geptadetseniloksi, octadecenyloxy, nonadecenyloxy, aykozeniloksi and isomers.

In the present invention, C2-20 alkynyloxy includes, for example, ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, nonynyloxy, decynyloxy, undecynyloxy, dodecynyloxy, tridecynyloxy, tetradecynoxy, hededecynoxy, hededecynoxy, hededecynoxy, hexadecynoxy isomers.

As used herein includes C1-20 alkylthio, e.g., methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio, undetsiltio, dodecylthio, tridetsiltio, tetradetsiltio, pentadetsiltio, geksadetsiltio, geptadetsiltio, oktadetsiltio, nonadetsiltio, aykoziltio and their isomers.

In the present specification, C2-20 alkenylthio includes, for example, ethenylthio, propenylthio, butenylthio, pentenylthio, hexenylthio, heptenylthio, octenylthio, nonenylthio, decenylthio, undecenylthio, dodecenylthioiodioethioentioethioentioethioentioethioentioethioentioethioentioethioentiomentio isomers.

As used herein, C2-20 alkynylthio includes, for example, etiniltio, propynylthio, butynylthio, Pentynylthio, geksiniltio, geptiniltio, oktiniltio, noniniltio, detsiniltio, undetsiniltio, dodetsiniltio, tridetsiniltio, tetradetsiniltio, pentadetsiniltio, geksadetsiniltio, geptadetsiniltio, oktadetsiniltio, nonadetsiniltio, aykoziniltio and isomers.

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

As used herein, C2-20 alkenylsulfinyl includes, for example, etenilsulfinil, propenilsulfinil, butenilsulfinil, pentenilsulfinil, geksenilsulfinil, geptenilsulfinil, oktenilsulfinil, nonenilsulfinil, detsenilsulfinil, undetsenilsulfinil, dodetsenilsulfinil, tridetsenilsulfinil, tetradetsenilsulfinil, pentadetsenilsulfinil, geksadetsenilsulfinil, geptadetsenilsulfinil, oktadetsenilsulfinil, nonadetsenilsulfinil, aykozenilsulfinil and isomers.

Herein C2-20 alkinilsulfinil includes, for example, etinilsulfinil, propinilsulfinil, butinilsulfinil, pentinilsulfinil, geksinilsulfinil, geptinilsulfinil, oktinilsulfinil, noninilsulfinil, detsinilsulfinil, undetsinilsulfinil, dodetsinilsulfinil, tridetsinilsulfinil, tetradetsinilsulfinil, pentadetsinilsulfinil, geksadetsinilsulfinil, geptadetsinilsulfinil, oktadetsinilsulfinil, nonadetsinilsulfinil, aykozinilsulfinil and isomers.

As used herein, C1-20 alkylsulfonyl includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, nonilsulfonil, detsilsulfonil, undetsilsulfonil, dodetsilsulfonil, tridetsilsulfonil, tetradetsilsulfonil, pentadetsilsulfonil, hexadecylsulfonio, geptadetsilsulfonil, oktadetsilsulfonil, nonadetsilsulfonil, aykozilsulfonil and their isomers.

Herein C2-20 alkenylsulfonyl include, for example, etenilsulfonil, propenilsulfonil, butenilsulfonil, pentenilsulfonil, geksenilsulfonil, geptenilsulfonil, oktenilsulfonil, nonenilsulfonil, detsenilsulfonil, undetsenilsulfonil, dodetsenilsulfonil, tridetsenilsulfonil, tetradetsenilsulfonil, pentadetsenilsulfonil, geksadetsenilsulfonil, geptadetsenilsulfonil, oktadetsenilsulfonil, nonadetsenilsulfonil, aykozenilsulfonil and isomers.

Herein C2-20 alkynylsulfonyl include, for example, etinilsulfonil, propinilsulfonil, butinilsulfonil, pentinilsulfonil, geksinilsulfonil, geptinilsulfonil, oktinilsulfonil, noninilsulfonil, detsinilsulfonil, undetsinilsulfonil, dodetsinilsulfonil, tridetsinilsulfonil, tetradetsinilsulfonil, pentadetsinilsulfonil, geksadetsinilsulfonil, geptadetsinilsulfonil, oktadetsinilsulfonil, nonadetsinilsulfonil, aykozinilsulfonil and isomers.

In the present specification, C1-20 acyl includes, for example, methanoyl, ethanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyanoyl, heptane and their isomers.

In the present specification, C1-20 acyloxy includes, for example, methanoyloxy, ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy, odecylodeoxy, tridecanoyloxy, tetradecanoyloxy, oxydoyloxy, tridecanoyloxy, tridecanoyloxy, tridecanoyloxy, tetradecanoyloxy, pentanoyloxy, tridecanoyloxy, tetradecanoyloxy, pentanoyloxy, tridecanoyloxy, tetradeecoyloxy, and their isomers.

In the present description, the protecting group for hydroxy, which may be protected, has the same meanings as the substituent for “which may be substituted” described above.

In the present description, a halogen atom includes, for example, fluorine, chlorine, bromine and iodine.

In the present description, a bond means that the atoms are directly connected through another atom.

In the present description, a spacer group containing from 1 to 10 atoms in its main chain means a distance where from 1 to 10 atoms are continuously connected in its main chain. In this case, the number of atoms in the form of the main chain should be calculated so that the number of atoms in this main chain is minimal. A spacer group containing from 1 to 10 atoms in its main chain includes, for example, a divalent group containing from 1 to 10 atoms in its main chain, which is from 1 to 4 combinations selected from C1-10 alkylene, which can to be substituted, C2-10 alkenylene which may be substituted, C2-10 alkynylene which may be substituted, nitrogen atom that may be substituted (-NH-), -CO-, -O-, -S-, -SO -, -SO ₂ -, - (a carbocyclic group which may be substituted) -, - (a heterocyclic group which may be substituted) - and the like.

In the present specification, C1-10 alkylene includes, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and their isomers.

In the present specification, C2-10 alkenylene includes, for example, ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene, decenyl and their isomers.

In the present specification, C2-10 alkynylene includes, for example, ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptinylene, octynylene, nonynylene, decynylene and their isomers.

In the present description, a spacer group containing from 1 to 9 atoms in its main chain means a distance where from 1 to 9 atoms are continuously connected in its main chain. In this case, the number of atoms in the form of the main chain should be calculated so that the number of atoms in this main chain is minimal. A spacer group containing from 1 to 9 atoms in its main chain includes, for example, a divalent group containing from 1 to 9 atoms in its main chain, which is from 1 to 4 combinations selected from C1-9 alkylene, which can to be substituted, C2-9 alkenylene which may be substituted, C2-9 alkynylene which may be substituted, nitrogen atom that may be substituted (-NH-), -CO-, -O-, -S-, -SO -, -SO ₂ -, - (a carbocyclic group which may be substituted) -, - (a heterocyclic group which may be substituted) - and the like.

In the present specification, C1-9 alkylene includes, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene and their isomers.

In the present specification, C2-9 alkenylene includes, for example, ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene and their isomers.

In the present description, C2-9 alkynylene includes, for example, ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptinylene, octynylene, nonylene and their isomers.

In the present description, a spacer group containing from 1 to 8 atoms in its main chain means a distance where from 1 to 9 atoms are continuously connected in its main chain. In this case, the number of atoms in the form of the main chain should be calculated so that the number of atoms in this main chain is minimal. A spacer group containing from 1 to 8 atoms in its main chain includes, for example, a divalent group containing from 1 to 8 atoms in its main chain, which is from 1 to 4 combinations selected from C1-8 alkylene, which can to be substituted, C2-8 alkenylene which may be substituted, C2-8 alkynylene which may be substituted, nitrogen atom that may be substituted (-NH-), -CO-, -O-, -S-, -SO -, -SO ₂ -, - (a carbocyclic group which may be substituted) -, - (a heterocyclic group which may be substituted) - and the like.

In the present specification, C1-8 alkylene includes, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and their isomers.

As used herein, C2-8 alkenylene includes, for example, ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene and their isomers.

In the present specification, C2-8 alkynylene includes, for example, ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptinylene, octynylene and their isomers.

In the present specification, C1-3 alkylene includes, for example, methylene, ethylene, trimethylene and their isomers.

As used herein, C3-6 cycloalkylene includes, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and their isomers.

In the present description, a ring group which may contain substituent (s) formed by combining one atom from the spacer group represented by X with a substituent in ring B means a ring group which may contain substituent (s) formed by combining one atom of the spacer group represented by X with a substituent on ring B. The ring group, which may contain a substituent (s), has the same meaning as the cyclic group, which may further contain amestitel (substituents).

As used herein, a ring group which may contain substituent (s) formed by combining one atom from the spacer group represented by Y with a substituent in ring B means a ring group which may contain substituent (s) formed by combining one atom of the spacer group represented by Y with a substituent in ring B. The ring group, which may contain a substituent (s), has the same meaning as the cyclic group, which may further contain amestitel (substituents).

In the present description, a nitrogen-containing heterocyclic group, which may contain substituent (s), formed by combining one atom from the spacer group represented by Y ¹ and / or Y ² , with R ⁷ , means a nitrogen-containing heterocyclic group, which may contain substituent (s), formed by combining one atom from the spacer group represented by Y ¹ and / or Y ² with R ⁷ and the nitrogen atom to which Y ¹ or Y ² is bound. The nitrogen-containing heterocyclic group in the nitrogen-containing heterocyclic group, which may contain substituent (s), includes, for example, a 3-15 membered heterocyclic group, which contains one nitrogen atom and may additionally contain from 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and sulfur atom, etc. A 3-15 membered heterocyclic group, which contains one nitrogen atom and may additionally contain from 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, includes a 3-15 membered monocyclic, bicyclic or tricyclic heterocyclic aryl, a bicyclic heterocyclic a group and a bridging group containing a bicyclic heterocyclic group, each of which contains one nitrogen atom, may additionally contain from 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and It can be partially or fully saturated. Examples include pyrrole, imidazole, triazole, tetrazole, pyrazole, azepine, diazepine, indole, isoindole, indazole, purine, pyrrolopyridine, benzimidazole, benzazepine, benzodiazepine, benzotriazole, carbazole, β-carboline, phenolazinoindin, pyroindirazino pyrindirazino pyrindrazino pyrindirazino pyrazido pyrazido pyrazido pyrazido pyrazido pyrazido pyrazido pyrazido pyrazidoindiazindinoind indolidinoindole, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine, dihydropyrazine, irimidin, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, digidroazepin, tetrahydroazepine, perhydroazepine, digidrodiazepin, tetragidrodiazepin, perhydrodiazepin, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazolyl, tetrahydroisothiazole (isothiazolidine ), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetra idrooksazin, digidrooksadiazin, tetragidrooksadiazin, digidrooksazepin, tetragidrooksazepin, pergidrooksazepin, digidrooksadiazepin, tetragidrooksadiazepin, pergidrooksadiazepin, digidrotiadiazol, tetragidrotiadiazol (thiadiazolidine), dihydrothiazinyl, tetrahydrothiazine, digidrotiadiazin, tetrahydrothiadiazine, digidrotiazepin, tetragidrotiazepin, pergidrotiazepin, digidrotiadiazepin, tetragidrotiadiazepin, pergidrotiadiazepin, morpholine, thiomorpholine, oxathiane , indoline, isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline, those ragidrohinolin, perhydroquinolino, dihydroisoquinoline, tetrahydroisoquinoline, perhydoisoquinoline, dihydrophthalazine, tetrahydrophthalazine, pergidroftalazin, dihydronaphthyridine, tetragidronaftiridin, pergidronaftiridin, dihydroquinoxaline, tetrahydroquinoxaline, pergidrohinoksalin, dihydroquinazoline, tetrahydroquinazoline, pergidrohinazolin, tetragidropirrolopiridin, digidrotsinnolin, tetragidrotsinnolin, pergidrotsinnolin, digidrobenzooksazin, digidrobenzotiazin, pirazinomorfolin, dihydrobenzoxazol, perhydrobenzoxazole, dihydrobenzothiaz ol, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine (2,3,4,5-tetrahydro-1H-2-benzazepine, 2,3,4,5-tetrahydro-1H-3-benzazepine, etc.), digidrobenzodiazepin, tetragidrobenzodiazepin, digidrobenzoksazepin, tetragidrobenzoksazepin, digidrokarbazol, tetrahydrocarbazole, pergidrokarbazol, dihydroacridin, tetrahydroacridine, pergidroakridin, tetrapiridonaftiridin, tetrahydro-β-carboline, digidroazepinoindol, geksagidroazepinoindol, tetragidropirazoloizohinolin, tetragidropirazolonaftiridin, d gidroazepinoindazol, geksagidroazepinoindazol, digidropirazolopiridoazepin, geksagidropirazolopiridoazepin, tetragidropirimidoindol, digidrotiadinoindol, tetragidrotiadinoindol, digidrooksadinoindol, tetragidrooksadinoindol, geksagidroindolidinoindol, digidroindolobenzodiazepin, oktagidroindolohinolizin, geksagidroimidazopiridoindol, geksagidropirrolotiazepinoindol, azaspiro [4.4] nonane, oksazaspiro [4,4] nonane, oksazaspiro [2.5] octane, azaspiro [4,5] decane, 1,3,8-triazaspiro [4,5] decane, 2,7-diazaspiro [4,5] decane, 1,4,9-triazaspiro [5.5] undecane, oxazas pyro [4.5] decane, azaspiro [5.5] undecane, azabicyclo [2.2.1] heptane, azabicyclo [3.1.1] heptane, azabicyclo [3.2.1] octane (8-azabicyclo [ 3,2,1] octane, etc.), azabicyclo [2.2.2] octane (2-azabicyclo [2.2.2] octane, etc.), azabicyclo [2,1,1] hexane (5-azabicyclo [2,1,1] hexane, etc.) and the like.

In the present invention, a nitrogen-containing heterocyclic group, which may contain substituent (s), formed by combining one nitrogen atom from the spacer group represented by Y ¹ with a substituent in ring B, has the same meanings as the nitrogen-containing heterocyclic group described above, which can contain a Deputy (deputies).

In the present invention, ring A is preferably a C3-15 carbocyclic group, more preferably a C5-12 monocyclic or bicyclic carbocyclic group, and even more preferably a benzene, indane, indene or naphthalene ring.

In the present invention, a cyclic group in a cyclic group which may contain substituent (s) represented by ring B is preferably a C3-15 carbocyclic group or a 3-15 membered heterocyclic group, more preferably a C5-12 monocyclic or bicyclic carbocyclic group or a 5-12 membered monocyclic or bicyclic heterocyclic group that contains from 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and may be partially or fully Saturation, and most preferably - benzene, indene, naphthalene, digidronaftalinovoe, 6,7-dihydro-5H-benzo [7] annulenovoe, pyridine, indole, chromene, benzofuran, benzothiophene, benzoxazole, digidrobenzoksepinovoe, tetrahydroisoquinoline, isoindoline or tetragidrobenzazepinovoe ring.

In the present invention, the nitrogen-containing heterocyclic group represented by ring B ¹ is preferably pyrrole, tetrahydropyridine, dihydropyrrole, tetrahydroazepine or the like.

In the present invention, a substituent in a cyclic group which may contain substituent (s) represented by ring B is preferably C1-20 alkyl which may be substituted, C1-20 alkyloxy which may be substituted, carboxy which may be substituted or a halogen atom, and more preferably it is methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, carboxy, fluoro, chloro or trifluoromethyl.

In the present invention, X is preferably a divalent group containing from 1 to 8 atoms in its main chain, which is from 1 to 4 combinations selected from C1-8 alkylene, which may be substituted, C2-8 alkenylene, which may be substituted, a nitrogen atom, which may be substituted (-NH-), -CO-, -O-, C3-6 cycloalkylene, which may be substituted, phenylene, which may be substituted, and the like, and more preferably -CH ₂ -, - (CH ₂ ) ₂ -, - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ -, - (CH ₂ ) ₅ -, - (CH ₂ ) ₆ -, - (CH ₂ ) ₇ -, - (CH ₂ ) ₈ -, -CH ₂ -O-, - (CH ₂ ) ₂ -O-, - (CH ₂ ) ₃ -O-, - (CH ₂ ) ₄ -O-, - (CH ₂ ) ₅ -O-, -CH = CH-C H ₂ -O- or -cyclopropylene-CH ₂ -O-, each of which may be substituted, where the right side of each group binds to ring B.

In the present invention, Y is preferably a divalent group containing from 1 to 10 atoms in its main chain, which is from 1 to 4 combinations selected from C1-10 alkylene, which may be substituted, C2-10 alkenylene, which may be substituted, C2-10 alkynylene which may be substituted, a nitrogen atom which may be substituted (-NH-), -CO-, -O-, -S-, phenylene which may be substituted, - (aziridine, which may be substituted) -, - (azetidine, which may be substituted) -, - (pyrrolidine, which may be substituted) -, - (piperi dyne which may be substituted) -, - (piperazine which may be substituted) -, - (morpholine which may be substituted) -, - (azabicyclo [3,2,1] octane which may be substituted) -, - (azabicyclo [2.2.2] octane which may be substituted) -, - (azabicyclo [2.1.1] hexane which may be substituted) -, - (tetrahydropyridine which may be substituted) -, and etc., and more preferably - (CH ₂ ) ₃ -NHCH ₂ -, - (CH ₂ ) ₃ -NCH ₃ -CH ₂ -, - (CH ₂ ) ₃ -NH- (CH ₂ ) ₂ -, - (CH ₂ ) ₂ -NH- (CH ₂ ) ₂ -, - (CH ₂ ) ₂ -CONHCH ₂ -, - (CH ₂ ) ₂ -CONH- (m-phenylene) -, -CR ^Y1 = CH-CH ₂ -NH- (CH ₂ ) ₄ -, -CR ^Y1 = CH-CH ₂ -NH- (CH ₂ ) ₅ -, -CR ^Y1 = CH-CH ₂ -NH- (CH ₂ ) ₂ -, -CH = CR ^Y1- CH ₂ -NH- (CH ₂ ) ₂ -, -CR ^Y1 = CH-CH ₂ -NH-CH ₂ -, -CH ₂ - (aseti din) -, - (CH ₂ ) ₂ - (azetidine) -, - (CH ₂ ) ₃ - (azetidine) -, -CR ^Y1 = CH-CH ₂ - (azetidine) -, -CH = CR ^Y1 -CH ₂ - (azetidine) -, - (CH ₂ ) ₃ - (piperidine) -, -CR ^Y1 = CH-CH ₂ - (piperidine) -, where R ^Y1 represents a hydrogen atom, a halogen atom, or C1-4 alkyl, which may be substituted by 1-3 halogen atoms, and the right side of each group binds to ring B.

In the present invention, Y ¹ is preferably a divalent group containing from 1 to 4 atoms in its main chain, which is from 1 to 4 combinations selected from C1-3 alkylene, which may be substituted, and -CO-, and more preferably —CH ₂ -, - (CH ₂ ) ₂ -, - (CH ₂ ) ₂ —CO— or - (CH ₂ ) ₃ -, each of which may be substituted.

In the present invention, Y ² is preferably a divalent group containing from 1 to 5 atoms in its main chain, which is from 1 to 4 combinations selected from C1-3 alkylene, which may be substituted, phenylene, which may be substituted, and the like, and more preferably is —CH ₂ -, - (CH ₂ ) ₂ - or - (m-phenylene) -, each of which may be substituted.

In the present invention, the substituent represented by R ¹ is preferably a halogen atom, C1-20 alkyl which may be substituted, or C1-20 alkyloxy which may be substituted, and more preferably fluoro, chloro, bromo, methyl, trifluoromethyl or methoxy.

In the present invention, R ⁷ preferably represents a hydrogen atom or C1-20 alkyl which may be substituted, and more preferably a hydrogen atom or methyl.

In the present invention, a nitrogen-containing heterocyclic group which may contain substituent (s) formed by combining one atom from the spacer group represented by Y ¹ with R ⁷ is preferably piperidine, tetrahydropyridine or pyrazine, each of which may be substituted, or etc., and more preferably tetrahydropyridine, which may contain substituent (s).

In the present invention, a nitrogen-containing heterocyclic group, which may contain substituent (s), formed by combining one atom from the spacer group represented by Y ² with R ⁷ , is azetidine, pyrrolidine, piperidine or tetrahydropyridine, which may be substituted, or the like. p., and more preferably azetidine, which may contain substituent (s).

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

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

As a compound of the present invention having binding ability to the S1P receptor, a compound that is capable of binding to EDG-6 and which may be capable of binding to EDG-1 is preferred. More preferably, the effect of the compound in binding to EDG-1 is agonistic activity.

Of the compounds represented by formula (I) in the present invention, preferred compounds are the carboxylic acid derivatives represented by formula (IA-1):

where all characters have the meanings defined above;

formula (IA-2):

where all characters have the meanings defined above;

formula (IA-3):

where all characters have the meanings defined above;

formula (IA-4):

where all characters have the meanings defined above; and

formula (IB):

where all characters have the meanings defined above;

their prodrugs and their salts.

More preferred compounds are the carboxylic acid derivatives represented by the formula (IA-1-1):

where Y ^1-1 is ethylene, which may contain a substituent (s), propylene, which may contain a substituent (s), or propenylene, which may contain a substituent (s); Y ^2-1 represents ethylene, which may contain a substituent (s); and other symbols have the meanings specified above;

formula (IA-1-2):

where Y ^2-2 represents methylene, which may contain a Deputy (deputies); and other symbols have the meanings specified above;

formula (IA-1-3):

where Y ^1-2 represents methylene, which may contain a Deputy (deputies); and other symbols have the meanings specified above;

formula (IA-2-1):

where the ring D ¹ represents a nitrogen-containing heterocyclic group; Y ^1-3 is methylene, which may contain substituent (s), ethylene, which may contain substituent (s), propylene, which may contain substituent (s), or propenylene, which may contain substituent (s); R ²⁷ represents a hydrogen atom or a substituent; t is 0 or an integer having a value from 1 to 5; and other symbols have the meanings specified above;

formula (IA-2-2):

where the ring D ² represents a nitrogen-containing heterocyclic group; and other symbols have the meanings specified above;

formula (IA-3-1):

where the ring D ³ represents a nitrogen-containing heterocyclic group; Y ^1-4 represents a bond or methylene, which may contain a Deputy (deputies); and other symbols have the meanings specified above;

formula (IA-3-2):

where the ring D ⁴ represents a nitrogen-containing heterocyclic group; and other symbols have the meanings specified above;

formula (IA-3-3):

where the ring D ⁵ represents a nitrogen-containing heterocyclic group; and other symbols have the meanings specified above;

formula (IB-1-1):

where the ring B ^1-1 represents a nitrogen-containing heterocyclic group; and other symbols have the meanings specified above;

formula (IB-1-2)

where ring B ^1-2 is a nitrogen-containing heterocyclic group; and other symbols have the meanings specified above;

the formula (I-1):

where all characters have the meanings defined above;

formula (I-2):

where all characters have the meanings defined above;

formula (I-S-1):

where all characters have the meanings defined above;

formula (I-S-2):

where all characters have the meanings defined above;

formula (I-S-3):

where all characters have the meanings defined above;

formula (I-S-3a):

where all characters have the meanings defined above;

formula (I-S-4):

where all characters have the meanings defined above;

formula (I-S-5):

where all characters have the meanings defined above;

formula (I-S-6):

where all characters have the meanings defined above;

formula (I-S-7):

where all characters have the meanings defined above;

formula (I-S-7a):

where all characters have the meanings defined above;

formula (I-T):

where all characters have the meanings defined above; and

formula (I-U):

where all characters have the meanings defined above;

their prodrugs and their salts.

In the present invention, R ^S0 is preferably a hydrogen atom, fluorine, chlorine, methyl or trifluoromethyl, and more preferably a hydrogen atom, methyl or trifluoromethyl.

A nitrogen-containing heterocyclic group represented by a ring D ¹ , a ring D ³ and a ring D ⁵ includes, for example, a 3-9 membered monocyclic heterocyclic aryl and a bicyclic heterocyclic group containing a bridging group, each of these groups contains one nitrogen atom and may additionally contain one or two heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and may be partially or fully saturated, and the like. Examples include pyrrole, imidazole, triazole, pyrazole, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazolin, triazolidine, pyrazoline, pyrazolidine, dihydropyridinopyridine pyridinopyridine pyridopyridine pyridopyridine pyridopyridinium tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydr isoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazolyl, tetrahydroisothiazole (isothiazolidine), digidrofurazan, tetragidrofurazan, digidrooksadiazol, tetragidrooksadiazol (oxadiazolidine), digidrooksazin, morpholine, digidrooksazepin, tetragidrooksazepin, pergidrooksazepin, digidrooksadiazepin, tetragidrooksadiazepin, pergidrooksadiazepin, digidrotiadiazol, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, di hydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathian, azabicyclo [2.2.1] heptane, azabicyclo [3.1.1] octane, 8-azabicyclo [3.1.1] octane, 8-azab azabicyclo [3.2.1] octane, etc.), azabicyclo [2.2.2] octane (2-azabicyclo [2.2.2] octane, etc.), diazabicyclo [2.2, 2] octane, azabicyclo [2,1,1] hexane (5-azabicyclo [2,1,1] hexane, etc.) and the like.

A nitrogen-containing heterocyclic group represented by a D ² ring and a D ⁴ ring includes, for example, a 4-9 membered monocyclic aryl and a bridged heterocyclic group, each of these groups contains one nitrogen atom and may additionally contain one or two heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and may be partially or fully saturated. Examples include pyrrole, pyrazole, azetidine, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, digidroazepin, tetrahydroazepine, perhydroazepine, digidrodiazepin, tetragidrodiazepin, perhydrodiazepin, dihydroisoxazole, tetrahydroisoxazole ( isoxazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxazepine, tetrahydroox zepin, pergidrooksazepin, digidrooksadiazepin, tetragidrooksadiazepin, pergidrooksadiazepin, dihydrothiazinyl, tetrahydrothiazine, digidrotiazepin, tetragidrotiazepin, pergidrotiazepin, digidrotiadiazepin, tetragidrotiadiazepin, pergidrotiadiazepin, azabicyclo [2.2.1] heptane, azabicyclo [3,1,1] heptane, azabicyclo [3, 2.1] octane (8-azabicyclo [3.2.1] octane, etc.), azabicyclo [2.2.2] octane (2-azabicyclo [2.2.2] octane, etc. ), diazabicyclo [2.2.2] octane, azabicyclo [2.1.1] hexane (5-azabicyclo [2.1.1] hexane) and the like.

The nitrogen-containing heterocyclic group represented by ring B ^1-1 includes, for example, a 4-9 membered monocyclic heterocyclic aryl which contains one nitrogen atom and may additionally contain one or two heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and may be partially or fully saturated, and the like. Examples include pyrrole, imidazole, triazole, pyrazole, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazo , Tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazolyl, tetrahydroisothiazole (isothiazolidine), digidrofurazan, tetragidrofurazan, digidrooksazin, morpholine, tetragidrooksadiazin, digidrooksazepin, tetragidrooksazepin, pergidrooksazepin, digidrooksadiazepin, tetragidrooksadiazepin, pergidrooksadiazepin, dihydrothiazinyl, tetrahydrothiazine, tetrahydrothiadiazine, digidrotiazepin, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, etc.

The nitrogen-containing heterocyclic group represented by ring B ^1-2 includes, for example, a 5-9 membered monocyclic heterocyclic aryl which contains one nitrogen atom and may additionally contain one or two heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and may be partially or fully saturated, and the like. Examples include pyrrole, pyrazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, digidroazepin, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazolyl, tetrahydroisothiazole (isothiazolidine), digidrooksazin, morpholine, digidrooksazepin, tetragidrooksazepin, pergidrooksazepin, digidrooksadiazepin, tetragidrooksadiazepin, pergidrooksadiazepin, dihydrothiazinyl, tetrahydrothiazine, tetrahydrothiadiazine, digidrotiazepin, tetragidrotiazepin, pergidrotiazepin, digidrotiadiazepin, tetragidrotiadiazepin, pergidrotiadiazepin, morpholine, thiomorpholine and the like.

Case studies

in the formula (IA-2-1) include

etc.

Case studies

in the formula (IA-2-2) include

etc.

Case studies

in the formula (IA-3-1) include

etc.

Case studies

in the formula (IA-3-2) include

etc.

Case studies

in the formula (IA-3-3) include

etc.

Case studies

in the formula (IB-1-1) include

etc.

Case studies

in the formula (IB-1-2) include

etc.

In the compound represented by formula (Ia), for the preparation of a pharmaceutical composition, R ^1a is preferably C1-8 alkyl, C1-8 alkoxy or a halogen atom, more preferably methyl, methoxy, chloro or fluoro; ring A ^a is preferably a C5-7 monocyclic carbocyclic group, more preferably a benzene ring; E ^a is preferably —O—, —S— or —NR ^6a -, and more preferably —O—; R ^2a is preferably C1-8 alkyl, C1-8 alkoxy or a halogen atom, and more preferably methyl, methoxy, chloro or fluoro; R ^3a preferably represents a hydrogen atom, C1-4 alkyl or a halogen atom, and more preferably a hydrogen atom, methyl or chlorine; R ^4a preferably represents a hydrogen atom; a group formed by combining R ^2a with R ^4a is preferably —CH ₂ CH ₂ -; G ^a is preferably —CONR ^7a -, NR ^7a CO—, —NR ^7a SO ₂ -, —CH ₂ NR ^7a - or —NR ^7a CH ₂ , and more preferably —CONR ^7a -, —CH ₂ NR ^7a - or -NR ^7a CH ₂ ; R ^7a preferably represents a hydrogen atom or C1-8 alkyl, and more preferably a hydrogen atom or methyl; Q ^a is preferably C1-4 alkylene or

where all characters have the meanings defined above,

and more preferably methylene, ethylene or phenylene; each J ¹ , J ² , J ³ and J ⁴ preferably represents a carbon atom or a nitrogen atom, and more preferably a carbon atom; R ^5a is preferably a halogen atom or —COOR ^11a , and more preferably chlorine or —COOH; p is preferably 0, 1 or 2, and more preferably 0 or 1; q is preferably 4, 5 or 6; r is preferably 0 or 1; and s is preferably 0 or 1.

In the present invention, all compounds of formula (I), including combinations of preferred groups and preferred rings, are indicated above as preferred compounds. In particular, more preferred compounds are those described in the Examples, and 2- [3- (4- (5-phenylpentyloxy) phenyl) propanoylamino] acetic acid, 3- [3- (4- (5-phenylpentyloxy) phenyl) propylamino ] propanoic acid, 3- [2- (4- (5-phenylpentyloxy) phenyl) ethylamino] propanoic acid, 2- [3- (4- (5-phenylpentyloxy) phenyl) propylamino] acetic acid, 2- [N-methyl -3- (4- (5-phenylpentyloxy) phenyl) propylamino] acetic acid, 3-carboxy-5- [3- (4- (5-phenylpentyloxy) phenyl) propanoylamino] benzoic acid or 2-chloro-5- [3 - (2-fluoro-4- (5-phenylpentyloxy) phenyl) propanoylamino] benz nitric acid, N - {(2E) -3- [4- (3-phenylpropoxy) phenyl] prop-2-enyl} -β-alanine, N - {[6- (3-phenylpropoxy) -2-naphthyl] methyl } -β-alanine, 1 - {[6- (3-phenylpropoxy) -2-naphthyl] methyl} azetidine-3-carboxylic acid, 1 - {[6- (3-phenylpropoxy) -2-naphthyl] methyl} piperidine -4-carboxylic acid, N - {(2E) -3- [2-methyl-4- (3-phenylpropoxy) phenyl] prop-2-enyl} -β-alanine, 1 - {(2E) -3- [ 4- (3-phenylpropoxy) phenyl] -2-propenyl} piperidine-4-carboxylic acid, 1 - {(2E) -3- [4- (3-phenylpropoxy) phenyl] -2-propenyl} azetidine-3-carboxylic acid, N- {3- [4- (3-phenylpropoxy) phenyl] propyl} -β-alanine, N - ((2E) -3- {2-methyl-4 - [(5-phenylpentyl) oxy] phenyl} prop-2-enyl) -β-alanine, N- ( (2E) -3- {4 - [(5-phenylpentyl) oxy] phenyl} -2-propenyl) alanine, their prodrugs and their salts.

More specific embodiments include the following compounds and their salts, their solvates and their prodrugs, the compounds described in the Examples, etc.

(1) 4- {3- [4- (4-phenylbutoxy) phenyl] propyl} morpholine-2-carboxylic acid,

(2) 4 - ((2E) -3- {4- [4- (4-chlorophenyl) butyl] -2-methylphenyl} -2-propenyl) -1-methylpiperazine-2-carboxylic acid,

(3) 5-oxo-1 - {[6- (5-phenylpentanoyl) -2-naphthyl] methyl} pyrrolidine-3-carboxylic acid,

(4) 1- (3- {2-methyl-4 - [(5-phenylpentyl) oxy] phenyl} -3-oxopropyl) piperidine-4-carboxylic acid,

(5) 4-hydroxy-1- (2- {6 - [(4-isobutylbenzyl) oxy] -1-naphthyl} ethyl) piperidine-4-carboxylic acid,

(6) 1- (2- {5- [3- (2,4-dichlorophenyl) propoxy] -1H-indol-1-yl} ethyl) azetidine-3-carboxylic acid,

(7) 1 - ((2E) -3- {4 - [(5-phenylpentyl) oxy] phenyl} -2-propenyl) aziridine-2-carboxylic acid,

(8) N - ({6- [4- (3-chlorophenyl) butoxy] -2-naphthyl} methyl) -N- (2-hydroxyethyl) -β-alanine,

(9) 5 - {(2E) -3- [2-methyl-4- (4-phenylbutoxy) phenyl] -2-propenyl} -5-azabicyclo [2,1,1] hexane-6-carboxylic acid,

(10) 8 - {[6- (4-phenylbutoxy) -3,4-dihydronaphthalen-2-yl] methyl} -8-azabicyclo [3.2.1] octane-3-carboxylic acid,

(11) 1 - ({7- [4- (4-chlorophenyl) butyl] -4-oxo-4H-chromen-3-yl} methyl) pyrrolidine-3-carboxylic acid,

(12) N - {[6- (3-phenylpropoxy) -3,4-dihydronaphthalen-2-yl] methyl} -β-alanine,

(13) 1 - ({2- [4- (2-chlorophenyl) butyl] -1-benzothien-5-yl} methyl) azetidine-3-carboxylic acid,

(14) 1 - ({2- [4- (2-naphthyl) butyl] -1,3-benzoxazol-5-yl} methyl) piperidine-4-carboxylic acid,

(15) N- (2-hydroxyethyl) -N - ({5 - [(7E) -8-phenyl-7-octenoyl] pyridin-2-yl} methyl) -β-alanine,

(16) N - ({3- [3- (2,4-dimethylphenyl) propoxy] -6,7-dihydro-5H-benzo [7] annylene-8-yl} methyl) -β-alanine,

(17) 1 - {[8- (4-phenylbutoxy) -2,3-dihydro-1-benzoxepin-4-yl] methyl} pyrrolidine-3-carboxylic acid,

(18) 1 - ({2 - [(3-isobutylbenzyl) oxy] -5-oxo-5H-benzo [7] annylene-6-yl} methyl) azetidine-3-carboxylic acid,

(19) N - [(5-nonyl-1-benzothien-2-yl) methyl] -β-alanine,

(20) 3- {4- [4- (3-phenylpropoxy) phenyl] piperidin-1-yl} propanoic acid,

(21) 3- [5- [4- (3-cyclohexylpropoxy) benzyl] -3,6-dihydropyridin-1 (2H) -yl] propanoic acid,

(22) 3- [5- {3 - [(6-phenylhexyl) oxy] phenyl} -3,6-dihydropyridin-1 (2H) -yl] propanoic acid,

(23) 3- {4- [3 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) phenyl] -2-azabicyclo [2.2.2] -2-octyl} propanoic acid,

(24) 3- (4- {3- [3- (3-isobutylphenyl) propoxy] phenyl} -2-azabicyclo [2.2.2] -2-octyl) propanoic acid,

(25) 3- [3- (3- {2- [3- (2-phenylethoxy) phenyl] ethoxy} phenyl) piperidin-1-yl] propanoic acid,

(26) 3- {4- [3- (octyloxy) phenyl] piperidin-1-yl} propanoic acid,

(27) 3- (3- {6- [2- (2-chloro-6-methylphenyl) ethoxy] -2-naphthyl} pyrrolidin-1-yl) propanoic acid,

(28) 3- (2- {4 - [(5-phenylpentyl) oxy] phenyl} azetidin-1-yl) propanoic acid,

(29) 3- (3- {3 - [(5-methylhexyl) oxy] phenyl} azetidin-1-yl) propanoic acid,

(30) 3-methyl-3- [6- {3- [4- (trifluoromethyl) phenyl] propoxy} -3,4-dihydroisoquinolin-2 (1H) -yl] butanoic acid,

(31) 3- (5-chloro-6- {3- [4-chloro-2- (trifluoromethyl) phenyl] propoxy} -1,3-dihydro-2H-isoindol-2-yl) propanoic acid,

(32) 3- [6-methoxy-5- (octyloxy) -1-oxo-1,3-dihydro-2H-isoindol-2-yl] propanoic acid,

(33) 3- [7- (3-cyclohexylpropoxy) -1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl] propanoic acid,

(34) 3- {7- [2- (1,1'-biphenyl-3-yl) ethyl] -8-chloro-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl} propanoic acid.

Isomers

Unless specifically indicated otherwise, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkyloxy, alkoxy, alkenyloxy, alkynyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylene, alkenylene, alkynylene, acyl and acyloxy can be either linear or branched. Moreover, all isomers formed by a double bond along a ring and a condensed ring (E-, Z-, cis- and trans-forms), isomers formed due to the presence of asymmetric carbon atom (s), etc. (R-, S-, α- and β-configuration, enantiomer and diastereomer), optically active compounds having optical rotation (D-, L-, d- and l-forms), polar compound obtained by chromatographic separation (more polar compound and less polar compound), equilibrium compounds, rotation isomers, their mixture in any proportions and the racemic mixture are included in the present invention.

означает, что заместитель находится в α-конфигурации, символ

означает, что заместитель находится в β-конфигурации, символ

означает α-конфигурацию, β-конфигурацию или смесь α-конфигурации и β-конфигурации при подходящем соотношении, и символ

означает смесь α-конфигурации и β-конфигурации при подходящем соотношении, как должно быть понятно специалистам в данной области.In the present invention, unless otherwise indicated, the symbol

means that the substituent is in the α-configuration, the symbol

means that the substituent is in the β-configuration, the symbol

means α-configuration, β-configuration or a mixture of α-configuration and β-configuration with a suitable ratio, and the symbol

means a mixture of α-configuration and β-configuration in a suitable ratio, as should be clear to experts in this field.

Salt and solvate

The compound of the present invention can be converted into a salt by known methods. The salt is preferably a non-toxic and water soluble salt.

The salt of the present invention includes, for example, 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), salts an organic amine (such as triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine and N-methyl-D-glucamine) and acid addition salts [such as salts of inorganic acids (e.g. g hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate) and salts of organic acids (for example, acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate gluconate gluconate ) etc.].

The compound of the present invention or a salt thereof can be converted to a solvate by known methods. The solvate is preferably a non-toxic and water soluble solvate.

The solvate of the present invention includes, for example, aqueous solvates, alcoholic (e.g. methanol, ethanol, etc.) solvates and the like.

Prodrugs

A prodrug of a compound represented by formula (I) means a compound that is converted to a compound represented by formula (I) by reaction with an enzyme, stomach acid, or the like. in a living organism. For example, with regard to a prodrug of a compound represented by formula (I), when a compound represented by formula (I) contains an amino group, compounds where the amino group is, for example, acylated, alkylated or phosphorylated (for example, a compound where the amino group of the compound represented by formula ( I), is aicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-doxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated oh atsetoksimetilirovannoy, tert-butylated, etc.); when the compound represented by formula (I) contains a hydroxy-group - compounds where the hydroxy group is, for example, acylated, alkylated, phosphorylated or boronated (for example, a compound where the hydroxy group of the compound represented by formula (I) is acetylated, palmitoylated, propanoylated, pivalovyl succinylated, fumarylated, alanylated or dimethylaminomethyl carbonylated); and when the compound represented by formula (I) contains a carboxy group, compounds where the carboxy group of the compound represented by formula (I) is, for example, esterified or amidated (for example, a compound where the carboxy group of the compound represented by formula (I) is converted to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-doc solen-4-yl) methyl ester, cyclohexyloxycarbonylethyl ester or methylamide). Such compounds can be prepared by known methods per se. The prodrug of the compound represented by formula (I) can be either in the form of a hydrate or in an unhydrated form. A prodrug of a compound represented by formula (I) may also be a compound that is converted to a compound represented by formula (I) under physiological conditions, as described in "Iyakuhin no kaihatsu, Vol. 7 (Bunshi-sekkei), p.163 -198 (Hirokawa-Shoten), 1990 ". Also, the compound represented by formula (I) can be labeled with a radioisotope (such as ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

Examples of a prodrug of a compound represented by formula (I) in the present invention include a compound represented by formula (I-A):

where R ²⁴ represents C1-8 alkyl or C1-8 alkyl substituted with one or two substituents selected from hydroxy or amino; and other symbols have the meanings specified above;

the compound represented by formula (I-B):

where R ²⁵ and R ²⁶ each independently represents a hydrogen atom, C1-8 alkyl or C1-8 alkyl substituted with one or two substituents selected from hydroxy or amino; and other symbols have the meanings specified above; and

the compound represented by formula (I-C):

where all characters have the meanings defined above.

The compounds represented by formula (I) in the present invention have excellent solubility and absorbability, exhibit a long-term effect (ability to bind to the S1P receptor (in particular, EDG-6, preferably EDG-1 and EDG-6)), they are slightly susceptible to influence metabolic enzymes affecting the drug and have low toxicity. Such characteristics are the most important physical, chemical and pharmaceutical characteristics that are required in drug development. Since the compounds represented by formula (I) in the present invention meet these requirements, they must be claimed as excellent drugs (see The Merck Manual of Diagnosis and Therapy, 17th Ed., Merck & Co.).

The compound represented by formula (I) in the present invention can be evaluated for its usefulness as a medicine using various experimental methods described below, the methods described in Biological Examples, and methods thereof, suitably modified. It can be easily estimated that the compound of the present invention has good pharmacokinetic properties, such as serum half-life, stability in the gastrointestinal tract, absorption of oral preparations, bioavailability, etc., by known methods, for example, by the method described in Yakubutsu bioavailability (Hyouka to kaizen no kagaku), July 6, 1998, Gendaiiryou-sha, etc.

(I) Compound Properties Assessment Experiments

Evaluation of the solubility of the compounds of the present invention

Way

About 3-5 mg of the test compound heated to 37 ° C is taken in a test tube for testing (measured in practice with a thermometer). Then a solvent is added (a medicine and pharmacopeia Solution I, as defined in The Japanese Pharmacopoeia, a medicine and pharmacopeia Solution II, as defined by The Japanese Pharmacopoeia, and a solution of bovine bile acid added in medicine and pharmacopeia in artificial bile juice (0.5% (w / w), SIGMA)), a buffer solution with pH 7.4 (obtained by 4-fold dilution of McIlvaine buffer), a buffer solution with pH pH 4.0 (obtained by 4-fold dilution of buffer McIlvaine), distilled water and physiological saline, heated to 37 ° C in a water bath, until tvetstvenno concentrations of 1.5 mg / ml. After stirring at a constant temperature of 37 ° C for 30 minutes, the mixture is filtered through a filter (typically DISMIC-13cp, cellulose acetate, hydrophilic, 0.20 μm, Advantec). Immediately after this, the filtrate is diluted 2 times with an organic solvent in which the test compound is highly soluble (acetonitrile or methanol) and mixed. The solubility of the test compound can be determined by concentrating its concentration by the method using an external standard using HPLC.

Oral Administration Test for a Compound of the Present Invention

Way

Adult beagle dogs that have not been fed before are given pentagastrin (10 μg / kg) by intramuscular (IM) injection. Fifteen minutes after this, each test compound was administered orally (100 mg to each dog) with water (20 ml). Fifteen minutes after this, pentagastrin (10 μg / kg) is administered by intramuscular (IM) injection. Then, after 15 and 30 minutes and 1, 2, 3, 4, 6, 8 and 10 hours after administration of the test compound, the animals were bled and extracted with acetonitrile. The plasma concentration of the compound is then measured by high performance liquid chromatography (method using the internal standard). Using the plasma concentrations thus obtained, it is possible to determine the area under the plasma concentration curve (AUC, μg min / ml) and the maximum plasma concentration (C _max , ng / ml).

(II) Experiments to evaluate the effectiveness of the compounds of the present invention (measurement of cytokines)

The effect of the compounds of the present invention on the production of cytokines can be confirmed by the following experiments. For example, the effects of the compounds can truly be evaluated in cytokine production systems using THP-1 (human monocyte cell line) diluted in whole human, mouse, or rat blood. An example experiment to evaluate the effect of inhibiting the production of TNF-α, which is one of the cytokines, is illustrated below.

The effect of inhibiting the production of TNF-α using a human cell line

Way

In a 96-well plate for cell incubation, add 50 μl of a portion of lipopolysaccharide (LPS; Difco # 3120-25-0), adjusted to a concentration of 40 ng / ml using RPMI-1640 medium containing 10% fetal bovine serum (hereinafter referred to as RPMI -1640), and RPMI-1640 containing the test compound. Then add 100 μl of a suspension of THP-1 cells (DAINIPPON PHARMA # 06-202), brought to a concentration of 2 · 10 ⁶ cells / ml using RPMI-1640, followed by incubation for 90 minutes at 37 ° C (5% CO ₂ 95% air). Upon completion of the reaction, culture supernatant was collected and the amount of TNF-α thus obtained was measured using an ELISA kit (Invitrogen # 850090192).

The inhibition activity of TNF-α production can be calculated as the percentage inhibition (%) according to the following formula.

Inhibition percentage (%) = {(A _C -A _X ) / (A _C -A _B )} · 100.

A _B : value measured without LPS manifestation.

A _C : value measured by LPS development in the absence of the test compound.

A _X : value measured by LPS development in the presence of a test compound.

The percent inhibition for the compound is measured at various concentrations. Thus, the concentration at which the compound shows a percent inhibition of 50% (IC ₅₀ ) can be determined using the inhibition curve.

The effect of inhibiting the production of TNF-α using diluted whole human blood

Way

Human peripheral blood is obtained by collecting heparinized blood taken from healthy male volunteers. The peripheral blood thus collected was adjusted to a final concentration by 10-fold dilution with RPM1640 medium (manufactured by Gibco BRL) before use.

A lipopolysaccharide solution (LPS) (final concentration 100 ng / ml) (Bacto WE coli 055: B5; manufactured by DIFCO Lab.), A solution of the test compound and diluted whole blood are added to a 96-well plate for cell incubation. After the mixture was incubated at 37 ° C for 6 hours, the 96-well plate was centrifuged and the supernatant was collected. Then, the amount of TNF-α thus obtained in the supernatant is measured using an ELISA kit (manufacturer of the R&D system). Taking the difference in TNF-α between the untreated group and the LPS development group as 100%, the percent inhibition (%) for the test compound is determined and the 50% inhibitory concentration (IC ₅₀ ) is calculated.

Inhibition effect of TNF-α production in mice (intravenous administration)

Way

The inhibition activity of TNF-α production can be measured by the method reported in the document (ed. By Kazuo Ouchi, Seibutsu Kagaku Jikken Koza 12 , 707 (1994), Hirokawa Shoten, Tokyo), if modified accordingly. For example, a test compound is intravenously administered at various concentrations to female mice (BALB / c, age 7 weeks) and then LPS (100 μg / mouse) is administered intraperitoneally (Bacto WE coli 055: B5; manufacturer of DIFCO Lab.). Ninety minutes after LPS administration, heparinized blood is collected, which is taken from the abdominal aorta under ether anesthesia. Then immediately receive plasma and stored at -80 ° C. Plasma TNF-α is determined using an ELISA kit for determination of mouse cytokines (manufacturer Genzyme). Taking the difference in TNF-α between the untreated group and the LPS development group as 100%, the percent inhibition (%) for the test compound is determined and the 50% inhibitory concentration (IC ₅₀ ) is calculated.

Inhibition effect of TNF-α production in mice (oral administration)

Way

A test compound suspended in a vehicle is orally administered to mice (C57BL / 6 males). Half an hour after that, a lipopolysaccharide (LPS, 055: B5, Sigma) was intraperitoneally administered using a dose of 60 mg / kg. The control group was orally administered with a vehicle. Sixty minutes after LPS treatment, heparinized blood was collected, which was taken from the abdominal aorta under ether anesthesia. Then the blood is centrifuged (12000 rpm) at 4 ° C for 3 minutes to obtain plasma. The resulting plasma samples are stored at -80 ° C until use. The amount of TNF-α in plasma is determined using an ELISA kit (R&D systems).

Inhibition effect of TNF-α production in rats (oral administration)

Way

The test compound contained in the vehicle was orally administered to female Lew rats (CHARLES RIVER LABORATORIES, JAPAN). Two hours later, a lipopolysaccharide (LPS, 055: B6, Difco) was administered intravenously using a dose of 10 μg / kg (5 animals in each group). The control group was orally administered with vehicle (5 animals). Ninety minutes after LPS treatment, heparinized blood is collected, which is taken from the abdominal aorta under ether anesthesia. Then the blood is centrifuged (12000 rpm, 3 min, 4 ° C) to obtain plasma. The resulting plasma samples are stored at -80 ° C until use. Plasma TNF-α is determined using an ELISA kit (Genzyme / Techne, # 10516).

The inhibition activity of TNF-α production can be calculated as the percentage inhibition (%) according to the following formula.

Percent Inhibition (%) = {(A _C -A _X ) / A _C } · 100.

A _B : value measured by LPS development without administration of the test compound.

A _C : value measured during LPS development with the administration of the test compound.

In the case of using another cytokine as a TNF-α substituent, the effect of the compounds of the present invention on the production of cytokines can be evaluated by appropriate modification of the methods described above. For example, the analysis can be performed by incubating a commercially available ELISA kit for another cytokine (e.g., a Th1 or Th2 type cytokine such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12, TGF-β, interferon γ, etc.) as a substitute for ELISA kits for TNF-α, for a period of time suitable for each cytokine, and using a substance capable of inducing each cytokine (e.g. phorbol- 12-myristate-13-acetate (PMA), concavalin A (ConA), etc.).

(III) Experiments to evaluate the effectiveness of the compounds of the present invention (animal model of the disease)

Using the experiments described below, it can be confirmed that the compounds of the present invention have a prophylactic and / or therapeutic effect against allergic diseases. For example, the prophylactic and / or therapeutic effect on atopic dermatitis or allergic rhinitis can be confirmed by the following experiments.

Mouse delayed dermatitis model

Way

Male BALB / cAnCrj mice (CHARLES RIVER LABORATORIES, JAPAN) aged 14 weeks shaved abdominal hair. The next day, 0.1 ml of a 7% solution of picryl chloride (PC, Tokyo Kasei Kogyo, cat. C0307) in ethanol was applied to the entire shaved area using an animal sensitizer pipette. Four days after this, a 2% PC solution in olive oil, 0.02 ml / ear, is applied to the front and back sides of both auricles with a pipette and, thus, delayed dermatitis is caused in the mouse. Twenty hours after that, the thickness of both auricles is measured using a digital thickness meter (Ozaki Seisakusho) and an average value is calculated to estimate the edema in each auricle. The test compound is suspended in a 0.5% methylcellulose solution 30 minutes before the induction of dermatitis and then orally administered once or used as a topical agent.

As hapten, 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one can also be used; oxalon or the like as a substitute for picryl chloride.

Mouse DTH Model

Way

In male BALB / c mice, the abdominal hair is shaved using a hair clipper and a 7% (w / v) solution of 2,4,6-trinitrochlorobenzene (TNCB) in ethanol (100 μl) is applied to the abdominal part for sensitization animals. Seven days after sensitization, a 1% (w / v) solution of TNCB in olive oil is applied to the auricle (right, on both sides) of the mouse to cause a manifestation of the disease. The test compound is dissolved in the vehicle and then orally administered or applied on both sides of the right ear (20 μl) prior to application of TNCB. The control group is coated with a carrier. Immediately before administration of the test compound and 24 hours after application of TNCB, the thickness of the auricle of the mouse was measured using a digital thickness meter (Ozaki Seisakusho) as an indicator of the effectiveness of the mouse model DTH.

As hapten, 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one can also be used; oxalon or the like as a replacement for TNCB.

Mouse model of dermatitis caused by continuous hapten application

Way

A 1% (w / v) TNCB solution (acetone: olive oil = 4: 1) was applied (20 μl) to the auricle (right, on both sides) of the mouse (Balb / c males) for primary sensitization. Seven days after sensitization, 20 μl of a 1% (w / v) TNCB solution (acetone: olive oil = 4: 1) is applied to cause the onset of the disease (day 0). The procedure used on day 0 is repeated on days 2, 4, 6, 8, 10, 12, 14 and 16. The test compound is dissolved in the vehicle and then orally administered or applied on both sides of the right ear (20 μl) before applying TNCB . The control group is coated with a carrier. Immediately prior to administration of the test compound and 24 hours after TNCB application, the thickness of the mouse auricle was measured using a digital thickness meter (Ozaki Seisakusho) as an indicator of the effectiveness of the mouse model of dermatitis induced by continuous application of hapten.

As hapten, 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one can also be used; oxalon or the like as a replacement for TNCB.

Inhibitory effect of a compound of the present invention on a spontaneous scratching reaction in an NC mouse with spontaneous onset dermatitis

Way

Male NC mice suffering from spontaneously manifested dermatitis are used. Mice were placed in a cage for observation and allowed to acclimatize in the environment for 30 minutes. Then, within one hour after that, their behavior, characterized by scratching, is recorded on a videotape in a room without the presence of a person. When watching a video, a series of movements, including scratching the muzzle, ears, upper back and around these areas with hind legs, are considered as separate scratching movements and these movements are counted. A test compound or control (0.5% aqueous methylcellulose solution) is orally administered 3-5 times at 30 minute intervals. Immediately after the second administration, their scratching movements are recorded on videotape, counted for 1 to 3 hours, and thus an estimate is made.

Inhibitory effect on spontaneous scratching reaction in BN rats with DNFB-induced dermatitis

First, 0.3% dinitrofluorobenzene (DNFB) is applied several times to the head of Brown Norway (BN) rats to cause dermatitis. Then, an increase in scratching movements is observed 24 to 27 hours after application. You can evaluate the effect of the compounds of the present invention on the behavior characterized by scratching.

Way

0.3% DNFB dissolved in a mixed solvent, acetone with olive oil, is applied as a hapten to the shaved skull of male BN rats. To a group that should not have a manifestation of the disease, a mixed solvent consisting of acetone and olive oil is applied. A week after that, these substances are again applied to the skull and the application procedure is repeated three times every other day. Then, 24-27 hours after the fourth application, the behavior of rats is recorded on videotape in the room without the presence of a person. When watching a video, a series of movements, including scratching around the hapten application areas with the hind legs, are considered as separate scratching movements and these movements are counted. The test compound or control (0.5% aqueous methylcellulose solution) is orally administered 12 to 48 hours after the third to sixth administrations. For a group that should not have a manifestation of the disease, a 0.5% aqueous solution of methylcellulose is orally administered. 30 minutes after administration, a video of scratching movements is started, which is carried out for 3 hours, and these movements are counted, thus making an assessment.

Allergic Rhinitis Model

Way

Male guinea pigs Crj Hartley (6 weeks old) are administered ovalbumin using the procedure as shown in Table 1, thus constructing a model of allergic rhinitis.

Table 1 Day Dose Route of administration 0 0.5 mg / 0.5 ml Intraperitoneal 2 1.0 mg / 0.5 ml Intraperitoneal 22 0.1% 40 μl Nasal (both sides) 24 0.2% 40 μl Nasal (both sides) 27 0.4% 40 μl Nasal (both sides) 31 0.5% 40 μl Nasal (both sides) 36 1.0% 40 μl Nasal (both sides) 41 1.0% 40 μl Nasal (both sides)

After the disease has been initiated for 42 days, a catheter tube is inserted into the airways of each guinea pig under anesthesia and maintained at a constant temperature using a heated cake. Then, 40 μl of the test compound or saline is added dropwise to both nasal passages. Ten minutes later, 40 μl of 1% ovalbumin is added dropwise to both nasal passages. Thirty minutes after instillation of ovalbumin, sputum is removed from the nose with absorbent cotton. Fifteen minutes after this, absorbent cotton, which is previously weighed, is inserted into the nose for 15 minutes. The difference in weight of the absorbent cotton is considered as nasal discharge, and thus an estimate is made.

The immunosuppressive effect of the compounds of the present invention can be confirmed by the following experiment. For example, the therapeutic effect of the compounds of the present invention on transplant rejection can be confirmed by the use of transplant models of the heart, kidney, liver, pancreas, lung, bone marrow and skin graft, or the like. As an example, a heart transplant model is described below.

Model of heterotopic rat heart transplantation

Way

Using rats, a heart is removed from the donor rat and transplanted into the chest of the recipient rat. The test compound is administered orally for prophylactic purposes, the number of days of survival after heart transplantation is counted, so that the therapeutic effect can be determined.

The prophylactic and / or therapeutic effect of the compounds of the present invention on autoimmune diseases can be confirmed by the following experiments. For example, the prophylactic and / or therapeutic effect on rheumatoid arthritis (e.g., arthritis, deforming arthritis, etc.) can be confirmed by the following experiments.

The effect obtained in a model of collagen-induced rat arthritis

Way

Female DA rats (SLC) of eight weeks old were used. Throughout the entire period of the experiment, animals are fed in a food room with artificially created conditions: temperature 24 ± 2 ° C, humidity 55 ± 5% and periodic illumination 12 hours a day. The animals are given solid food (CE-2; CLEA Japan) and tap water ad libitum. After preliminary exposure to such a diet for 1 week, the animals are used in the experiment. A model of collagen-induced arthritis is constructed as follows. Namely, type II bovine collagen (0.3% solution, COLLAGEN GIJUTSU KENSHUKAI; # K-41, lot. 11214, hereinafter indicated as CII) and Freund's incomplete adjuvant (DIDCO # 0639-60, hereinafter indicated as IFA) are mixed in the ratio of CII: physiological saline: IFA 1: 1: 2 and the mixture is treated with ultrasound (20 s · 3 times at intervals of 1 min) to obtain an emulsion. This emulsion (0.75 mg CII / ml) is administered by subcutaneous injection in 0.1 ml portions at 4 sites on the rat’s back. For additional sensitization, 0.15 ml of this emulsion is subcutaneously injected into the base of the tail to induce arthritis. The test compound is suspended in a 0.5% solution of carboxymethyl cellulose and is administered orally to the stomach by force using an oral probe twice a day (morning and evening), starting from the day of administration until day 28. Arthritis is evaluated using a scoring system to assess the degree of arthritis in accordance with with the method of Ostermann T., et al. (Inflamm. Res., 44 , 258-263 (1995)). The foot volume of each individual animal can be measured using a plethysmometer (UNICOM, TK-101CMP).

Antibody Induced Mouse Arthritis

Way

A mixture of anti-collagen type II antibodies was intravenously administered to male DBA / 1 JNCrj mice using a dose of 2 mg / 0.5 ml / mouse. Three days after this, a lipopolysaccharide is administered intraperitoneally using a dose of 25 μg / 0.1 ml / mouse for arthritis. On day 10, the four legs of each animal can be assessed by a 4-point system depending on the edema and the increase in volume. The test compound is dissolved in an equimolar 0.02 mol / L sodium hydroxide solution, then diluted with distilled water and orally administered three times a day 30 minutes before the administration of the lipopolysaccharide.

Adjuvant-Induced Arthritis Model

Way

For evaluation, male or female Lewis rats of 7 weeks of age are used. After measuring the volume of the rat’s left hind paw, 600 μg / 100 μl of Mycobacterium butyricum (Difco) dry cell suspension, which is used as an adjuvant in liquid paraffin, is injected subcutaneously into the cushion of the right hind paw. Thus, a model of adjuvant-induced arthritis is built. By comparing the test group to which the test compound was orally administered with the control group to which the compound was not administered, the therapeutic or prophylactic effect is evaluated.

The effect of a compound of the present invention on pain response in an adjuvant-induced arthritis model

The inhibitory effect of the test compound on the pain response in an adjuvant-induced arthritis model (i.e., a model of pain in chronic arthritis) can be evaluated using an abnormal phonation response as an indicator.

Way

Seven weeks old male Lewis rats may be used. After measuring the volume of the rat’s left hind paw, 600 μg / 100 μl of Mycobacterium butyricum (Difco) dry cell suspension, which is used as an adjuvant in liquid paraffin, is injected subcutaneously into the cushion of the right hind paw. Thus, a model of adjuvant-induced arthritis is built. Twenty-two days after the adjuvant injection, the knee joint of the left hind paw is bent and unbent 5 times before oral administration of the test compound. In the experiment, animals are used that each time demonstrate an abnormal phonation response. Depending on the volume of edema of the left hind paw on the day before the experiment, rats are divided into groups of 10 animals each. The test compound is orally administered in various doses and 5 ml / kg of an aqueous solution of methylcellulose (control). One, two, three, and four hours after administration, abnormal phonation responses are observed. The analgesic effect is evaluated by flexion and extension of the knee joint of the left hind paw 5 times at each time that they are being monitored, and animals that show no abnormal phonation response are considered negative by the phonation response, and animals that exhibit an abnormal phonation response in one or several points of the assessment are considered positive for the analgesic effect.

Rabbit external meniscus removal model

Way

Rabbits (female rabbits Kbs: NZW (Healthy)) are pre-fed for 1 week and then subjected to meniscus removal in the following way.

An injection of a 2% solution of seractal (0.05 ml / kg) was subcutaneously injected into the cervical spine of rabbits. The animals are then anesthetized by intravenous injection of nembutal (20 mg / kg) at the edge of the auricle. The right knee is disinfected with 5 times diluted tincture of iodine, if necessary, the animals are given local anesthesia by instillation of 2% xylocaine with a syringe into the incised part.

Then the external epithelium and the shell of the joint of the right hind paw are cut at an angle of 90 ° to the knee ligament. The external collateral ligament is excised, and then the sesamoid ligament is excised. At this stage, Bosmin is instilled with a syringe to stop the bleeding. Tissues associated with the front tissue of the external meniscus are lifted with forceps and the meniscus is advanced and cut 1/3 in the center. The operated area is washed by injection of saline and the synovial membrane and joint shell are sutured. Then, the muscle layer and the outer layer of the skin are sutured separately.

After surgery, crystalline penicillin G potassium (5000 U / animal) and streptomycin sulfate (100 mg / animal) are administered by intramuscular injection into the left hind paw to prevent infection. Rabbits are fed until they are killed on day 7 after surgery. During the feeding period, the test compound is administered to rabbits at each specific dose, twice a day.

Animals are anesthetized by intravenous injection of nembutal (40 mg / kg) at the edge of the joint and then euthanized by bleeding. The right-handed joint is removed. The knee joint is cut and the femur and tibia are removed and stored in a neutral 10% formalin buffer solution at room temperature. After collecting all samples, the femur and tibial head are isolated. Then the affected area is measured using a stereoscopic microscope.

The assessment is made by statistical processing of data comparing the affected area of the joint in the control group (vehicle) and the group to which the test compound was administered using the Williams multiple comparisons method (EXSAS, Ver 5.00).

The experimental model described above, in which a joint crack can be induced that closely resembles human deforming arthritis, is generally recognized as an OA model.

Using the experiments described below, it can be confirmed that the compounds of the present invention have a prophylactic and / or therapeutic effect on autoimmune diseases. For example, using the experiments described below, it can be confirmed that the compounds of the present invention have a prophylactic and / or therapeutic effect on nervous diseases (multiple sclerosis), inflammatory bowel disease, and hepatitis.

Model EAE (experimental allergic encephalomyelitis)

Way

Using Lewis rats, experimental allergic encephalomyelitis is induced using various antigens such as the spinal cord or MOG (myelinoligodendrocytelicoprotein). When comparing a group to which a test compound was orally administered with a group to which this compound was not administered, the therapeutic or prophylactic effect is evaluated.

Acetic acid-induced colitis model

Way

The required amount of a 5% solution of acetic acid is collected in a 1 ml syringe equipped with a suitable oral probe (for a mouse). For 7-week-old male SD (CD) IGS rats, a probe (up to 5 cm from the end) was inserted through the anus into the colon under somnopentil anesthesia. After the introduction of the probe, a 5% solution of acetic acid (0.25 ml) is injected into the colon for 10 seconds. Then the probe is removed and the anus is closed for about 1 minute. The required amount of saline is collected in a 50 ml syringe equipped with a suitable oral probe (for a mouse). Then the probe (up to 8 cm from the end) is inserted through the anus into the colon. After the introduction of the probe, the intestinal tract is washed with saline (about 10 ml).

The test compound and the carrier are administered orally in a certain amount 30 minutes before the induction of colitis and 8 hours after its manifestation.

Twenty hours after the manifestation of the disease, the animals are killed and the entire colon (from the anus to the base of the cecum) is removed. The contents of the colon are washed with saline. After extraction and washing of the colon, a part of 9 cm from the anus is excised. Excess moisture is blotted out of the excised colon and the wet weight is determined using an electronic balance. The affected area (mm ² ) of the excised section of the colon is determined by image analysis.

TNBS-induced colitis model

Way

Under anesthesia with somnopentyl, a flexible oral probe (up to 8 cm from the end) is inserted through the anus into the colon of male SD (CD) IGS rats (7 weeks of age). Then, 50 mg of TNBS (2,4,6-trinitrobenzenesulfonic acid) / 20% ethanol / 0.25 ml / rat or 20% ethanol / 0.25 ml / rat are injected. The injection site is closed, the animals are left for about 2 hours so that they have colitis. The test compound is orally administered 30 minutes before the onset of the disease and 8 hours after the onset of the disease and twice a day (morning and evening), starting the next day. Three days after the onset of the disease, rats are euthanized by bleeding under ether anesthesia. The colon is removed and the contents of the colon are washed with saline. Then measure the length of the colon. After extraction and washing of the colon, a part of 9 cm from the anus is excised. Excess moisture is blotted out of the excised colon and the wet weight is determined using an electronic balance.

Chronic ulcerative colitis model

Way

Under anesthesia with pentobarbital, a 1% aqueous solution of acetic acid (10 ml / kg) is administered by injection through the anus into the colon to Syrian hamster bags (6-7 weeks old) using a flexible oral rat probe. Then the anus is clamped for 30 minutes to cause colitis. Distilled water is administered to the normal group by injection, as described above. The test compound is orally administered 18 hours and an hour before the induction of colitis and 6 hours after its onset, i.e. just three times. Twenty hours after the onset of the disease, the animals are killed and a piece of the colon is removed (7 cm from the anus). The selected sample is dissected along the adjacent part of the intestinal membrane and the inner part of the intestinal membrane is washed with physiological saline (5 ml). The cut colon is photographed and the relative ulcer area is calculated (total ulcer area · 100 / total colon area). The supernatant of the washing fluid used to flush the colon is used in a hidden bleeding test.

The effect of inhibiting chronic ulcerative colitis

Way

Male C57BL / 6 mice are incubated in a 7% aqueous solution of sodium dextran sulfate (hereinafter referred to as DSS), which they receive ad libitum. From the moment you start taking the aqueous solution, your body weight and clinical score are determined every day. The clinical score is calculated as the sum of the diarrhea score (normal: 0, loose stools: 2, diarrhea: 4) and the blood stool score (normal: 0, bleeding: 2, heavy bleeding: 4). On day 10 of receiving an aqueous solution of DSS, heparinized blood was collected, which was taken from the inferior genital vein under ether anesthesia. Using a blood cell counter, a hematocrit value is measured. From day 0 to day 10 of receiving an aqueous solution of DSS, the test compound is continuously administered orally at a specific dose twice a day.

Inhibitory effect in the galactosamine / LPS-induced hepatopathy model

Way

The test compound at various concentrations was administered to male mice (BALB / c, 7-8 weeks old) who were starving overnight. Thirty minutes after this, a solution of a mixture of galactosamine (700 mg / kg) and LPS (10 μg / kg) (Bacto W.E. coli 055: B5; manufactured by DIFCO Lab.) Was injected to cause hepatopathy. Each test compound is suspended in 0.5% methylcellulose.

Seven hours after the onset of the disease, heparinized blood is collected, which is taken from the abdominal aorta under ether anesthesia. Then immediately receive plasma. The degree of hepatopathy is evaluated using an increase in plasma GPT as an indicator. Plasma GPT levels are measured using an automatic analyzer using a GPT reagent (manufactured by Wako Pure Chemicals). Given the 100% difference in GPT plasma level between the untreated group and the group in which hepatopathy was induced, the inhibition coefficient (%) of the test compound can be calculated.

Using the experiments described below, it can be confirmed that the compounds of the present invention have a prophylactic and / or therapeutic effect on multiple organ failure and sepsis.

Multiple organ failure model

Way

Rats that were previously fasting for about 24 hours are anesthetized by the intravenous administration of pentobarbital (40 mg / kg). After the catheters are inserted into both femoral veins and the pterygoid needle into the tail vein, lipopolysaccharide (LPS; 0.3 mg / kg / h) and the test compound or vehicle used to administer the test compound (in the case of the control group) are continuously introduced through either of these veins . During administration, animals are additionally anesthetized, if necessary, depending on the awakening from anesthesia. Six hours after the start of continuous intravenous administration, blood is taken from the abdominal aorta. Then, elastase activity, coagulation parameters during fibrinolysis (fibrinogen, FDP, platelet count, etc.) and blood biochemical parameters (GOT, GPT, creatinine, BUN, etc.) are measured. The lung lesion index is then determined by removing the lungs and measuring wet weight or measuring the expiration of a protein that is systemically injected into the lung as a fluorescently labeled protein.

(IV) Experiments for evaluating the effect of a compound of the present invention in inhibiting a drug metabolizing enzyme and / or the effect of inhibiting the induction of a drug metabolizing enzyme

Inhibitory effect on CYP1A2 using a microsomal expression system

Way

A microsome expressing CYP1A2 (Gentest) obtained by expression in human lymphoblasts is used as an enzyme system. As a fluorescent substrate using 3-cyano-7-ethoxycoumarin (CEC, Molecular Probes).

A phosphate buffer (100 mmol / L, 200 μl; pH 7.4) containing CYP1A2-expressing microsomes (0.05 mg / ml), MgCl ₂ (5 mmol / L) and NADPH (1 mmol / L) are used as the reaction system. ) A CEC fluorescent substrate (final concentration of 10 μmol / L) and a test compound (final concentration of 3, 10 or 30 μmol / L) or α-naphthoflavone (final concentration of 0.003 or 0.01 μmol / L; TOKYO KASEI) are added to this reaction system. - an inhibitor used as a positive control, and the reaction is carried out at 37 ° C for 30 minutes. Measure the fluorescence intensity (Ex = 409 nm, Em = 409 nm) of the substrate metabolite (fluorescence detector: Spectra Max Geminin (Molecular Devices)).

The inhibitory effect is evaluated as the coefficient of inhibition (%) based on the inhibition of metabolite formation using the test compound.

Inhibitory activity against human CYP2C9

Way

The inhibitory activity of a compound of the present invention against human CYP2C9 can be determined using the method of Sato, et al. (Yakubutsudotai (Xenobio. Metabol. And Dispos.), 16 (2), 115-126 (2001)), modified to increase its accuracy and / or sensitivity.

Inhibitory activity against human CYP3A4

Way

The inhibitory activity of a compound of the present invention against human CYP3A4 can be determined using a modified method described in Drug Metabolism and Disposition, 28 (12), 1440-1448 (2000).

For example, a reaction solution is prepared consisting of potassium phosphate buffer (pH 7.4) (final concentration: 200 mM), magnesium chloride hexahydrate (final concentration: 5 mM), substrate (7-benzyloxyquinoline (7-BQ), final concentration: 40 μM), and microsomal expression system (Daiichikagakuyakuhin, final concentration: 0.25 mg / ml). Then, 100 μl of the reaction solution was dispensed into a 96-well plate, and 50 μl of an aqueous solution containing the test compound and 0.8% acetonitrile was added to carry out a 10-minute pre-incubation at 37 ° C. Then, 50 μl of reduced nicotinamide adenine dinucleotide phosphate (NADPH, 4 mM) was added to initiate the reaction. The fluorescence intensity in each well is measured during the addition of NADPH and after a 30-minute incubation. The excitation wavelength at 409 nm and the emission wavelength at 530 nm of quinolinol, which is a metabolite of the substrate, are measured. The inhibition coefficient (%) of the test compound is calculated using the following formula to obtain an IC ₅₀ value.

Inhibition Ratio (%) = [1- {value measured when adding the test compound) - (value measured before adding) / (control value - value measured before adding)}] x100

Human induction effect of CYP3A4

Method:

HepG2 cells were cultured in an incubator at 37 ° C and 5% CO ₂ using medium (MEM (+)) obtained by mixing the minimum basic medium Eagle (MOD.) With Earle salts without L-glutathione (manufacturer ICN, product No.1210254) with 1/100 amount of non-essential amino acids for the MEM Needle (100 ×) (manufacturer ICN, product No.1681049), antibiotic-antimycotic agent ((100 ×), manufacturer GIBCO, product No.15240-096), L-glutamine -200 mM ((100 ×), GIBCO, product No. 25030-081) and 1/10 the amount of fetal bovine serum (Sigma, product No.F9423). The medium is replaced periodically every 2-3 days and approximately 1/5 of the cells that achieve confluency are subcultured once a week. Almost confluent HepG2 cells, which were cultured in a culture flask (225 cm ² ), were plated on a 24-well plate (IWAKI, product No.3820-024) at a density of 5 × 10 ⁴ cells / MEM (+) 500 μl / well and cultured in an incubator at 37 ° C and 5% CO ₂ for 2 days. Then carry out transduction in the following way. To each well (MEM 100 μl) of a 24-well plate, a solution containing the autogenously obtained hPXR vector (10 ng), CYP3A4 vector (200 ng) and pRL-TK vector (200 ng) and the previously prepared Tfx reagent (Trademark) - 20 (0.75 μl, Promega, product No.E2391, obtained in accordance with the attached instructions). After stirring by tipping over several times, the mixture is allowed to stand at room temperature for 15 minutes (a solution of DNA-liposome mixture). Cells that were cultured for 2 days were washed with PBS (-) (1 ml per well) and then the DNA-liposome mixture solution prepared as described above (100 μl) was added. After culturing the cells in an incubator at 37 ° C and 5% CO ₂ for 1 hour, MEM (+) (440 μl / well) and test compound (adjusted to 10 times the final concentration using MEM (+) containing 1% DMSO, 60 μl / well) and cells were cultured in an incubator at 37 ° C and 5% CO ₂ for another 2 days. Then, cells that were cultured for 2 days after adding the test compound were washed once with PBS (-) (1 ml per well) and passive lysis buffer (PLB) (100 μl / well) was added. The mixture was allowed to stand at room temperature for 15 minutes or more (lysis solution). Portions of the thus obtained 20 μl / well lysis solution were transferred to a 96-well white plate (Perkin Elmer, product No.23300) and luciferase assay reagent II (LARII) (100 μl / well) was added. After 2-24 seconds, stop & glob reagent (100 μl / well) was added and then chemical luminescence was measured in each well for 2-14 seconds using a luminometer (Microlumat LB96P, Berthold JAPAN). The reagents used (PLB, LARII and stop & glob reagent) are prepared and handled in accordance with the instructions supplied with the Dual-Luciferase ^R Reporter Assay System (Promega, product No. E1910).

The inducible activity of CYP3A4 is calculated by taking the increase in transcriptional activity of CYP3A4 in the case of rifampicin (10 μmol / L) as a positive control of 100%.

(V) Experiments to assess the toxicity of the compounds of the present invention

Mutagenicity test

The mutagenicity of the compounds of the present invention can be evaluated in accordance with the method described in Anei-ho ni Okeru Henigensei Shiken-Tesuto Gaidorain to GLP (Mutagenicity Test according to Occupational Health and Safety Law-Test Guideline and GLP-) (Ed. By Chemical Substance Investigation Division, Industrial Safety and Health Department, Ministry of Labor; Japan Industrial Safety and Health Association, 1991, chapter 4).

Single Acute Rat Toxicity Test

The test compound is administered to Crj: CD (SD) rats six weeks old with a single intravenous dose or single oral administration. Toxicity can be assessed by comparison with the value obtained without administration of the test compound. A basic assessment of toxicity can be carried out, for example, by observing the nature of behavior or physical activity, etc.

Cardiotoxicity in rats (bradycardia)

Using SD rats, catheters are inserted into the jugular vein and carotid artery (or into the femoral vein and femoral artery) under anesthesia. The end of the arterial cannula is connected to a pressure sensor (DX-100, NIHON KOHDEN) and, accordingly, blood pressure and heart rate are measured using a load pressure amplifier (AP-641G, NIHON KOHDEN) and using a direct heart rate meter (AT-601G, NIHON KOHDEN). Under anesthesia or during forced awakening from anesthesia, the test compound is administered intravenously or orally and changes in blood pressure and heart rate are monitored.

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

Way

According to a report by Zou, et al. (Biophys. J., 74 , 230-241 (1998)) using HEK293 cells that overexpressed the human hERG gene (human ether-a-go-go-related gene), the maximum current potential of hERG I _Kr induced by depolarization pulse followed by a repolarization pulse, measured by recording the fixation of the potential (patch clamp method). The rate of change (inhibition coefficient) is calculated by comparing the maximum current potential before adding the test compound and 10 minutes after adding. The effect of the test compound on the hERG I _Kr current can be determined by the inhibition coefficient.

Methods for preparing a compound of the present invention

The compound represented by formula (I) in the present invention can be obtained by methods that are suitably modified and combined known methods, such as the methods described in WO 02/092068, Synth. Commun., 33 (19), 3347 (2003), Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Ed., (Richard C. Larock, John Wiley & Sons Inc. (1999)), etc., by the methods described below and / or by methods based on those described below or by methods described in the Examples. In each method described below, the starting material may be used as a salt of this material. An example of a salt includes various types of salts described as a salt of a compound represented by formula (I) described above.

Of the compounds represented by formula (I), a compound wherein X is bonded to ring B via an oxygen atom, i.e. the compound represented by formula (I-D):

where X 'represents a bond or spacer group containing from 1 to 7 atoms in its main chain; and other symbols have the meanings specified above;

can be obtained by the following method (1) or (2).

(1) A compound represented by formula (I-D) can be prepared by subjecting a compound represented by formula (II):

where all characters have the meanings defined above;

and the compound represented by formula (III):

where R ²⁸ represents a hydrogen atom or a group to protect a carboxy group; and other symbols have the meanings specified above;

Mitsunobu reaction, followed by removal of the protective group, if necessary. This Mitsunobu reaction, which is widely known, is carried out, for example, by reacting these compounds at 0-60 ° C in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.), in the presence of an azo compound (diethyl azodicarboxylate (DEAD), diisopropylazodicarboxylate, 1,1 '- (azodicarbonyl) dipiperidine, 1,1'-azobis (N, N-dimethylformamide), etc.) and a phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, triphenylphosphine on a polymer carrier and etc.). Removal of the group to protect the carboxy group can be accomplished by a known method, for example, a method described in WO 02/092068, or a similar method and / or a method described in Protective Groups in Organic Synthesis, T.W. Greene, John Wiely & Sons Inc. (1999). The carboxy protecting groups are not particularly limited, and, in addition to those described above, any arbitrarily selected group can be used, provided that it can be easily and selectively removed.

(2) A compound represented by formula (I-D) can be prepared by subjecting a compound represented by formula (II):

where all characters have the meanings defined above;

and the compound represented by formula (IV):

where L represents a leaving group such as a halogen atom, methanesulfonyloxy (OMs), toluenesulfonyloxy (OTs), trifluoromethanesulfonyloxy (OTf), alkylthio, alkylsulfinyl, alkylsulfonyl or hydroxysulfonyl; and other symbols have the meanings specified above;

or a compound represented by formula (V):

where all characters have the meanings defined above;

and the compound represented by formula (III):

where all characters have the meanings defined above;

according to esterification reactions followed by deprotection, if necessary. Such etherification reactions, which are widely known, are carried out, for example, by reacting these compounds at 0-100 ° C in an organic solvent (N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl tert-butyl ether and t etc.) in the presence of an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate , cesium carbonate, etc.), their water of a solution or mixtures thereof. Removal of the protective group can be accomplished by a method similar to that described above.

Of the compounds of the present invention represented by formula (I), a compound wherein Y is:

where Y ² and Y ³ each independently represents a bond or spacer group containing from 1 to 8 atoms in its main chain (provided that the sum of the atoms in the main chains of such a group of Y ² and Y ³ does not exceed 8); and R ⁷ represents a hydrogen atom or a substituent, or an atom in the spacer group represented by Y ² taken together with R ⁷ forms a heterocyclic group which may contain a substituent (s);

namely, the compound represented by formula (I-E):

where all characters have the meanings defined above;

can be obtained by exposing the compound represented by formula (VI):

where all characters have the meanings defined above;

and the compound represented by formula (VII):

where all characters have the meanings defined above;

reductive amination reactions followed by deprotection, if necessary. Such a reductive amination reaction, which is widely known, is carried out, for example, by reacting these compounds at a temperature of 0-100 ° C in an organic solvent (N, N-dimethylformamide, dichloromethane, etc., taken separately or in the form of a mixture comprising two or more such solvents in an arbitrary ratio), in the presence or absence of an organic acid (acetic acid, etc.), or in the presence or absence of an organic base (triethylamine, sodium bicarbonate, etc.), using a reducing agent (Sodium triacetoxyborohydride, sodium cyanoborohydride, tetrabutylammonium borohydride, etc.). Removal of the protective group can be accomplished by a method similar to that described above.

Of the compounds of the present invention represented by formula (I), a compound wherein Y is:

where all characters have the meanings defined above;

namely, the compound represented by formula (I-F):

where all characters have the meanings defined above;

can be obtained by exposing the compound represented by formula (VIII):

where all characters have the meanings defined above;

and the compound represented by formula (IX):

where all characters have the meanings defined above;

or a compound represented by formula (X):

where all characters have the meanings defined above;

and the compound represented by formula (XI):

where all characters have the meanings defined above;

respectively, alkylation reactions followed by deprotection, if necessary. Such alkylation reactions, which are widely known, are carried out, for example, by reacting these compounds at 0-100 ° C in an organic solvent (N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl tert-butyl ether and t etc.) in the presence of an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate , cesium carbonate, etc.), their aq second solution or mixture thereof. Removal of the protective group can be accomplished by a method similar to that described above.

Of the compounds of the present invention represented by formula (I), a compound wherein Y is:

where Y ⁴ represents a bond or spacer group containing from 1 to 7 atoms in its main chain; R ²⁹ , R ³⁰ and R ³¹ each independently represents a hydrogen atom or a substituent; and other symbols have the meanings specified above;

namely, the compound represented by formula (I-G):

where all characters have the meanings defined above;

can be obtained by exposing the compound represented by formula (XII):

where all characters have the meanings defined above;

and the compound represented by formula (XIII):

where all characters have the meanings defined above;

amine addition reactions followed by deprotection, if necessary. The amine addition reaction, which is widely known, is carried out, for example, by reacting these compounds at a temperature of −78 ° C. to a boiling point under reflux in an organic solvent (for example, methanol, ethanol, propanol, benzene, toluene, diethyl ether, tetrahydrofuran, dimethoxyethane, etc.) or without solvent. Removal of the protective group can be accomplished by a method similar to that described above.

The compounds represented by formulas (II) to (XIII), which are used as starting materials in the present invention, are widely known per se or can be easily prepared by known methods.

In each reaction disclosed herein, a solid phase reagent on a polymer support (for example, such as polystyrene, polyacrylamide, polypropylene or polyethylene glycol and the like) can be used.

In each reaction disclosed herein, the resulting products can be purified by conventional methods. For example, purification can be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography on silica gel or magnesium silicate, by thin layer chromatography, using ion exchange resins, using an impurity trap, using column chromatography, washing or recrystallization. Cleaning can be carried out after each reaction or after several reactions.

Pharmaceutical application

Compounds having the ability to bind to the S1P receptor (in particular EDG-6, preferably EDG-1 and EDG-6) are useful as immunosuppressants. The binding pattern to EDG-1 is preferably an agonistic effect.

The compounds of the present invention represented by formula (I), their salts, their solvates or their prodrugs are compounds that are capable of binding to EDG-6, and exhibit a long pharmacological effect. Therefore, they are useful as prophylactic and / or medicines for mammals, in particular for humans, in the treatment of transplant rejection, organ transplant rejection, transplant versus host disease, autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, etc. p.), allergic diseases (atopic dermatitis, asthma, etc.), inflammation, infection, ulcers, lymphomas, malignant tumors, leukemia, arteriosclerosis, acute heart failure, walls ardia, stroke, traumatic injury, genetic diseases, etc.

In addition to the ability to bind to EDG-6, some compounds of the present invention have agonistic activity against EDG-1 and therefore exhibit an immunosuppressive effect and a long-lasting pharmacological effect. Due to these characteristics, they are more useful as prophylactic and / or drugs for rejection during transplantation, graft versus host disease, autoimmune diseases, allergic diseases, etc.

When a compound represented by formula (I) in the present invention or a combination preparation comprising a compound of the present invention represented by formula (I) and other medication (s) is used for the above purposes, it is usually administered systemically or topically, usually by oral or parenteral administration. The doses required for administration are determined, for example, depending on age, body weight, symptoms, desired therapeutic effect, route of administration and duration of treatment. For an adult, doses per person are usually from 1 ng to 100 mg when administered orally up to several times a day and from 0.1 ng to 100 mg when administered parenterally up to several times a day or when given continuously for 1 to 24 hours a day through a vein. As described above, the doses used are selected depending on various conditions. Therefore, in some cases, the doses used may be lower or higher than the specified limits.

When a compound represented by formula (I) in the present invention or a combination preparation comprising a compound of the present invention represented by formula (I) and another drug (s) are administered, it is used in solid form for oral administration, liquid forms for oral administration administration, in the form of injections, liniments, suppositories, eye drops or an inhalation preparation for parenteral administration or the like.

Solid forms for oral administration include compressed tablets, pills, capsules, dispersible powders and granules. Capsules include hard capsules and soft capsules. Tablets include sublingual tablets, buccal adhesive tablets, buccal rapidly decomposing tablets, or the like. Also in such solid forms, one, two or more active compounds can be mixed with a carrier (such as lactose, mannitol, glucose, microcrystalline cellulose or starch), a binder (such as hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium aluminum metasilicate), a disintegrant (such as such as cellulose calcium glycolate), lubricants (such as magnesium stearate), a stabilizer and an adjuvant solution (such as glutamic acid or aspartic acid), and they are obtained in accordance with methods well known E in normal pharmaceutical practice. The solid forms may, if desired, be coated with a coating agent (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl methyl cellulose phthalate), or they may have two or more film coatings. In addition, the coating may include capsules of absorbable release control agents such as gelatin.

Sublingual tablets are prepared according to a conventional method. For example, one, two or more active substances are used to produce pharmaceuticals using methods known in the art, mixing these substances with a carrier (such as lactose, mannitol, glucose, microcrystalline cellulose, colloidal silicon dioxide, starch, etc. .) a binder (such as hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium aluminum metasilicate, etc.), a disintegrant (such as starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium, cellulose calcium glycolate, etc. .), a lubricant (such as magnesium stearate, etc.), a swelling agent (such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carbopol, carboxymethyl cellulose, polyvinyl alcohol, xanthan gum, guar gum, etc.), an auxiliary substance for swelling (such as glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine, etc.), a stabilizer, a solubilizing substance (such as polyethylene glycol, propylene glycol, glutamic acid, and paraginovaya acid, etc.), fragrances (such as orange, strawberry, mint, lemon, vanilla, etc.) etc. Also, if necessary, they may be coated with a coating agent (such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, etc.), or they may have two or more film coatings. In addition, if necessary, a preservative, an antioxidant, a coloring agent, a sweetener and similar commonly used additives can also be added.

Buccal adhesive tablets are prepared according to a conventional method. For example, one, two or more active substances are used to produce pharmaceuticals using methods known in the art, mixing these substances with a carrier (such as lactose, mannitol, glucose, microcrystalline cellulose, colloidal silicon dioxide, starch, etc. .) a binder (such as hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium aluminum metasilicate, etc.), a disintegrant (such as starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium, cellulose calcium glycolate, etc. .), a lubricant (such as magnesium stearate, etc.), an adhesion agent (such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carbopol, carboxymethyl cellulose, polyvinyl alcohol, xanthan gum, guar gum, etc.), an auxiliary substance for adhesion (such as glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine, etc.), a stabilizer, a solubilizing substance (such as polyethylene glycol, propylene glycol, glutamic acid, aspar ginovaya acid, etc.), fragrances (such as orange, strawberry, mint, lemon, vanilla, etc.) etc. Also, if necessary, they may be coated with a coating agent (such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, etc.), or they may have two or more coating layers. In addition, if necessary, a preservative, an antioxidant, a coloring agent, a sweetener and similar commonly used additives can also be added.

Quickly decomposing buccal tablets are prepared according to a conventional method. For example, one, two or more active substances are used as such or for the manufacture of pharmaceutical preparations using methods known in the art by mixing the active substances obtained by applying to a powder or granular particles a substance of a suitable coating agent (such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, acrylate-methacrylate copolymer, etc.) and a plasticizer (such as polyethylene glycol, triethyl citrate, etc.), with a carrier (such as lactose, m nitrite, glucose, microcrystalline cellulose, colloidal silicon dioxide, starch, etc.), a binder (such as hydroxypropyl cellulose, polyvinyl pyrrolidone, magnesium aluminum metasilicate, etc.), a disintegrant (such as starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium, cellulose calcium glycolate, etc.), a lubricant (such as magnesium stearate, etc.), a dispersant (such as glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine, gluta other acid, arginine, etc.), a stabilizer, a solubilizing substance (such as polyethylene glycol, propylene glycol, glutamic acid, aspartic acid, etc.), a fragrance (such as orange, strawberry, peppermint, citric, vanilla and etc.) etc. Also, if necessary, they may be coated with a coating agent (such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, etc.), or they may have two or more coating layers. In addition, if necessary, a preservative, an antioxidant, a coloring agent, a sweetener and similar commonly used additives can also be added.

Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs. In such forms, one, two or more active compounds may be dissolved, suspended or emulsified in a diluent (s) conventionally used in the art (such as distilled water, ethanol, or a mixture thereof). In addition, such liquid forms may also include certain additives, such as wetting agents, suspending agents, emulsifiers, sweeteners, perfumes, flavors, preservatives or buffering agents.

The substance for parenteral administration may be, for example, in the form of an ointment, gel, cream, wet compress, paste, liniment, aerosol, inhalation preparation, spray, eye drops, solution for irrigation of the nasal cavity, or the like. Each such preparation contains one or more active substances, and they are obtained in a known manner or using the traditional method of formulation.

The ointment is obtained in a known manner or using the traditional method of formulation. For example, to obtain such an ointment, one, two or more active substances are ground or dissolved in a base. The ointment base is selected from known or conventionally used substances. For the purposes of a somewhat more detailed disclosure, higher aliphatic acid or a higher aliphatic acid ester (e.g., myristic acid, palmitic acid, stearic acid, oleic acid, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester), wax ( e.g. beeswax, whale wax, ceresin), a surfactant (e.g. polyoxyethylene alkyl ether phosphoric acid ester), higher alcohol (e.g. cetanol, stearyl alcohol, setostea silt alcohol), silicone oil (e.g. dimethyl polysiloxane), hydrocarbon (e.g. hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin), glycol (e.g. ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol), vegetable oil (e.g. castor oil, olive oil, sesame oil, turpentine oil), water, an absorption accelerator and a drug rash prophylaxis that can be used individually or in a mixture of two or more of these substances. The base may also include a moisturizer, preservative, stabilizer, antioxidant, perfume, etc.

The gel is prepared in a known manner or using a traditional formulation method. For example, to obtain such a gel, one, two or more active substances are dissolved in the base. The gel base is selected from known or conventionally used substances. For example, lower alcohol (e.g., ethanol, isopropyl alcohol), a gelling agent (e.g., carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose), a neutralizing agent (e.g. triethanolamine, diisopropanolamine), a surfactant (e.g., mono-ethylene glycol) are used. , water, an absorption accelerator, and a drug rash prophylaxis that can be used individually or in a mixture of two or more thereof. The gel base may also include a moisturizer, antioxidant, perfume, etc.

The cream is obtained in a known manner or using a traditional formulation method. For example, to obtain such a cream, one, two or more active substances are dissolved in the base. The basis for the cream is selected from known or traditionally used substances. For example, a higher aliphatic acid ester, a lower alcohol, a hydrocarbon, a multivalent alcohol (e.g., propylene glycol, 1,3-butylene glycol), a higher alcohol (e.g., 2-hexyldecanol, cetanol), an emulsifier (e.g., polyoxyethylene alkyl ether, an aliphatic acid ester) are used , water, an absorption accelerator, and a drug rash prophylaxis that can be used individually or in a mixture of two or more thereof. The base for the cream may also include a moisturizer, antioxidant, perfume, etc.

A wet compress is obtained in a known manner or using a traditional formulation method. For example, to obtain such a wet compress, one, two or more active substances are dissolved in a base to produce a thoroughly mixed mixture, which is then distributed on a substrate. The base for the wet compress is selected from known or traditionally used substances. For example, a thickener (e.g., such as polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose), a wetting agent (e.g., urea, glycerin, propylene glycol), a filler (e.g., kaolin, zinc oxide, talc, calcium) are used (magnesium), water, a dissolution aid, a tackifier, and a drug rash prophylaxis that can be used individually or in a mixture of two or more thereof. The base for the wet compress may also include a moisturizer, antioxidant, perfume, etc.

The paste product is prepared in a known manner or using a traditional formulation method. For example, to obtain such a paste-like agent, two or more active substances are dissolved in a base to form a thoroughly mixed mixture, which is then distributed on a substrate. The paste base is selected from known or conventionally used substances. For example, a polymer base, fat and oil, a higher aliphatic acid, a tackifier, and a drug rash prevention agent that can be used individually or in a mixture of two or more thereof are used. The basis for the preparation in the form of a paste may also include a moisturizer, antioxidant, perfume, etc.

Liniment is obtained in a known manner or using a traditional formulation method. For example, to obtain such a liniment, one, two or more active substances are dissolved, suspended or emulsified in water, alcohol (for example, ethanol, polyethylene glycol), higher aliphatic acid, glycerin, soap, emulsifier, suspending agent, etc., which are used individually or as a combination of two or more of these substances. Liniment may also include a moisturizer, antioxidant, perfume, etc.

The nebulizer, inhaler, spray and aerosol each may include a stabilizer, such as sodium hydrosulfite and a buffer capable of imparting isotonicity, such as an isotonic substance (e.g., sodium chloride, sodium citrate, citric acid). Regarding the method for producing the spray, reference can be made to US Pat. Nos. 2,868,691 and 3,095,355.

An injection for parenteral administration may be in the form of a solution, suspension, emulsion or in the form of a solid injection for injection, which is dissolved or suspended in a solvent when used. An injection preparation is prepared by dissolving, suspending or emulsifying one, two or more active substances in a solvent. As such a solvent, distilled water for injection, physiological saline, vegetable oil, alcohol such as propylene glycol, polyethylene glycol and ethanol, etc., alone or in combination can be used. An injection preparation may also include a stabilizer, a dissolving agent (e.g., such as glutamic acid, aspartic acid, Polysolvate 80 (trade name)), suspending agent, emulsifier, sedative, buffer, preservative, etc. The drug for injection is sterilized at the final stage or obtained by a method carried out under aseptic conditions. Alternatively, an aseptic solid, such as a lyophilized product that has been previously prepared, can be made aseptic or dissolved in aseptic distilled water for injection or another solvent before use.

Eye drops for parenteral administration may be in the form of a liquid, suspension, emulsion or ointment, or they may be dissolved in a solvent when used. Such eye drops are prepared in a known manner. For example, one, two or more active substances are dissolved, suspended or emulsified in a solvent. As such a solvent for eye drops, sterilized distilled water, physiological saline and other aqueous or non-aqueous solvents (e.g., vegetable oil) can be used, alone or in combination. Eye drops may include an isotonic substance (e.g., sodium chloride, concentrated glycerin), a buffering agent (e.g., sodium phosphate, sodium acetate), a surfactant (e.g., Polysolvate 80 (trade name), polyoxyl stearate 40, polyoxyethylene cured castor oil) , a stabilizer (sodium citrate, sodium edetate), a preservative (for example, benzalkonium chloride, paraben), etc., which can be correctly selected, as necessary for a particular case. Eye drops are sterilized at the final stage or obtained by a method carried out under aseptic conditions. Alternatively, an aseptic solid, such as a lyophilized product that has been previously prepared, can be made aseptic or dissolved in aseptic distilled water for injection or another solvent before use.

The parenteral inhalation agent may be in the form of an aerosol powder for inhalation or a liquid for inhalation. The inhalation fluid can be dissolved or suspended in water or other suitable medium when used. Such inhalation agents are prepared in a known manner. For example, an inhalation liquid is obtained from substances suitably selected from preservatives (e.g., benzalkonium chloride, paraben), colorants, buffers (e.g., sodium phosphate, sodium acetate), isotonic substances (e.g., sodium chloride, concentrated glycerin), thickeners ( e.g. carboxyvinyl polymer), absorption accelerators, etc., as needed.

The inhalation powder is obtained from substances suitably selected from glidants (e.g. stearic acid and its salt), binders (e.g. starch, dextrin), carriers (e.g. lactose, cellulose), colorants, preservatives (e.g. benzalkonium chloride, paraben ), absorption accelerators, etc., if necessary.

For administration of a liquid for inhalation, a spray device (e.g., nebulizer, sprinkler) is usually used. For administration of powder for inhalation, a powder inhaler is usually used.

Other examples of compositions for oral administration include sublingual drugs for sublingual administration, suppositories for rectal administration and pessaries for vaginal administration, which are obtained by the usual formulation of a composition comprising one or more active substances.

The compound of formula (I) of the present invention can be administered in the form of a combined preparation in combination with other pharmaceuticals in order to:

1) supplementing and / or enhancing the prophylactic and / or therapeutic effect of the compound,

2) improving the pharmacokinetic properties and absorption and reducing the dose of the compound

and / or

3) reducing the side effects of the compound.

A combination preparation comprising a compound of formula (I) of the present invention and other pharmaceuticals can be administered in the form of a compounded preparation, where both components are combined into one preparation, or it can be in a form that can be administered as separate preparations. Administration as separate preparations includes simultaneous administration and administration with a time difference. In the case of administration with a time difference, you can first introduce the compound of formula (I) of the present invention followed by the administration of another pharmaceutical agent, or you can first introduce another pharmaceutical agent with the subsequent administration of the compound of formula (I) of the present invention. The methods for each administration may be the same or different from each other.

A combination preparation comprising other pharmaceutical agents that complement and / or enhance the prophylactic and / or therapeutic effect of a compound of the present invention is not limited to the agents indicated by way of example in the present invention. Also, a combination preparation, including other pharmaceuticals that complement and / or enhance the prophylactic and / or therapeutic effect of the compounds of the present invention, includes not only a drug that has been discovered to date, but also such a drug that will be discovered in the future based on the mechanism described above.

Diseases for which the combination drugs described above have a prophylactic and / or therapeutic effect are not particularly limited. Namely, these can be diseases for which the prophylactic and / or therapeutic effect of the compounds of the present invention represented by formula (I) can be supplemented and / or enhanced. For example, you can specify other immunosuppressants, antibiotics, etc. as drugs suitable for use to supplement and / or enhance the prophylactic and / or therapeutic effect of rejection during transplantation, where an EDG-6 agonist is applicable. As medicines that can be used to prevent and / or treat autoimmune diseases, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARD, slow-acting antirheumatic drugs), other immunosuppressants, T-cell inhibitors can be mentioned , anti-inflammatory enzyme preparations, joint protectants, prostaglandins, prostaglandin synthase inhibitors, IL-1 inhibitors, inhibitory IL-6 (including protein preparations, such as anti-IL-6 receptor antibodies), TN-α inhibitors (including protein preparations, such as anti-TNF-α antibodies), interferon γ agonists, phosphodiesterase inhibitors, metalloproteinase inhibitors, etc. P. In combination with them, EDG-6 agonists can be used. As for drugs that can be used to supplement and / or enhance the prophylactic and / or therapeutic effect on allergic diseases, examples of drugs that can be used to supplement and / or enhance the preventive and / or therapeutic effect on atopic dermatitis include immunosuppressants , steroids, non-steroidal anti-inflammatory drugs, prostaglandins, antiallergic drugs, mediator release inhibitors, antihistamines Twa, forskolin preparations, phosphodiesterase inhibitors, cannabinoid-2 receptor stimulants, etc.

Examples of immunosuppressants include azathioprine (trade name: IMULAN AZANIN), misoribine (trade name: BREDININ), methotrexate (trade name: METOTREXAT, RHEUMATREX), mycophenolate mofetil (trade name: CELLCEPT), cyclophosphamide P (EN), cyclophosphamide P (trade name: NEORAL, SANDIMMUN), tacrolimus (FK506, trade name: PROGRAF), sirolimus (RAPAMYCIN), everolimus (trade name: CERTICAN), prednisolone (trade name: PREDONIN), methylprednisolone (trade name ORTOL3, ORROL3) (trade name sc: MUROMONAB CD3), anti human lymphocyte globulin (ALG, trade name: ALBULIN), deoxyspergualin (DSG, gusperimus hydrochloride, trade name: SPANIDIN) etc.

Examples of antibiotics include cefuroxime sodium, meropenem trihydrate, netilmicin sulfate, sisomycin sulfate, ceftibutene, PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromycin sulfate or cefetamed pivoxyl hydrochloride, etc.

Examples of antibiotics as inhalants include PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromycin sulfate or cefetamed pivoxyl hydrochloride, etc.

In the case of steroids, in the case of topical preparations, examples include clobetasol propionate, diflorazone diacetate, fluocinonide, mometasone furancarboxylate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, budesonide diacetone diazonone diazonone diacetone diacidone dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, deprodon propionate, prednisone valerate acetate, fluocinolo acetonide, beclomethasone propionate, triamcinolone acetonide, flumethasone pivalate, alclometasone dipropionate, clobetasone butyrate, prednisolone, beclomethasone dipropionate, and the like 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, halopredredone acetate, halopredredone acetone sodium succinate, triamcinolone, triamcinolone diacetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexametase he palmitate, parametasone acetate, betamethasone, etc. Examples of inhalation agents include beclomethasone dipropionate, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, cyclesonide, dexamethasone palmitate, mometasone furoate, sodium prasterone sulfate, deflazacort, methylprednisolone sulfonate sodium and the like, etc.

Examples of non-steroidal anti-inflammatory drugs (NSAIDs) include sasapirin, sodium salicylate, aspirin, aspirin dialiminate, diflunisal, indomethacin, suprofen, ufenamate, dimethyl isopropyl azulene, bufexamak, felbinak, diclofenac, http://wwse?google = Tolmetin% 20Sodium "\ t" _blank, clinoril, fenbufen, napmeton, http://www.google.com/search?q=Proglumetacin%20Maleate "\ t" _blank, indomethacin http://www.google.com/ search? q = Farnesol "\ t" _blank, http://www.google.com/search?q=Acemetacin "\ t" _blank, http://www.google.com/search?q=Proglumetacin%20Maleate " \ t "_blank maleate, http://www.google.com/search?q=Amfenac%20Sodium" \ t "_blank, http://www.google.com/search?q=Mofezolac" \ t "_blank, http://www.google.com / search? q = Etodolac "\ t" _blank, http://www.google.com/search?q=Ibuprofen "\ t" _blank, http://www.google.com/search?q=Ibuprofen "\ t "_blank piconol, http://www.google.com/search?q=Naproxen" \ t "_blank, http://www.google.com/search?q=Flurbiprofen" \ t "_blank, http: / /www.google.com/search?q=Flurbiprofen "\ t" _blank axetil, http://www.google.com/search?q=Ketoprofen "\ t" _blank, calcium phenoprofen, http://www.google .com / search? q = Tiaprofenic% 20Acid "\ t" _blankhttp: //www.google.com/search? q = Oxaprozin "\ t" _blankhttp: //www.google.com/search? q = Pranoprofen "\ t "_blankhttp: //www.google.com/search? q = Loxoprofen% 20Sodium" \ t "_blankhttp: //www.google.com/search? q = Zaltoprofen" \ t "_blank mefenamic acid, mefenamate aluminum, tolfenamic acid, flactaphenin, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam, antiroxicam, napag new cream, epirisole, thiaramide hydrochloride, tinoridine hydrochloride, emorphazone, sulpirin, migraine, saridone, Cedes G, amipilo N, sorbon, pyrine antipyretic drugs, acetaminophen, phenacetin, dimethothiazine mesylate, antipyretin, antimetrin, etc.

Examples of disease modifying anti-rheumatic drugs (DMARD, slow-acting anti-rheumatic drugs) include, for example, gold thioglucose, sodium aurothiomalate, auranofin, actarite, D-penicillamine drugs, lobenzaride disodium, bucillamine, hydroxychloroquine, salazosulfludapidiridin, salazosulfrefidapridine, salazosulfrefidapridine, salazosulfludapididin .

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

Examples of cartilage preservatives include, for example, sodium hyaluronate, glucosamine, chondroitin sulfate and glucosaminoglycan polysulfate, etc.

Examples of prostaglandins (hereinafter referred to as "PG") include PG receptor agonists and PG receptor antagonists, etc. 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), etc.

Examples of a prostaglandin synthase inhibitor include, for example, salazosulfapyridine, mesalazine, olsalazine, 4-aminosalicylic acid, JTE-522, auranofin, carprofen, diphenpyramide, flunoxaprofen, flurbiprofenfen, loproxprofenfenprofenfenprofenfenoprofenfenprofenfenoprofenprofen, phenoproxprofenfenprofenfenprofenfenoprofenfenprofenfenoprofenfenprofenfenoprofenfenprofenfenoprofenfenprofenfenoprofenfenprofenfenoprofen piroxicam betadex, piroxicam cinnamate, tropin indomethacinate, zaltoprofen and pranoprofen, etc.

Examples of an IL-1 inhibitor (including a protein preparation, such as a human IL-1 receptor antagonist) include, for example, anakinra, etc.

Examples of an IL-6 inhibitor (including a protein preparation, such as an anti-IL-6 receptor antibody) include, for example, MRA, etc.

Examples of TNF-α inhibitors (including a protein preparation such as an anti-TNF-α antibody) include, for example, infliximab, adalimumab, etanercept, etc.

Examples of a phosphodiesterase inhibitor include, for example, rolipram, cilomilast (trade name: Ariflo), Bay 19-8004, NIK-616, roflumilast (BY-217), cipamphillin (BGL-61063), atisolam (CP-80633), SCH-351591 , YM-976, V-11294A, PD-168787, D-4386, IC-485 or ONO-6126 as an inhibitor of PDE-4, etc.

Examples of a mediator release inhibitor include tranylast, sodium chromoglacate, anlexanox, repirinast, ibudilast, http://www.google.com/search?q=tazanolast "\ t" _blank, peminolast sodium, etc.

Examples of antihistamines include http://www.google.com/search?q=Ketotifen%20Fumarate "\ t" _blank, http://www.google.com/search?q=Mequitazine "\ t" _blank, azelastine hydrochloride , http://www.google.com/search?q=Oxatomide "\ t" _blank, http://www.google.com/search?q=Terfenadine "\ t" _blank, emedastine fumarate, epinastine hydrochloride, astemizole , ebastine, cetirizine hydrochloride, bepotastine, fexofenadine, lolatadine, deslolatadine, olopatadine hydrochloride, TAK-427, ZCR-2060, NIP-530, mometasone furoate, misolastine, BP-294, andolast, auranofin and auranofin etc.

Toxicity

The compounds of the present invention have low toxicity and are therefore considered safe enough for use as medicaments.

The effect of the present invention

Compounds having the ability to bind to the S1P receptor (in particular EDG-6, preferably EDG-1 and EDG-6) are useful as immunosuppressants.

The compounds of the present invention represented by formula (I), their salts, their solvates or their prodrugs are compounds that are capable of binding to EDG-6, and exhibit a long pharmacological effect. Therefore, they are useful as prophylactic and / or medicines for mammals, in particular humans, for the treatment of transplant rejection, organ transplant rejection, transplant versus host disease, autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, etc. .), allergic diseases (atopic dermatitis, asthma, etc.), inflammation, infections, ulcers, lymphomas, malignant tumors, leukemia, arteriosclerosis, diseases associated with lymphatic infiltration cytosis into tissue, etc.

In addition to the ability to bind to EDG-6, some compounds of the present invention have agonistic activity against EDG-1 and therefore exhibit an immunosuppressive effect and a long pharmacological effect. Due to these characteristics, they are more useful as prophylactic and / or medicines for rejection during transplantation, graft versus host disease, autoimmune diseases, allergic diseases, etc.

The best way to implement the present invention

The present invention is further described in more detail using the examples below. However, the present invention should not be construed as being limited to these examples. Regarding chromatographic separation or TLC, the solvent in parentheses corresponds to the eluting solvent or developing solvent used, and its relative content is expressed as volumetric. The aqueous ammonia solution used in the TLC analysis is a commercially available 28% aqueous ammonia solution. As for NMR, the solvent in parentheses corresponds to the solvent for measurement. Unless otherwise indicated, MS analysis was performed using the ESI method (electrospray ionization) with the detection of only cationic ions (positive).

The nomenclature of compounds in the present invention was obtained using a computerized system for naming compounds, mainly in accordance with the IUPAC nomenclature, such as ACD / Name (registered trade name, manufacturer Advanced Chemistry Development Inc.) or ACD / Name Batch (registered trade name , manufacturer of Advanced Chemistry Development Inc.), or in accordance with the IUPAC system nomenclature.

Example 1

methyl 3- [4- (3-phenylpropoxy) phenyl] propanoate

To a solution of methyl 3- (4-hydroxyphenyl) propanoate (2.50 g) and 3-phenylpropan-1-ol (2.8 ml) in tetrahydrofuran (70 ml) was added triphenylphosphine (5.46 g) at room temperature. Then, diethyl azodicarboxylate (9.4 ml, 40% solution in toluene) was added dropwise to the mixture, followed by stirring at room temperature for 2 hours. Then, the reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1 to 5: 1) to obtain the title compound (3.02 g) having the following physical characteristics.

TLC: Rf 0.45 (hexane: ethyl acetate = 5: 1);

¹ H-NMR (CDCl ₃ ): δ 2.09 (m, 2H), 2.60 (t, 2H), 2.80 (m, 2H), 2.89 (t, 2H), 3.67 ( s, 3H), 3.94 (t, 2H), 6.82 (d, 2H), 7.10 (d, 2H), 7.20 (m, 3H), 7.29 (m, 2H).

Example 2

3- [4- (3-phenylpropoxy) phenyl] propanal

To a solution of the compound (1.0 g) obtained in Example 1 in anhydrous dichloromethane (15 ml) was added dropwise at -78 ° C diisobutylaluminum hydride (3.5 ml; 0.95 M solution in n-hexane) and the mixture was stirred at -78 ° C for 30 minutes. Methanol (0.5 ml) was added dropwise to the reaction mixture, followed by stirring at room temperature for 40 minutes. The reaction mixture was filtered through Celite (trade name) and the filtrate was concentrated. Then, the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 6: 1) to obtain the title compound (614 mg) having the following physical characteristics.

TLC: Rf 0.20 (hexane: ethyl acetate = 7: 1);

¹ H-NMR (CDCl ₃ ): δ 2.09 (m, 2H), 2.77 (m, 4H), 2.90 (t, 2H), 3.94 (t, 2H), 6.82 ( d, 2H), 7.09 (d, 2H), 7.20 (m, 3H), 7.27 (m, 2H), 9.82 (t, 1H).

Example 3

N- {3- [4- (3-phenylpropoxy) phenyl] propyl} alanine:

To a suspension of alanine (7.1 mg) in methanol (0.30 ml) was added sodium hydroxide (3.4 mg) at room temperature. Then, the compound (30 mg) obtained in Example 2 was added, and the mixture was stirred at room temperature for 15 minutes. Sodium borohydride (4.0 mg) was added to the reaction mixture at 0 ° C, and the mixture was stirred at 0 ° C for one hour. The reaction mixture was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 80: 20: 4) to obtain the title compound (14 mg) having the following physical characteristics.

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

¹ H-NMR (DMSO-d ₆ ): δ 1.23 (d, 3H), 1.81 (m, 2H), 1.98 (m, 2H), 2.53 (m, 2H), 2, 72 (m, 4H), 3.14 (q, 1H), 3.91 (t, 2H), 6.83 (d, 2H), 7.09 (d, 2H), 7.23 (m, 5H )

Examples 3 (1) -3 (38)

A procedure similar to that of Example 3 was carried out except that the corresponding amine compound was used as a substituent for alanine, using the compound obtained in Example 2 or the corresponding aldehyde compound as its substituent, followed by conversion to the corresponding salt in a known manner, if necessary. Thus, the following compounds were obtained.

Example 3 (1)

N- {3- [4- (3-phenylpropoxy) phenyl] propyl} glycine:

TLC: Rf 0.52 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 2.03 (m, 4H), 2.64 (t, 2H), 2.78 (m, 2H), 2.96 (m, 2H), 3.45 (s, 2H); 3.92 (t, 2H); 6.83 (d, 2H); 7.18 (m, 7H).

Example 3 (2)

4 - ({3- [4- (3-phenylpropoxy) phenyl] propyl} amino) butanoic acid:

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

¹ H-NMR (CD ₃ OD): δ 1.83 (m, 2H), 1.94 (m, 2H), 2.04 (m, 2H), 2.37 (m, 2H), 2.65 (t, 2H), 2.78 (m, 2H), 2.93 (m, 2H), 3.00 (m, 2H), 3.92 (t, 2H), 6.83 (d, 2H) 7.19 (m, 7H).

Example 3 (3)

5 - ({3- [4- (3-phenylpropoxy) phenyl] propyl} amino) pentanoic acid:

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

¹ H-NMR (CD ₃ OD): δ 1.66 (m, 4H), 2.03 (m, 4H), 2.21 (t, 2H), 2.65 (t, 2H), 2.78 (m, 2H), 2.94 (m, 4H), 3.92 (t, 2H), 6.83 (d, 2H), 7.18 (m, 7H).

Example 3 (4)

2-methyl-N- {3- [4- (3-phenylpropoxy) phenyl] propyl} alanine:

TLC: Rf 0.36 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CDCl ₃ : CD ₃ OD = 5: 1): δ 1.34 (s, 6H), 1.89 (m, 2H), 2.03 (m, 2H), 2.57 (m , 2H), 2.73 (m, 4H), 3.87 (t, 2H), 6.76 (d, 2H), 7.01 (d, 2H), 7.13 (m, 3H), 7 , 20 (m, 2H).

Example 3 (5)

N- {3- [4- (3-phenylpropoxy) phenyl] propyl} valine:

TLC: Rf 0.42 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CDCl ₃ : CD ₃ OD = 5: 1): δ 0.94 (m, 6H), 1.89 (m, 2H), 2.01 (m, 2H), 2.12 (m , 1H), 2.54 (m, 2H), 2.72 (m, 4H), 3.13 (d, 1H), 3.86 (t, 2H), 6.75 (d, 2H), 6 99 (d, 2H); 7.12 (m, 3H); 7.20 (m, 2H).

Example 3 (6)

N- {3- [4- (3-phenylpropoxy) phenyl] propyl} phenylalanine:

TLC: Rf 0.41 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CDCl ₃ : CD ₃ OD = 5: 1): δ 1.72 (m, 2H), 2.02 (m, 2H), 2.41 (m, 2H), 2.62 (m , 4H), 2.87 (m, 1H), 3.20 (m, 1H), 3.46 (m, 1H), 3.88 (m, 2H), 6.71 (d, 2H), 6 89 (d, 2H) 7.16 (m, 10H).

Example 3 (7)

N- {3- [4- (3-phenylpropoxy) phenyl] propyl} serine:

TLC: Rf 0.12 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CDCl ₃ : CD ₃ OD = 5: 1): δ 2.10 (m, 4H), 2.67 (m, 2H), 2.81 (t, 2H), 3.01 (m , 2H), 3.44 (t, 1H), 3.93 (m, 4H), 6.84 (d, 2H), 7.10 (d, 2H), 7.22 (m, 3H), 7 29 (m, 2H).

Example 3 (8)

N- {3- [4- (3-phenylpropoxy) phenyl] propyl} homoserine:

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

¹ H-NMR (CDCl ₃ : CD ₃ OD = 5: 1): δ 1.99 (m, 6H), 2.57 (t, 2H), 2.73 (m, 2H), 2.91 (m , 2H), 3.43 (m, 1H), 3.72 (m, 2H), 3.87 (t, 2H), 6.76 (d, 2H), 7.01 (d, 2H), 7 12 (m, 3H); 7.20 (m, 2H).

Example 3 (9)

2-hydroxy-3 - ({3- [4- (3-phenylpropoxy) phenyl] propyl} amino) propanoic acid:

TLC: Rf 0.12 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CDCl ₃ : CD ₃ OD = 5: 1): δ 2.06 (m, 4H), 2.65 (t, 2H), 2.81 (m, 2H), 2.97 (m , 3H), 3.25 (m, 1H), 3.97 (m, 2H), 4.03 (t, 1H), 6.84 (d, 2H), 7.09 (d, 2H), 7 22 (m, 3H); 7.29 (m, 2H).

Example 3 (10)

2-methyl-N- {3- [4- (3-phenylpropoxy) phenyl] propyl} serine:

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

¹ H-NMR (CDCl ₃ : CD ₃ OD = 5: 1): δ 1.34 (s, 3H), 2.07 (m, 4H), 2.67 (t, 2H), 2.81 (m , 2H), 2.92 (m, 2H), 3.54 (d, 1H), 3.94 (m, 3H), 6.84 (d, 2H), 7.10 (d, 2H), 7 21 (m, 3H); 7.29 (m, 2H).

Example 3 (11)

N - {[6- (3-phenylpropoxy) -2-naphthyl] methyl} glycine:

TLC: Rf 0.13 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CDCl ₃ : CD ₃ OD = 5: 1): δ 2.19 (m, 2H), 2.87 (t, 2H), 3.43 (s, 2H), 4.10 (t , 2H), 4.22 (s, 2H), 7.12 (d, 1H), 7.27 (m, 6H), 7.44 (dd, 1H), 7.77 (d, 2H), 7 82 (d, 1H).

Example 3 (12)

4 - ({[6- (3-phenylpropoxy) -2-naphthyl] methyl} amino) butanoic acid:

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

¹ H-NMR (CDCl ₃ : CD ₃ OD = 5: 1): δ 1.84 (m, 2H), 2.18 (m, 2H), 2.44 (m, 2H), 2.86 (m , 2H), 2.97 (m, 2H), 4.09 (t, 2H), 4.13 (s, 2H), 7.11 (d, 1H), 7.27 (m, 6H), 7 43 (dd, 1H); 7.76 (m, 3H).

Example 3 (13)

2-hydroxy-3 - ({[6- (3-phenylpropoxy) -2-naphthyl] methyl} amino) propanoic acid:

TLC: Rf 0.11 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CDCl ₃ : CD ₃ OD = 5: 1): δ 2.19 (m, 2H), 2.87 (m, 2H), 3.11 (dd, 1H), 3.20 (dd , 1H), 4.09 (m, 3H), 4.23 (d, 1H), 4.29 (d, 1H), 7.12 (d, 1H), 7.27 (m, 6H), 7 44 (dd, 1H); 7.77 (d, 2H); 7.82 (s, 1H).

Example 3 (14)

N - {(2E) -3- [4- (3-phenylpropoxy) phenyl] prop-2-enyl} -β-alanine:

TLC: Rf 0.13 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 2.07 (m, 2H), 2.49 (t, 2H), 2.79 (t, 2H), 3.16 (t, 2H), 3.76 (dd, 2H), 3.96 (t, 2H), 6.12 (dt, 1H), 6.78 (d, 1H), 6.88 (d, 2H), 7.20 (m, 5H) 7.39 (d, 2H).

Example 3 (15)

1- {3- [4- (3-phenylpropoxy) phenyl] propyl} azetidine-3-carboxylic acid, acetate:

TLC: Rf 0.44 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 1.71-1.92 (m, 2H), 1.98 (s, 3H), 1.99-2.12 (m, 2H), 2.61 ( t, 2H), 2.78 (t, 2H), 3.09-3.20 (m, 2H), 3.32-3.46 (m, 1H), 3.92 (t, 2H), 4 09-4.26 (m, 4H), 6.79-6.88 (m, 2H), 7.07-7.13 (m, 2H), 7.14-7.29 (m, 5H) .

Example 3 (16)

1- {3- [4- (3-phenylpropoxy) phenyl] propyl} proline:

TLC: Rf 0.46 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 1.82-2.19 (m, 7H), 2.32-2.48 (m, 1H), 2.64 (t, 2H), 2.78 ( t, 2H), 2.96-3.16 (m, 2H), 3.15-3.29 (m, 1H), 3.61-3.77 (m, 1H), 3.80 (dd, 1H), 3.91 (t, 2H), 6.76-6.90 (m, 2H), 7.07-7.13 (m, 2H), 7.14-7.35 (m, 5H) .

Example 3 (17)

1- {3- [4- (3-phenylpropoxy) phenyl] propyl} pyrrolidine-3-carboxylic acid:

TLC: Rf 0.46 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 1.92-2.12 (m, 4H), 2.13-2.38 (m, 2H), 2.64 (t, 2H), 2.78 ( t, 2H), 2.98-3.09 (m, 1H), 3.10-3.20 (m, 2H), 3.22-3.47 (m, 3H), 3.52-3, 65 (m, 1H), 3.92 (t, 2H), 6.84 (d, 2H), 7.12 (d, 2H), 7.16-7.33 (m, 5H).

Example 3 (18):

1- {3- [4- (3-phenylpropoxy) phenyl] propyl} piperidine-2-carboxylic acid:

TLC: Rf 0.51 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 1.44-1.64 (m, 1H), 1.65-1.91 (m, 4H), 1.97-2.12 (m, 4H), 2.12-2.27 (m, 1H), 2.49-2.70 (m, 2H), 2.78 (t, 2H), 2.83-3.06 (m, 2H), 3, 16-3.29 (m, 1H), 3.34-3.47 (m, 1H), 3.47-3.62 (m, 1H), 3.92 (t, 2H), 6.77- 6.87 (m, 2H), 7.08-7.14 (m, 2H), 7.14-7.31 (m, 5H).

Example 3 (19)

1- {3- [4- (3-phenylpropoxy) phenyl] propyl} piperidine-3-carboxylic acid:

TLC: Rf 0.44 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 1.66-1.99 (m, 4H), 1.99-2.15 (m, 4H), 2.57-2.71 (m, 3H), 2.78 (t, 2H), 2.88-3.39 (m, 6H), 3.92 (t, 2H), 6.77-6.89 (m, 2H), 7.10-7, 17 (m, 2H); 7.16-7.31 (m, 5H).

Example 3 (20)

1- {3- [4- (3-phenylpropoxy) phenyl] propyl} piperidine-4-carboxylic acid:

TLC: Rf 0.51 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 1.78-2.15 (m, 8H), 2.31-2.47 (m, 1H), 2.63 (t, 2H), 2.78 ( t, 2H), 2.88-3.08 (m, 4H), 3.34-3.50 (m, 2H), 3.92 (t, 2H), 6.79-6.88 (m, 2H), 7.09-7.15 (m, 2H), 7.14-7.31 (m, 5H).

Example 3 (21)

N - {[6- (3-phenylpropoxy) -2-naphthyl] methyl} -β-alanine:

TLC: Rf 0.13 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CDCl ₃ ): δ 2.14-2.24 (m, 2H), 2.47 (t, 2H), 2.87 (t, 2H), 3.09 (t, 2H), 4.10 (t, 2H), 4.23 (s, 2H), 7.12 (d, 1H), 7.18-7.33 (m, 6H), 7.43 (dd, 1H), 7 75-7.82 (m, 3H).

Example 3 (22)

N - {[6- (3-phenylpropoxy) -2-naphthyl] methyl} -β-alanine hydrochloride:

TLC: Rf 0.13 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 2.09-2.19 (m, 2H), 2.76 (t, 2H), 2.84 (t, 2H), 3.30-3.34 ( m, 2H), 4.09 (t, 2H), 4.36 (s, 2H), 7.13-7.29 (m, 7H), 7.50 (dd, 1H), 7.79-7 86 (m, 2H); 7.91 (s, 1H).

Example 3 (23)

1 - {[6- (3-phenylpropoxy) -2-naphthyl] methyl} -azetidine-3-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 2.09-2.19 (m, 2H), 2.84 (t, 2H), 3.64-3.76 (m, 1H), 4.09 ( t, 2H), 4.28-4.38 (m, 4H), 4.52 (s, 2H), 7.13-7.29 (m, 7H), 7.45 (dd, 1H), 7 81-7.85 (m, 2H); 7.90 (s, 1H).

Example 3 (24)

1 - {[6- (3-phenylpropoxy) -2-naphthyl] methyl} -piperidine-4-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.75-1.93 (m, 2H), 2.09-2.27 (m, 4H), 2.56-2.65 (m, 1H), 2.84 (t, 2H), 3.03-3.14 (m, 2H), 3.53-3.61 (m, 2H), 4.10 (t, 2H), 4.43 (s, 2H), 7.13-7.29 (m, 7H), 7.50 (dd, 1H), 7.81-7.87 (m, 2H), 7.93 (s, 1H).

Example 3 (25)

N - {(2E) -3- [2-methyl-4- (3-phenylpropoxy) phenyl] prop-2-enyl} -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.99-2.12 (m, 2H), 2.34 (s, 3H), 2.74-2.81 (m, 4H), 3.27- 3.31 (m, 2H), 3.83 (d, 2H), 3.95 (t, 2H), 6.02 (dt, 1H), 6.71-6.76 (m, 2H), 7 07 (d, 1H); 7.12-7.29 (m, 5H); 7.44 (d, 1H).

Example 3 (26)

N - ((2E) -3- {2-methyl-4 - [(5-phenylpentyl) oxy] phenyl} prop-2-enyl) -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.44-1.55 (m, 2H), 1.61-1.84 (m, 4H), 2.34 (s, 3H), 2.63 ( t, 2H), 2.76 (t, 2H), 3.25-3.30 (m, 2H), 3.82 (d, 2H), 3.95 (t, 2H), 6.02 (dt , 1H), 6.70-6.74 (m, 2H), 7.06 (d, 1H), 7.10-7.26 (m, 5H), 7.43 (d, 1H).

Example 3 (27)

1 - {(2E) -3- [4- (3-phenylpropoxy) phenyl] -2-propenyl} piperidine-4-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.81-2.16 (m, 6H), 2.36-2.48 (m, 1H), 2.79 (t, 2H), 2.90- 3.07 (m, 2H), 3.38-3.51 (m, 2H), 3.78 (d, 2H), 3.97 (t, 2H), 6.07-6.18 (m, 1H), 6.80 (d, 1H), 6.89 (d, 2H), 7.11-7.29 (m, 5H), 7.41 (d, 2H).

Example 3 (28)

1 - {(2E) -3- [4- (3-phenylpropoxy) phenyl] -2-propenyl} azetidine-3-carboxylic acid hydrochloride:

TLC: Rf 0.10 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 2.01-2.12 (m, 2H), 2.79 (t, 2H), 3.63-3.71 (m, 1H), 3.92- 3.99 (m, 4H), 4.23-4.40 (m, 4H), 5.97-6.09 (m, 1H), 6.81-6.92 (m, 3H), 7, 11-7.28 (m, 5H); 7.40 (d, 2H).

Example 3 (29)

N - ((2E) -3- {4 - [(5-phenylpentyl) oxy] phenyl} -2-propenyl) -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.41-1.57 (m, 2H), 1.61-1.74 (m, 2H), 1.74-1.85 (m, 2H), 2.63 (t, 2H), 2.76 (t, 2H), 3.25-3.33 (m, 2H), 3.80 (d, 2H), 3.97 (t, 2H), 6 11 (dt, 1H), 6.81 (d, 1H), 6.88 (d, 2H), 7.08-7.30 (m, 5H), 7.39 (d, 2H).

Example 3 (30)

N - ({6 - [(5-phenylpentyl) oxy] -2-naphthyl} methyl) -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.48-1.63 (m, 2H), 1.64-1.79 (m, 2H), 1.80-1.94 (m, 2H), 2.65 (t, 2H), 2.76 (t, 2H), 3.18-3.42 (m, 2H), 4.10 (t, 2H), 4.35 (s, 2H), 7 07-7.29 (m, 7H), 7.50 (dd, 1H), 7.80 (d, 1H), 7.85 (d, 1H), 7.88-7.93 (m, 1H) )

Example 3 (31)

1 - ({6 - [(5-phenylpentyl) oxy] -2-naphthyl} methyl) -azetidine-3-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.46-1.64 (m, 2H), 1.64-1.79 (m, 2H), 1.79-1.95 (m, 2H), 2.65 (t, 2H), 3.58-3.76 (m, 1H), 4.09 (t, 2H), 4.26-4.39 (m, 4H), 4.51 (s, 2H), 7.06-7.29 (m, 7H), 7.45 (dd, 1H), 7.81 (d, 1H), 7.85 (d, 1H), 7.88-7.92 (m, 1H).

Example 3 (32)

1 - ({6 - [(5-phenylpentyl) oxy] -2-naphthyl} methyl) piperidine-4-carboxylic acid hydrochloride:

TLC: Rf 0.16 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 1.46-1.64 (m, 2H), 1.63-1.79 (m, 2H), 1.79-1.97 (m, 4H), 2.10-2.32 (m, 2H), 2.55-2.74 (m, 1H), 2.65 (t, 2H), 2.98-3.23 (m, 2H), 3, 45-3.65 (m, 2H), 4.10 (t, 2H), 4.43 (s, 2H), 7.07-7.30 (m, 7H), 7.50 (dd, 1H) 7.82 (d, 1H); 7.87 (d, 1H); 7.90-7.97 (m, 1H).

Example 3 (33)

N - {[6- (4-phenylbutoxy) -2-naphthyl] methyl} -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.78-1.95 (m, 4H), 2.64-2.79 (m, 4H), 3.23-3.36 (m, 2H), 4.07-4.16 (m, 2H), 4.35 (s, 2H), 7.09-7.31 (m, 7H), 7.50 (dd, 1H), 7.80 (d, 1H), 7.85 (d, 1H), 7.87-7.92 (m, 1H).

Example 3 (34)

1 - {[6- (4-phenylbutoxy) -2-naphthyl] methyl} -azetidine-3-carboxylic acid hydrochloride:

TLC: Rf 0.13 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 1.79-1.94 (m, 4H), 2.64-2.77 (m, 2H), 3.65-3.77 (m, 1H), 4.06-4.17 (m, 2H), 4.22-4.42 (m, 4H), 4.52 (s, 2H), 7.08-7.30 (m, 7H), 7, 46 (dd, 1H), 7.83 (t, 2H), 7.88-7.94 (m, 1H).

Example 3 (35)

1 - {[6- (4-phenylbutoxy) -2-naphthyl] methyl} -piperidine-4-carboxylic acid hydrochloride:

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

Example 3 (36)

N - ({6- [3- (4-chlorophenyl) propoxy] -2-naphthyl} methyl) -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 2.03-2.24 (m, 2H), 2.76 (t, 2H), 2.84 (t, 2H), 3.25-3.36 ( m, 2H), 4.09 (t, 2H), 4.36 (s, 2H), 7.16-7.30 (m, 6H), 7.50 (dd, 1H), 7.83 (t , 2H); 7.88-7.94 (m, 1H).

Example 3 (37)

1 - ({6- [3- (4-chlorophenyl) propoxy] -2-naphthyl} methyl) azetidine-3-carboxylic acid hydrochloride:

TLC: Rf 0.11 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 2.05-2.21 (m, 2H), 2.84 (t, 2H), 3.60-3.79 (m, 1H), 4.09 ( t, 2H), 4.24-4.40 (m, 4H), 4.52 (s, 2H), 7.17-7.31 (m, 6H), 7.46 (dd, 1H), 7 79-7.87 (m, 2H); 7.88-7.94 (m, 1H).

Example 3 (38)

1 - ({6- [3- (4-chlorophenyl) propoxy] -2-naphthyl} methyl) piperidine-4-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.72-1.97 (m, 2H), 2.03-2.32 (m, 4H), 2.52-2.71 (m, 1H), 2.83 (t, 2H), 2.95-3.20 (m, 2H), 3.47-3.69 (m, 2H), 4.09 (t, 2H), 4.43 (s, 2H), 7.13-7.32 (m, 6H), 7.52 (dd, 1H), 7.76-7.90 (m, 2H), 7.90-7.99 (m, 1H) .

Example 4

tert-butyl N- [3- (4-hydroxyphenyl) propyl] -β-alaninate

To a solution in methanol (25 ml) of 4- (3-aminopropyl) phenol (1.83 g) was added dropwise tert-butyl acrylate (1.7 ml) at room temperature, followed by stirring at room temperature overnight. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 3: 1) to obtain the title compound (1.55 g) having the following physical characteristics.

TLC: Rf 0.24 (ethyl acetate: methanol = 5: 1);

¹ H-NMR (CDCl ₃ ): δ 1.45 (s, 9H), 1.79 (m, 2H), 2.44 (t, 2H), 2.60 (m, 4H), 2.83 ( t, 2H); 6.68 (d, 2H); 6.99 (d, 2H).

Example 5

tert-butyl N- (tert-butoxycarbonyl) -N- [3- (4-hydroxyphenyl) propyl] -β-alaninate

To a solution in tetrahydrofuran (30 ml) of the compound obtained in Example 4 (1.55 g), a solution of di-tert-butyl dicarbonate (1.15 g) in tetrahydrofuran (3 ml) was added dropwise at 0 ° C, followed by stirring at 0 ° C for 2 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1 to 3: 1) to obtain the title compound (1.57 g) having the following physical characteristics.

TLC: Rf 0.45 (hexane: ethyl acetate = 2: 1);

¹ H-NMR (CDCl ₃ ): δ 1.43 (m, 18H), 1.79 (m, 2H), 2.51 (m, 4H), 3.22 (m, 2H), 3.42 ( m, 2H), 4.92 (s, 1H), 6.75 (d, 2H), 7.03 (d, 2H).

Example 6

tert-butyl N- (tert-butoxycarbonyl) -N- {3- [4- (3-phenylpropoxy) phenyl] propyl} -β-alaninate

To a solution of the compound obtained in Example 5 (3.6 g) in dimethylformamide (36 ml) was added potassium carbonate (4.20 g) at room temperature and (3 bromopropyl) benzene (2.31 ml) was added dropwise, followed by stirring at room temperature overnight. The reaction mixture was poured into ice water and extracted with a solvent mixture (hexane: ethyl acetate = 2: 1, twice). The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1 to 4: 1) to obtain the title compound (4.44 mg) having the following physical characteristics.

TLC: Rf 0.18 (hexane: ethyl acetate = 10: 1);

¹ H-NMR (CDCl ₃ ): δ 1.43 (s, 18H), 1.81 (m, 2H), 2.09 (m, 2H), 2.52 (m, 4H), 2.81 ( t, 2H), 3.22 (m, 2H), 3.42 (m, 2H), 3.94 (t, 2H), 6.81 (d, 2H), 7.08 (d, 2H), 7.21 (m, 3H); 7.29 (m, 2H).

Example 7

N- {3- [4- (3-phenylpropoxy) phenyl] propyl} -β-alanine hydrochloride:

To a solution of the compound obtained in Example 6 (4.68 g) in 1,4-dioxane (9 ml) was added 4 N at room temperature. a solution of hydrogen chloride in 1,4-dioxane (38 ml), followed by stirring at room temperature overnight. The precipitated material was collected by filtration and dried. Thus, the title compound (2.87 g) was obtained having the following physical characteristics.

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

¹ H-NMR (CD ₃ OD): δ 2.02 (m, 4H), 2.65 (t, 2H), 2.71 (t, 2H), 2.78 (t, 2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.92 (t, 2H), 6.84 (d, 2H), 7.12 (d, 2H), 7.20 (m, 5H) .

Examples 8-8 (3)

Carried out procedures similar to the procedures of Examples 6 and 7, but used the corresponding derivative as a substituent for (3-bromopropyl) benzene, followed by conversion to the corresponding salt in a known manner, if necessary. Thus, the following compounds were obtained.

Example 8

N- (3- {4- [3- (4-methoxyphenyl) propoxy] phenyl} propyl) -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 2.00 (m, 4H), 2.69 (m, 6H), 3.01 (m, 2H), 3.23 (t, 2H), 3.74 (s, 3H), 3.90 (t, 2H), 6.82 (m, 4H), 7.11 (m, 4H).

Example 8 (1)

N- (3- {4- [3- (3,4-dimethoxyphenyl) propoxy] phenyl} propyl) -β-alanine acetate:

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

¹ H-NMR (CD ₃ OD): δ 1.90 (s, 3H), 2.02 (m, 4H), 2.47 (t, 2H), 2.64 (t, 2H), 2.73 (t, 2H), 2.96 (m, 2H), 3.11 (t, 2H), 3.73 (s, 3H), 3.78 (s, 3H), 3.91 (t, 2H) 6.76 (m, 2H); 6.84 (m, 3H); 7.12 (d, 2H).

Example 8 (2)

N- (3- {4- [3- (4-chlorophenyl) propoxy] phenyl} propyl) -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 2.02 (m, 4H), 2.65 (t, 2H), 2.72 (t, 2H), 2.78 (t, 2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.92 (t, 2H), 6.84 (d, 2H), 7.12 (d, 2H), 7.18 (d, 2H) 7.25 (d, 2H).

Example 8 (3)

N- (3- {4 - [(7-chloroquinolin-2-yl) methoxy] phenyl} propyl) -β-alanine hydrochloride:

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

¹ H-NMR (DMSO-d ₆ ): δ 1.84 (m, 2H), 2.56 (t, 2H), 2.65 (t, 2H), 2.86 (m, 2H), 3, 08 (m, 2H), 5.34 (s, 2H), 6.99 (d, 2H), 7.14 (d, 2H), 7.66 (dd, 1H), 7.69 (d, 1H) ), 8.06 (m, 2H), 8.47 (d, 1H), 8.66 (s, 2H).

Example 9

methyl N- [2- (4-hydroxyphenyl) ethyl] -N- (trifluoroacetyl) -β-alaninate

To a solution of tyramine (3.0 g) in methanol (40 ml), acrylate (0.98 ml) in methanol (5.0 ml) was added dropwise at room temperature, followed by stirring at room temperature for 13 hours. Then the mixture was concentrated and subjected to azeotropic distillation with toluene. The residue was dissolved in dichloromethane (30 ml) and trifluoroacetic anhydride (4.6 ml) and pyridine (2.6 ml) were added at 0 ° C, followed by stirring at room temperature for 2 hours. Then, chloroform (30 ml) was added to the reaction mixture. The organic layer was washed successively with a saturated aqueous solution of ammonium chloride, water and 1 N. hydrochloric acid solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain the title compound (1.43 mg) having the following physical characteristics.

TLC: Rf 0.63 (chloroform: methanol: aqueous ammonia = 8: 1: 0.1);

¹ H-NMR (DMSO-d ₆ ): δ 2.63 (t, 2H), 2.77 (t, 2H), 2.90-2.96 (m, 3H), 3.55 (t, 2H ), 3.59-3.68 (m, 2H), 6.71 (d, 2H), 7.01 (d, 2H), 8.83 (s, 1H).

Example 10

methyl N- (2- {4 - [(3-phenylprop-2-ynyl) oxy] phenyl} ethyl) -N- (trifluoroacetyl) -β-alaninate

A procedure similar to that of Example 1 was carried out except that the compound obtained in Example 9 was used as a substituent for methyl 3- (4-hydroxyphenyl) propanoate, while 3-phenylprop-2-in-1-ol was used. as a substituent for 3-phenylpropan-1-ol. Thus, the title compound was obtained having the following physical characteristics.

TLC: Rf 0.43 (hexane: ethyl acetate = 3: 1);

¹ H-NMR (CDCl ₃ ): δ 2.55 (t, 1.2H), 2.68 (t, 0.8H), 2.79-2.92 (m, 2H), 3.51-3 70 (m, 4H), 3.67-3.70 (m, 3H), 4.90 (s, 2H), 6.93-7.04 (m, 2H), 7.08-7.19 (m, 2H), 7.27-7.35 (m, 3H), 7.39-7.47 (m, 2H).

Example 11

N- (2- {4 - [(3-phenylprop-2-ynyl) oxy] phenyl} ethyl) -β-alanine:

To a solution of the compound (39 mg) obtained in Example 10 in a mixture of tetrahydrofuran (1 ml) and methanol (0.5 ml) was added 1 N. an aqueous solution of sodium hydroxide (0.5 ml), followed by stirring for 3 hours. Then the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol: formic acid = 15: 1: 0.5) to obtain the title compound (18 mg) having the following physical characteristics.

TLC: Rf 0.26 (chloroform: methanol: formic acid = 10: 1: 0.5);

¹ H-NMR (CD ₃ OD): δ 2.48 (t, 2H), 2.95 (t, 2H), 3.11-3.26 (m, 4H), 4.93 (s, 2H) 7.02 (d, 2H); 7.24 (d, 2H); 7.27-7.35 (m, 3H); 7.35-7.43 (m, 2H).

Examples 12-12 (2)

Carried out procedures similar to the procedures of Examples 1 and 11, but they used the corresponding alcohol compound as a substituent for methyl 3- (4-hydroxyphenyl) propanoate, and also used the corresponding alcohol compound as a substituent for 3-phenylpropan-1-ol, s subsequent conversion to the corresponding salt in a known manner, if necessary. Thus, the following compounds were obtained.

Example 12

N- [2- (4 - {[(2E) -3-phenylprop-2-enyl] oxy} phenyl) ethyl] -β-alanine formate

TLC: Rf 0.28 (chloroform: methanol: formic acid = 10: 1: 0.5);

¹ H-NMR (CD ₃ OD): δ 2.52 (t, 2H), 2.93 (t, 2H), 3.14-3.27 (m, 4H), 4.69 (dd, 2H) 6.43 (dt, 1H), 6.73 (d, 1H), 6.96 (d, 2H), 7.14-7.26 (m, 3H), 7.30 (t, 2H), 7.41 (d, 2H); 8.32 (s, 1H).

Example 12 (1)

N- (3- {4 - [(3-phenylprop-2-ynyl) oxy] phenyl} propyl) -β-alanine:

TLC: Rf 0.31 (chloroform: methanol: formic acid = 10: 1: 0.5);

¹ H-NMR (CD ₃ OD): δ 1.89-2.05 (m, 2H), 2.58 (t, 2H), 2.67 (t, 2H), 2.94-3.05 ( m, 2H), 3.17 (t, 2H), 4.91 (s, 2H), 6.98 (d, 2H), 7.17 (d, 2H), 7.28-7.35 (m , 3H), 7.35-7.42 (m, 2H).

Example 12 (2)

N- [3- (4 - {[(2E) -3-phenylprop-2-enyl] oxy} phenyl) propyl] -β-alanine:

TLC: Rf 0.35 (chloroform: methanol: formic acid = 10: 1: 0.5);

¹ H-NMR (CD ₃ OD): δ 1.83-2.06 (m, 2H), 2.51 (t, 2H), 2.67 (t, 2H), 2.92-3.05 ( m, 2H), 3.14 (t, 2H), 4.68 (dd, 2H), 6.43 (dt, 1H), 6.73 (d, 1H), 6.92 (d, 2H), 7.15 (d, 2H), 7.19-7.26 (m, 1H), 7.27-7.34 (m, 2H), 7.37-7.45 (m, 2H).

Example 13

ethyl (2E) -2-cyano-3- [4- (3-phenylpropoxy) phenyl] acrylate

4- (3-phenylpropoxy) benzaldehyde (240 mg), ethyl cyanoacetate (0.094 ml) and ammonium acetate (74 mg) were mixed and subjected to interaction under microwave irradiation (50 W, 100 ° C, 10 minutes). Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. This procedure was repeated three times to obtain three residues. These residues were combined and purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 7: 1) to obtain the title compound (629 mg) having the following physical characteristics.

TLC: Rf 0.28 (hexane: ethyl acetate = 5: 1);

¹ H-NMR (CDCl ₃ ): δ 1.39 (t, 3H), 2.15 (m, 2H), 2.83 (m, 2H), 4.04 (t, 2H), 4.37 ( q, 2H), 6.97 (d, 2H), 7.21 (m, 3H), 7.29 (m, 2H), 7.99 (d, 2H), 8.17 (s, 1H).

Example 14

ethyl 2-cyano-3- [4- (3-phenylpropoxy) phenyl] propanoate

In an argon atmosphere, ethanol (1 ml) was added to palladium on carbon with 10% moisture content (250 mg). Then, a solution of the compound obtained in Example 13 (620 mg) in a mixture of ethanol (4 ml) and ethyl acetate (4 ml) was added to the mixture. After purging with hydrogen, the mixture was stirred at room temperature for 2 hours. Then the reaction mixture was filtered through Celite (trade name). The filtrate was concentrated to obtain the title compound (594 mg) having the following physical characteristics.

TLC: Rf 0.26 (hexane: ethyl acetate = 5: 1);

¹ H-NMR (CDCl ₃ ): δ 1.28 (t, 3H), 2.10 (m, 2H), 2.81 (m, 2H), 3.18 (m, 2H), 3.67 ( dd, 1H), 3.95 (t, 2H), 4.24 (q, 2H), 6.85 (d, 2H), 7.19 (m, 5H), 7.28 (m, 2H).

Example 15

3-amino-2- [4- (3-phenylpropoxy) benzyl] propan-1-ol

Anhydrous tetrahydrofuran (10 ml) was added to lithium aluminum hydride (131 mg). Then, a solution of the compound obtained in Example 14 (290 mg) in anhydrous tetrahydrofuran (15 ml) was added dropwise to the mixture, followed by stirring at 60 ° C. for 3 hours. 1N was added to the reaction mixture at 0 ° C. hydrochloric acid solution, followed by stirring at room temperature for 1 hour. Anhydrous sodium sulfate was added to the reaction mixture, and the mixture was filtered through Celite (trade name). The filtrate was concentrated to obtain the title compound (284 mg) having the following physical characteristics as a crude product. The resulting compound was used in the next reaction without further purification.

TLC: Rf 0.43 (chloroform: methanol: aqueous ammonia = 80: 20: 4).

Example 16

N- {3-hydroxy-2- [4- (3-phenylpropoxy) benzyl] propyl} -β-alanine:

To a solution of tert-butyl N- {3-hydroxy-2- [4- (3-phenylpropoxy) benzyl] propyl} -β-alaninate (65 mg; obtained in accordance with the procedure of Example 4 using the compound obtained in Example 15, as a substituent for 4- (3-aminopropyl) phenol) in dichloromethane (3 ml), trifluoroacetic acid (3 ml) was added dropwise at 0 ° C, followed by stirring at room temperature for 2 hours. Then the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 80: 20: 4). The resulting crude product was washed with diethyl ether to give the title compound (38 mg) having the following physical characteristics.

TLC: Rf 0.56 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (DMSO-d ₆ ): δ 1.86 (m, 1H), 1.99 (m, 2H), 2.18 (t, 2H), 2.59 (m, 1H), 2, 71 (m, 3H), 2.80 (t, 2H), 3.37 (m, 4H), 3.91 (t, 2H), 6.83 (d, 2H), 7.09 (d, 2H) ), 7.23 (m, 5H).

Example 17

cyano [4- (3-phenylpropoxy) phenyl] methyl acetate

To anhydrous dichloromethane (3 ml), a solution of titanium tetraisopropoxide (0.074 ml) and 4- (3-phenylpropoxy) benzaldehyde (300 mg) in anhydrous dichloromethane (3 ml) and trimethylsilyl cyanide was successively added dropwise, followed by stirring at room temperature overnight. 1N was added to the reaction mixture at 0 ° C. hydrochloric acid solution (3 ml), followed by stirring at room temperature for 6.5 hours. After adding water, the reaction mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. Acetic anhydride (0.24 ml) and pyridine (0.20 ml) were successively added dropwise to the filtrate at room temperature, followed by stirring at room temperature overnight. Then the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound (160 mg) having the following physical characteristics.

TLC: Rf 0.30 (hexane: ethyl acetate = 5: 1);

¹ H-NMR (CDCl ₃ ): δ 2.05-2.20 (m, 5H), 2.81 (t, 2H), 3.98 (t, 2H), 6.35 (s, 1H), 6.93 (d, 2H), 7.16-7.24 (m, 3H), 7.27-7.34 (m, 2H), 7.44 (d, 2H).

Example 18

3-hydroxy-3- [4- (3-phenylpropoxy) phenyl] propannitrile

To anhydrous tetrahydrofuran (14 ml), n-butyllithium (0.94 ml; 1.6 M solution in hexane) and anhydrous acetonitrile (0.082 ml) were successively added dropwise at -78 ° C. After stirring for 30 minutes, a solution of 4- (3-phenylpropoxy) benzaldehyde (300 mg) in anhydrous tetrahydrofuran (3 ml) was added dropwise to the mixture at -78 ° C. The reaction mixture was stirred at room temperature for 1 hour, then poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with a solvent mixture of diethyl ether and hexane and filtered to give the title compound (238 mg) having the following physical characteristics.

TLC: Rf 0.52 (hexane: ethyl acetate = 1: 1);

¹ H-NMR (CDCl ₃ ): δ 2.11 (m, 2H), 2.18 (d, 1H), 2.76 (m, 4H), 3.97 (t, 2H), 5.00 ( td, 1H), 6.91 (d, 2H), 7.20 (m, 3H), 7.30 (m, 4H).

Examples 19-19 (1)

Using the compound obtained in Example 17 or 18 as a substituent for the compound obtained in Example 14, and following the procedures of Example 15, Example 4 and Example 11 in this order, the following compounds were obtained.

Example 19

N- {2-hydroxy-2- [4- (3-phenylpropoxy) phenyl] ethyl} -β-alaninate, sodium salt

TLC: Rf 0.55 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 2.00-2.10 (m, 2H), 2.38 (t, 2H), 2.68-2.90 (m, 6H), 3.94 ( t, 2H), 4.70 (dd, 1H), 6.86 (d, 2H), 7.12-7.28 (m, 7H).

Example 19 (1)

N- {3-hydroxy-3- [4- (3-phenylpropoxy) phenyl] propyl} -β-alanine

TLC: Rf 0.48 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 1.98-2.10 (m, 4H), 2.48 (t, 2H), 2.78 (t, 2H), 3.04-3.20 ( m, 4H), 3.94 (t, 2H), 4.78 (t, 1H), 6.89 (d, 2H), 7.12-7.31 (m, 7H).

Example 20

1- [4- (3-phenylpropoxy) phenyl] prop-2-en-1-ol

To a solution of 4- (3-phenylpropoxy) benzaldehyde (10.4 g) in anhydrous tetrahydrofuran (100 ml) was added a solution of bromine (vinyl) magnesium in tetrahydrofuran (14%, about 1 M) at 0 ° C. After stirring for 15 minutes, the reaction mixture was added to a cooled saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 3: 1) to obtain the title compound (10.01 g) having the following physical characteristics.

TLC: Rf 0.24 (hexane: ethyl acetate = 4: 1);

¹ H-NMR (CDCl ₃ ): δ 1.85 (d, 1H), 2.04-2.17 (m, 2H), 2.81 (t, 2H), 3.96 (t, 2H), 5.14-5.21 (m, 2H), 5.34 (dt, 1H), 6.05 (ddd, 1H), 6.88 (d, 2H), 7.16-7.23 (m, 3H), 7.25-7.32 (m, 4H).

Example 21

oxiran-2-yl [4- (3-phenylpropoxy) phenyl] methanol

To a solution of the compound (3.0 g) obtained in Example 20, m-chloroperbenzoic acid (7.67 g; mCPBA) was added at room temperature. After stirring for 4 hours, the reaction mixture was poured into chilled 0.1 N. an aqueous solution of sodium hydroxide and was extracted with a mixture of solvents (hexane: ethyl acetate = 1: 5). The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 2: 1) to obtain the title compound (1.96 g) having the following physical characteristics.

TLC: Rf 0.29 (hexane: ethyl acetate = 2: 1);

¹ H-NMR (CDCl ₃ ): δ 2.06-2.15 (m, 2H), 2.23 (d, 0.5H), 2.76-2.89 (m, 3.5H), 2 98 (dd, 0.5H), 3.17-3.27 (m, 1H), 3.97 (t, 2H), 4.43 (t, 0.5H), 4.89 (d, 0 5H), 6.87-6.93 (m, 2H), 7.16-7.24 (m, 3H), 7.26-7.36 (m, 4H).

Example 22

N- {2,3-dihydroxy-3- [4- (3-phenylpropoxy) phenyl] propyl} -β-alanine:

To β-alanine (550 mg) in 2.5 N. an aqueous solution of sodium hydroxide (2.2 ml) was added dropwise a solution of the compound obtained in Example 21 (350 mg) in 2-propanol (2.2 ml), followed by stirring at 50 ° C for 2 hours. Then the reaction mixture was cooled and 1N was added to it at 0 ° C. hydrochloric acid solution (5.5 ml) and then concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 80: 20: 4) to obtain the title compound (313 mg) having the following physical characteristics.

TLC: Rf 0.16 (chloroform: methanol: aqueous ammonia = 80: 40: 4);

¹ H-NMR (CD ₃ OD): δ 2.01-2.10 (m, 2H), 2.42-2.51 (m, 2H), 2.78 (t, 2H), 2.85- 3.18 (m, 4H), 3.84-3.97 (m, 3H), 4.52 (d, 0.5H), 4.59 (d, 0.5H), 6.88-6, 92 (m, 2H), 7.11-7.26 (m, 5H), 7.26-7.34 (m, 2H).

Example 23

N- {2-hydroxy-3- [4- (3-phenylpropoxy) phenyl] propyl} -β-alanine:

Using 1-allyl-4- (3-phenylpropoxy) benzene as a substituent for the compound obtained in Example 20 and following the procedures of Example 21 and Example 22, the title compound was obtained having the following physical characteristics.

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

¹ H-NMR (CD ₃ OD): δ 2.00-2.10 (m, 2H), 2.46 (t, 2H), 2.66-2.90 (m, 5H), 2.99- 3.19 (m, 3H), 3.92 (t, 2H), 3.96-4.04 (m, 1H), 6.84 (d, 2H), 7.11-7.29 (m, 7H).

Example 24

N- (tert-butoxycarbonyl) -N- [3- (4-hydroxyphenyl) propyl] -β-alanine:

Using 3- (4-hydroxyphenyl) propannitrile as a substituent for the compound obtained in Example 14, and following the procedures of Example 15, Example 4, Example 5 and Example 11 in this order, the title compound was obtained having the following physical characteristics.

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

¹ H-NMR (CDCl ₃ ): δ 1.45 (s, 9H), 1.81 (m, 2H), 2.52 (t, 2H), 2.61 (t, 2H), 3.22 ( m, 2H), 3.47 (t, 2H), 6.76 (d, 2H), 7.02 (d, 2H).

Example 25

N- [3- (4-hydroxyphenyl) propyl] -β-alanine hydrochloride:

Using the compound obtained in Example 24 as a substituent for the compound obtained in Example 6 and following the procedure of Example 7, the title compound was obtained having the following physical characteristics.

TLC: Rf 0.69 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 1.95 (m, 2H), 2.62 (t, 2H), 2.72 (t, 2H), 3.00 (m, 2H), 3.24 (t, 2H); 6.71 (d, 2H); 7.03 (d, 2H).

Example 26

N- [2- (4- {2- [4- (benzyloxy) phenyl] ethoxy} phenyl) ethyl] -β-alanine trifluoroacetate:

Stage A:

to a suspension of Wang resin (manufacturer Argonaut Technology; Cat No. 800296) (1.06 mmol / g, 10.6 g, 11.2 mmol) in dichloromethane (100 ml) was added at -78 ° CN, N-diisopropylethylamine (17 4 ml; 100 mmol). Then, acrylic acid chloride (4.06 ml; 50 mmol) was added and the mixture was shaken at room temperature overnight. After removing the solvent using an exhaust fan, the resulting resin was washed 4 times with dichloromethane to give an acrylate resin (10.9 g).

Stage B:

to an acrylate resin (1.5 g), a solution of 4- (2-aminoethyl) phenol (20 mmol) in N-methylpyrrolidone (20 ml) was added at room temperature, and the mixture was shaken at room temperature overnight. After removing the solvent using an exhaust fan, the resulting resin was washed 4 times with dichloromethane to give a phenolic resin (1.78 g, 1.2 mmol / g).

Stage C:

2- [4- (benzyloxy) phenyl] ethanol (0.30 mmol) was added to phenolic resin (50 mg, 0.060 mmol) at room temperature. Then a solvent mixture (1 ml; dichloromethane: anhydrous tetrahydrofuran = 1: 1) was added followed by tri-n-butylphosphine (0.30 mmol) and 1,1'-azobis (N, N-dimethylformamide) (0.30 mmol) ) The mixture was then shaken at room temperature overnight. The resin was isolated by filtration and washed successively 3 times with a solvent mixture (dichloromethane: tetrahydrofuran = 1: 1), 3 times with dichloromethane, 4 times with methanol, 2 times with a solvent mixture (dichloromethane: methanol = 3: 1) and 3 times with dichloromethane. Then trifluoroacetic acid (0.5 ml) and dichloromethane (0.5 ml) were added and the mixture was shaken at room temperature for 4 hours. After the resin was filtered and washed 4 times with dichloromethane, the filtrate was concentrated to obtain the title compound having the following physical characteristics.

Retention time in HPLC analysis (minutes): 3.67; MS (m / z): 839 (2M + H) +, 420 (M + H) +.

Unless otherwise indicated, HPLC was performed under the following conditions:

Column: Xterra (trade name) MS C ₁₈ 5 μm, 4.6 × 50 mm east

Flow rate: 3 ml / min.

Solvent A: 0.1% trifluoroacetic acid aqueous solution.

Solvent B: 0.1% solution of trifluoroacetic acid in acetonitrile.

Within 0.5 minutes after the start of the measurement, the ratio in the mixture of solution A and solution B was fixed as 95/5. Then the ratio in the mixture of solution A and solution B was linearly changed to 0/100 for 2.5 minutes and remained unchanged 0/100 for 0.5 minutes. Over the next 0.01 minutes, the ratio in the mixture of solution A and solution B was linearly changed to 95/5.

Examples 26 (1) -26 (244)

A procedure similar to that of Example 26 was carried out except that 4- (2-aminoethyl) phenol or the corresponding derivative was used as its substituent and 2- [4- (benzyloxy) phenyl] ethanol or the corresponding derivative was used as its substituent, with obtaining the following compounds.

Example 26 (1)

N- {2- [4- (2-phenoxyethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 659 (2M + H) ⁺ , 330 (M + H) ⁺ , 266.

Example 26 (2)

N- {2- [4- (3-phenylpropoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.48; MS (m / z): 655 (2M + H) ⁺ , 328 (M + H) ⁺ .

Example 26 (3)

N- {2- [4- (4-phenylbutoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,58; MS (m / z): 683 (2M + H) ⁺ , 342 (M + H) ⁺ .

Example 26 (4)

N- (2- {4- [4- (4-methoxyphenyl) butoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.54; MS (m / z): 743 (2M + H) ⁺ , 372 (M + H) ⁺ .

Example 26 (5)

N- (2- {4- [2- (benzylsulfanyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.48; MS (m / z): 719 (2M + H) ⁺ , 360 (M + H) ⁺ .

Example 26 (6)

N- {2- [4- (3-phenoxypropoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 687 (2M + H) ⁺ , 344 (M + H) ⁺ .

Example 26 (7)

N- {2- [4- (cyclohexylmethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.56; MS (m / z): 611 (2M + H) ⁺ , 306 (M + H) ⁺ .

Example 26 (8)

N- (2- {4- [2- (2,4-difluorophenyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.46; MS (m / z): 699 (2M + H) ⁺ , 350 (M + H) ⁺ .

Example 26 (9)

N- (2- {4 - [(3-phenoxybenzyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.62; MS (m / z): 783 (2M + H) ⁺ , 392 (M + H) ⁺ .

Example 26 (10)

N- {2- [4- (2-cyclohexylethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.64; MS (m / z): 639 (2M + H) ⁺ , 320 (M + H) ⁺ .

Example 26 (11)

N- {2- [4- (Benzyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 599 (2M + H) ⁺ , 300 (M + H) ⁺ .

Example 26 (12)

N- {2- [4- (2-phenylethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.41; MS (m / z): 627 (2M + H) ⁺ , 314 (M + H) ⁺ .

Example 26 (13)

N- {2- [4- (3,3-dimethylbutoxy) phenyl] ethyl} -β-alanine trifluoroacetate

Retention time in HPLC analysis (minutes): 3.51; MS (m / z): 587 (2M + H) ⁺ , 294 (M + H) ⁺ .

Example 26 (14)

N- {2- [4- (3-cyclohexylpropoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.77; MS (m / z): 667 (2M + H) ⁺ , 334 (M + H) ⁺ .

Example 26 (15)

N- (2- {4 - [(4-tert-butylbenzyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,50; MS (m / z): 711 (2M + H) ⁺ , 356 (M + H) ⁺ .

Example 26 (16)

N- (2- {4 - [(4-cyclohexylbenzyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.65; MS (m / z): 763 (2M + H) ⁺ , 382 (M + H) ⁺ .

Example 26 (17)

N- {3- [4- (2-phenylethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.39; MS (m / z): 655 (2M + H) ⁺ , 328 (M + H) ⁺ .

Example 26 (18)

N- (3- {4- [2- (2-methylphenyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.46; MS (m / z): 683 (2M + H) ⁺ , 342 (M + H) ⁺ .

Example 26 (19)

N- (3- {4- [2- (3-methylphenyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.47; MS (m / z): 683 (2M + H) ⁺ , 342 (M + H) ⁺ .

Example 26 (20)

N- (3- {4- [2- (4-methylphenyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.48; MS (m / z): 683 (2M + H) ⁺ , 342 (M + H) ⁺ .

Example 26 (21)

N- {3- [4- (Benzyloxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.30; MS (m / z): 627 (2M + H) ⁺ , 314 (M + H) ⁺ .

Example 26 (22)

N- (4- {2- [4- (benzyloxy) phenyl] ethoxy} benzyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.56; MS (m / z): 406 (M + H) ⁺ .

Example 26 (23)

N- [4- (2-phenoxyethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.22; MS (m / z): 316 (M + H) ⁺ , 227.

Example 26 (24)

N- {4- [2- (Benzyloxy) ethoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.21; MS (m / z): 330 (M + H) ⁺ , 241.

Example 26 (25)

N- [4- (3-phenylpropoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.35; MS (m / z): 314 (M + H) ⁺ , 225.

Example 26 (26)

N- [4- (4-phenylbutoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.43; MS (m / z): 328 (M + H) ⁺ , 239.

Example 26 (27)

N- {4 - [(5-phenylpentyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.54; MS (m / z): 342 (M + H) ⁺ , 253.

Example 26 (28)

N- [4- (2-thien-2-yl-ethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.21; MS (m / z): 306 (M + H) ⁺ , 217.

Example 26 (29)

N- {4- [2- (Benzylsulfanyl) ethoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.33; MS (m / z): 346 (M + H) ⁺ , 151.

Example 26 (30)

N- {4 - [(6-phenylhexyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.61; MS (m / z): 356 (M + H) ⁺ .

Example 26 (31)

N- {4- [3- (Benzyloxy) propoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.28; MS (m / z): 344 (M + H) ⁺ , 255.

Example 26 (32)

N- {4 - [(7-phenylheptyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.72; MS (m / z): 370 (M + H) ⁺ .

Example 26 (33)

N- [4- (3-phenoxypropoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.32; MS (m / z): 330 (M + H) ⁺ , 241.

Example 26 (34)

N- {4 - [(9-phenylnonyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.91; MS (m / z): 398 (M + H) ⁺ , 309.

Example 26 (35)

N- {4 - [(8-phenylloctyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.82; MS (m / z): 384 (M + H) ⁺ , 295.

Example 26 (36)

N- [4- (cyclohexylmethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.41; MS (m / z): 292 (M + H) ⁺ , 203.

Example 26 (37)

N- [4- (2-cyclopentylethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.41; MS (m / z): 292 (M + H) ⁺ , 203.

Example 26 (38)

N- (4 - {[5- (benzyloxy) pentyl] oxy} benzyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.43; MS (m / z): 372 (M + H) ⁺ , 283.

Example 26 (39)

N- {4- [4- (benzyloxy) butoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.36; MS (m / z): 358 (M + H) ⁺ , 269.

Example 26 (40)

N- {4 - [(3-phenoxybenzyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.48; MS (m / z): 378 (M + H) ⁺ , 289.

Example 26 (41)

N- [4- (2-cyclohexylethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,50; MS (m / z): 306 (M + H) ⁺ , 217.

Example 26 (42)

N- (4-butoxybenzyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.15; MS (m / z): 252 (M + H) ⁺ , 163.

Example 26 (43)

N- [4- (cyclopentylmethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.31; MS (m / z): 278 (M + H) ⁺ , 189.

Example 26 (44)

N- [4- (Benzyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.18; MS (m / z): 286 (M + H) ⁺ , 197.

Example 26 (45)

N- [4- (2-phenylethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.26; MS (m / z): 300 (M + H) ⁺ , 211.

Example 26 (46)

N- (4-isobutoxybenzyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.17; MS (m / z): 252 (M + H) ⁺ , 163.

Example 26 (47)

N- {4 - [(4-methylpentyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.38; MS (m / z): 280 (M + H) ⁺ , 191.

Example 26 (48)

N- [4- (3,3-dimethylbutoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 280 (M + H) ⁺ , 191.

Example 26 (49)

N- {4 - [(2-propylpentyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,59; MS (m / z): 308 (M + H) ⁺ , 219.

Example 26 (50)

N- [4- (3-cyclohexylpropoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.61; MS (m / z): 320 (M + H) ⁺ , 231.

Example 26 (51)

N- [4- (pentyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.29; MS (m / z): 266 (M + H) ⁺ , 177.

Example 26 (52)

N- [4- (hexyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 280 (M + H) ⁺ , 191.

Example 26 (53)

N- [4- (heptyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,50; MS (m / z): 294 (M + H) ⁺ , 205.

Example 26 (54)

N- [4- (octyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.62; MS (m / z): 308 (M + H) ⁺ , 219.

Example 26 (55)

N- {4 - [(4-chlorobenzyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.32; MS (m / z): 320 (M + H) ⁺ , 231.

Example 26 (56)

N- [3- (4- {2- [4- (benzyloxy) phenyl] ethoxy} phenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.60; MS (m / z): 434 (M + H) ⁺ , 219.

Example 26 (57)

N- {3- [4- (2-phenoxyethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.33; MS (m / z): 344 (M + H) ⁺ .

Example 26 (58)

N- (3- {4- [2- (Benzyloxy) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.31; MS (m / z): 358 (M + H) ⁺ .

Example 26 (59)

N- {3- [4- (3-phenylpropoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 342 (M + H) ⁺ .

Example 26 (60)

N- {3- [4- (2-thien-2-yl-ethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 334 (M + H) ⁺ .

Example 26 (61)

N- (3- {4- [2- (benzylsulfanyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.44; MS (m / z): 374 (M + H) ⁺ .

Example 26 (62)

N- (3- {4- [3- (benzyloxy) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.38; MS (m / z): 372 (M + H) ⁺ .

Example 26 (63)

N- {3- [4- (3-phenoxypropoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.42; MS (m / z): 358 (M + H) ⁺ .

Example 26 (64)

N- (3- {4 - [(9-phenylnonyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 4.00; MS (m / z): 426 (M + H) ⁺ .

Example 26 (65)

N- (3- {4 - [(8-phenylloctyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.93; MS (m / z): 412 (M + H) ⁺ .

Example 26 (66)

N- {3- [4- (cyclohexylmethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,55; MS (m / z): 320 (M + H) ⁺ , 219.

Example 26 (67)

N- {3- [4- (2-cyclopentylethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.53; MS (m / z): 320 (M + H) ⁺ .

Example 26 (68)

N- [3- (4 - {[5- (benzyloxy) pentyl] oxy} phenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.53; MS (m / z): 400 (M + H) ⁺ .

Example 26 (69)

N- (3- {4- [4- (benzyloxy) butoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 386 (M + H) ⁺ .

Example 26 (70)

N- (3- {4 - [(3-phenoxybenzyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,58; MS (m / z): 406 (M + H) ⁺ , 219.

Example 26 (71)

N- {3- [4- (2-cyclohexylethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.60; MS (m / z): 334 (M + H) ⁺ , 219.

Example 26 (72)

N- {3- [4- (Cyclopentylmethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.44; MS (m / z): 306 (M + H) ⁺ .

Example 26 (73)

N- [3- (4-isobutoxyphenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.31; MS (m / z): 280 (M + H) ⁺ .

Example 26 (74)

N- (3- {4 - [(4-methylpentyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.51; MS (m / z): 308 (M + H) ⁺ .

Example 26 (75)

N- {3- [4- (3,3-dimethylbutoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.49; MS (m / z): 308 (M + H) ⁺ .

Example 26 (76)

N- (3- {4 - [(2-propylpentyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.71; MS (m / z): 336 (M + H) ⁺ .

Example 26 (77)

N- {3- [4- (3-cyclohexylpropoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.75; MS (m / z): 348 (M + H) ⁺ .

Example 26 (78)

N- (3- {4 - [(4-chlorobenzyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.42; MS (m / z): 350, 348 (M + H) ⁺ .

Example 26 (79)

N- (3- {4- [2- (4-tert-butylphenyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.69; MS (m / z): 384 (M + H) ⁺ .

Example 26 (80)

N- (3- {4- [2- (2-naphthyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.56; MS (m / z): 378 (M + H) ⁺ .

Example 26 (81)

N- {3- [4- (decyloxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,99; MS (m / z): 364 (M + H) ⁺ .

Example 26 (82)

N- {2- [4- (2-thien-2-yl-ethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.27; MS (m / z): 320 (M + H) ⁺ .

Example 26 (83)

N- (2- {4 - [(6-phenylhexyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.67; MS (m / z): 370 (M + H) ⁺ , 219.

Example 26 (84)

N- (2- {4- [3- (Benzyloxy) propoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 358 (M + H) ⁺ .

Example 26 (85)

N- (2- {4 - [(7-phenylheptyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.77; MS (m / z): 384 (M + H) ⁺ .

Example 26 (86)

N- (2- {4 - [(9-phenylnonyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.95; MS (m / z): 412 (M + H) ⁺ .

Example 26 (87)

N- (2- {4 - [(8-phenylloctyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.86; MS (m / z): 398 (M + H) ⁺ .

Example 26 (88)

N- {2- [4- (2-cyclopentylethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.47; MS (m / z): 306 (M + H) ⁺ .

Example 26 (89)

N- [2- (4 - {[5- (benzyloxy) pentyl] oxy} phenyl) ethyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.49; MS (m / z): 386 (M + H) ⁺ .

Example 26 (90)

N- (2- {4- [4- (benzyloxy) butoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 372 (M + H) ⁺ .

Example 26 (91)

N- [2- (4-butoxyphenyl) ethyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.23; MS (m / z): 266 (M + H) ⁺ .

Example 26 (92)

N- {2- [4- (cyclopentylmethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.38; MS (m / z): 292 (M + H) ⁺ .

Example 26 (93)

N- [2- (4-isobutoxyphenyl) ethyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.23; MS (m / z): 266 (M + H) ⁺ .

Example 26 (94)

N- (2- {4 - [(4-methylpentyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.44; MS (m / z): 294 (M + H) ⁺ .

Example 26 (95)

N- (2- {4 - [(2-propylpentyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.64; MS (m / z): 322 (M + H) ⁺ , 219.

Example 26 (96)

N- {2- [4- (pentyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 280 (M + H) ⁺ .

Example 26 (97)

N- {2- [4- (hexyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 294 (M + H) ⁺ .

Example 26 (98)

N- {2- [4- (heptyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.56; MS (m / z): 308 (M + H) ⁺ , 219.

Example 26 (99)

N- {2- [4- (octyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.67; MS (m / z): 322 (M + H) ⁺ .

Example 26 (100)

N- (2- {4 - [(4-chlorobenzyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.38; MS (m / z): 336, 334 (M + H) ⁺ .

Example 26 (101)

N- (2- {4- [2- (4-tert-butylphenyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.66; MS (m / z): 370 (M + H) ⁺ .

Example 26 (102)

N- (2- {4- [2- (2-naphthyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.49; MS (m / z): 364 (M + H) ⁺ .

Example 26 (103)

N- (2- {4- [2- (4-methylphenyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 328 (M + H) ⁺ .

Example 26 (104)

N- {2- [4- (nonyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.80; MS (m / z): 336 (M + H) ⁺ .

Example 26 (105)

N- (2- {4- [2- (3-methylphenyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 328 (M + H) ⁺ .

Example 26 (106)

N- {2- [4- (decyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.89; MS (m / z): 350 (M + H) ⁺ .

Example 26 (107)

N- (2- {4- [2- (2-methylphenyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 328 (M + H) ⁺ .

Example 26 (108)

N- [2- (3- {2- [4- (benzyloxy) phenyl] ethoxy} phenyl) ethyl] -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,58; MS (m / z): 420 (M + H) ⁺ .

Example 26 (109)

N- {2- [3- (2-phenoxyethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.27; MS (m / z): 330 (M + H) ⁺ .

Example 26 (110)

N- {2- [3- (3-phenylpropoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.38; MS (m / z): 328 (M + H) ⁺ .

Example 26 (111)

N- {2- [3- (4-phenylbutoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.47; MS (m / z): 342 (M + H) ⁺ .

Example 26 (112)

N- (2- {3 - [(5-phenylpentyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.56; MS (m / z): 356 (M + H) ⁺ , 219.

Example 26 (113)

N- (2- {3- [2- (Benzylsulfanyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.38; MS (m / z): 360 (M + H) ⁺ .

Example 26 (114)

N- (2- {3 - [(6-phenylhexyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.64; MS (m / z): 370 (M + H) ⁺ .

Example 26 (115)

N- (2- {3- [3- (Benzyloxy) propoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 358 (M + H) ⁺ .

Example 26 (116)

N- (2- {3 - [(7-phenylheptyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.75; MS (m / z): 384 (M + H) ⁺ .

Example 26 (117)

N- (2- {3 - [(9-phenylnonyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.95; MS (m / z): 412 (M + H) ⁺ .

Example 26 (118)

N- (2- {3 - [(8-phenylloctyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.84; MS (m / z): 398 (M + H) ⁺ .

Example 26 (119)

N- {2- [3- (cyclohexylmethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 320, 306 (M + H) ⁺ .

Example 26 (120)

N- {2- [3- (2-cyclopentylethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 306 (M + H) ⁺ .

Example 26 (121)

N- [2- (3 - {[5- (benzyloxy) pentyl] oxy} phenyl) ethyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.47; MS (m / z): 386 (M + H) ⁺ .

Example 26 (122)

N- (2- {3- [4- (Benzyloxy) butoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.42; MS (m / z): 372 (M + H) ⁺ .

Example 26 (123)

N- (2- {3 - [(3-phenoxybenzyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.51; MS (m / z): 392 (M + H) ⁺ .

Example 26 (124)

N- {2- [3- (2-cyclohexylethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,58; MS (m / z): 320 (M + H) ⁺ , 219.

Example 26 (125)

N- [2- (3-butoxyphenyl) ethyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.22; MS (m / z): 266 (M + H) ⁺ .

Example 26 (126)

N- {2- [3- (Cyclopentylmethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 336, 320, 292 (M + H) ⁺ .

Example 26 (127)

N- {2- [3- (Benzyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.23; MS (m / z): 300 (M + H) ⁺ .

Example 26 (128)

N- {2- [3- (2-phenylethoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.33; MS (m / z): 314 (M + H) ⁺ .

Example 26 (129)

N- [2- (3-isobutoxyphenyl) ethyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.23; MS (m / z): 266 (M + H) ⁺ .

Example 26 (130)

N- (2- {3 - [(4-methylpentyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.44; MS (m / z): 294 (M + H) ⁺ .

Example 26 (131)

N- {2- [3- (3,3-dimethylbutoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 294 (M + H) ⁺ .

Example 26 (132)

N- (2- {3 - [(2-propylpentyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.62; MS (m / z): 322 (M + H) ⁺ .

Example 26 (133)

N- {2- [3- (3-cyclohexylpropoxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.66; MS (m / z): 334 (M + H) ⁺ .

Example 26 (134)

N- {2- [3- (pentyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.33; MS (m / z): 280 (M + H) ⁺ .

Example 26 (135)

N- {2- [3- (hexyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.44; MS (m / z): 294 (M + H) ⁺ .

Example 26 (136)

N- {2- [3- (heptyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.56; MS (m / z): 308 (M + H) ⁺ .

Example 26 (137)

N- {2- [3- (octyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.67; MS (m / z): 322 (M + H) ⁺ .

Example 26 (138)

N- (2- {3 - [(4-chlorobenzyl) oxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.37; MS (m / z): 336, 334 (M + H) ⁺ .

Example 26 (139)

N- (2- {3- [2- (4-tert-butylphenyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.62; MS (m / z): 370 (M + H) ⁺ .

Example 26 (140)

N- (2- {3- [2- (2-naphthyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.47; MS (m / z): 364 (M + H) ⁺ .

Example 26 (141)

N- (2- {3- [2- (4-methylphenyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 328 (M + H) ⁺ .

Example 26 (142)

N- {2- [3- (nonyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.78; MS (m / z): 336 (M + H) ⁺ .

Example 26 (143)

N- (2- {3- [2- (3-methylphenyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 328 (M + H) ⁺ .

Example 26 (144)

N- {2- [3- (decyloxy) phenyl] ethyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.88; MS (m / z): 350 (M + H) ⁺ .

Example 26 (145)

N- (2- {3- [2- (2-methylphenyl) ethoxy] phenyl} ethyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.38; MS (m / z): 328 (M + H) ⁺ .

Example 26 (146)

N- (3- {2- [4- (benzyloxy) phenyl] ethoxy} benzyl) -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,55; MS (m / z): 406 (M + H) ⁺ .

Example 26 (147)

N- [3- (3-phenylpropoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.33; MS (m / z): 314 (M + H) ⁺ .

Example 26 (148)

N- [3- (4-phenylbutoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.42; MS (m / z): 328 (M + H) ⁺ .

Example 26 (149)

N- {3 - [(5-phenylpentyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.51; MS (m / z): 342 (M + H) ⁺ .

Example 26 (150)

N- {3- [2- (Benzylsulfanyl) ethoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 360, 346 (M + H) ⁺ .

Example 26 (151)

N- {3 - [(6-phenylhexyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.60; MS (m / z): 356 (M + H) ⁺ .

Example 26 (152)

N- {3- [3- (Benzyloxy) propoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.29; MS (m / z): 344 (M + H) ⁺ .

Example 26 (153)

N- {3 - [(7-phenylheptyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.69; MS (m / z): 370 (M + H) ⁺ .

Example 26 (154)

N- [3- (3-phenoxypropoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.31; MS (m / z): 330 (M + H) ⁺ .

Example 26 (155)

N- {3 - [(9-phenylnonyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.88; MS (m / z): 330 (M + H) ⁺ .

Example 26 (156)

N- {3 - [(8-phenylloctyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.77; MS (m / z): 384 (M + H) ⁺ .

Example 26 (157)

N- [3- (2-cyclopentylethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.38; MS (m / z): 292 (M + H) ⁺ .

Example 26 (158)

N- (3 - {[5- (Benzyloxy) pentyl] oxy} benzyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.42; MS (m / z): 372 (M + H) ⁺ .

Example 26 (159)

N- {3- [4- (Benzyloxy) butoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.33; MS (m / z): 358 (M + H) ⁺ .

Example 26 (160)

N- {3 - [(3-phenoxybenzyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 378 (M + H) ⁺ .

Example 26 (161)

N- [3- (2-cyclohexylethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 306 (M + H) ⁺ .

Example 26 (162)

N- (3-butoxybenzyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.14; MS (m / z): 252 (M + H) ⁺ .

Example 26 (163)

N- [3- (cyclopentylmethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.29; MS (m / z): 278 (M + H) ⁺ .

Example 26 (164)

N- [3- (Benzyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.16; MS (m / z): 286 (M + H) ⁺ .

Example 26 (165)

N- [3- (2-phenylethoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.25; MS (m / z): 300 (M + H) ⁺ .

Example 26 (166)

N- (3-isobutoxybenzyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.16; MS (m / z): 252 (M + H) ⁺ .

Example 26 (167)

N- {3 - [(4-methylpentyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.36; MS (m / z): 280 (M + H) ⁺ .

Example 26 (168)

N- [3- (3,3-dimethylbutoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.33; MS (m / z): 280 (M + H) ⁺ .

Example 26 (169)

N- {3 - [(2-propylpentyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.56; MS (m / z): 308 (M + H) ⁺ .

Example 26 (170)

N- [3- (3-cyclohexylpropoxy) benzyl] -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,58; MS (m / z): 320 (M + H) ⁺ .

Example 26 (171)

N- [3- (pentyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.25; MS (m / z): 266 (M + H) ⁺ .

Example 26 (172)

N- [3- (hexyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 280 (M + H) ⁺ .

Example 26 (173)

N- [3- (heptyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.47; MS (m / z): 294 (M + H) ⁺ .

Example 26 (174)

N- [3- (octyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.60; MS (m / z): 308 (M + H) ⁺ .

Example 26 (175)

N- {3 - [(4-chlorobenzyl) oxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.31; MS (m / z): 322, 320 (M + H) ⁺ .

Example 26 (176)

N- {3- [2- (4-tert-butylphenyl) ethoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,58; MS (m / z): 356 (M + H) ⁺ .

Example 26 (177)

N- {3- [2- (2-naphthyl) ethoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.42; MS (m / z): 350 (M + H) ⁺ .

Example 26 (178)

N- {3- [2- (4-methylphenyl) ethoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 314 (M + H) ⁺ .

Example 26 (179)

N- [3- (nonyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.71; MS (m / z): 322 (M + H) ⁺ .

Example 26 (180)

N- {3- [2- (3-methylphenyl) ethoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 314 (M + H) ⁺ .

Example 26 (181)

N- [3- (decyloxy) benzyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.80; MS (m / z): 336 (M + H) ⁺ .

Example 26 (182)

N- {3- [2- (2-methylphenyl) ethoxy] benzyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.33; MS (m / z): 314 (M + H) ⁺ .

Example 26 (183)

N- [3- (3- {2- [4- (benzyloxy) phenyl] ethoxy} phenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.64; MS (m / z): 434 (M + H) ⁺ .

Example 26 (184)

N- {3- [3- (2-phenoxyethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.33; MS (m / z): 344 (M + H) ⁺ .

Example 26 (185)

N- {3- [3- (3-phenylpropoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 342 (M + H) ⁺ .

Example 26 (186)

N- {3- [3- (4-phenylbutoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.53; MS (m / z): 356 (M + H) ⁺ .

Example 26 (187)

N- (3- {3 - [(5-phenylpentyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.64; MS (m / z): 370 (M + H) ⁺ .

Example 26 (188)

N- (3- {3 - [(6-phenylhexyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.73; MS (m / z): 384 (M + H) ⁺ .

Example 26 (189)

N- (3- {3- [3- (Benzyloxy) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.40; MS (m / z): 372 (M + H) ⁺ .

Example 26 (190)

N- (3- {3 - [(7-phenylheptyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.82; MS (m / z): 398 (M + H) ⁺ .

Example 26 (191)

N- (3- {3 - [(9-phenylnonyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 4.00; MS (m / z): 426 (M + H) ⁺ .

Example 26 (192)

N- (3- {3 - [(8-phenylloctyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.89; MS (m / z): 412 (M + H) ⁺ .

Example 26 (193)

N- {3- [3- (2-cyclopentylethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.51; MS (m / z): 320 (M + H) ⁺ .

Example 26 (194)

N- [3- (3 - {[5- (benzyloxy) pentyl] oxy} phenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.51; MS (m / z): 400 (M + H) ⁺ .

Example 26 (195)

N- (3- {3- [4- (Benzyloxy) butoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 386 (M + H) ⁺ .

Example 26 (196)

N- (3- {3 - [(3-phenoxybenzyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,55; MS (m / z): 406 (M + H) ⁺ .

Example 26 (197)

N- {3- [3- (2-cyclohexylethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.60; MS (m / z): 334 (M + H) ⁺ .

Example 26 (198)

N- [3- (3-butoxyphenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.29; MS (m / z): 280 (M + H) ⁺ .

Example 26 (199)

N- {3- [3- (Cyclopentylmethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.42; MS (m / z): 306 (M + H) ⁺ .

Example 26 (200)

N- {3- [3- (Benzyloxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.29; MS (m / z): 314 (M + H) ⁺ .

Example 26 (201)

N- {3- [3- (2-phenylethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.38; MS (m / z): 328 (M + H) ⁺ .

Example 26 (202)

N- [3- (3-isobutoxyphenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.29; MS (m / z): 280 (M + H) ⁺ .

Example 26 (203)

N- (3- {3 - [(4-methylpentyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.49; MS (m / z): 308 (M + H) ⁺ .

Example 26 (204)

N- {3- [3- (3,3-dimethylbutoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 308 (M + H) ⁺ .

Example 26 (205)

N- (3- {3 - [(2-propylpentyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.69; MS (m / z): 336 (M + H) ⁺ .

Example 26 (206)

N- {3- [3- (3-cyclohexylpropoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.71; MS (m / z): 348 (M + H) ⁺ .

Example 26 (207)

N- {3- [3- (pentyloxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.42; MS (m / z): 294 (M + H) ⁺ .

Example 26 (208)

N- {3- [3- (hexyloxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.51; MS (m / z): 308 (M + H) ⁺ .

Example 26 (209)

N- {3- [3- (heptyloxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.60; MS (m / z): 322 (M + H) ⁺ .

Example 26 (210)

N- {3- [3- (octyloxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.71; MS (m / z): 336 (M + H) ⁺ .

Example 26 (211)

N- (3- {3 - [(4-chlorobenzyl) oxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.42; MS (m / z): 350, 348 (M + H) ⁺ .

Example 26 (212)

N- (3- {3- [2- (4-tert-butylphenyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.67; MS (m / z): 384 (M + H) ⁺ .

Example 26 (213)

N- (3- {3- [2- (2-naphthyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.53; MS (m / z): 378 (M + H) ⁺ .

Example 26 (214)

N- (3- {3- [2- (4-methylphenyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 342 (M + H) ⁺ .

Example 26 (215)

N- {3- [3- (nonyloxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.84; MS (m / z): 350 (M + H) ⁺ .

Example 26 (216)

N- (3- {3- [2- (3-methylphenyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.45; MS (m / z): 342 (M + H) ⁺ .

Example 26 (217)

N- {3- [3- (decyloxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.93; MS (m / z): 364 (M + H) ⁺ .

Example 26 (218)

N- (3- {3- [2- (2-methylphenyl) ethoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.44; MS (m / z): 342 (M + H) ⁺ .

Example 26 (219)

N- (3- {4- [3- (4-fluorophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.49; MS (m / z): 360 (M + H) ⁺ .

Example 26 (220)

N- (3- {4- [3- (4-bromophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate

Retention time in HPLC analysis (minutes): 3.60; MS (m / z): 422, 420 (M + H) ⁺ .

Example 26 (221)

N- [3- (4- {3- [4- (trifluoromethyl) phenyl] propoxy} phenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.62; MS (m / z): 410 (M + H) ⁺ .

Example 26 (222)

N- (3- {4- [3- (3-methylphenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,55; MS (m / z): 356 (M + H) ⁺ .

Example 26 (223)

N- (3- {4- [3- (2-chlorophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,55; MS (m / z): 378, 376 (M + H) ⁺ .

Example 26 (224)

N- (3- {4- [3- (2,6-dichlorophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.64; MS (m / z): 412, 410 (M + H) ⁺ .

Example 26 (225)

N- (3- {4- [3- (4-chlorophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,58; MS (m / z): 378, 376 (M + H) ⁺ .

Example 26 (226)

N- (3- {4- [3- (2-methylphenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.49; MS (m / z): 356 (M + H) ⁺ .

Example 26 (227)

N- (3- {4- [3- (3-chlorophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.56; MS (m / z): 378, 376 (M + H) ⁺ .

Example 26 (228)

N- (3- {4- [3- (4-methoxyphenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.44; MS (m / z): 372 (M + H) ⁺ .

Example 26 (229)

N- (3- {4- [3- (2-bromophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,58; MS (m / z): 422, 420 (M + H) ⁺ .

Example 26 (230)

N- (3- {4- [3- (3-nitrophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.44; MS (m / z): 387 (M + H) ⁺ .

Example 26 (231)

N- (3- {4- [3- (3-fluorophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.49; MS (m / z): 360 (M + H) ⁺ .

Example 26 (232)

N- (3- {4- [3- (3,4-dimethoxyphenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.34; MS (m / z): 402 (M + H) ⁺ .

Example 26 (233)

N- (3- {4- [3- (3-phenoxyphenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.71; MS (m / z): 434 (M + H) ⁺ .

Example 26 (234)

N- (3- {4- [3- (3,4-difluorophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.53; MS (m / z): 378 (M + H) ⁺ .

Example 26 (235)

N- (3- {4- [3- (3,4,5-trimethoxyphenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.31; MS (m / z): 432 (M + H) ⁺ .

Example 26 (236)

N- [3- (4- {3- [3- (trifluoromethoxy) phenyl] propoxy} phenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.64; MS (m / z): 426 (M + H) ⁺ .

Example 26 (237)

N- [3- (4- {3- [2,5-bis (trifluoromethyl) phenyl] propoxy} phenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.69; MS (m / z): 478 (M + H) ⁺ .

Example 26 (238)

N- (3- {4- [3- (3-bromophenyl) propoxy] phenyl} propyl) -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.60; MS (m / z): 422, 420 (M + H) ⁺ .

Example 26 (239)

N- [3- (4- {3- [3,5-bis (trifluoromethyl) phenyl] propoxy} phenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.75; MS (m / z): 478 (M + H) ⁺ .

Example 26 (240)

N- [3- (4- {3- [3- (trifluoromethyl) phenyl] propoxy} phenyl) propyl] -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.60; MS (m / z): 410 (M + H) ⁺ .

Example 26 (241)

N- {3- [4- (3-phenylbutoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.53; MS (m / z): 356 (M + H) ⁺ .

Example 26 (242)

N- {3- [4- (bicyclo [4.2.0] octa-1,3,5-trien-7-ylmethoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.44; MS (m / z): 340 (M + H) ⁺ .

Example 26 (243)

N- {3- [4- (2-methyl-3-phenylpropoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in the analysis of HPLC (minutes): 3,55; MS (m / z): 356 (M + H) ⁺ .

Example 26 (244)

N- {3- [4- (3,3-diphenylpropoxy) phenyl] propyl} -β-alanine trifluoroacetate:

Retention time in HPLC analysis (minutes): 3.62; MS (m / z): 418 (M + H) ⁺ .

Example 27

N- {3- [4- (4-phenylbutoxy) phenyl] propyl} -β-alanine hydrochloride:

Stage A:

to a suspension of chlorotrityl resin (manufacturer Argonaut Technology; Cat No.800380) (1.00 mmol / g, 1.0 g, 1.0 mmol) in dichloromethane (5 ml) was added dropwise at 0 ° C a solution of the compound obtained in Example 24 (323 mg), in a mixture of solvents of N, N-diisopropylethylamine (0.70 ml) and dichloromethane (5 ml). After washing with dichloromethane (2 ml), the mixture was shaken at room temperature for 5 hours. The resin was then isolated by filtration and washed successively 3 times with a solvent mixture (dichloromethane: methanol: diisopropylethylamine = 51: 6: 3), 3 times with dichloromethane, 2 times with N, N-dimethylformamide and 2 times with dichloromethane and dried to give a phenolic resin (1.195 g) .

Stage B:

4-phenylbutan-1-ol (0.42 mmol) was added to phenolic resin (100 mg) at room temperature, followed by anhydrous tetrahydrofuran (0.4 ml) and dichloromethane (0.4 ml). At room temperature, tri-n-butylphosphine (0.42 mmol) was added dropwise to the mixture, and then 1,1'-azobis (N, N-dimethylformamide) (0.42 mmol) was added. The mixture was shaken at room temperature for 5 hours. The resin was isolated by filtration, washed 4 times with a mixture of solvents (dichloromethane: tetrahydrofuran = 1: 1) and 2 times with dichloromethane, and then dried to obtain a phenylether resin (about 100 mg).

Stage C:

acetic acid (0.2 ml), trifluoroethanol (0.2 ml) and dichloromethane (0.6 ml) were added to the phenylether resin (about 100 mg) at room temperature, and the mixture was shaken at room temperature for 3 hours. The resin was isolated by filtration and washed 2 times with a mixture of solvents (acetic acid: trifluoroethanol: dichloromethane = 1: 1: 3) and 4 times with dichloromethane. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to ethyl acetate, thereby obtaining N- (tert-butoxycarbonyl) -N- {3- [4- (4-phenylbutoxy) phenyl] - propyl} -β-alanine (2 mg; Boc compound).

Stage D:

4N was added to the Compound at room temperature. a solution of hydrogen chloride in ethyl acetate (1 ml), followed by stirring for 1 hour. The reaction mixture was concentrated to obtain the title compound (2 mg) having the following physical characteristics.

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

¹ H-NMR (CD ₃ OD): δ 1.76 (m, 4H), 1.96 (m, 2H), 2.68 (m, 6H), 3.01 (m, 2H), 3.24 (t, 2H); 3.94 (m, 2H); 6.83 (d, 2H); 7.17 (m, 7H).

Examples 27 (1) -27 (9)

A procedure similar to that of Example 27 was carried out except that the corresponding compound was used as a substituent for 4-phenylbutan-1-ol, whereby the following compounds were obtained. In the case of the compound of Example 27 (9), step D was skipped.

Example 27 (1)

N- (3- {4 - [(6-phenylhexyl) oxy] phenyl} propyl) -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.42 (m, 4H), 1.64 (m, 2H), 1.74 (m, 2H), 1.96 (m, 2H), 2.66 (m, 6H), 3.01 (m, 2H), 3.24 (t, 2H), 3.91 (t, 2H), 6.83 (d, 2H), 7.13 (m, 5H) 7.22 (m, 2H).

Example 27 (2)

N- (3- {4 - [(7-phenylheptyl) oxy] phenyl} propyl) -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.38 (m, 6H), 1.62 (m, 2H), 1.72 (m, 2H), 1.96 (m, 2H), 2.66 (m, 6H), 3.01 (m, 2H), 3.23 (t, 2H), 3.92 (t, 2H), 6.83 (d, 2H), 7.12 (m, 5H) 7.23 (m, 2H).

Example 27 (3)

N- [3- (4-butoxyphenyl) propyl] -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 0.97 (t, 3H), 1.47 (m, 2H), 1.73 (m, 2H), 1.96 (m, 2H), 2.67 (m, 4H), 3.01 (m, 2H), 3.23 (t, 2H), 3.93 (t, 2H), 6.84 (d, 2H), 7.12 (d, 2H) .

Example 27 (4)

N- {3- [4- (pentyloxy) phenyl] propyl} -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 0.94 (t, 3H), 1.41 (m, 4H), 1.72 (m, 2H), 1.96 (m, 2H), 2.65 (t, 2H), 2.71 (t, 2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.92 (t, 2H), 6.84 (d, 2H) 7.12 (d, 2H).

Example 27 (5)

N- {3- [4- (hexyloxy) phenyl] propyl} -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 0.91 (m, 3H), 1.35 (m, 4H), 1.48 (m, 2H), 1.74 (m, 2H), 1.96 (m, 2H), 2.65 (t, 2H), 2.71 (t, 2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.93 (t, 2H) 6.84 (d, 2H); 7.12 (d, 2H).

Example 27 (6)

N- {3- [4- (heptyloxy) phenyl] propyl} -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 0.90 (m, 3H), 1.32 (m, 8H), 1.72 (m, 2H), 1.96 (m, 2H), 2.65 (t, 2H), 2.70 (t, 2H), 3.01 (m, 2H), 3.23 (t, 2H), 3.92 (t, 2H), 6.84 (d, 2H) 7.12 (d, 2H).

Example 27 (7)

N- {3- [4- (octyloxy) phenyl] propyl} -β-alanine hydrochloride:

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 0.90 (m, 3H), 1.31 (m, 10H), 1.74 (m, 2H), 1.96 (m, 2H), 2.65 (t, 2H), 2.71 (t, 2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.92 (t, 2H), 6.84 (d, 2H) 7.12 (d, 2H).

Example 27 (8)

N- {3- [4- (nonyloxy) phenyl] propyl} -β-alanine hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 0.89 (m, 3H), 1.29 (m, 12H), 1.73 (m, 2H), 1.96 (m, 2H), 2.65 (t, 2H), 2.71 (t, 2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.92 (t, 2H), 6.84 (d, 2H) 7.12 (d, 2H).

Example 27 (9)

N- (tert-butoxycarbonyl) -N- (3- {4 - [(5-phenylpentyl) oxy] phenyl} propyl) -β-alanine:

TLC: Rf 0.40 (chloroform: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ): δ 1.45 (s, 9H), 1.67 (m, 8H), 2.53 (t, 2H), 2.64 (m, 4H), 3.23 ( t, 2H), 3.47 (t, 2H), 3.92 (t, 2H), 6.81 (d, 2H), 7.07 (d, 2H), 7.18 (m, 2H), 7.27 (m, 3H).

Example 28

N- {3- [4- (3-phenylpropoxy) phenyl] propyl} -N- (3-phenylpropyl) -β-alanine trifluoroacetate:

To a solution of tert-butyl N {3- [4- (4-phenylbutoxy) phenyl] propyl} -β-alaninate (8.0 mg) in dichloroethane (0.2 ml) was added 3-phenylpropanal (0.008 ml) and sodium triacetoxyborohydride (21 mg) and the mixture was shaken at room temperature for 17 hours. Then the reaction mixture was diluted by adding methanol (1.0 ml). After addition of a resin based on a compound of lanthanum and toluenesulfonic acid (manufacturer MIMOTOPE; Cat No. MIL1025) (2 needles, 0.3 mmol), the mixture was allowed to stand for 1 hour. The resin was then removed from the reaction mixture, washed with dichloromethane and methanol, and then immersed for 30 minutes in a 5% solution of triethylamine in methanol (1.0 ml × 2). The resulting solutions were isolated, combined and then concentrated. Trifluoroacetic acid (1.0 ml) and dichloromethane (1.0 ml) were added to the residue, followed by stirring at room temperature for 16 hours and concentration, whereby the title compound (10 mg) having the following physical characteristics was obtained.

TLC: Rf 0.81 (ethyl acetate: acetic acid: water = 3: 1: 1);

¹ H-NMR (CD ₃ OD): δ 1.83-2.00 (m, 4H), 1.99-2.13 (m, 2H), 2.57-2.69 (m, 4H), 2.70-2.84 (m, 4H), 3.04-3.20 (m, 4H), 3.40 (t, 2H), 3.91 (t, 2H), 6.83 (d, 1H), 7.11 (d, 2H), 7.14-7.33 (m, 10H).

Example 29

3 - ({((2E) -3- [4- (3-phenylpropyl) phenyl] -2-butenyl} amino) propanoic acid hydrochloride:

Sodium hydroxide (204 mg) was added to a suspension of β-alanine (433 mg) in methanol (30 ml). Then, trimethoxymethane (532 μl) was added to the mixture at 0 ° C. Then a solution of (2E) -3- [4- (3-phenylpropoxy) phenyl] but-2-enal (1.43 g) in a mixture of methanol (30 ml) and tetrahydrofuran (10 ml) was added. The reaction mixture was stirred at 0 ° C for 30 minutes. Sodium borohydride (221 mg) was added to the mixture at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 minutes. After adding 2 n. hydrochloric acid solution (5.5 ml), the reaction mixture was concentrated. To the resulting residue was added a solvent mixture of chloroform: methanol: aqueous ammonia = 80: 10: 1, followed by filtration. Water was added to the resulting precipitated substance, and the mixture was centrifuged to obtain a precipitate. The resulting residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 80: 20: 4). To a suspension of the purified product in dioxane (100 ml) and water (15 ml), a 4 mol / L solution of hydrogen chloride in dioxane (0.9 ml) was added at 0 ° C. The reaction mixture was concentrated, the residue was washed with diethyl ether and dried to obtain the title compound (1.16 g) having the following physical characteristics.

Melting point: 181-186 ° C;

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

¹ H-NMR (CD ₃ OD): δ 7.39 (d, J = 9.00 Hz, 2H), 7.11-7.28 (m, 5H), 6.88 (d, J = 9, 00 Hz, 2H), 5.77 (tq, J = 7.50, 1.50 Hz, 1H), 3.96 (t, J = 6.50 Hz, 2H), 3.88 (d, J = 7.50 Hz, 2H), 3.30-3.34 (m, 2H), 2.74-2.83 (m, 4H), 2.15 (d, J = 1.50 Hz, 3H), 2.00-2.11 (m, 2H).

Examples 29 (1) -29 (4)

A procedure similar to that of Example 29 was carried out except that the corresponding aldehyde compound was used as a substituent for (2E) -3- [4- (3-phenylpropoxy) phenyl] but-2-enal and the corresponding amine compound, resulting in received the compounds of the present invention, indicated below. In the case of the compound of Example 29 (4), hydrochloride conversion was not carried out.

Example 29 (1)

3 - ({((2E) -3- [4- (3-cyclohexylpropoxy) -2-methylphenyl] -2-propenyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 0.84-1.01 (m, 2H), 1.13-1.40 (m, 6H), 1.61-1.83 (m, 7H), 2.34 (s, 3H), 2.77 (t, J = 6.50 Hz, 2H), 3.22-3.29 (m, 2H), 3.82 (d, J = 7.00 Hz , 2H), 3.93 (t, J = 6.50 Hz, 2H), 5.95-6.09 (m, 1H), 6.68-6.76 (m, 2H), 7.06 ( d, J = 15.50 Hz, 1H), 7.43 (d, J = 9.50 Hz, 1H).

Example 29 (2)

3 - ({[1-methyl-6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} amino} propanoic acid hydrochloride:

Melting point: 162.5-163.3 ° C;

TLC: Rf 0.16 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.09-7.33 (m, 6H), 6.66-6.80 (m, 2H), 3.95-4.01 (m, 2H), 3.93 (s, 2H), 3.25-3.34 (m, 2H), 2.71-2.83 (m, 4H), 2.61-2.71 (m, 2H), 2, 26-2.38 (m, 2H), 2.15 (s, 3H), 1.72-1.83 (m, 4H).

Example 29 (3)

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

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

¹ H-NMR (CD ₃ OD): δ 7.03-7.39 (m, 6H), 6.64-6.82 (m, 2H), 4.20-4.48 (m, 2H), 4.16 (s, 2H), 3.92-4.06 (m, 2H), 3.57-3.82 (m, 1H), 3.24-3.36 (m, 2H), 2, 61-2.79 (m, 4H), 2.17-2.29 (m, 5H), 1.72-1.83 (m, 4H);

Melting point: 121-122 ° C.

Example 29 (4)

N - {[1- (5-phenylpentyl) -1H-indol-5-yl] methyl} -β-alanine:

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

¹ H-NMR (CD ₃ OD): δ 7.66 (d, J = 1.50 Hz, 1H), 7.46 (d, J = 8.50 Hz, 1H), 7.16-7.26 (m, 4H), 7.06-7.14 (m, 3H), 6.46 (d, J = 3.00 Hz, 1H), 4.25 (s, 2H), 4.18 (t, J = 7.00 Hz, 2H), 3.15 (t, J = 6.50 Hz, 2H), 2.53 (t, J = 7.50 Hz, 2H), 2.48 (t, J = 6.50 Hz, 2H), 1.78-1.90 (m, 2H), 1.54-1.66 (m, 2H), 1.23-1.36 (m, 2H).

Example 30

3- [4- [4- (3-phenylpropoxy) phenyl] -3,6-dihydropyridin-1 (2H) -yl] propanoic acid trifluoroacetate:

The procedure of Example 4 and Example 16 was carried out in this order, but using 4- [4- (3-phenylpropoxy) phenyl-1,2,3,6-tetrahydropyridine as a substituent for 4- (3-aminopropyl) phenol, in resulting in the title compound having the following physical characteristics.

TLC: Rf 0.24 (chloroform: methanol: aqueous ammonia = 8: 2: 0.4);

¹ H-NMR (CD ₃ OD): δ 7.40 (d, J = 8.97 Hz, 2H), 7.10-7.30 (m, 5H), 6.90 (d, J = 8, 97 Hz, 2H), 5.92-6.09 (m, 1H), 3.96 (t, J = 6.22 Hz, 2H), 3.89-4.00 (m, 2H), 3, 52 (t, J = 7.04 Hz, 2H), 3.47-3.68 (m, 2H), 2.88 (t, J = 7.04 Hz, 2H), 2.83-2.92 (m, 2H), 2.79 (t, J = 7.80 Hz, 2H), 1.97-2.14 (m, 2H).

Examples 31-01 to 31-94

A procedure similar to that of Example 29 was carried out except that the corresponding amine compound was used as a substituent for β-alanine and the corresponding aldehyde compound was a substituent for (2E) -3- [4- (3-phenylpropoxy) phenyl] but- 2-enal, whereby the title compound was obtained having the following physical characteristics.

Example 31-01

3 - ({(2E) -3- [3-methyl-4- (3-phenylpropoxy) phenyl] -2-propenyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 2.05-2.13 (m, 2H), 2.23 (s, 3H), 2.73-2.86 (m, 4H), 3.24- 3.29 (m, 2H), 3.79 (d, J = 7.50 Hz, 2H), 3.97 (t, J = 6.00 Hz, 2H), 6.03-6.14 (m , 1H); 6.72-6.83 (m, 2H); 7.11-7.29 (m, 7H).

Example 31-02

3 - ({((2E) -3- [3-methyl-4- (4-phenylbutoxy) phenyl] -2-propenyl} amino) propanoic acid hydrochloride:

TLC: Rf 0.16 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 1.78-1.86 (m, 4H), 2.19 (s, 3H), 2.64-2.79 (m, 4H), 3.23- 3.28 (m, 2H), 3.78 (d, J = 7.00 Hz, 2H), 3.96-4.03 (m, 2H), 6.03-6.14 (m, 1H) 6.76 (d, J = 15.50 Hz, 1H); 6.83 (d, J = 8.00 Hz, 1H); 7.09-7.28 (m, 7H).

Example 31-03:

3 - [((2E) -3- {3-methyl-4 - [(5-phenylpentyl) oxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.48-1.58 (m, 2H), 1.65-1.75 (m, 2H), 1.77-1.87 (m, 2H), 2.15 (s, 3H), 2.64 (t, J = 7.50 Hz, 2H), 2.75 (t, J = 6.50 Hz, 2H), 3.19-3.28 (m , 2H), 3.78 (d, J = 7.50 Hz, 2H), 3.97 (t, J = 6.00 Hz, 2H), 6.02-6.14 (m, 1H), 6 76 (d, J = 16.00 Hz, 1H); 6.83 (d, J = 8.00 Hz, 1H); 7.08-7.27 (m, 7H).

Example 31-04

3 - ({((2E) -3- [4- (4-phenylbutoxy) phenyl] -2-butenyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.76-1.82 (m, 4H), 2.14 (d, J = 1.50 Hz, 3H), 2.64-2.71 (m, 2H), 2.76 (t, J = 6.50 Hz, 2H), 3.30-3.35 (m, 2H), 3.87 (d, J = 7.50 Hz, 2H), 3, 96-4.01 (m, 2H), 5.75 (tq, J = 7.50, 1.50 Hz, 1H), 6.88 (d, J = 9.00 Hz, 2H), 7.09 -7.28 (m, 5H); 7.38 (d, J = 9.00 Hz, 2H).

Example 31-05

3 - [((2E) -3- {4 - [(5-phenylpentyl) oxy] phenyl} -2-butenyl) amino] propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.45-1.56 (m, 2H), 1.63-1.74 (m, 2H), 1.74-1.85 (m, 2H), 2.15 (d, J = 1.50 Hz, 3H), 2.63 (t, J = 7.50 Hz, 2H), 2.76 (t, J = 6.50 Hz, 2H), 3, 31-3.37 (m, 2H), 3.87 (d, J = 7.50 Hz, 2H), 3.96 (t, J = 6.50 Hz, 2H), 5.75 (tq, J = 7.50, 1.50 Hz, 1H), 6.87 (d, J = 9.00 Hz, 2H), 7.10-7.26 (m, 5H), 7.38 (d, J = 9.00 Hz, 2H).

Example 31-06

3 - ({[6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.75-1.82 (m, 4H), 2.34 (t, J = 8.00 Hz, 2H), 2.63-2.71 (m, 2H), 2.77 (t, J = 6.50 Hz, 2H), 2.85 (t, J = 8.00 Hz, 2H), 3.23-3.28 (m, 2H), 3, 79 (s, 2H), 3.97 (t, J = 6.00 Hz, 2H), 6.62 (s, 1H), 6.68-6.73 (m, 2H), 7.00 (d , J = 7.50 Hz, 1H), 7.11-7.28 (m, 5H).

Example 31-07

3 - ({[6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} amino) butanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.42 (d, J = 7.00 Hz, 3H), 1.75-1.81 (m, 4H), 2.29-2.44 (m, 2H), 2.64-2.71 (m, 2H), 2.73-2.78 (m, 2H), 2.86 (t, J = 8.00 Hz, 2H), 3.61-3 72 (m, 1H), 3.82 (s, 2H), 3.97 (t, J = 6.00 Hz, 2H), 6.64 (s, 1H), 6.68-6.73 ( m, 2H), 7.00 (d, J = 7.50 Hz, 1H), 7.11-7.28 (m, 5H).

Example 31-08

2-methyl-3 - ({[6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} amino} propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.30 (d, J = 7.00 Hz, 3H), 1.73-1.82 (m, 4H), 2.33 (t, J = 7, 50 Hz, 2H), 2.63-2.71 (m, 2H), 2.81-2.95 (m, 3H), 3.06 (dd, J = 13.00, 4.50 Hz, 1H ), 3.21-3.29 (m, 1H), 3.79 (s, 2H), 3.97 (t, J = 6.00 Hz, 2H), 6.62 (s, 1H), 6 68-6.74 (m, 2H); 7.01 (d, J = 8.00 Hz, 1H); 7.10-7.28 (m, 5H).

Example 31-09

2-fluoro-3 - ({[6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} amino} propanoic acid hydrochloride:

TLC: Rf 0.16 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 1.74-1.82 (m, 4H), 2.35 (t, J = 8.00 Hz, 2H), 2.64-2.71 (m, 2H), 2.86 (t, J = 8.00 Hz, 2H), 3.47-3.72 (m, 2H), 3.85 (s, 2H), 3.97 (t, J = 6 00 Hz, 2H), 5.36 (ddd, J = 48.50, 8.00, 3.50 Hz, 1H), 6.64 (s, 1H), 6.67-6.76 (m, 2H), 7.01 (d, J = 8.00 Hz, 1H), 7.10-7.30 (m, 5H).

Example 31-10

3 - ({((2E) -3- [2-methyl-4- (4-phenylbutoxy) phenyl] -2-propenyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 1.72-1.83 (m, 4H), 2.34 (s, 3H), 2.64-2.71 (m, 2H), 2.77 ( t, J = 6.50 Hz, 2H), 3.23-3.29 (m, 2H), 3.82 (d, J = 7.00 Hz, 2H), 3.96 (t, J = 6 , 00 Hz, 2H), 5.96-6.08 (m, 1H), 6.70-6.75 (m, 2H), 7.06 (d, J = 15.50 Hz, 1H), 7 09-7.28 (m, 5H); 7.42 (d, J = 9.50 Hz, 1H).

Example 31-11

3 - ({((2E) -3- [4- (4-cyclohexylbutoxy) -2-methylphenyl] -2-propenyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 0.81-1.00 (m, 2H), 1.13-1.35 (m, 6H), 1.41-1.54 (m, 2H), 1.62-1.80 (m, 7H), 2.34 (s, 3H), 2.77 (t, J = 6.50 Hz, 2H), 3.24-3.29 (m, 2H) 3.82 (d, J = 7.50 Hz, 2H), 3.95 (t, J = 6.50 Hz, 2H), 5.95-6.10 (m, 1H), 6.70- 6.76 (m, 2H), 7.06 (d, J = 15.50 Hz, 1H), 7.43 (d, J = 9.00 Hz, 1H).

Example 31-12

3 - ({((2E) -3- [4- (4-phenylbutoxy) phenyl] -2-propenyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.39 (d, J = 8.79 Hz, 2H), 7.09-7.30 (m, 5H), 6.89 (d, J = 8, 79 Hz, 2H), 6.80 (d, J = 16.11 Hz, 1H), 6.10 (dt, J = 16.11, 7.32 Hz, 1H), 3.92-4.04 ( m, 2H), 3.79 (dd, J = 7.32, 1.01 Hz, 2H), 3.24-3.29 (m, 2H), 2.75 (t, J = 6.59 Hz , 2H); 2.60-2.71 (m, 2H); 1.71-1.86 (m, 4H).

Example 31-13

3 - [((2E) -3- {4- [3- (4-chlorophenyl) propoxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.40 (d, J = 8.79 Hz, 2H), 7.25 (d, J = 8.60 Hz, 2H), 7.19 (d, J = 8.60 Hz, 2H), 6.89 (d, J = 8.79 Hz, 2H), 6.81 (d, J = 15.74 Hz, 1H), 6.11 (dt, J = 15 , 74, 7.14 Hz, 1H), 3.96 (t, J = 6.13 Hz, 2H), 3.79 (d, J = 7.14 Hz, 2H), 3.20-3.29 (m, 2H), 2.69-2.84 (m, 4H), 1.98-2.11 (m, 2H).

Example 31-14

3 - [((2E) -3- {4 - [(4-methylpentyl) oxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.40 (d, J = 8.79 Hz, 2H), 6.89 (d, J = 8.79 Hz, 2H), 6.81 (d, J = 15.74 Hz, 1H), 6.11 (dt, J = 15.74, 7.32 Hz, 1H), 3.96 (t, J = 6.50 Hz, 2H), 3.80 (d , J = 7.32 Hz, 2H), 3.22-3.29 (m, 2H), 2.75 (t, J = 6.59 Hz, 2H), 1.70-1.84 (m, 2H), 1.51-1.68 (m, 1H), 1.28-1.43 (m, 2H), 0.93 (d, J = 6.59 Hz, 6H).

Example 31-15

3 - [((2E) -3- {2-chloro-4 - [(5-phenylpentyl) oxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.59 (d, J = 8.79 Hz, 1H), 7.08-7.28 (m, 6H), 6.95 (d, J = 2, 56 Hz, 1H), 6.87 (dd, J = 8.79, 2.56 Hz, 1H), 6.18 (dt, J = 15.70, 7.16 Hz, 1H), 3.97 ( t, J = 6.41 Hz, 2H), 3.85 (dd, J = 7.16, 1.01 Hz, 2H), 3.25-3.34 (m, 2H), 2.77 (t , J = 6.59 Hz, 2H), 2.63 (t, J = 7.69 Hz, 2H), 1.74-1.87 (m, 2H), 1.61-1.74 (m, 2H), 1.41-1.57 (m, 2H).

Example 31-16

3 - ({((2E) -3- [2-chloro-4- (4-phenylbutoxy) phenyl] -2-propenyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.58 (d, J = 8.79 Hz, 1H), 7.08-7.31 (m, 6H), 6.96 (d, J = 2, 56 Hz, 1H), 6.88 (dd, J = 8.79, 2.56 Hz, 1H), 6.18 (dt, J = 15.84, 7.19 Hz, 1H), 3.93- 4.04 (m, 2H), 3.85 (dd, J = 7.19, 1.10 Hz, 2H), 3.25-3.33 (m, 2H), 2.77 (t, J = 6.59 Hz, 2H), 2.62-2.72 (m, 2H), 1.74-1.84 (m, 4H).

Example 31-17

3 - [((2E) -3- {2-chloro-4- [3- (4-chlorophenyl) propoxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.59 (d, J = 8.79 Hz, 1H), 7.12-7.31 (m, 5H), 6.96 (d, J = 2, 56 Hz, 1H), 6.88 (dd, J = 8.79, 2.56 Hz, 1H), 6.18 (dt, J = 15.74, 7.32 Hz, 1H), 3.97 ( t, J = 6.22 Hz, 2H), 3.85 (dd, J = 7.32, 1.10 Hz, 2H), 3.26-3.34 (m, 2H), 2.71-2 84 (m, 4H); 1.96-2.14 (m, 2H);

Melting point: 119-124 ° C.

Example 31-18

3 - ({[6- (3-phenylpropoxy) -2-naphthyl] methyl} amino) propanoic acid:

TLC: Rf 0.13 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CDCl ₃ + CD ₃ OD = 5: 1): δ 2.19 (m, 2H), 2.47 (t, J = 6.00 Hz, 2H), 2.87 (m, 2H ), 3.10 (t, J = 6.00 Hz, 2H), 4.10 (t, J = 6.50 Hz, 2H), 4.22 (s, 2 H), 7.12 (d, J = 2.00 Hz, 1H), 7.26 (m, 6H), 7.43 (dd, J = 8.50, 2.00 Hz, 1H), 7.79 (m, 3H).

Example 31-19

3 - [((2E) -3- {4 - [(4-tert-butylbenzyl) oxy] -2-chlorophenyl} -2-propenyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.40 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.61 (d, J = 8.78 Hz, 1H), 7.41 (d, J = 8.70 Hz, 2H), 7.34 (d, J = 8.70 Hz, 2H), 7.17 (d, J = 15.92 Hz, 1H), 7.05 (d, J = 2.56 Hz, 1H), 6.96 (dd, J = 8 78, 2.56 Hz, 1H), 6.21 (dt, J = 15.92, 7.25 Hz, 1H), 5.06 (s, 2H), 3.86 (dd, J = 7, 25, 0.82 Hz, 2H), 3.25-3.35 (m, 2H), 2.78 (t, J = 6.68 Hz, 2H), 1.31 (s, 9H).

Example 31-20

3 - ({(2E) -3- [4- (1,1'-biphenyl-4-ylmethoxy) -2-chlorophenyl] -2-propenyl} amino) propanoic acid hydrochloride

TLC: Rf 0.41 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.57-7.67 (m, 5H), 7.50 (d, J = 8.40 Hz, 2H), 7.39-7.46 (m, 2H), 7.29-7.37 (m, 1H), 7.19 (d, J = 15.73 Hz, 1H), 7.10 (d, J = 2.38 Hz, 1H), 7, 00 (dd, J = 8.78, 2.38 Hz, 1H), 6.19 (dt, J = 15.73, 7.25 Hz, 1H), 5.16 (s, 2H), 3.85 (dd, J = 7.25, 1.10 Hz, 2H), 3.26-3.36 (m, 2H), 2.76 (t, J = 6.59 Hz, 2H).

Example 31-21

3 - [((2E) -3- {2-chloro-4- [3- (2-fluorophenyl) propoxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.39 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.61 (d, J = 8.78 Hz, 1H), 7.12-7.30 (m, 3H), 6.96-7.13 (m, 2H), 6.95 (d, J = 2.38 Hz, 1H), 6.88 (dd, J = 8.60, 2.38 Hz, 1H), 6.21 (dt, J = 15.74 , 7.32 Hz, 1H), 3.99 (t, J = 6.13 Hz, 2H), 3.86 (dd, J = 7.32, 1.10 Hz, 2H), 3.27-3 36 (m, 2H); 2.75-2.88 (m, 4H); 2.00-2.13 (m, 2H).

Example 31-22

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

TLC: Rf 0.11 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 1.75-1.80 (m, 4H), 2.27 (t, J = 8.00 Hz, 2H), 2.63-2.71 (m, 2H), 2.82 (t, J = 8.00 Hz, 2H), 3.64-3.78 (m, 1H), 3.93-4.01 (m, 4H), 4.16-4 46 (m, 4H), 6.62 (s, 1H), 6.68-6.72 (m, 2H), 7.03 (d, J = 9.00 Hz, 1H), 7.10- 7.27 (m, 5H);

Melting point: 152-155 ° C.

Example 31-23

3 - ({((2E) -3- [2-methoxy-4- (3-phenylpropoxy) phenyl] -2-propenyl} amino) propanoic acid hydrochloride:

TLC: Rf 0.27 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.36 (d, J = 8.4 Hz, 1H), 7.11-7.30 (m, 5H), 7.03 (d, J = 16, 1 Hz, 1H), 6.35-6.62 (m, 2H), 6.05-6.26 (m, 1H), 3.89-4.06 (m, 2H), 3.64-3 89 (m, 5H); 3.15-3.37 (m, 2H); 2.65-2.89 (m, 4H); 1.94-2.16 (m, 2H).

Example 31-24

3 - ({(2E) -3- [2-methoxy-4- (4-phenylbutoxy) phenyl] -2-propenyl} amino) propanoic acid hydrochloride:

TLC: Rf 0.28 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.36 (d, J = 8.23 Hz, 2H), 7.09-7.30 (m, 5H), 7.02 (d, J = 16, 28 Hz, 1H), 3.88-4.07 (m, 2H), 3.62-3.88 (m, 5H), 3.16-3.40 (m, 2H), 2.46-2 85 (m, 4H); 1.71-1.87 (m, 4H).

Example 31-25

3 - [((2E) -3- {2-methoxy-4 - [(5-phenylpentyl) oxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.30 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.36 (d, J = 8.4 Hz, 1H), 7.09-7.29 (m, 5H), 7.02 (d, J = 15, 9 Hz, 1H), 6.41-6.58 (m, 2H), 6.04-6.30 (m, 1H), 3.98 (t, J = 6.4 Hz, 2H), 3, 67-3.89 (m, 5H), 3.05-3.43 (m, 2H), 2.74 (t, J = 6.6 Hz, 2H), 2.54-2.71 (m, 2H), 1.76-1.88 (m, 2H), 1.60-1.76 (m, 2H), 1.42-1.59 (m, 2H).

Example 31-26

3 - {[(6- {3- [3,5-bis (trifluoromethyl) phenyl] propoxy} -2-naphthyl) methyl] amino} propanoic acid hydrochloride:

TLC: Rf 0.16 (chloroform: methanol: acetic acid = 9: 1: 0.5);

¹ H-NMR (CD ₃ OD): δ 7.73-7.97 (m, 6H), 7.52 (dd, J = 8.32, 1.56 Hz, 1H), 7.25 (d, J = 2.47 Hz, 1H), 7.19 (dd, J = 8.87, 2.47 Hz, 1H), 4.37 (s, 2H), 4.14 (t, J = 5.95 Hz, 2H), 3.28-3.37 (m, 2H), 3.01-3.13 (m, 2H), 2.71-2.86 (m, 2H), 2.15-2, 31 (m, 2H).

Example 31-27

3 - [({6- [3- (2-chlorophenyl) propoxy] -2-naphthyl} methyl) amino] propanoic acid acetate:

TLC: Rf 0.17 (chloroform: methanol: acetic acid = 9: 1: 0.5);

¹ H-NMR (CD ₃ OD): δ 7.89 (s, 1H), 7.82 (d, J = 8.42 Hz, 1H), 7.80 (d, J = 8.42 Hz, 1H ), 7.49 (dd, J = 8.60, 1.65 Hz, 1H), 7.33-7.39 (m, 1H), 7.27-7.33 (m, 1H), 7, 11-7.26 (m, 4H), 4.31 (s, 2H), 4.12 (t, J = 6.13 Hz, 2H), 3.20 (t, J = 6.22 Hz, 2H ), 2.92-3.04 (m, 2H), 2.52 (t, J = 6.22 Hz, 2H), 2.08-2.24 (m, 2H), 1.95 (s, 3H).

Example 31-28

3 - [({6- [3- (2,6-dichlorophenyl) propoxy] -2-naphthyl} methyl) amino] propanoic acid acetate:

TLC: Rf 0.17 (chloroform: methanol: acetic acid = 9: 1: 0.5);

¹ H-NMR (CD ₃ OD): δ 7.89 (s, 1H), 7.83 (d, J = 8.50 Hz, 1H), 7.80 (d, J = 8.50 Hz, 1H ), 7.50 (dd, J = 8.42, 1.46 Hz, 1H), 7.35 (d, J = 8.50 Hz, 2H), 7.25 (d, J = 2.38 Hz , 1H), 7.14-7.21 (m, 2H), 4.32 (s, 2H), 4.19 (t, J = 6.04 Hz, 2H), 3.15-3.25 ( m, 4H), 2.49-2.57 (m, 2H), 2.08-2.20 (m, 2H), 1.93 (s, 3H).

Example 31-29

3 - ({((2Z) -3- [4- (3-phenylpropoxy) phenyl] -2-butenyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.10-7.29 (m, 7H), 6.94 (d, J = 9.00 Hz, 2H), 5.55 (tq, J = 7, 00, 1.50 Hz, 1H), 3.97 (t, J = 6.00 Hz, 2H), 3.63 (dd, J = 7.00, 1.00 Hz, 2H), 3.12 ( t, J = 6.50 Hz, 2H), 2.80 (t, J = 7.50 Hz, 2H), 2.62 (t, J = 6.50 Hz, 2H), 2.12-2, 15 (m, 3H); 2.02-2.11 (m, 2H).

Example 31-30

3 - [((2E) -3- {2-chloro-4 - [(4-propylbenzyl) oxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.25 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.59 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.14-7.23 (m, 3H), 7.06 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.8, 2.6 Hz, 1H), 6.18 (dt, J = 9.0, 8.8 Hz, 1H), 5.06 (s, 2H), 3.85 (dd, J = 7.3, 0.9 Hz, 2H), 3.26-3.34 (m , 2H), 2.76 (t, J = 6.6 Hz, 2H), 2.55-2.63 (m, 2H), 1.56-1.71 (m, 2H), 0.93 ( t, J = 7.3 Hz, 3H).

Example 31-31

3 - [((2E) -3- {2-chloro-4 - [(4-pentylbenzyl) oxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.22 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.60 (d, J = 8.78 Hz, 1H), 7.32 (d, J = 8.23 Hz, 2H), 7.12-7.23 (m, 3H), 7.06 (d, J = 2.56 Hz, 1H), 6.96 (dd, J = 8.60, 2.56 Hz, 1H), 6.09-6.31 ( m, 1H), 5.06 (s, 2H), 3.85 (dd, J = 7.23, 1.01 Hz, 2H), 3.22-3.39 (m, 2H), 2.76 (t, J = 6.59 Hz, 2H), 2.61 (t, J = 8.10 Hz, 2H), 1.54-1.68 (m, 2H), 1.25-1.42 ( m, 4H), 0.89 (t, J = 6.90 Hz, 3H).

Example 31-32

3 - [((2E) -3- {2-chloro-4 - [(4-hexylbenzyl) oxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.25 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.59 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.11-7.25 (m, 3H), 7.06 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.8, 2.6 Hz, 1H), 6.06-6.30 ( m, 1H), 5.06 (s, 2H), 3.85 (dd, J = 7.2, 1.0 Hz, 2H), 3.19-3.40 (m, 2H), 2.76 (t, J = 6.3 Hz, 2H), 2.54-2.66 (m, 2H), 1.50-1.69 (m, 2H), 1.26-1.38 (m, 6H ), 0.83-0.93 (m, 3H).

Example 31-33

3 - [((2E) -3- {2-chloro-4 - [(4-cyclohexylbenzyl) oxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.22 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.59 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.13-7.25 (m, 3H), 7.06 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.9, 2.6 Hz, 1H), 6.04-6.30 ( m, 1H), 5.06 (s, 2H), 3.84 (d, J = 6.6 Hz, 2H), 2.70-2.79 (m, 2H), 2.42-2.58 (m, 2H), 1.69-1.89 (m, 5H), 1.20-1.52 (m, 6H).

Example 31-34

3 - [((2E) -3- {2-chloro-4 - [(4-isobutylbenzyl) oxy] phenyl} -2-propenyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.24 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.60 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7.12-7.25 (m, 3H), 7.07 (d, J = 2.6 Hz, 1H), 6.97 (dd, J = 9.0, 2.6 Hz, 1H), 6.18 (dt, J = 15.6, 7.2 Hz, 1H), 5.06 (s, 2H), 3.85 (dd, J = 7.2, 1.2 Hz, 2H), 3.25-3.35 (m , 2H), 2.75 (t, J = 6.5 Hz, 2H), 2.48 (d, J = 7.3 Hz, 2H), 1.76-1.95 (m, 1H), 0 89 (d, J = 6.6 Hz, 6H).

Example 31-35

3 - [((2E) -3- {4- [2- (1,1'-biphenyl-4-yl) ethoxy] -2-chlorophenyl} -2-propenyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.25 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.48-7.68 (m, 5H), 7.24-7.47 (m, 4H), 7.18 (d, J = 15.92 Hz, 1H), 6.99 (d, J = 2.56 Hz, 1H), 6.91 (dd, J = 8.69, 2.56 Hz, 1H), 6.05-6.28 (m, 1H ), 4.25 (t, J = 6.68 Hz, 2H), 3.85 (dd, J = 7.32, 1.10 Hz, 2H), 3.20-3.39 (m, 2H) 3.11 (t, J = 6.68 Hz, 2H); 2.76 (t, J = 6.68 Hz, 2H).

Example 31-36

3 - [((2E) -3- {4 - [(4-butylbenzyl) oxy] -2-chlorophenyl} -2-propenyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.20 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.60 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.11-7.24 (m, 3H), 7.06 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.8, 2.3 Hz, 1H), 6.18 (dt, J = 15.9, 7.1 Hz, 1H), 5.06 (s, 2H), 3.85 (dd, J = 7.1, 1.1 Hz, 2H), 3.24-3.38 (m , 2H), 2.76 (t, J = 6.6 Hz, 2H), 2.61 (t, J = 7.8 Hz, 2H), 1.50-1.68 (m, 2H), 1 25-1.43 (m, 2H); 0.93 (t, J = 7.3 Hz, 3H).

Example 31-37

3 - {[((2E) -3- (2-chloro-4- {3- [4- (trifluoromethyl) phenyl] propoxy} phenyl) -2-propenyl] amino} propanoic acid hydrochloride:

TLC: Rf 0.19 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.49-7.67 (m, 3H), 7.41 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 15, 7 Hz, 1H), 6.97 (d, J = 2.6 Hz, 1H), 6.89 (dd, J = 8.8, 2.6 Hz, 1H), 6.07-6.29 ( m, 1H), 4.00 (t, J = 6.1 Hz, 2H), 3.85 (d, J = 7.2 Hz, 2H), 3.17-3.41 (m, 2H), 2.89 (dd, J = 8.1, 7.3 Hz, 2H), 2.68-2.82 (m, 2H), 2.01-2.19 (m, 2H).

Example 31-38

3 - ({[1-methyl-6- (3-phenylpropoxy) -3,4-dihydro-2-naphthalenyl] methyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.50 Hz, 1H), 7.11-7.28 (m, 5H), 6.71-6.79 (m, 2H), 3.92-3.99 (m, 4H), 3.27-3.33 (m, 2H), 2.73-2.82 (m, 6H), 2.33 (t, J = 7.00 Hz, 2H), 2.16 (s, 3H), 2.01-2.11 (m, 2H).

Example 31-39

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

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

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.50 Hz, 1H), 7.11-7.28 (m, 5H), 6.76 (dd, J = 8, 50, 2.50 Hz, 1H), 6.72 (d, J = 2.50 Hz, 1H), 4.20-4.45 (m, 4H), 4.16 (s, 2H), 3, 96 (t, J = 6.50 Hz, 2H), 3.67-3.78 (m, 1H), 2.69-2.83 (m, 4H), 2.20-2.29 (m, 5H), 2.01-2.11 (m, 2H).

Example 31-40

3 - ({[6- (4-phenylbutoxy) -1H-inden-2-yl] methyl} amino) propanoic acid:

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

¹ H-NMR (CD ₃ OD): δ 7.04-7.33 (m, 7H), 6.92-6.97 (m, 1H), 6.74-6.84 (m, 1H), 4.03-4.10 (m, 2H), 3.96-4.02 (m, 2H), 3.44-3.52 (m, 2H), 3.14-3.21 (m, 2H) ), 2.63-2.72 (m, 2H), 2.46-2.54 (m, 2H), 1.75-1.83 (m, 4H).

Example 31-41

3 - ({((2E) -2-methyl-3- [4- (3-phenylpropoxy) phenyl] -2-propenyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.12-7.29 (m, 7H), 6.91 (d, J = 8.50 Hz, 2H), 6.65-6.68 (m, 1H), 3.97 (t, J = 6.00 Hz, 2H), 3.77 (s, 2H), 3.25-3.30 (m, 2H), 2.75-2.85 (m , 4H), 2.01-2.12 (m, 2H), 2.00 (d, J = 1.00 Hz, 3H).

Example 31-42

3 - ({((2E) -2-methyl-3- [4- (4-phenylbutoxy) phenyl] -2-propenyl} amino) propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.10-7.29 (m, 7H), 6.91 (d, J = 8.50 Hz, 2H), 6.64-6.67 (m, 1H), 3.97-4.02 (m, 2H), 3.76 (s, 2H), 3.25-3.29 (m, 2H), 2.78 (t, J = 6.50 Hz , 2H), 2.64-2.71 (m, 2H), 2.00 (d, J = 1.00 Hz, 3H), 1.76-1.82 (m, 4H).

Example 31-43

3 - [({6- [3- (4-chlorophenyl) propoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) amino] propanoic acid hydrochloride:

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.50 Hz, 1H), 7.25 (d, J = 8.50 Hz, 2H), 7.19 (d, J = 8.50 Hz, 2H), 6.75 (dd, J = 8.50, 2.50 Hz, 1H), 6.72 (d, J = 2.50 Hz, 1H), 3.91-3 99 (m, 4H), 3.27-3.34 (m, 2H), 2.73-2.82 (m, 6H), 2.29-2.38 (m, 2H), 2.16 (t, J = 1.5 Hz, 3H), 2.00-2.11 (m, 2H).

Example 31-44

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

TLC: Rf 0.22 (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), 7.19 (d, J = 8.50 Hz, 2H), 6.76 (dd, J = 8.50, 2.50 Hz, 1H), 6.71 (d, J = 2.50 Hz, 1H), 4.15-4 47 (m, 6H), 3.96 (t, J = 6.00 Hz, 2H), 3.65-3.80 (m, 1H), 2.69-2.82 (m, 4H), 2.20-2.29 (m, 5H); 1.99-2.11 (m, 2H);

Melting point: 147-150 ° C.

Example 31-45

3 - ({[6- (3-cyclohexylpropoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} amino) propanoic acid hydrochloride:

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.50 Hz, 1H), 6.71-6.78 (m, 2H), 3.90-3.98 (m, 4H), 3.26-3.34 (m, 2H), 2.73-2.82 (m, 4H), 2.29-2.37 (m, 2H), 2.16 (t, J = 1.50 Hz, 3H), 1.61-1.83 (m, 7H), 1.12-1.40 (m, 6H), 0.84-1.01 (m, 2H).

Example 31-46

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

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

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.50 Hz, 1H), 6.76 (dd, J = 8.50, 2.50 Hz, 1H), 6.71 (d, J = 2.50 Hz, 1H), 4.18-4.48 (m, 4H), 4.16 (s, 2H), 3.94 (t, J = 6.50 Hz, 2H) 3.67-3.79 (m, 1H), 2.70-2.77 (m, 2H), 2.20-2.29 (m, 5H), 1.61-1.82 (m, 7H), 1.11-1.39 (m, 6H), 0.83-1.00 (m, 2H);

Melting point: 160-163 ° C.

Example 31-47

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

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

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.50 Hz, 1H), 7.06-7.08 (m, 4H), 6.75 (dd, J = 8, 50, 2.50 Hz, 1H), 6.71 (d, J = 2.50 Hz, 1H), 4.17-4.48 (m, 4H), 4.16 (s, 2H), 3, 94 (t, J = 6.00 Hz, 2H), 3.65-3.78 (m, 1H), 2.69-2.77 (m, 4H), 2.19-2.29 (m, 8H), 1.97-2.09 (m, 2H).

Example 31-48

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

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.56 (d, J = 8.00 Hz, 2H), 7.40 (d, J = 8.00 Hz, 2H), 7.33 (d, J = 8.50 Hz, 1H), 6.76 (dd, J = 8.50, 2.50 Hz, 1H), 6.71 (d, J = 2.50 Hz, 1H), 4.17-4 49 (m, 4H), 4.16 (s, 2H), 3.98 (t, J = 6.00 Hz, 2H), 3.64-3.78 (m, 1H), 2.89 ( t, J = 7.50 Hz, 2H), 2.69-2.77 (m, 2H), 2.20-2.29 (m, 5H), 2.05-2.15 (m, 2H) .

Example 31-49

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

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.25-7.38 (m, 3H), 7.13-7.24 (m, 2H), 6.77 (dd, J = 8.50, 2 , 50 Hz, 1H), 6.73 (d, J = 2.50 Hz, 1H), 4.18-4.43 (m, 4H), 4.16 (s, 2H), 3.99 (t , J = 6.00 Hz, 2H), 3.65-3.76 (m, 1H), 2.90-2.97 (m, 2H), 2.70-2.77 (m, 2H), 2.20-2.29 (m, 5H); 2.02-2.13 (m, 2H).

Example 31-50

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

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.50 Hz, 1H), 7.16-7.27 (m, 2H), 6.98-7.10 (m, 2H), 6.76 (dd, J = 8.50, 2.50 Hz, 1H), 6.72 (d, J = 2.50 Hz, 1H), 4.19-4.46 (m, 4H ), 4.16 (s, 2H), 3.98 (t, J = 6.00 Hz, 2H), 3.65-3.78 (m, 1H), 2.83 (t, J = 7, 50 Hz, 2H), 2.70-2.77 (m, 2H), 2.20-2.29 (m, 5H), 2.00-2.11 (m, 2H);

Melting point: 133-135 ° C.

Example 31-51

1 - {[1-chloro-6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid hydrochloride:

TLC: Rf 0.15 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.56 (d, J = 8.60 Hz, 1H), 7.06-7.35 (m, 5H), 6.63-6.88 (m, 2H), 4.29 (s, 2H), 4.22-4.59 (m, 4H), 3.94-4.06 (m, 2H), 3.61-3.81 (m, 1H) 2.84 (t, J = 8.40 Hz, 2H), 2.60-2.75 (m, 2H), 2.47 (t, J = 7.20 Hz, 2H), 1.67- 1.90 (m, 4H).

Example 31-52

3 - ({[1-chloro-6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} amino) propanoic acid hydrochloride:

TLC: Rf 0.27 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.55 (d, J = 8.4 Hz, 1H), 7.00-7.35 (m, 5H), 6.64-6.86 (m, 2H), 4.08 (s, 2H), 3.94-4.04 (m, 2H), 3.19-3.45 (m, 2H), 2.88 (t, J = 7.5 Hz , 2H), 2.79 (t, J = 6.5 Hz, 2H), 2.63-2.72 (m, 2H), 2.53 (t, J = 7.5 Hz, 2H), 1 74-1.84 (m, 4H).

Example 31-53

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

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.50 Hz, 1H), 7.20 (dd, J = 8.50, 5.50 Hz, 2H), 6.98 (t, J = 8.50 Hz, 2H), 6.76 (dd, J = 8.50, 2.50 Hz, 1H), 6.72 (d, J = 2.50 Hz, 1H), 4 , 18-4.43 (m, 4H), 4.16 (s, 2H), 3.95 (t, J = 6.00 Hz, 2H), 3.66-3.75 (m, 1H), 2.69-2.82 (m, 4H), 2.20-2.28 (m, 5H), 1.99-2.10 (m, 2H);

Melting point: 135-137 ° C.

Example 31-54

1 - ({6- [2- (4-tert-butylphenyl) ethoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.30-7.35 (m, 3H), 7.20 (d, J = 8.50 Hz, 2H), 6.77 (dd, J = 8, 50, 2.50 Hz, 1H), 6.72 (d, J = 2.50 Hz, 1H), 4.20-4.46 (m, 4H), 4.13-4.19 (m, 4H ), 3.61-3.78 (m, 1H), 3.01 (t, J = 7.00 Hz, 2H), 2.69-2.76 (m, 2H), 2.18-2, 28 (m, 5H); 1.30 (s, 9H).

Example 31-55

1 - {[6- (1,1'-biphenyl-4-ylmethoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.58-7.64 (m, 4H), 7.49 (d, J = 8.00 Hz, 2H), 7.42 (t, J = 8, 00 Hz, 2H), 7.29-7.36 (m, 2H), 6.87 (dd, J = 8.50, 2.50 Hz, 1H), 6.83 (d, J = 2.50 Hz, 1H), 5.14 (s, 2H), 4.21-4.44 (m, 4H), 4.15 (s, 2H), 3.64-3.77 (m, 1H), 2 70-2.79 (m, 2H); 2.19-2.30 (m, 5H).

Example 31-56

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

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

¹ H-NMR (CD ₃ OD): δ 7.30-7.37 (m, 3H), 7.14-7.20 (m, 1H), 6.77 (dd, J = 8.7, 2 6 Hz, 1H), 6.72 (d, J = 2.6 Hz, 1H), 4.19-4.45 (m, 4H), 4.16 (s, 2H), 4.06 (t , J = 6.1 Hz, 2H), 3.62-3.78 (m, 1H), 3.07-3.18 (m, 2H), 2.68-2.78 (m, 2H), 2.22 (s, 3H), 2.19-2.29 (m, 2H), 1.97-2.10 (m, 2H).

Example 31-57

1 - [(6- {3- [3,5-bis (trifluoromethyl) phenyl] propoxy} -1-methyl-3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid hydrochloride:

TLC: Rf 0.20 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.82 (s, 2H), 7.77 (s, 1H), 7.33 (d, J = 8.6 Hz, 1H), 6.75 (dd , J = 8.6, 2.6 Hz, 1H), 6.70 (d, J = 2.6 Hz, 1H), 4.19-4.45 (m, 4H), 4.16 (s, 2H), 4.00 (t, J = 6.0 Hz, 2H), 3.62-3.77 (m, 1H), 2.95-3.04 (m, 2H), 2.67-2 76 (m, 2H), 2.22 (s, 3H), 2.19-2.30 (m, 2H), 2.07-2.18 (m, 2H).

Example 31-58

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

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

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.6 Hz, 1H), 6.76 (dd, J = 8.6, 2.6 Hz, 1H), 6.72 (d, J = 2.6 Hz, 1H), 4.18-4.44 (m, 4H), 4.16 (s, 2H), 3.96 (t, J = 6.4 Hz, 2H) 3.63-3.77 (m, 1H), 2.69-2.77 (m, 2H), 2.22 (s, 3H), 2.17-2.31 (m, 2H), 1 68-1.81 (m, 2H); 1.23-1.53 (m, 10H); 0.84-0.95 (m, 3H).

Example 31-59

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

TLC: Rf 0.27 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.10-7.37 (m, 11H), 6.63-6.73 (m, 2H), 4.19-4.45 (m, 5H), 4.15 (s, 2H), 3.88 (t, J = 6.3 Hz, 2H), 3.64-3.77 (m, 1H), 2.66-2.76 (m, 2H) 2.44-2.57 (m, 2H); 2.20 (s, 3H); 2.16-2.29 (m, 2H);

Melting point: 77-83 ° C.

Example 31-60

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

TLC: Rf 0.23 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.27-7.36 (m, 3H), 7.18 (d, J = 8.1 Hz, 2H), 6.84 (dd, J = 8, 1, 2.7 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 5.04 (s, 2H), 4.21-4.43 (m, 4H), 4, 15 (s, 2H), 3.62-3.76 (m, 1H), 2.68-2.78 (m, 2H), 2.58 (t, J = 7.8 Hz, 2H), 2 22 (s, 3H), 2.19-2.30 (m, 2H), 1.56-1.71 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H);

Melting point: 144-150 ° C.

Example 31-61

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

TLC: Rf 0.20 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.24-7.43 (m, 3H), 7.15 (d, J = 8.1 Hz, 2H), 6.73-6.94 (m, 2H), 5.04 (s, 2H), 4.16 (s, 2H), 4.06-4.47 (m, 4H), 3.60-3.82 (m, 1H), 2.73 (t, J = 8.4 Hz, 2H), 2.48 (d, J = 7.1 Hz, 2H), 2.13-2.31 (m, 5H), 1.69-1.98 ( m, 1H), 0.90 (d, J = 6.6 Hz, 6H).

Example 31-62

1 - ({6 - [(4-tert-butylbenzyl) oxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid hydrochloride:

TLC: Rf 0.20 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.37-7.43 (m, 2H), 7.29-7.36 (m, 3H), 6.84 (dd, J = 8.4, 2 , 7 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 5.04 (s, 2H), 4.19-4.43 (m, 4H), 4.16 (s , 2H), 3.62-3.78 (m, 1H), 2.69-2.77 (m, 2H), 2.21 (s, 3H), 2.19-2.29 (m, 2H ), 1.31 (s, 9H).

Example 31-63

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

TLC: Rf 0.22 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.6 Hz, 1H), 7.02-7.15 (m, 4H), 6.77 (dd, J = 8, 6, 2.6 Hz, 1H), 6.73 (d, J = 2.6 Hz, 1H), 4.21-4.42 (m, 4H), 4.16 (s, 2H), 3, 98 (t, J = 6.0 Hz, 2H), 3.63-3.77 (m, 1H), 2.68-2.84 (m, 4H), 2.30 (s, 3H), 2 22 (s, 3H), 2.19-2.32 (m, 2H), 1.96-2.07 (m, 2H);

Melting point: 160-165 ° C.

Example 31-64

1 - ({1-methyl-6 - [(4-phenylbutyl) sulfanyl] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid hydrochloride:

TLC: Rf 0.17 (chloroform: methanol: aqueous ammonia = 20: 5: 1);

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.2 Hz, 1H), 7.05-7.27 (m, 7H), 4.23-4.42 (m, 4H), 4.18 (s, 2H), 3.62-3.77 (m, 1H), 2.95 (t, J = 7.0 Hz, 2H), 2.67-2.78 (m , 2H), 2.61 (t, J = 7.4 Hz, 2H), 2.22 (s, 3H), 2.20-2.30 (m, 2H), 1.57-1.81 ( m, 4H).

Example 31-65

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

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

¹ H-NMR (CD ₃ OD): δ 7.81-7.91 (m, 4H), 7.54 (dd, J = 8.50, 1.50 Hz, 1H), 7.44-7, 51 (m, 2H), 7.35 (d, J = 8.50 Hz, 1H), 6.91 (dd, J = 8.50, 2.50 Hz, 1H), 6.87 (d, J = 2.50 Hz, 1H), 5.26 (s, 2H), 4.19-4.45 (m, 4H), 4.16 (s, 2H), 3.64-3.77 (m, 1H), 2.74 (t, J = 8.00 Hz, 2H), 2.20-2.29 (m, 5H).

Example 31-66

1 - {[1-methyl-6- (2-quinolinylmethoxy) -3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid dihydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 9.17 (d, J = 8.50 Hz, 1H), 8.32-8.41 (m, 2H), 8.15-8.24 (m, 2H), 7.95-8.03 (m, 1H), 7.44 (d, J = 9.00 Hz, 1H), 7.03-7.07 (m, 2H), 5.73 (s , 2H), 4.38-4.49 (m, 2H), 4.16-4.34 (m, 4H), 3.65-3.82 (m, 1H), 2.80 (t, J = 8.00 Hz, 2H); 2.23-2.34 (m, 5H).

Example 31-67

1 - {[6- (1-Benzothien-2-ylmethoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.80-7.84 (m, 1H), 7.73-7.79 (m, 1H), 7.27-7.39 (m, 4H), 6.91 (dd, J = 8.50, 2.50 Hz, 1H), 6.86 (d, J = 2.50 Hz, 1H), 5.38 (d, J = 1.00 Hz, 2H ), 4.18-4.43 (m, 4H), 4.16 (s, 2H), 3.63-3.77 (m, 1H), 2.75 (t, J = 8.00 Hz, 2H), 2.20-2.29 (m, 5H).

Example 31-68

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

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

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.50 Hz, 1H), 7.07-7.18 (m, 2H), 6.96-7.03 (m, 1H), 6.76 (dd, J = 8.50, 2.50 Hz, 1H), 6.72 (d, J = 2.50 Hz, 1H), 4.18-4.47 (m, 4H ), 4.16 (s, 2H), 3.96 (t, J = 6.00 Hz, 2H), 3.66-3.78 (m, 1H), 2.68-2.82 (m, 4H), 2.20-2.30 (m, 5H), 2.00-2.10 (m, 2H);

Melting point: 132-133 ° C.

Example 31-69

1 - {[6- (4-butylphenoxy) -1-methyl-3,4-dihydronaphthalen-2-yl] methyl} azetidine-3-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.38 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 6.85-6.98 (m, 2H), 6.73-6.83 (m, 2H), 4.20-4.45 (m, 4H), 4.17 (s, 2H), 3.58-3.81 (m , 1H), 2.67-2.79 (m, 2H), 2.60 (t, J = 7.8 Hz, 2H), 2.23 (s, 3H), 2.17-2.32 ( m, 2H), 1.52-1.66 (m, 2H), 1.29-1.44 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

Example 31-70

1 - {[6- (1-Benzofuran-2-ylmethoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.55-7.59 (m, 1H), 7.44-7.49 (m, 1H), 7.36 (d, J = 8.50 Hz, 1H), 7.25-7.32 (m, 1H), 7.18-7.24 (m, 1H), 6.92 (dd, J = 8.50, 2.50 Hz, 1H), 6 85-6.88 (m, 2H), 5.20 (s, 2H), 4.20-4.45 (m, 4H), 4.16 (s, 2H), 3.66-3.78 (m, 1H), 2.75 (t, J = 7.50 Hz, 2H), 2.19-2.29 (m, 5H).

Example 31-71

1 - ({1-methyl-6 - [(3-phenyl-1,2,4-oxadiazol-5-yl) methoxy] -3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 8.03-8.09 (m, 2H), 7.47-7.57 (m, 3H), 7.39 (d, J = 8.50 Hz, 1H), 6.90-6.97 (m, 2H), 5.46 (s, 2H), 4.20-4.43 (m, 4H), 4.16 (s, 2H), 3.63 -3.76 (m, 1H), 2.77 (t, J = 7.50 Hz, 2H), 2.20-2.31 (m, 5H).

Example 31-72

1 - [(1-methyl-6 - {[((2E) -3-phenyl-2-propenyl] oxy} -3,4-dihydro-2-naphthalenyl) methyl] -3-azetidinecarboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.37-7.45 (m, 2H), 7.27-7.38 (m, 3H), 7.19-7.26 (m, 1H), 6.85 (dd, J = 8.50, 2.50 Hz, 1H), 6.81 (d, J = 2.50 Hz, 1H), 6.74 (dt, J = 16.00, 1, 50 Hz, 1H), 6.44 (dt, J = 16.00, 5.50 Hz, 1H), 4.71 (dd, J = 5.50, 1.50 Hz, 2H), 4.19- 4.44 (m, 4H), 4.16 (s, 2H), 3.65-3.76 (m, 1H), 2.72-2.79 (m, 2H), 2.20-2, 30 (m, 5H).

Example 31-73

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

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

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.50 Hz, 1H), 7.21-7.30 (m, 1H), 7.02 (d, J = 8, 00 Hz, 1H), 6.84-6.98 (m, 2H), 6.76 (dd, J = 8.50, 2.50 Hz, 1H), 6.72 (d, J = 2.50 Hz, 1H), 4.20-4.43 (m, 4H), 4.16 (s, 2H), 3.96 (t, J = 6.00 Hz, 2H), 3.64-3.78 (m, 1H), 2.81 (t, J = 7.50 Hz, 2H), 2.73 (t, J = 8.00 Hz, 2H), 2.19-2.29 (m, 5H) 2.01-2.12 (m, 2H);

Melting point: 157-161 ° C.

Example 31-74

1 - ({6- [3- (2,4-dichlorophenyl) propoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.41 (d, J = 2.2 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.4, 2.2 Hz, 1H), 6.76 (dd, J = 8.6, 2.4 Hz, 1H), 6 71 (d, J = 2.4 Hz, 1H), 4.19-4.42 (m, 4H), 4.16 (s, 2H), 3.99 (t, J = 6.0 Hz, 2H), 3.62-3.76 (m, 1H), 2.87-2.96 (m, 2H), 2.69-2.78 (m, 2H), 2.22 (s, 3H) 2.18-2.29 (m, 2H); 2.00-2.12 (m, 2H);

Melting point: 121-126 ° C.

Example 31-75

1 - ({6- [3- (2,4-dimethylphenyl) propoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.93 (s, 1H ), 6.88 (d, J = 7.5 Hz, 1H), 6.76 (dd, J = 8.6, 2.6 Hz, 1H), 6.72 (d, J = 2.6 Hz , 1H), 4.19-4.43 (m, 4H), 4.16 (s, 2H), 3.96 (t, J = 6.1 Hz, 2H), 3.62-3.77 ( m, 1H), 2.67-2.80 (m, 4H), 2.25 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 2.15-2 32 (m, 2H); 1.91-2.04 (m, 2H);

Melting point: 132-136 ° C.

Example 31-76

1 - ({6 - [(4-ethylbenzyl) oxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.29-7.37 (m, 3H), 7.20 (d, J = 8.1 Hz, 2H), 6.84 (dd, J = 8, 5, 2.8 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 5.04 (s, 2H), 4.22-4.42 (m, 4H), 4, 15 (s, 2H), 3.63-3.78 (m, 1H), 2.70-2.79 (m, 2H), 2.64 (q, J = 7.6 Hz, 2H), 2 21 (s, 3H), 2.19-2.30 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H).

Example 31-77

1 - ({6 - [(4-cyclohexylbenzyl) oxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.27-7.41 (m, 3H), 7.20 (d, J = 7.8 Hz, 2H), 6.84 (dd, J = 8, 4, 2.6 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 5.03 (s, 2H), 4.20-4.43 (m, 4H), 4, 15 (s, 2H), 3.62-3.77 (m, 1H), 2.66-2.78 (m, 2H), 2.45-2.57 (m, 1H), 2.21 ( s, 3H), 2.17-2.29 (m, 2H), 1.70-1.90 (m, 5H), 1.34-1.54 (m, 5H);

Melting point: 154-158 ° C.

Example 31-78

1 - ({6- [3- (4-chlorophenyl) propoxy] -1-ethyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid hydrochloride:

TLC: Rf 0.27 (chloroform: methanol: aqueous ammonia = 80: 5: 1);

¹ H-NMR (CD ₃ OD): δ 7.34 (d, J = 8.60 Hz, 1H), 7.23-7.28 (m, 2H), 7.17-7.22 (m, 2H), 6.77 (dd, J = 8.60, 2.56 Hz, 1H), 6.72 (d, J = 2.56 Hz, 1H), 4.15 (s, 2H), 4, 09-4.54 (m, 4H), 3.96 (t, J = 6.13 Hz, 2H), 3.63-3.78 (m, 1H), 2.64-2.85 (m, 6H), 2.20 (t, J = 7.80 Hz, 2H), 1.96-2.13 (m, 2H), 1.11 (t, J = 7.50 Hz, 3H);

Melting point: 102-105 ° C.

Example 31-79

1 - {[3-methyl-6- (4-phenylbutoxy) -1-benzofuran-2-yl] methyl} azetidine-3-carboxylic acid:

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (DMSO-D ₆ ): δ 7.36 (d, J = 8.60 Hz, 1H), 7.13-7.32 (m, 5H), 7.06 (d, J = 2 , 20 Hz, 1H), 6.82 (dd, J = 8.60, 2.20 Hz, 1H), 3.97-4.03 (m, 2H), 3.60 (s, 2H), 3 , 36-3.44 (m, 2H), 3.25 (t, J = 6.68 Hz, 2H), 3.08-3.20 (m, 1H), 2.60-2.70 (m , 2H), 2.15 (s, 3H), 1.68-1.79 (m, 4H).

Example 31-80

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

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

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.50 Hz, 1H), 7.21-7.30 (m, 1H), 6.82-6.92 (m, 2H), 6.76 (dd, J = 8.50, 2.50 Hz, 1H), 6.72 (d, J = 2.50 Hz, 1H), 4.18-4.44 (m, 4H ), 4.16 (s, 2H), 3.97 (t, J = 6.00 Hz, 2H), 3.66-3.77 (m, 1H), 2.81 (t, J = 7, 50 Hz, 2H), 2.69-2.77 (m, 2H), 2.20-2.29 (m, 5H), 1.99-2.10 (m, 2H);

Melting point: 126-129 ° C.

Example 31-81

1 - ({6- [2- (2,3-dihydro-1H-inden-2-yl) ethoxy] -1-methyl-3,4-dihydro-2-naphthalenyl} methyl) -3-azetidinecarboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.34 (d, J = 8.50 Hz, 1H), 7.12-7.17 (m, 2H), 7.03-7.10 (m, 2H), 6.80 (dd, J = 8.50, 2.50 Hz, 1H), 6.75 (d, J = 2.50 Hz, 1H), 4.19-4.43 (m, 4H ), 4.16 (s, 2H), 4.08 (t, J = 6.50 Hz, 2H), 3.64-3.77 (m, 1H), 2.99-3.14 (m, 2H), 2.60-2.79 (m, 5H), 2.20-2.30 (m, 5H), 1.92-2.02 (m, 2H);

Melting point: 129-132 ° C.

Example 31-82

1 - {[6- (2,3-dihydro-1H-inden-2-ylmethoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.50 Hz, 1H), 7.15-7.21 (m, 2H), 7.07-7.13 (m, 2H), 6.79 (dd, J = 8.50, 2.50 Hz, 1H), 6.74 (d, J = 2.50 Hz, 1H), 4.21-4.41 (m, 4H ), 4.15 (s, 2H), 3.97 (d, J = 7.00 Hz, 2H), 3.63-3.76 (m, 1H), 3.06-3.18 (m, 2H), 2.78-2.99 (m, 3H), 2.69-2.77 (m, 2H), 2.19-2.29 (m, 5H).

Example 31-83

hydrochloride 1 - {[6- (bicyclo [4.2.0] octa-1,3,5-trien-7-ylmethoxy) -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 7.33 (d, J = 8.50 Hz, 1H), 7.05-7.24 (m, 4H), 6.81 (dd, J = 8, 50, 2.50 Hz, 1H), 6.77 (d, J = 2.50 Hz, 1H), 4.24-4.43 (m, 4H), 4.20 (d, J = 7.00 Hz, 2H), 4.16 (s, 2H), 3.85-3.95 (m, 1H), 3.64-3.77 (m, 1H), 3.38 (dd, J = 14, 00, 5.00 Hz, 1H), 2.96 (dd, J = 14.00, 2.50 Hz, 1H), 2.70-2.78 (m, 2H), 2.20-2.29 (m, 5H).

Example 31-84

1 - [(1-methyl-6- {3- [3- (trifluoromethyl) phenyl] propoxy} -3,4-dihydronaphthalen-2-yl) methyl] azetidine-3-carboxylic acid:

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 20: 5: 1);

¹ H-NMR (CD ₃ OD): δ 7.42-7.54 (m, 4H), 7.31 (d, J = 8.60 Hz, 1H), 6.76 (dd, J = 8, 60, 2.75 Hz, 1H), 6.71 (d, J = 2.75 Hz, 1H), 4.11-4.27 (m, 4H), 4.08 (s, 2H), 3, 97 (t, J = 6.13 Hz, 2H), 3.33-3.51 (m, 1H), 2.89 (t, J = 7.87 Hz, 2H), 2.72 (t, J = 8.05 Hz, 2H), 2.18-2.29 (m, 2H), 2.20 (s, 3H), 2.00-2.16 (m, 2H);

Melting point: 125-133 ° C.

Example 31-85

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

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 20: 5: 1);

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.60 Hz, 1H), 7.06-7.19 (m, 1H), 6.92-7.04 (m, 3H), 6.74 (dd, J = 8.60, 2.74 Hz, 1H), 6.70 (d, J = 2.74 Hz, 1H), 4.07-4.24 (m, 4H ), 4.05 (s, 2H), 3.94 (t, J = 6.22 Hz, 2H), 3.33-3.49 (m, 1H), 2.64-2.81 (m, 4H), 2.28 (s, 3H), 2.19 (s, 3H), 2.16-2.29 (m, 2H), 1.95-2.10 (m, 2H);

Melting point: 148-153 ° C.

Example 31-86

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

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 20: 5: 1);

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.60 Hz, 1H), 7.20-7.28 (m, 2H), 7.08-7.20 (m, 2H), 6.75 (dd, J = 8.60, 2.74 Hz, 1H), 6.71 (d, J = 2.74 Hz, 1H), 4.10-4.26 (m, 4H ), 4.07 (s, 2H), 3.96 (t, J = 6.13 Hz, 2H), 3.34-3.51 (m, 1H), 2.79 (t, J = 7, 87 Hz, 2H), 2.66-2.75 (m, 2H), 2.20 (s, 3H), 2.16-2.28 (m, 2H), 1.98-2.11 (m , 2H);

Melting point: 151-153 ° C.

Example 31-87

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

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 20: 5: 1);

¹ H-NMR (CD ₃ OD): δ 7.39 (d, J = 8.23 Hz, 1H), 7.36-7.39 (m, 1H), 7.30 (d, J = 8, 42 Hz, 1H), 7.14 (dd, J = 8.23, 2.20 Hz, 1H), 6.75 (dd, J = 8.42, 2.65 Hz, 1H), 6.70 ( d, J = 2.65 Hz, 1H), 4.06-4.25 (m, 4H), 4.04 (s, 2H), 3.96 (t, J = 6.13 Hz, 2H), 3.33-3.47 (m, 1H), 2.79 (t, J = 8.05 Hz, 2H), 2.67-2.75 (m, 2H), 2.19 (s, 3H) 2.16-2.28 (m, 2H); 1.99-2.12 (m, 2H);

Melting point: 74-81 ° C.

Example 31-88

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

TLC: Rf 0.28 (chloroform: methanol: aqueous ammonia = 20: 5: 1);

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.42 Hz, 1H), 7.19 (d, J = 7.80 Hz, 2H), 7.12 (d, J = 7.80 Hz, 2H), 6.76 (dd, J = 8.42, 2.56 Hz, 1H), 6.71 (d, J = 2.56 Hz, 1H), 4.07-4 , 27 (m, 6H), 4.08 (s, 2H), 3.34-3.48 (m, 1H), 3.01 (t, J = 6.86 Hz, 2H), 2.66- 2.76 (m, 2H), 2.60 (q, J = 7.75 Hz, 2H), 2.18-2.27 (m, 2H), 2.19 (s, 3H), 1.20 (t, J = 7.68 Hz, 3H);

Melting point: 158-163 ° C.

Example 31-89

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

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

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.42 Hz, 1H), 7.20 (d, J = 8.24 Hz, 2H), 7.15 (d, J = 8.24 Hz, 2H), 6.76 (dd, J = 8.42, 2.65 Hz, 1H), 6.71 (d, J = 2.65 Hz, 1H), 4.10-4 27 (m, 6H), 4.07 (s, 2H), 3.33-3.49 (m, 1H), 3.01 (t, J = 6.86 Hz, 2H), 2.77- 2.93 (m, 1H), 2.62-2.77 (m, 2H), 2.19 (s, 3H), 2.15-2.29 (m, 2H), 1.22 (d, J = 6.95 Hz, 6H);

Melting point: 148-152 ° C.

Example 31-90

1 - [(1-methyl-6- {3- [3- (trifluoromethoxy) phenyl] propoxy} -3,4-dihydronaphthalen-2-yl) methyl] azetidine-3-carboxylic acid:

TLC: Rf 0.28 (chloroform: methanol: aqueous ammonia = 20: 5: 1);

¹ H-NMR (CD ₃ OD): δ 7.28-7.40 (m, 2H), 7.18-7.25 (m, 1H), 7.02-7.15 (m, 2H), 6.76 (dd, J = 8.60, 2.75 Hz, 1H), 6.71 (d, J = 2.75 Hz, 1H), 4.12-4.28 (m, 4H), 4 08 (s, 2H), 3.97 (t, J = 6.13 Hz, 2H), 3.35-3.52 (m, 1H), 2.84 (t, J = 7.86 Hz, 2H), 2.65-2.78 (m, 2H), 2.21 (s, 3H), 2.16-2.31 (m, 2H), 1.97-2.14 (m, 2H) ;

Melting point: 136-139 ° C.

Example 31-91

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

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.10-7.34 (m, 6H), 6.68 (dd, J = 8.50, 2.50 Hz, 1H), 6.64 (d, J = 2.50 Hz, 1H), 4.18-4.46 (m, 4H), 4.15 (s, 2H), 3.65-3.94 (m, 3H), 2.91-3 04 (m, 1H), 2.67-2.75 (m, 2H), 2.18-2.28 (m, 5H), 1.93-2.12 (m, 2H), 1.30 (d, J = 7.00 Hz, 3H);

Melting point: 127-133 ° C.

Example 31-92

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

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.32 (d, J = 8.50 Hz, 1H), 7.21-7.28 (m, 2H), 7.12-7.19 (m, 3H), 6.75 (dd, J = 8.50, 2.50 Hz, 1H), 6.70 (d, J = 2.50 Hz, 1H), 4.36-4.48 (m, 2H ), 4.19-4.33 (m, 2H), 4.16 (s, 2H), 3.65-3.86 (m, 3H), 2.84 (dd, J = 13.00, 6 , 50 Hz, 1H), 2.73 (t, J = 8.00 Hz, 2H), 2.55 (dd, J = 13.00, 7.50 Hz, 1H), 2.15-2.29 (m, 6H), 1.01 (d, J = 7.00 Hz, 3H);

Melting point: 105-110 ° C.

Example 31-93

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

TLC: Rf 0.30 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.50 Hz, 1H), 7.20-7.27 (m, 2H), 7.10-7.18 (m, 3H), 6.72 (dd, J = 8.50, 2.50 Hz, 1H), 6.65 (d, J = 2.50 Hz, 1H), 4.20-4.47 (m, 5H ), 4.16 (s, 2H), 3.64-3.80 (m, 1H), 2.66-2.79 (m, 4H), 2.19-2.31 (m, 5H), 1.80-2.09 (m, 2H); 1.29 (d, J = 6.00 Hz, 3H).

Example 31-94

1 - ({6- [1- (4-isobutylphenyl) ethoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid hydrochloride:

TLC: Rf 0.18 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.19-7.29 (m, 3H), 7.09 (d, J = 7.9 Hz, 2H), 6.65-6.75 (m, 2H), 5.37 (q, J = 6.4 Hz, 1H), 4.18-4.40 (m, 4H), 4.12 (s, 2H), 3.60-3.75 (m , 1H), 2.59-2.73 (m, 2H), 2.43 (d, J = 7.1 Hz, 2H), 2.16 (s, 3H), 2.11-2.25 ( m, 2H), 1.75-1.88 (m, 1H), 1.57 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.6 Hz, 6H).

Example 32

3- [methyl ({6 - [(5-phenylpentyl) oxy] -2-naphthyl} methyl) amino] propanoic acid

Acrylic acid (6.2 μl) was added to methyl ({6 - [(5-phenylpentyl) oxy] -2-naphthyl} methyl) amine (15 mg). Then methanol was added to the mixture to a total volume of 390 μl, followed by stirring at 60 ° C for 24 hours. After concentrating the reaction mixture, the residue was purified by preparative TLC (chloroform: methanol: aqueous ammonia = 80: 20: 4) to obtain the compound of the present invention (11.2 mg) having the following physical characteristics.

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

¹ H-NMR (CD ₃ OD): δ 7.79 (s, 1H), 7.77 (d, J = 8.51 Hz, 1H), 7.76 (d, J = 8.97 Hz, 1H ), 7.46 (dd, J = 8.51, 1.74 Hz, 1H), 7.03-7.31 (m, 7H), 4.01-4.11 (m, 4H), 3, 09 (t, J = 7.04 Hz, 2H), 2.63 (t, J = 7.50 Hz, 2H), 2.53 (s, 3H), 2.48-2.57 (m, 2H ), 1.77-1.93 (m, 2H), 1.63-1.77 (m, 2H), 1.43-1.62 (m, 2H).

Examples 32-01 to 32-12

A procedure similar to that of Example 32 was carried out except that the corresponding amine compound was used as a substituent for methyl ({6 - [(5-phenylpentyl) oxy] -2-naphthyl} methyl) amine, whereby the compounds of the present the invention having the following physical characteristics.

Example 32-01

3- [ethyl ({6 - [(5-phenylpentyl) oxy] -2-naphthyl} methyl) amino] propanoic acid:

TLC: Rf 0.43 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.84 (s, 1H), 7.72-7.82 (m, 2H), 7.47 (dd, J = 8.42, 1.83 Hz, 1H), 7.06-7.29 (m, 7H), 4.22 (s, 2H), 4.05 (t, J = 6.31 Hz, 2H), 3.20 (t, J = 6 , 86 Hz, 2H), 3.00 (q, J = 7.20 Hz, 2H), 2.62 (t, J = 7.50 Hz, 2H), 2.53 (t, J = 6.86 Hz, 2H), 1.76-1.93 (m, 2H), 1.62-1.75 (m, 2H), 1.43-1.61 (m, 2H), 1.25 (t, J = 7.20 Hz, 3H).

Example 32-02

3 - [({6 - [(5-phenylpentyl) oxy] -2-naphthyl} methyl) (propyl) amino] propanoic acid:

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

¹ H-NMR (CD ₃ OD): δ 7.89 (s, 1H), 7.84 (d, J = 8.78 Hz, 1H), 7.80 (d, J = 9.15 Hz, 1H ), 7.49 (dd, J = 8.42, 1.65 Hz, 1H), 7.06-7.30 (m, 7H), 4.39 (s, 2H), 4.08 (t, J = 6.40 Hz, 2H), 3.26-3.40 (m, 2H), 2.93-3.13 (m, 2H), 2.64 (t, J = 7.68 Hz, 2H ), 2.59 (t, J = 6.31 Hz, 2H), 1.80-1.94 (m, 2H), 1.62-1.79 (m, 4H), 1.46-1, 62 (m, 2H), 0.90 (t, J = 7.41 Hz, 3H).

Example 32-03

3- [isopropyl ({6 - [(5-phenylpentyl) oxy] -2-naphthyl} methyl) amino] propanoic acid:

TLC: Rf 0.54 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.79 (s, 1H), 7.75 (d, J = 8.60 Hz, 1H), 7.73 (d, J = 9.15 Hz, 1H ), 7.48 (dd, J = 8.60, 1.74 Hz, 1H), 7.04-7.29 (m, 7H), 4.07 (t, J = 6.31 Hz, 2H) 4.01-4.13 (m, 2H), 2.93-3.13 (m, 2H), 2.65 (t, J = 7.50 Hz, 2H), 2.44 (t, J = 6.68 Hz, 2H), 1.79-1.94 (m, 2H), 1.64-1.79 (m, 2H), 1.47-1.63 (m, 2H), 1, 25-1.34 (m, 1H); 1.21 (d, J = 6.59 Hz, 6H).

Example 32-04

3 - [(2-hydroxyethyl) ({6 - [(5-phenylpentyl) oxy] -2-naphthyl} methyl) amino] propanoic acid:

TLC: Rf 0.28 (chloroform: methanol: aqueous ammonia = 80: 10: 1);

¹ H-NMR (CD ₃ OD): δ 7.90 (s, 1H), 7.75-7.87 (m, 2H), 7.52 (dd, J = 8.32, 1.74 Hz, 1H), 7.05-7.30 (m, 7H), 4.46 (s, 2H), 4.09 (t, J = 6.40 Hz, 2H), 3.83 (t, J = 5 , 20 Hz, 2H), 3.37 (t, J = 6.31 Hz, 2H), 3.20 (t, J = 5.20 Hz, 2H), 2.65 (t, J = 7.55 Hz, 2H), 2.60 (t, J = 6.31 Hz, 2H), 1.80-1.95 (m, 2H), 1.64-1.79 (m, 2H), 1.46 -1.63 (m, 2H).

Example 32-05

3- {4-methoxy-4- [4- (3-phenylpropoxy) phenyl] -1-piperidinyl} propanoic acid

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

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.97 Hz, 2H), 7.09-7.29 (m, 5H), 6.93 (d, J = 8, 97 Hz, 2H), 3.97 (t, J = 6.31 Hz, 2H), 3.38-3.52 (m, 2H), 3.17-3.38 (m, 4H), 2, 95 (s, 3H), 2.79 (t, J = 7.55 Hz, 2H), 2.57 (t, J = 6.59 Hz, 2H), 2.26-2.41 (m, 2H ), 1.98-2.24 (m, 4H).

Example 32-06

3- {4- [4- (3-phenylpropoxy) phenyl] -1-piperidinyl} propanoic acid trifluoroacetate:

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

¹ H-NMR (CD ₃ OD): δ 7.09-7.30 (m, 7H), 6.86 (d, J = 8.78 Hz, 2H), 3.93 (t, J = 6, 31 Hz, 2H), 3.60-3.74 (m, 2H), 3.44 (t, J = 7.04 Hz, 2H), 3.06-3.23 (m, 2H), 2, 84 (t, J = 7.04 Hz, 2H), 2.78 (t, J = 7.04 Hz, 2H), 2.71-2.91 (m, 1H), 1.98-2.17 (m, 4H), 1.86-1.98 (m, 2H).

Example 32-07

3- [5-methyl-4- [4- (3-phenylpropoxy) phenyl] -3,6-dihydropyridin-1 (2H) -yl] propanoic acid:

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

¹ H-NMR (CD ₃ OD): δ 7.13-7.31 (m, 5H), 7.11 (d, J = 8.78 Hz, 2H), 6.90 (d, J = 8, 78 Hz, 2H), 3.95 (t, J = 6.22 Hz, 2H), 3.64 (s, 2H), 3.26-3.37 (m, 4H), 2.79 (t, J = 7.50 Hz, 2H), 2.52-2.69 (m, 4H), 1.95-2.13 (m, 2H), 1.64 (s, 3H).

Example 32-08

3- {4- [4- (3-phenylpropoxy) phenyl] -1-piperadinyl} propanoic acid dihydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.10-7.33 (m, 5H), 6.97-7.10 (m, 2H), 6.88 (d, J = 7.32 Hz, 2H), 3.92 (t, J = 6.31 Hz, 2H), 3.52 (t, J = 7.23 Hz, 2H), 3.34-3.78 (m, 8H), 2, 89 (t, J = 7.23 Hz, 2H), 2.78 (t, J = 7.59 Hz, 2H), 1.93-2.14 (m, 2H).

Example 32-09

3- [6- (3-phenylpropoxy) -3,4-dihydro-2 (1H) -isoquinolinyl] propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 6.99-7.37 (m, 6H), 6.85 (dd, J = 8.60, 2.74 Hz, 1H), 6.79 (d, J = 2.74 Hz, 1H), 4.21-4.66 (m, 2H), 3.95 (t, J = 6.31 Hz, 2H), 3.55 (t, J = 7.04 Hz, 2H), 3.35-3.85 (m, 2H), 3.03-3.26 (m, 2H), 2.93 (t, J = 7.04 Hz, 2H), 2.78 (t, J = 7.59 Hz, 2H), 1.96-2.15 (m, 2H).

Example 32-10

3- [6 - [(5-phenylpentyl) oxy] -3,4-dihydro-2 (1H) -isoquinolinyl] propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.01-7.32 (m, 6H), 6.83 (dd, J = 8.42, 2.56 Hz, 1H), 6.79 (d, J = 2.56 Hz, 1H), 4.40 (s, 2H), 3.95 (t, J = 6.31 Hz, 2H), 3.51-3.68 (m, 2H), 3, 54 (t, J = 7.04 Hz, 2H), 3.09-3.23 (m, 2H), 2.91 (t, J = 7.04 Hz, 2H), 2.63 (t, J = 7.55 Hz, 2H), 1.73-1.90 (m, 2H), 1.59-1.73 (m, 2H), 1.36-1.59 (m, 2H).

Example 32-11

3 - {((3Z) -3- [4- (3-phenylpropoxy) benzylidene] -1-piperidinyl} propanoic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.15-7.30 (m, 5H), 7.13 (d, J = 8.78 Hz, 2H), 6.91 (d, J = 8, 78 Hz, 2H), 6.67 (s, 1H), 3.95 (t, J = 6.31 Hz, 2H), 3.87-3.96 (m, 2H), 3.31-3, 35 (m, 2H), 3.21 (t, J = 6.68 Hz, 2H), 2.79 (t, J = 7.50 Hz, 2H), 2.45-2.54 (m, 2H ), 2.42 (t, J = 6.68 Hz, 2H), 2.00-2.14 (m, 2H), 1.88-2.01 (m, 2H).

Example 32-12

3 - {((3E) -3- [4- (3-phenylpropoxy) benzylidene] -1-piperidinyl} propanoic acid hydrochloride:

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.06-7.30 (m, 7H), 6.89 (d, J = 8.78 Hz, 2H), 6.61 (s, 1H), 3 96 (t, J = 6.22 Hz, 2H), 3.84 (s, 2H), 3.19-3.40 (m, 4H), 2.79 (t, J = 7.50 Hz, 2H), 2.58-2.68 (m, 2H), 2.58 (t, J = 6.68 Hz, 2H), 1.98-2.12 (m, 2H), 1.79-1 96 (m, 2H).

Example 33

3 - [(3- {4- [3- (4-methylphenyl) propoxy] phenyl} propyl) amino] propanoic acid hydrochloride

To a solution of the compound obtained in Example 5 (48 mg) in tetrahydrofuran (3 ml) was added 3- (4-methylphenyl) propanol (19 mg), diethyl azodicarboxylate (60 mg) and triphenylphosphine on a polymer carrier (2.3 mmol / g , 60 mg), followed by stirring at room temperature for 2 days. Insoluble matters were filtered off and the mixture was concentrated, after which the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain an ether compound. To a solution of the obtained compound in 1,4-dioxane (2 ml) was added 4 N. a solution of hydrogen chloride in 1,4-dioxane (0.8 ml), followed by stirring at 40 ° C for 1 hour. The reaction mixture was concentrated and washed with ethyl acetate, whereby a compound of the present invention (32.5 mg) was obtained having the following physical characteristics.

TLC: Rf 0.29 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.01-7.17 (m, 6H), 6.76-6.91 (m, 2H), 3.90 (t, J = 6.31 Hz, 2H), 3.24 (t, J = 6.59 Hz, 2H), 2.93-3.08 (m, 2H), 2.57-2.80 (m, 6H), 2.28 (s , 3H); 1.87-2.10 (m, 4H).

Example 34

[6- (4-phenylbutoxy) -3,4-dihydronaphthalene-1 (2H) -ilidene] acetonitrile (E / Z mixture)

To a solution of 6- (4-phenylbutoxy) -3,4-dihydronaphthalen-1 (2H) -one (300 mg) in tetrahydrofuran (10 ml) was added diethyl cyanomethylphosphonate (199 mg) and sodium hydride (60%, 97.8 mg ) followed by stirring at room temperature for 24 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, concentrated and then purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), whereby the title compound (E / Z mixture, 207 mg) having the following physical characteristics was obtained.

TLC: Rf 0.68 (hexane: ethyl acetate = 3: 1).

Example 35

3 - ({2- [6- (4-phenylbutoxy) -3,4-dihydro-1-naphthalenyl] ethyl} amino) propanoic acid hydrochloride:

To a solution of the compound obtained in Example 34 (205 mg) in tetrahydrofuran (6.5 ml) was added at 0 ° C a solution of 1M diisobutylaluminum hydride in toluene (1.4 ml), followed by stirring at room temperature for 3 hours. After adding 2 n. hydrochloric acid solution, the reaction mixture was stirred for 15 minutes and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain an aldehyde compound. Then, a procedure similar to that of Example 29 was carried out except that the obtained aldehyde compound was used as a substituent for (2E) -3- [4- (3-phenylpropoxy) phenyl] but-2-enal, whereby the compound was prepared according to the present invention having the following physical characteristics.

TLC: Rf 0.25 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.08-7.32 (m, 6H), 6.67-6.82 (m, 2H), 5.89 (t, J = 4.57 Hz, 1H), 3.89-4.07 (m, 2H), 3.23-3.40 (m, 2H), 3.19 (t, J = 7.50 Hz, 2H), 2.83 (t , J = 7.59 Hz, 2H), 2.62-2.77 (m, 6H), 2.19-2.29 (m, 2H), 1.72-1.85 (m, 4H).

Examples 36-1 to 36-2

The procedure of Example 1 and Example 2 was carried out as described in WO 02/092068 in that order, but using the corresponding amine compound as a substituent for methyl 2-methoxy-5-aminobenzoate, whereby the compounds of the present invention were prepared having the following physical characteristics.

Example 36-1

{3 - [(3- {4 - [(5-phenylpentyl) oxy] phenyl} propanoyl) amino] phenyl} acetic acid:

Retention time in an HPLC analysis (minutes: HPLC measurement conditions are described in Example 26): 4.31;

MS (m / z): 891 (2M + H) ⁺ , 446 (M + H) ⁺ .

Example 36-2

{4 - [(3- {4 - [(5-phenylpentyl) oxy] phenyl} propanoyl) amino] phenyl} acetic acid:

Retention time in an HPLC analysis (minutes: HPLC measurement conditions are described in Example 26): 4.27;

MS (m / z): 891 (2M + H) ⁺ , 446 (M + H) ⁺ .

Examples 37-01 to 37-32

A procedure similar to that of Example 29 was carried out except that the corresponding amine compound was used as a substituent for β-alanine and the corresponding aldehyde compound was a substituent for (2E) -3- [4- (3-phenylpropoxy) phenyl] but- 2-enal, resulting in the compounds of the present invention having the following physical characteristics.

Example 37-01

1 - [(1-methyl-6 - {[(1R, 2R) -2-phenylcyclopropyl] methoxy} -3,4-dihydronaphthalen-2-yl) methyl] azetidine-3-carboxylic acid:

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.60 Hz, 1H), 7.17-7.26 (m, 2H), 7.04-7.16 (m, 3H), 6.79 (dd, J = 8.60, 2.74 Hz, 1H), 6.74 (d, J = 2.74 Hz, 1H), 4.11-4.28 (m, 4H ), 4.09 (s, 2H), 3.90-4.08 (m, 2H), 3.36-3.50 (m, 1H), 2.65-2.78 (m, 2H), 2.15-2.30 (m, 5H), 1.86-2.02 (m, 1H), 1.44-1.64 (m, 1H), 1.03 (t, J = 6.68 Hz, 2H);

Melting point: 70-84 ° C.

Example 37-02

1 - ({6- [3- (4-fluoro-3-methylphenyl) propoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid:

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.60 Hz, 1H), 6.95-7.10 (m, 2H), 6.81-6.94 (m, 1H), 6.75 (dd, J = 8.60, 2.75 Hz, 1H), 6.70 (d, J = 2.75 Hz, 1H), 4.11-4.27 (m, 4H ), 4.08 (s, 2H), 3.94 (t, J = 6.22 Hz, 2H), 3.35-3.48 (m, 1H), 2.66-2.78 (m, 4H), 2.15-2.31 (m, 8H), 1.94-2.10 (m, 2H).

Melting point: 149-152 ° C.

Example 37-03

1 - {[1-methyl-6- (quinolin-7-ylmethoxy) -3,4-dihydronaphthalen-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 8.83 (dd, J = 4.5, 1.0 Hz, 1H), 8.36 (dd, J = 8.5, 1.0 Hz, 1H) , 8.07 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.52 (dd, J = 8.5, 4.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 6.83-6.97 (m, 2H), 5.33 (s, 2H), 4.11-4.28 (m, 4H), 4.08 (s, 2H), 3.34-3.52 (m, 1H), 2.66-2.79 (m, 2H), 2, 13-2.28 (m, 5H).

Example 37-04

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

TLC: Rf 0.23 (chloroform: methanol: aqueous ammonia = 50: 10: 1);

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.6 Hz, 1H), 7.14-7.29 (m, 1H), 6.85-6.95 (m, 2H), 6.74 (dd, J = 8.6, 2.6 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 4.12-4.27 (m, 4H ), 4.10 (s, 2H), 3.99 (t, J = 6.0 Hz, 2H), 3.34-3.52 (m, 1H), 2.87 (t, J = 7, 3 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H), 2.17-2.28 (m, 5H), 1.95-2.10 (m, 2H);

Melting point: 144-150 ° C.

Example 37-05

1 - [(1-methyl-6- {3- [2- (trifluoromethyl) phenyl] propoxy} -3,4-dihydronaphthalen-2-yl) methyl] azetidine-3-carboxylic acid:

TLC: Rf 0.18 (chloroform: methanol: aqueous ammonia = 50: 10: 1);

¹ H-NMR (CD ₃ OD): δ 7.64 (d, J = 7.7 Hz, 1H), 7.49-7.57 (m, 1H), 7.44 (d, J = 7, 8 Hz, 1H), 7.30-7.39 (m, 2H), 6.78 (dd, J = 8.5, 2.7 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 4.13-4.26 (m, 4H), 4.10 (s, 2H), 4.02 (t, J = 6.2 Hz, 2H), 3.34-3.50 (m, 1H), 2.98 (t, J = 7.8 Hz, 2H), 2.73 (t, J = 8.1 Hz, 2H), 2.18-2.29 (m, 5H) 1.99-2.14 (m, 2H);

Melting point: 125-127 ° C.

Example 37-06

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

TLC: Rf 0.17 (chloroform: methanol: aqueous ammonia = 50: 10: 1);

¹ H-NMR (CD ₃ OD): δ 7.31 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 1.5 Hz, 1H), 6.89 (dd, J = 7.5, 1.5 Hz, 1H), 6.75 (dd, J = 8.4, 2.4 Hz, 1H), 6 70 (d, J = 2.4 Hz, 1H), 4.12-4.28 (m, 4H), 4.10 (s, 2H), 3.94 (t, J = 6.3 Hz, 2H), 3.33-3.49 (m, 1H), 2.66-2.76 (m, 4H), 2.15-2.28 (m, 11H), 1.89-2.09 ( m, 2H);

Melting point: 167-172 ° C.

Example 37-07

1 - {[1-methyl-6- (1,2,3,4-tetrahydronaphthalen-2-ylmethoxy) -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 7.33 (d, J = 8.50 Hz, 1H), 7.04-7.06 (m, 4H), 6.81 (dd, J = 8, 50, 2.50 Hz, 1H), 6.77 (d, J = 2.50 Hz, 1H), 4.11-4.24 (m, 4H), 4.08 (s, 2H), 3, 96 (d, J = 6.50 Hz, 2H), 3.35-3.47 (m, 1H), 2.96 (dd, J = 16.00, 5.00 Hz, 1H), 2.80 -2.88 (m, 2H), 2.70-2.77 (m, 2H), 2.61 (dd, J = 16.00, 10.50 Hz, 1H), 2.19-2.28 (m, 6H), 2.06-2.14 (m, 1H), 1.53-1.64 (m, 1H).

Example 37-08

1 - ({6 - [(4'-fluoro-1,1'-biphenyl-4-yl) methoxy] -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 (DMSO-d ₆ ): δ 7.63-7.73 (m, 4H), 7.51 (d, J = 8.00 Hz, 2H), 7.28 (t, J = 9 , 00 Hz, 2H), 7.17 (d, J = 9.50 Hz, 1H), 6.81-6.85 (m, 2H), 5.13 (s, 2H), 3.13-3 56 (m, 7H); 2.53-2.65 (m, 2H); 2.10-2.21 (m, 2H); 2.01 (s, 3H).

Example 37-09

1 - ({6- [3,3-bis (4-fluorophenyl) propoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid:

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

¹ H-NMR (CD ₃ OD): δ 7.25-7.32 (m, 5H), 6.99 (t, J = 9.00 Hz, 4H), 6.69 (dd, J = 8, 50, 2.50 Hz, 1H), 6.65 (d, J = 2.50 Hz, 1H), 4.14-4.31 (m, 5H), 4.10 (s, 2H), 3, 87 (t, J = 6.00 Hz, 2H), 3.38-3.49 (m, 1H), 2.66-2.74 (m, 2H), 2.42-2.51 (m, 2H), 2.17-2.27 (m, 5H).

Example 37-10

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

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

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.50 Hz, 1H), 7.20-7.27 (m, 2H), 7.09-7.19 (m, 3H), 6.74 (dd, J = 8.50, 2.50 Hz, 1H), 6.70 (d, J = 2.50 Hz, 1H), 4.12-4.26 (m, 4H ), 4.09 (s, 2H), 3.96 (t, J = 6.50 Hz, 2H), 3.36-3.49 (m, 1H), 2.67-2.76 (m, 2H), 2.63 (t, J = 8.00 Hz, 2H), 2.17-2.28 (m, 5H), 1.73-1.84 (m, 2H), 1.62-1 72 (m, 2H); 1.43-1.55 (m, 2H);

Melting point: 129-133 ° C.

Example 37-11

1 - [(6- {3- [4-chloro-2- (trifluoromethyl) phenyl] propoxy} -1-methyl-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 7.64 (d, J = 2.56 Hz, 1H), 7.55 (dd, J = 8.23, 2.56 Hz, 1H), 7.46 (d, J = 8.23 Hz, 1H), 7.32 (d, J = 8.23 Hz, 1H), 6.77 (dd, J = 8.23, 2.74 Hz, 1H), 6 72 (d, J = 2.74 Hz, 1H), 4.09-4.24 (m, 4H), 4.06 (s, 2H), 4.03 (t, J = 6.04 Hz, 2H), 3.33-3.49 (m, 1H), 2.88-3.03 (m, 2H), 2.64-2.79 (m, 2H), 2.16-2.30 ( m, 5H); 1.98-2.14 (m, 2H);

Melting point: 127-128 ° C.

Example 37-12

1 - {[6- (1,1'-biphenyl-3-ylmethoxy) -1-methyl-3,4-dihydronaphthalen-2-yl] methyl} azetidine-3-carboxylic acid hydrochloride:

TLC: Rf 0.15 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.67 (s, 1H), 7.54-7.62 (m, 3H), 7.39-7.47 (m, 4H), 7.30- 7.36 (m, 2H), 6.89 (dd, J = 8.70, 2.38 Hz, 1H), 6.85 (d, J = 2.38 Hz, 1H), 5.17 (s , 2H), 4.21-4.43 (m, 4H), 4.16 (s, 2H), 3.63-3.81 (m, 1H), 2.69-2.78 (m, 2H ), 2.14-2.30 (m, 5H);

Melting point: 119-120 ° C.

Example 37-13

1 - [(6- {3- [2,5-bis (trifluoromethyl) phenyl] 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 7.87 (d, J = 8.23 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J = 8.23 Hz, 1H ), 7.32 (d, J = 8.60 Hz, 1H), 6.77 (dd, J = 8.60, 2.38 Hz, 1H), 6.72 (d, J = 2.38 Hz , 1H), 4.12-4.27 (m, 4H), 4.09 (s, 2H), 4.04 (t, J = 5.95 Hz, 2H), 3.35-3.48 ( m, 1H), 3.03-3.11 (m, 2H), 2.69-2.77 (m, 2H), 2.20-2.29 (m, 5H), 2.03-2, 17 (m, 2H);

Melting point: 119-124 ° C.

Example 37-14

1 - ({1-methyl-6- [3- (2,4,5-trifluorophenyl) propoxy] -3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid:

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.60 Hz, 1H), 7.14-7.26 (m, 1H), 7.02-7.13 (m, 1H), 6.75 (dd, J = 8.60, 2.56 Hz, 1H), 6.70 (d, J = 2.56 Hz, 1H), 4.04-4.22 (m, 4H ), 4.02 (s, 2H), 3.98 (t, J = 6.04 Hz, 2H), 3.32-3.46 (m, 1H), 2.80 (t, J = 7, 59 Hz, 2H), 2.66-2.75 (m, 2H), 2.15-2.29 (m, 5H), 1.96-2.11 (m, 2H);

Melting point: 159-164 ° C.

Example 37-15

1 - [(6- {3- [4-fluoro-3- (trifluoromethyl) phenyl] propoxy} -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 7.45-7.55 (m, 2H), 7.31 (d, J = 8.60 Hz, 1H), 7.21 (t, J = 10, 43 Hz, 1H), 6.77 (dd, J = 8.60, 2.65 Hz, 1H), 6.70 (d, J = 2.65 Hz, 1H), 4.11-4.27 ( m, 4H), 4.08 (s, 2H), 3.97 (t, J = 6.13 Hz, 2H), 3.33-3.50 (m, 1H), 2.80-2.91 (m, 2H), 2.66-2.78 (m, 2H), 2.16-2.29 (m, 5H), 2.00-2.13 (m, 2H).

Example 37-16

1 - [(6- {3- [4-fluoro-2- (trifluoromethyl) phenyl] propoxy} -1-methyl-3,4-dihydronaphthalen-2-yl) methyl] azetidine-3-carboxylic acid:

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.48 (dd, J = 8.60, 5.49 Hz, 1H), 7.39 (dd, J = 9.24, 2.65 Hz, 1H) 7.24-7.34 (m, 2H); 6.77 (dd, J = 8.60, 2.56 Hz, 1H); 6.72 (d, J = 2.56 Hz, 1H), 4.11-4.27 (m, 4H), 4.08 (s, 2H), 4.02 (t, J = 6.04 Hz, 2H), 3.33-3.49 (m, 1H) 2.90-3.03 (m, 2H), 2.66-2.78 (m, 2H), 2.16-2.32 (m, 5H), 1.93-2.13 (m, 2H);

Melting point: 126-128 ° C.

Example 37-17

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

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

¹ H-NMR (DMSO-d ₆ ): δ 7.09-7.30 (m, 3H), 6.65-6.75 (m, 2H), 3.94 (t, J = 6.13 Hz , 2H), 3.38 (s, 2H), 3.09-3.22 (m, 5H), 2.78 (t, J = 7.50 Hz, 2H), 2.53-2.62 ( m, 2H), 2.10-2.19 (m, 2H), 1.92-2.04 (m, 5H);

Melting point: 151-155 ° C.

Example 37-18

1 - ({1-methyl-6- [3- (3,4,5-trifluorophenyl) propoxy] -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 7.31 (d, J = 8.42 Hz, 1H), 6.93-7.03 (dd, J = 9.00, 7.00 Hz, 2H) 6.76 (dd, J = 8.42, 2.74 Hz, 1H), 6.71 (d, J = 2.74 Hz, 1H), 4.09-4.26 (m, 4H), 4.07 (s, 2H), 3.97 (t, J = 6.04 Hz, 2H), 3.33-3.51 (m, 1H), 2.75-2.84 (m, 2H) 2.72 (t, J = 8.41 Hz, 2H); 2.17-2.29 (m, 5H); 1.98-2.13 (m, 2H);

Melting point: 140-144 ° C.

Example 37-19

1 - ({6- [3- (4-fluoro-2,6-dimethylphenyl) propoxy] -1-methyl-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 7.32 (d, J = 8.60 Hz, 1H), 6.78 (dd, J = 8.60, 2.84 Hz, 1H), 6.74 (d, J = 2.84 Hz, 1H), 6.71 (d, J = 9.15 Hz, 2H), 4.11-4.25 (m, 4H), 4.07 (s, 2H) 4.02 (t, J = 5.85 Hz, 2H), 3.35-3.49 (m, 1H), 2.77-2.86 (m, 2H), 2.69-2.76 (m, 2H), 2.31 (s, 6H), 2.17-2.28 (m, 5H), 1.81-1.98 (m, 2H);

Melting point: 144-146 ° C.

Example 37-20

1 - ({6- [3- (3-chloro-4-fluorophenyl) 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 7.27-7.34 (m, 2H), 7.05-7.20 (m, 2H), 6.75 (dd, J = 8.51, 2 , 65 Hz, 1H), 6.70 (d, J = 2.65 Hz, 1H), 4.11-4.27 (m, 4H), 4.08 (s, 2H), 3.96 (t , J = 6.13 Hz, 2H), 3.34-3.48 (m, 1H), 2.67-2.83 (m, 4H), 2.20-2.29 (m, 5H), 1.98-2.10 (m, 2H);

Melting point: 118-119 ° C.

Example 37-21

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

TLC: Rf 0.26 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.30-7.37 (m, 2H), 7.10 (dd, J = 10.43, 2.01 Hz, 1H), 7.02 (dd, J = 7.96, 2.01 Hz, 1H), 6.75 (dd, J = 8.60, 2.65 Hz, 1H), 6.71 (d, J = 2.65 Hz, 1H), 4.10-4.26 (m, 4H), 4.07 (s, 2H), 3.97 (t, J = 6.22 Hz, 2H), 3.36-3.50 (m, 1H) 2.77-2.86 (m, 2H), 2.66-2.76 (m, 2H), 2.16-2.30 (m, 5H), 1.99-2.12 (m, 2H);

Melting point: 126-128 ° C.

Example 37-22

1 - ({6- [3- (4-chloro-2-fluorophenyl) propoxy] -1-methyl-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 7.31 (d, J = 8.42 Hz, 1H), 7.24 (t, J = 8.42 Hz, 1H), 7.06-7.16 (m, 2H), 6.75 (dd, J = 8.42, 2.47 Hz, 1H), 6.70 (d, J = 2.47 Hz, 1H), 4.10-4.27 ( m, 4H), 4.07 (s, 2H), 3.97 (t, J = 6.13 Hz, 2H), 3.35-3.50 (m, 1H), 2.78-2.87 (m, 2H), 2.67-2.76 (m, 2H), 2.15-2.32 (m, 5H), 1.96-2.12 (m, 2H);

Melting point: 160-162 ° C.

Example 37-23

1 - [(6- {3- [4-chloro-3- (trifluoromethyl) phenyl] propoxy} -1-methyl-3,4-dihydronaphthalen-2-yl) methyl] azetidine-3-carboxylic acid hydrochloride:

TLC: Rf 0.20 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.60 (d, J = 1.10 Hz, 1H), 7.41-7.53 (m, 2H), 7.32 (d, J = 8, 60 Hz, 1H), 6.75 (dd, J = 8.60, 2.38 Hz, 1H), 6.70 (d, J = 2.38 Hz, 1H), 4.20-4.45 ( m, 4H), 4.16 (s, 2H), 3.98 (t, J = 6.04 Hz, 2H), 3.59-3.78 (m, 1H), 2.88 (t, J = 7.80 Hz, 2H), 2.67-2.77 (m, 2H), 2.18-2.30 (m, 5H), 2.00-2.14 (m, 2H);

Melting point: 120-124 ° C.

Example 37-24

1 - ({6- [3- (2-chloro-4-fluorophenyl) propoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid hydrochloride:

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

¹ H-NMR (CD ₃ OD): δ 7.26-7.36 (m, 2H), 7.17 (dd, J = 8.78, 2.74 Hz, 1H), 6.98 (td, J = 8.42, 2.74 Hz, 1H), 6.77 (dd, J = 8.40, 2.38 Hz, 1H), 6.72 (d, J = 2.38 Hz, 1H), 4.21-4.41 (m, 4H), 4.16 (s, 2H), 3.99 (t, J = 6.13 Hz, 2H), 3.62-3.77 (m, 1H) , 2.91 (t, J = 7.50 Hz, 2H), 2.73 (t, J = 6.30 Hz, 2H), 2.19-2.29 (m, 5H), 2.00- 2.12 (m, 2H);

Melting point: 125-127 ° C.

Example 37-25

1 - ({6- [3- (2-chloro-3,6-difluorophenyl) propoxy] -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 (DMSO-d ₆ ): δ 7.35 (td, J = 9.01, 4.94 Hz, 1H), 7.26 (td, J = 9.01, 4.67 Hz, 1H ), 7.14 (d, J = 8.23 Hz, 1H), 6.65-6.72 (m, 2H), 3.97 (t, J = 5.95 Hz, 2H), 3.38 (s, 2H), 3.13-3.20 (m, 5H), 2.86-2.97 (m, 2H), 2.52-2.62 (m, 2H), 2.09-2 20 (m, 2H); 1.89-2.00 (m, 5H);

Melting point: 156-159 ° C.

Example 37-26

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

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

¹ H-NMR (CD ₃ OD): δ 7.30 (d, J = 8.50 Hz, 1H), 6.80 (dd, J = 9.00, 8.00 Hz, 2H), 6.73 (dd, J = 8.50, 2.50 Hz, 1H), 6.68 (d, J = 2.50 Hz, 1H), 4.11-4.25 (m, 4H), 4.07 ( s, 2H), 3.98 (t, J = 6.00 Hz, 2H), 3.35-3.48 (m, 1H), 2.84 (t, J = 7.50 Hz, 2H), 2.68-2.76 (m, 2H); 2.18-2.28 (m, 5H); 1.97-2.08 (m, 2H);

Melting point: 159-162 ° C.

Example 37-27

1 - {[6- (2,2-dimethyl-3-phenylpropoxy) -1-methyl-3,4-dihydronaphthalen-2-yl] methyl} azetidine-3-carboxylic acid hydrochloride:

TLC: Rf 0.19 (n-butanol: acetic acid: water = 20: 4: 1)

¹ H-NMR (CD ₃ OD): δ 7.34 (d, J = 8.23 Hz, 1H), 7.03-7.26 (m, 5H), 6.70-6.85 (m, 2H), 4.20-4.50 (m, 4H), 4.17 (s, 2H), 3.60-3.81 (m, 1H), 3.54 (s, 2H), 2.67 -2.81 (m, 4H), 2.20-2.32 (m, 5H), 1.01 (s, 6H);

Melting point: 124-127 ° C.

Example 37-28

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

TLC: Rf 0.37 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.50 Hz, 1H), 7.09-7.15 (m, 1H), 7.01-7.08 (m, 3H), 6.79 (dd, J = 8.50, 2.50 Hz, 1H), 6.74 (d, J = 2.50 Hz, 1H), 4.03-4.25 (m, 8H ), 3.34-3.49 (m, 1H), 3.01-3.10 (m, 1H), 2.69-2.80 (m, 4H), 2.09-2.29 (m 6H); 1.70-2.03 (m, 5H);

Melting point: 99-107 ° C.

Example 37-29

1 - ({6- [2- (2,3-dihydro-1H-inden-1-yl) ethoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid

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

¹ H-NMR (CD ₃ OD): δ 7.33 (d, J = 8.50 Hz, 1H), 7.16-7.22 (m, 2H), 7.08-7.13 (m, 2H), 6.79 (dd, J = 8.50, 2.50 Hz, 1H), 6.75 (d, J = 2.50 Hz, 1H), 4.14-4.25 (m, 4H ), 4.07-4.14 (m, 4H), 3.35-3.48 (m, 1H), 3.28-3.32 (m, 1H), 2.69-3.01 (m , 4H); 2.19-2.39 (m, 7H); 1.71-1.91 (m, 2H);

Melting point: 163-167 ° C.

Example 37-30

1 - ({6- [2- (5-fluoro-2,3-dihydro-1H-inden-1-yl) ethoxy] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidin-3 -carboxylic acid:

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), 7.16 (dd, J = 8.50, 5.00 Hz, 1H), 6.91 (dd, J = 9.00, 2.50 Hz, 1H), 6.76-6.87 (m, 2H), 6.74 (d, J = 2.50 Hz, 1H), 4.05- 4.24 (m, 8H), 3.34-3.47 (m, 1H), 3.28-3.32 (m, 1H), 2.69-3.02 (m, 4H), 2, 19-2.43 (m, 7H); 1.76-1.92 (m, 2H);

Melting point: 149-153 ° C.

Example 37-31

1 - ({6- [2- (4-isobutylphenyl) ethyl] -1-methyl-3,4-dihydronaphthalen-2-yl} methyl) azetidine-3-carboxylic acid hydrochloride:

TLC: Rf 0.19 (n-butanol: acetic acid: water = 20: 4: 1);

¹ H-NMR (CD ₃ OD): δ 7.29 (d, J = 7.87 Hz, 1H), 6.99-7.10 (m, 5H), 6.94 (s, 1H), 4 24-4.46 (m, 4H), 4.17 (s, 2H), 3.53-3.86 (m, 1H), 2.84-2.86 (m, 4H), 2.63 -2.75 (m, 2H), 2.41 (d, J = 7.14 Hz, 2H), 2.15-2.30 (m, 5H), 1.68-1.90 (m, 1H ), 0.87 (d, J = 6.77 Hz, 6H);

Melting point: 154-157 ° C.

Example 37-32

1 - {[9-methyl-3- (4-phenylbutoxy) -6,7-dihydro-5H-benzo [7] annulin-8-yl] methyl} azetidine-3-carboxylic acid:

TLC: Rf 0.42 (chloroform: methanol: aqueous ammonia = 80: 20: 4);

MS (m / z): 420 (M + H) ⁺ , 319, 187.

Reference Example 01

6- (benzyloxy) -3,4-dihydronaphthalene-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 followed by stirring at 40 ° C for 3.5 hours. Insoluble matters were filtered off and the mixture was concentrated, after which the residue was washed with a solvent mixture of tert-butyl methyl ether-hexane (1: 4), whereby the title compound (34.5 g) having the following physical characteristics was obtained.

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

Reference Example 02

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

To a solution of the compound obtained in Reference Example 01 (34.5 g) in tetrahydrofuran (300 ml), methylmagnesium bromide (3 M solution in diethyl ether, 55 ml) was added at 0 ° C, followed by stirring at room temperature for 1 hour. Then the reaction mixture was cooled to 0 ° C and poured into an ice-saturated aqueous solution of ammonium chloride. After adding 2 n. hydrochloric acid solution, the mixture was stirred at room temperature for 3 hours. The mixture was then extracted with ethyl acetate, and the organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound (24.8 g) having the following physical characteristics.

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

Reference Example 03

6- (benzyloxy) -1-methyl-3,4-dihydronaphthalene-2-carboaldehyde

To phosphorus oxychloride (26.7 g), N, N-dimethylformamide (60 ml) was added dropwise at 0 ° C., followed by stirring for 20 minutes. Then, a solution of the compound (24.8 g) obtained in Reference Example 02 in dichloromethane (60 ml) was slowly added dropwise to the mixture, followed by stirring at room temperature for 90 minutes. The reaction mixture was cooled to 0 ° C, poured onto ice and then allowed to stand for some time. The mixture was then extracted with a solvent mixture of hexane-ethyl acetate (1: 2). The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, 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 characteristics.

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

Reference Example 04

6-hydroxy-1-methyl-3,4-dihydronaphthalene-2-carboaldehyde

Trifluoroacetic acid (140 ml) was added to thioanisole (35 ml) at 0 ° C. Then, the compound obtained in Reference Example 03 (9.17 g) was added portionwise to the mixture, followed by stirring at room temperature for 4 hours. The reaction mixture was poured onto ice and then 5N was added. aqueous solution of sodium hydroxide. After washing with tert-butyl methyl ether, 1N was added to the aqueous layer. hydrochloric acid solution, followed by extraction 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 obtain the title compound (6.03 g) having the following physical characteristics.

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

Reference Example 05

6- [3- (4-fluorophenyl) propoxy] -1-methyl-3,4-dihydronaphthalene-2-carboaldehyde

A procedure similar to that of Reference Example 01 was carried out except that the compound obtained in Reference Example 04 was used as a substituent for 6-hydroxy-3,4-dihydronaphthalen-1 (2H) -one and 1-bromo-3- (4-fluorophenyl) propane as a substituent for benzyl bromide, to give the title compound having the following physical characteristics.

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).

Reference Example 06

5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate

To a solution of 6-hydroxy-3,4-dihydronaphthalen-1 (2H) -one (2.0 g) in dichloromethane (20 ml) was added triethylamine (5.16 ml) and trifluoromethanesulfonic anhydride at 2.78 ° C (2.49) ml), followed by stirring at 0 ° C for 1 hour. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was stirred and extracted with diethyl ether. The organic layer was washed successively with 1 N. a solution of hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the title compound (2.34 g) having the following physical characteristics.

TLC: Rf 0.34 (hexane: ethyl acetate = 85:15).

Reference Example 07

6 - [(4-isobutylphenyl) ethynyl] -3,4-dihydronaphthalene-1 (2H) -one

To copper iodide (48 mg) was added a solution of the compound obtained in Reference Example 06 (353 mg) in N, N-dimethylformamide (3 ml), triethylamine (279 μl) and a solution of 1-ethynyl-4-isobutylbenzene (158 mg) in N, N-dimethylformamide (5 ml), followed by stirring at room temperature for 5 minutes. Then tetrakis (triphenylphosphine) palladium (0) (58 mg) was added to the mixture, followed by stirring for 19 hours. After adding 1 N. hydrochloric acid solution, the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 N. a solution of hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to obtain the title compound (209 mg) having the following physical characteristics.

TLC: Rf 0.35 (hexane: ethyl acetate = 9: 1).

Reference Example 08

6 - [(4-isobutylphenyl) ethynyl] -1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol

To a solution of the compound obtained in Reference Example 07 (200 mg) in tetrahydrofuran (5 ml) was added methylmagnesium bromide (3 M solution in diethyl ether, 0.33 ml) at 0 ° C., followed by stirring for 30 minutes. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 87: 13) to obtain the title compound (154 mg) having the following physical characteristics.

TLC: Rf 0.36 (hexane: ethyl acetate = 4: 1).

Reference Example 09

6 - [(4-isobutylphenyl) ethyl] -1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol:

To a solution of the compound obtained in Reference Example 08 (150 mg) in ethanol (4 ml) was added 10% palladium on carbon (15 mg), followed by stirring in a hydrogen atmosphere for 15 minutes. After the catalyst was filtered through celite, the filtrate was concentrated to obtain the title compound (153 mg) having the following physical characteristics.

TLC: Rf 0.40 (hexane: ethyl acetate = 4: 1).

Reference Example 10

7- [2- (4-isobutylphenyl) ethyl] -4-methyl-1,2-dihydronaphthalene

To a solution of the compound obtained in Reference Example 09 (150 mg) in dichloromethane (3 ml) was added p-toluenesulfonic acid monohydrate (1 mg), followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane) to obtain the title compound (129 mg) having the following physical characteristics.

TLC: Rf 0.35 (hexane).

Reference Example 11

6- [2- (4-isobutylphenyl) ethyl] -1-methyl-3,4-dihydronaphthalene-2-carboaldehyde

A procedure similar to that of Reference Example 03 was carried out except that the compound obtained in Reference Example 10 was used as a substituent for the compound obtained in Reference Example 02 to obtain the title compound having the following physical characteristics.

TLC: Rf 0.66 (hexane: ethyl acetate = 3: 1);

¹ H-NMR (CDCl ₃ ): δ 10.35 (s, 1H), 7.46 (d, J = 7.87 Hz, 1H), 7.00-7.14 (m, 6H), 2, 90 (s, 4H), 2.71 (t, J = 7.32 Hz, 2H), 2.42-2.56 (m, 7H), 1.76-1.93 (m, 1H), 0 90 (d, J = 6.59 Hz, 6H).

Reference Example 12

3- (methoxymethoxy) benzaldehyde

To a solution of 3-hydroxybenzaldehyde (5.0 g) in acetone (120 ml) was added potassium carbonate (8.5 g) and methoxymethyl chloride (4.0 g), followed by stirring at 50 ° C. for 6 hours. The reaction mixture was concentrated and water was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound (6.0 g) having the following physical characteristics.

TLC: Rf 0.56 (hexane: ethyl acetate = 3: 1).

Reference Example 13

ethyl 5- (3-hydroxyphenyl) pentanoate

To a solution of vinyl magnesium bromide (a solution of 1 M in tetrahydrofuran, 24.4 ml) in tetrahydrofuran (50 ml) was added the compound obtained in Reference Example 12 (2.7 g) at -20 ° C, followed by stirring for 1 hour. After adding water, the reaction mixture was concentrated. Then, a saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried and concentrated. To a solution of the obtained residue in toluene (50 ml) was added triethyl orthoacetate (14.9 ml) and propionic acid (122 μl), followed by stirring at 130 ° C for 2 hours. The reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1). To a solution of the obtained compound in methanol (60 ml) was added 10% palladium on carbon (285 mg), followed by stirring in a hydrogen atmosphere for 2 hours. After the catalyst was filtered through celite, the filtrate was concentrated. Concentrated hydrochloric acid (4 ml) was added to a solution of the obtained compound in ethanol (40 ml), followed by stirring at 70 ° C for 1 hour. The reaction mixture was concentrated, and thus, the title compound (2.37 g) having the following physical characteristics was obtained.

TLC: Rf 0.37 (hexane: ethyl acetate = 3: 1).

Reference Example 14

5- [3- (4-phenylbutoxy) phenyl] pentanoic acid

A procedure similar to that of Reference Example 01 was carried out except that the compound obtained in Reference Example 13 (1.13 g) was used as a substituent for 6-hydroxy-3,4-dihydronaphthalen-1 (2H) -one, and 1-bromo-4-phenylbutane (1.63 g) was used as a substituent for benzyl bromide. To a solution of the obtained compound in a solvent mixture, methanol (2 ml) -tetrahydrofuran (10 ml) was added 5N sodium hydroxide solution (10 ml), followed by stirring for 3 days. After adding 5 n. hydrochloric acid solution, the mixture was extracted with dichloromethane. The organic layer was dried and concentrated to obtain the title compound (1.45 g) having the following physical characteristics.

TLC: Rf 0.56 (hexane: ethyl acetate = 1: 1).

Reference Example 15

2- (4-phenylbutoxy) -6,7,8,9-tetrahydro-5H-benzo [7] annullen-5-one

To a solution of the compound obtained in Reference Example 14 (100 mg) in dichloromethane (1 ml) was added a catalytic amount of N, N-dimethylformamide and oxalyl chloride (40 μl), followed by stirring for 30 minutes. The reaction mixture was concentrated. To a solution of the obtained residue in toluene (2 ml) was added tin chloride (43 μl), followed by stirring at room temperature for 1 hour. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1 to 6: 1) to obtain the title compound (88 mg) having the following physical characteristics.

TLC: Rf 0.34 (hexane: ethyl acetate = 6: 1).

Reference Example 16

9-methyl-3- (4-phenylbutoxy) -6,7-dihydro-5H-benzo [7] annullen-8-carboaldehyde

The procedures of Reference Example 2 and Reference Example 3 were performed in that order, but the compound obtained in Reference Example 15 was used as a substitute for the compound obtained in Reference Example 1, whereby the title compound having the following physical characteristics was obtained.

TLC: Rf 0.47 (hexane: ethyl acetate = 6: 1).

Biological Examples

The pharmacological effect of the compounds of the present invention was confirmed using the following biological examples. All operations were carried out by traditional methods by obtaining cells with high gene expression based on fundamental genetic engineering methods. Also, the measurement methods used in the present invention for evaluating the compounds of the present invention were carried out, for example, by improving measurement methods, measurement accuracy and / or measurement sensitivity. Details are described below. Obtaining a histological preparation was also carried out by traditional methods based on fundamental methods of genetic engineering with appropriate modifications.

Biological example 1

Measurement of the activity of a compound of the present invention in inhibiting the binding of [ ³ H] -S1P to EDG-6

Way

First, cells in which overexpression of EDG-6 occurred were plated at a density of 2 × 10 ⁵ cells / well in a 12-well plate. After 12 hours, the cells were washed twice with 0.5 ml of assay buffer. In a saturation binding assay to determine the K _D value and the B _max value, cells were incubated in 0.4 ml assay buffer containing D-erythro-sphingosin-3- [ ³ H] -1-phosphate at various concentrations and 2 μl 0. 01 n. NaOH, for 60 minutes on ice. Then the wells were washed twice with 0.8 ml of assay buffer and whole cells were destroyed by adding 0.1 ml of 0.5% TCA (trichloroacetic acid), 0.4 ml of lysis buffer (2% Na ₂ CO ₃ , 4% NaOH, 0 , 1% SDS) and 0.1 ml of 1 N. hydrochloric acid solution. Then 0.5 ml of the lysed solution was collected in a glass vial (Packard) using a pipette. After adding 7 ml of ACSII (Amersham), the mixture was thoroughly mixed and the radioactivity was measured using a liquid scintillation counter (TRI-CARB 2900TR Packard), thus determining the K _D value. Non-specific binding was determined by adding unlabeled S1P at a final concentration of 25 μM as a substitute for 0.01 n. NaOH. In a competitive binding assay to determine K _i based on the determined as described above, K _D cells were incubated in 0.4 ml assay buffer containing 5 nm D-erythro-sphingosine-3- [ ³ H] -1-phosphate and 0-1 μM of the test compound, for 60 minutes on ice. The procedures following the washing were carried out as in a saturation binding assay, and the radioactivity was measured as described above.

results

The compounds of the present invention showed inhibitory activity of 50% or higher with respect to the binding of S1P to EDG-6 at a concentration of 100 μmol / L. For example, the K _i value of 3- [3- (4- (5-phenylpentyloxy) phenyl) propylamino] propanoic acid was 0.352 μmol / L.

Biological example 2

Measurement of the activity of a compound of the present invention in inhibiting the binding of [ ³ H] -PhS1P to EDG-6

Way

A similar experiment was performed using a fraction of the cell membranes of CHO cells in which overexpression of EDG-6 occurred. Using 1 mg protein / ml membrane fraction, the reaction was carried out in a 96-well plate. To each well was added 80 μl of a carrier solution (DMSO) diluted with 2x binding buffer (100 mmol / L Tris pH 7.5, 200 mm NaCl, 30 mm NaF, 1% BSA), or a ligand solution with twice the concentration and 40 μl 10 nmol / L [ ³ H] -PhS1P (5,5,6,6, -tetralitium phytosphingosine 1 phosphate. This compound was prepared as follows. 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 in accordance with the method described in (Tetrahedron Lett ., 38 (34), 6027-6030 (1997)), were reacted with benzyl bromide in those trahydrofuran in the presence of potassium hexamethyldisilylamide to protect the hydroxy group, then it was treated in hydrogen chloride / methanol to remove the acetonide group. The resulting compound was reacted with N, N-diethyl-1,5-dihydro-2,4,3-benzodioxaphosphepin-3-amine in dichloromethane in the presence of tetrazole and then oxidized with m-chloroperbenzoic acid, then it was reacted in the presence of an ASCA-2 catalyst (manufactured by NE Chemcat, a catalyst based on 4.5% palladium-0.5% platinum on an activated carbon support See. Fine Chemical, October 1, 2002, pages 5 to 14) in methanol in an atmosphere of tritium. The resulting compound was treated with a solution of 4 N. hydrogen chloride / 1,4-dioxane in dichloromethane to give the desired compound). Then, 40 μl of the membrane fraction solution was added and reacted at room temperature for 60 minutes. Upon completion of the reaction, the reaction mixture was suction filtered using a Unifilter for a 96-well plate, washed three times with 50 ml of washing buffer (50 mmol / L Tris pH 7.5, 0.5% BSA) and dried at 60 ° C for 45 minutes . Then, 50 μl / well of Micro Scint 20 was added and the plate was closed using Top Seal-P. Then, radioactivity was measured using a Top Count counter (Perkin Elmer).

results

The compounds of the present invention showed inhibitory activity of 50% or higher with respect to the binding of S1P to EDG-6 at a concentration of 100 μmol / L.

Biological example 3

Evaluation of the agonistic activity of the compounds of the present invention against EDG by monitoring changes in the intracellular concentration of calcium ions [Ca ²⁺ ] _i

Way

Chinese Hamster Ovary (CHO) cells that overexpressed the human gene EDG-1, EDG-3, EDG-5, or EDG-8 were cultured in Ham F12 medium (manufactured by GIBCO BRL) containing 10% FBS (fetal bovine serum) penicillin / streptomycin and blasticidin (5 μg / ml). The cultured cells were incubated in a 5 μM Fura2-AM solution (F12 Ham medium containing 10% FBS, 20 mM HEPES buffer (pH 7.4) and 2.5 mM probenecid) at 37 ° C for 60 minutes. After a single wash with a Hanks solution containing 20 mM HEPES buffer (pH 7.4) and 2.5 mM probenecid, the plate was kept in the same solution until analysis. The plate was then mounted on a fluorescent drug screening system (FDSS 6000; Hamamatsu Photonics) and the intracellular concentration of calcium ions was measured without stimulation for 30 seconds. The test compound was added (final concentration: 1 nm - 10 μM, solution in dimethyl sulfoxide (DMSO)) and 5 minutes after that S1P was added (final concentration: 100 nm). Then, the increase in the intracellular concentration of calcium ions was measured before and after the addition of S1P at 3 second intervals (excitation wavelength: 340 nm and 380 nm, fluorescence wavelength: 500 nm).

The agonistic activity of the compounds of the present invention for each EDG was determined using the maximum value obtained by S1P stimulation in a well containing DMSO as a substitute for the test compound as a control value (A), comparing the value before adding the test compound with an increased value ( B) by the relative amount of fluorescence after addition and calculating the percentage (%) increase in the intracellular concentration of calcium ions [Ca ²⁺ ] _i as: percentage increase (%) = (B / A) × 100. The increase indices for the test compound at individual concentrations were determined and the EC _{50 was} calculated.

results

For example, the EC ₅₀ value for 3- [3- (4- (5-phenylpentyloxy) phenyl) propylamino] propanoic acid for EDG-1 was 0.255 μmol / L.

Biological example 4

Blood Lymphocyte Count (1)

Way

Test compounds were orally administered to male Sprague-Dawley rats (Charles Riber Laboratories, Japan, Ltd., 6 weeks of age at time of use). 4-72 hours after administration, blood was taken from the abdominal aorta under ether anesthesia. Using a portion of the taken blood, the number of hemocytes was determined and the number of lymphocytes, neutrophils and platelets was counted. Each group included 4 or 5 animals.

results

It was shown that the compounds of the present invention reduced the number of lymphocytes in the blood, thereby demonstrating the strong effect of homing lymphocytes. It was also found that the effects of lymphopenia of the compounds of the present invention persisted even 72 hours after administration. For example, 3- [3- (4- (5-phenylpentyloxy) phenyl) propylamino] propanoic acid reduced the concentration of lymphocytes in the blood in a concentration-dependent manner at 10, 30 and 100 mg / kg 4 hours after administration.

It was found that the compounds of the present invention have agonistic activity against EDG-1 and the ability to bind to EDG-6 and, moreover, the effect of lymphopenia over a long period of time.

Biological example 5

Blood Lymphocyte Count (2)

Way

Test compounds were orally administered to male BALB / c mice. 72 hours after administration, blood was taken from the abdominal aorta under ether anesthesia. The total number of leukocytes, the number of lymphocytes, the number of neutrophils, the number of red blood cells, the number of platelets in the blood and the hematocrit were determined using a multi-purpose automatic counter of blood cells (SF-3000, Sysmex). In the calculation, the average number of blood cells in the carrier administration group (carrier group) was taken as 100%, and the percentage of the carrier of the average number of blood cells for each administration group of the test compound was calculated. Based on the doses of the test compound and the percentage of the carrier, a calibration curve was constructed and the dose of the compound necessary to reduce the number of blood cells by 50% was calculated as ED ₅₀ .

Biological example 6

Blood Lymphocyte Count (3)

Way

The test compounds of the present invention or vehicle were orally administered daily to male Sprague-Dawley rats (Charles Riber Laboratories, Japan, Ltd., 6 weeks of age at time of use). Then, the administration of the test compounds or vehicle was stopped and the rate of recovery of the number of lymphocytes in the blood was monitored at time intervals. For example, rats were divided into 10 groups and the test compound was administered over 5 days to 5 groups, while the other 5 groups were administered over 10 days. After administration for 10 days, the number of lymphocytes in the blood was calculated using rats from one of the vehicle administration groups and one of the test compound administration groups on days 1, 2, 3, 4, and 5 after the administration was stopped. Whole blood was collected from the abdominal aorta under ether anesthesia. Using a portion of the taken blood, the number of hematocytes was counted and the number of lymphocytes, the number of neutrophils and the number of platelets were determined using a multipurpose automatic counter of blood cells (SF-3000, Sysmex). Each group included 4 or 5 animals.

Biological Example 7

Investigation of the effect of the compound of the present invention on promoting homing of lymphocytes into the lymphatic organ (1: histological staining of the lymph node)

Way

Lymph nodes were taken from Sprague-Dawley rats (Charles Riber Laboratories, Japan, age 6 weeks at the time of use), which were used in Biological Example 4, which were administered test compounds or vehicle before testing. In accordance with a method traditionally used in the art, tissues were fixed in formalin and tissue pieces were obtained. Using a double method of hematoxylin and eosin staining, the state of lymphatic tissues was observed, i.e. parts of the cortex, medulla, marginal sinus and lymphatic minus, etc.

Biological example 8

A study of the effect of a compound of the present invention on promoting homing of lymphocytes to a lymphatic organ (1: counting the number of lymphocytes in a lymphatic organ)

Way

Male BALB / c mice were orally administered test compounds. Twenty hours after this, the mice were killed by bleeding under ether anesthesia. Immediately afterwards, various lymphatic organs were removed, such as Peyer's plaques and thymus. Then, lymphocytes were obtained from them, which were subjected to further analysis. Namely, the cells were labeled using anti-CD3 antibodies, anti-CD4 antibodies, anti-CD8, anti-B220 antibodies, etc. and various positive cells were measured using a flow cytometry counter.

Biological example 9

Chemotaxis analysis

Way

The spleen or lymph node was removed from mice and lymphocytes were obtained from them in accordance with a method that is commonly used in the art (J. Immunol., 171 , 3500-3507 (2003)). The lymphocytes thus obtained (for example, 1 × 10 ⁷ cells / ml) were placed in the upper layer of the chemotactic chamber, while S1P or various chemokines, such as CCL-5 and CCL-21, were placed in the lower layer. The test compounds (either separately or simultaneously) were added to the lower layer or to the upper layer and, thus, the effect of inhibiting or promoting lymphocyte migration was observed.

Biological example 10

Phenotypic blood cell analysis

Way

Whole blood was taken from rats that were administered the test compounds or only the carrier. Cells were then labeled using anti-CD3 antibodies, anti-CD45RA antibodies, anti-CD4 antibodies, anti-CD8a antibodies, anti-CD161a antibodies and the like. Thus, the effect of test compounds on the phenotype of blood cells was observed. For example, cells were suspended in a Spitz tube and 7-AAD dye was added to determine cell viability, FITC-labeled anti-CD3RA antibody, FITC-labeled anti-CD45RA antibody, FITC-labeled anti-CD8b antibody, PE-labeled anti-CD4 antibody, and FITC-labeled anti-CD161a antibody and mixed. The mixture was then allowed to stand at room temperature in a dark place for 15 minutes. IO Test 3 Lysing Solution hemolytic reagent was then added, followed by stirring, and then the mixture was allowed to stand at room temperature in a dark place for 10 minutes. The mixture was then centrifuged at 1300 rpm (320 g) for 5 minutes. The precipitated material was suspended in 1 ml of DPBS and 10,000 or more cells were measured using an EPICS XL flow cytometry counter (Beackman Coulter).

Biological example 11

Analysis of the internalization of the protein EDG-1

Way

Using CHO cells in which overexpression of EDG-1 occurred, internalization of the EDG-1 protein was observed as a result of stimulation with the test compound in accordance with the method reported in FASEB, 18 , 551-553 (2004).

Formulation Examples

Examples of the preparation of compositions were carried out in the present invention, as described below.

An example of obtaining a composition 1

3- [3- (4- (5-phenylpentyloxy) phenyl) propylamino] propanoic acid (100 g), calcium carboxymethyl cellulose (baking powder, 20.0 g), magnesium stearate (lubricant, 10.0 g) and microcrystalline cellulose ( 870 g) were mixed in the usual manner and compressed into tablets to obtain 10,000 tablets, each containing 10 mg of the active ingredient.

An example of obtaining a composition 2

3- [3- (4- (5-phenylpentyloxy) phenyl) propylamino] propanoic acid (200 g), mannitol (2 kg) and distilled water (50 L) were mixed in the usual way. Then the solution was filtered through a dust filter, after which 5 ml aliquots were loaded into ampoules, which were autoclaved, to obtain 10,000 ampoules, each of which contained 20 mg of the active ingredient.

Industrial applicability

The present invention is applicable for the preparation of medicaments as indicated below.

The compounds of the present invention represented by formula (I), their salts, their solvates or their prodrugs are compounds that are capable of binding to the S1P receptor, in particular EDG-6, and exhibit a long pharmacological effect. Therefore, they are useful as prophylactic and / or medicines for mammals, in particular for humans, during rejection during transplantation, rejection of a transplanted organ, graft versus host disease, autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, etc. .), allergic diseases (atopic dermatitis, asthma, etc.), inflammation, infection, ulcer, lymphoma, cancer, leukemia, a disease associated with lymphocyte infiltration into the tissue, etc.

In addition to the ability to bind to EDG-6, some compounds of the present invention have agonistic activity against EDG-1 and, therefore, exhibit immunosuppressive effect and long-term pharmacological action. Due to these characteristics, they are more useful as prophylactic and / or drugs for rejection during transplantation, graft versus host disease, autoimmune diseases, allergic diseases, etc.

Claims (12)

1. The compound represented by formula (I)

where the ring, A represents a C5-C12 monocyclic or bicyclic carbocyclic aryl group, which optionally is partially or fully saturated, benzofuran or benzothiophene; ring B is a dihydronaphthalene, indene, 6,7-dihydro-5H-benzo [7] annuline ring, which may be substituted with a C1-8 alkyl group, a halogen atom (s) or trifluoromethyl; X represents a divalent group containing from 1 to 8 atoms in its main chain, which represents from 1 to 4 combinations selected from the group consisting of (i) C1-8 alkylene, which may be substituted by C1-8 alkyl or phenyl, (ii) C2-8 alkenylene, which may be substituted with C1-8 alkyl, (iii) -O-, (iv) -S-, (v) C3-6-cycloalkylene, which may be substituted with C1-8 alkyl;
Y represents a divalent group containing from 1 to 10 atoms in its main chain, which represents from 1 to 4 combinations selected from
(i) C1-10 alkylene, which may be substituted by a halogen atom (s), C1-8-alkyl, which may be substituted by a halogen atom (s), or C1-8 alkoxy, which may be substituted by a halogen atom (s),
(ii) C2-10 alkenylene, which may be substituted by a halogen atom (s),
C1-8 alkyl, which may be substituted with a halogen atom (s), or
C1-8 alkoxy, which may be substituted by a halogen atom (s),
(iii) a nitrogen atom which may be substituted with C1-8-alkyl, which may be substituted by a halogen atom (s),
(vi) - (aziridine, which may be substituted with C1-8 alkyl) -, and
(vii) - (azetidine, which may be substituted with C1-8 alkyl);
n is 0 or 1,
wherein when n has a value of 0, m has a value of 1 and R ¹ represents a hydrogen atom or (i) a halogen atom,
(ii) C1-10 alkyl, which may be substituted by halogen atom (s), (iii) C1-10 alkoxy, which may be substituted by halogen atom (s), (iv) C3-6 cycloalkylene, which may be substituted by C1- 8 by alkyl, and (v) phenyl, which may be substituted by a halogen atom (s), and when
n is 1, m is 0 or an integer having a value of 1 to 3, and
R ¹ represents
(i) a halogen atom,
(ii) C1-10 alkyl, which may be substituted by a halogen atom (s),
(iii) C1-10 alkoxy, which may be substituted by a halogen atom (s),
(iv) C3-6 cycloalkylene, which may be substituted with C1-8 alkyl,
(v) phenyl, which may be substituted by a halogen atom (s), wherein when m is 2 or more,
R ¹ substituents are the same or different from each other, and where the compound represented by formula (1a) is excluded

where R ^1a represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl;
ring A ^a represents a C5-7 monocyclic carbocyclic group or a 5-7-membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom;
E ^a represents —CH ₂ -, —O—, —S— or —NR ^6a , where R ^6a represents a hydrogen atom or a C1-8 alkyl;
R ^2a represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl;
R ^3a represents a hydrogen atom or C1-8 alkyl;
R ^4a represents a hydrogen atom or C1-8 alkyl, or
R ^2a and R ^4a may be coupled together to form —CH ₂ CH ₂ - or —CH = CH—;
G ^a is —CONR ^7a -, —NR ^7a CO—, SO ₂ NR ^7a -, —NR ^7a SO ₂ -, —CH ₂ NR ^7a or —NR ^7a CH ₂ -, where R ^7a represents a hydrogen atom, C1 -8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1, and Cyc1 represents a C5-7 monocyclic carbocyclic group or a 5-7 membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom ;
Q ^a represents C1-4 alkylene or

where J ¹ , J ² , J ³ and J ⁴ each independently represent a carbon atom or a nitrogen atom, where the number of nitrogen atoms is 2 or less; R ^5a represents (1) C1-8 alkyl, (2) halogen atom, (3) nitro, (4) cyano, (5) trifluoromethyl, (6) trifluoromethoxy, (7) phenyl, (8) tetrazolyl, (9 ) -OR ^9a , (10) -SR ^10a , (11) -COOR ^11a , (12) -NR ^12a R ^13a , (13) -CONR ^14a R ^15a , (14) -SO ₂ NR ^16a R ^17a , (15 ) -NR ^18a COR ^19a , (16) -NR ^20a SO ₂ R ^21a , (17) -SO ₂ R ^22a or (18) -OP (O) (OR ^23a ) ₂ , where R ^9a -R ^18a , R ^20a and R ^23a each independently represents a hydrogen atom, C1-8 alkyl, Cuc2 or C1-8 alkyl substituted with Cuc2, or R ^12a and R ^13a , R ^14a and R ^15a or R ^16a and R ^17a , taken together with the atom the nitrogen to which they are attached form a 5-7 membered monocyclic heterocyclic group containing one or two nitrogen atoms One oxygen atom and / or one sulfur atom, wherein the heterocyclic group may be substituted with C1-8 alkyl, hydroxy or amino; R ^19a and R ^21a each independently represent C1-8 alkyl, Cus2 or C1-8 alkyl substituted with Cus2; R ^22a represents hydroxy, C1-8 alkyl, Cus2 or C1-8 alkyl substituted with Cus2; and Cus2 represents a C5-7 monocyclic carbocyclic group or a 5-7 membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and / or one sulfur atom;
p represents 0 or an integer having a value from 1 to 5;
q is an integer of 4 to 6;
r represents 0 or an integer having a value from 1 to 4;
s is 0 or an integer having a value from 1 to 4; and

represents a single bond or a double bond;
its non-toxic water-soluble salt or its methyl or ethyl ester. 2. The compound according to claim 1, where ring A represents a benzene, indane, indene or naphthalene ring. 3. The compound according to claim 1, where X is —CH ₂ -, - (CH ₂ ) ₂ -, - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ -, - (CH ₂ ) ₅ -. - (CH ₂ ) _b -, - (CH ₂ ) ₇ -, - (CH ₂ ) ₈ -, -CH ₂ -O-, - (CH ₂ ) ₂ -O-, - (CH ₂ ) ₃ -O- , - (CH ₂ ) ₄ -O-, - (CH ₂ ) ₅ -O-, -CH = CH-CH ₂ -O- or -cyclopropylene-CH ₂ -O-, each of which may be substituted with C1-8 alkyl or phenyl, where the right side of each group is bonded to ring B. 4. The compound according to claim 1, where Y represents - (CH ₂ ) ₃ -NHCH ₂ -, - (CH ₂ ) ₃ -NCH ₃ -CH ₂ -, - (CH ₂ ) ₃ -NH- (CH ₂ ) ₂ -, - (CH ₂ ) ₂ -NH- (CH ₂ ) ₂ -, -CR ^Y1 = CH-CH ₂ -NH- (CH ₂ ) ₄ -, -CR ^Y1 = CH-CH ₂ -NH- (CH ₂ ) ₅ -, -CR ^Y1 = CH-CH ₂ -NH- (CH ₂ ) ₂ -, -CH = CR ^Y1 -CH ₂ -NH- (CH ₂ ) ₂ -, -CR ^Y1 = CH-CH ₂ - NH-CH ₂ -, -CH ₂ - (azetidine) -, - (CH ₂ ) ₂ - (azetidine) -, - (CH ₂ ) ₃ - (azetidine) -, -CR ^Yl = CH-CH ₂ - (azetidine ) -, -CH = CR ^Yl -CH ₂ - (azetidine) -, each of which may be substituted, where R ^Y1 represents a hydrogen atom, a halogen atom or C1-4 alkyl, which may be substituted by 1-3 halogen atoms, and the right side of each group is connected to ring B. 5. The compound according to claim 1, where R ¹ represents fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, trifluoromethyl, methoxy or trifluoromethoxy. 6. The compound according to claim 1, which is a compound represented by formula (IS-3a)

where X ^S has the meanings indicated for X in claim 1, where X ^{S is} not - (CH ₂ ) q-E ^a ; R ^S0 , R ^S1 , R ^S2 , R ^S3 , R ^S4 , R ^S5 , R ^S6 , R ^S7 , R ^S8 , R ^S9 , R ^S10 and R ¹¹ each independently represent a hydrogen atom, a halogen atom, or C1- 4 alkyl, which may be substituted by 1-3 halogen atoms; E ^a , q and other symbols have the meanings indicated in claim 1, or
formula (IS-7a)

where each of R ^S0 , R ^S1 , R ^S2 , R ^S3 , R ^S4 , R ^S5 and R ^S6 has the above meaning; R ^S12 , R ^S13 , R ^S14 and R ^S15 each independently represent a hydrogen atom, a halogen atom, or C1-4 alkyl, which may be substituted by 1-3 halogen atoms; E ^a , q and other symbols have the meanings indicated in paragraph 1. 7. The compound according to claim 1, which is a
(11) 1 - {[1-methyl-6- (4-phenylbutoxy) -3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid,
(14) 1- (6- [3- (4-chlorophenyl) propoxy] -1-methyl-3,4-dihydro-2-naphthalenylmethyl) -3-azetidinecarboxylic acid or
(15) 1- (6- [3- (4-fluorophenyl) propoxy] -1-methyl-3,4-dihydro-2-naphthalenylmethyl) -3-azetidinecarboxylic acid. 8. A pharmaceutical composition capable of binding to the S1P receptor, comprising an effective amount of a compound of formula (I) according to claim 1, a non-toxic water-soluble salt thereof, or a methyl or ethyl ester thereof and a carrier. 9. The pharmaceutical composition of claim 8, which is a binding agent to EDG-6, which may have the ability to bind to EDG-1. 10. The pharmaceutical composition according to claim 9, where the binding agent to EDG-6, which may have the ability to bind to EDG-1, is an agonist of EDG-6, which may have agonistic activity against EDG-1. 11. An immunosuppressant and / or agent that causes lymphopenia, which includes a compound characterized by formula (I) according to claim 1, a non-toxic water-soluble salt thereof, or a methyl or ethyl ester thereof having binding to EDG-6, and which may have ability to bind to EDG-1. 12. The immunosuppressant and / or agent that causes lymphopenia according to claim 11, which is an agent for preventing and / or treating rejection during transplantation, an autoimmune disease and / or allergic disease.