RU2006110027A - CONNECTION ARE ABLE TO LINK TO SIP RECEPTOR AND ITS PHARMACEUTICAL APPLICATION - Google Patents

Claims (43)

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, may 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 an integer having a value of 1 to 7 and R ¹ is a substituent in which 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 according to claim 1, which is a compound represented by formula (I)

where all the characters have the meanings specified in paragraph 1, 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 is 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 represent 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 nitrogen atom to which they are attached form a 5-7 membered monocyclic heterocyclic group containing one or two nitrogen atoms, dynes 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, 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

represents a single bond or double bond. 3. The compound according to claim 2, represented by formula (IA)

where Y ¹ and Y ² each independently represent a bond or spacer group containing from 1 to 9 atoms in its main chain, in which the total number of atoms of the main chain 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. 4. The compound according to claim 2, represented by formula (IB)

where the B ¹ ring is 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 B ring and Y ¹ ; and other symbols have the meanings specified in paragraphs 1 and 3. 5. The compound according to claim 2, where ring A represents a benzene, indane, indene or naphthalene ring. 6. The compound according to claim 2, where ring B is a C5-12 monocyclic or bicyclic carbocyclic group, which may contain substituent (s). 7. The compound according to claim 6, where ring B is a benzene or naphthalene ring, which may contain a substituent (s). 8. The compound according to claim 2, where ring B is 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 can be partially or fully saturated. 9. The compound according to claim 2, where ring B is dihydronaphthalene, indene, 6,7-dihydro-5H-benzo [7] annuline, pyridine, indole, chromene, benzofuran, benzothiophene, benzoxazole, dihydrobenzoxenoin, tetrahydroisoquinidino azino, a ring that may contain a substituent (s). 10. The compound according to claim 4, where the nitrogen-containing heterocyclic group represented by the B ¹ ring is a pyrrole, tetrahydropyridine, dihydropyrrole or tetrahydroazepine ring. 11. The compound according to claim 2, where 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 comprising C1-8 alkylene, which may be substituted, C2-8 alkenylene which may be substituted, a nitrogen atom which may be substituted, -CO-, -O-, C3-6 cycloalkylene which may be substituted, and phenylene which may be substituted. 12. The compound according to claim 11, where 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 can be substituted, where the right side each group is associated with ring B. 13. The compound according to claim 2, where 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 comprising C1-10 alkylene, which may be substituted, C2-10 alkenylene which may be substituted, C2-10 alkynylene which may be substituted, nitrogen atom which 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 substituted) -, - (piperidine, which may be substituted) -, - (piperazine, which may be substituted) - and - (tetrahydropyridine, which may be substituted). 14. The compound according to item 13, 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 -, - (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 1- 3 halogen atoms, and the right side of each group Knit with the ring B. 15. The compound according to claim 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 consisting of C1-3 alkylene and -CO-. 16. The compound according to clause 15, where Y ¹ represents -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 according to claim 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 of claim 17, wherein Y ² is —CH ₂ -, - (CH ₂ ) ₂ - or - (m-phenylene) -, each of which may be substituted. 19. The compound according to claim 2, where the substituent represented by R ¹ represents a halogen atom, C1-20 alkyl, which may be substituted, or C1-20 alkyloxy, which may be substituted. 20. The compound of claim 19, wherein the substituent represented by R ¹ is fluoro, chloro, bromo, methyl, trifluoromethyl or methoxy. 21. The compound according to claim 3, where R ⁷ represents a hydrogen atom or C1-20 alkyl, which may be substituted. 22. The compound according to claim 2, which is a compound represented by formula (I-S-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 ^S11 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 any of claims 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 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 any of claims 1 and 2. 23. The compound according to claim 2, which is a compound represented by 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 in any of paragraphs 1, 2 and 22. 24. The compound according to claim 2, which is a compound represented by formula (I-U)

where R ^S21 , R ^S22 , R ^S23 , R ^S24 , R ^S25 and R ^S26 each independently represent 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 in any of paragraphs 1, 2 and 22. 25. The compound according to claim 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 claim 1, which is a (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 of formula (I) according to claim 1, a salt thereof, a solvate thereof or a prodrug thereof. 28. The pharmaceutical composition of claim 27, which is an S1P receptor binding agent. 29. The pharmaceutical composition according to p, which is an agent for binding to EDG-6, which may have the ability to bind to EDG-1. 30. The pharmaceutical composition according to clause 29, 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. 31. The pharmaceutical composition according to item 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 p, where the disease associated with EDG-1 and / or EDG-6, is a rejection during transplantation, an autoimmune disease and / or allergic disease. 33. The pharmaceutical composition according to p, where 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 marrow cells and / or pancreatic islet cells, 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 according to item 27, which is an immunosuppressant. 35. The pharmaceutical composition according to item 27, which is an agent that causes lymphopenia. 36. The pharmaceutical composition according to any one of p, 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 salt, their solvate or their prodrug. 37. A medicament comprising a compound represented by formula (I) according to claim 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, an inhibitor T-cell activation, calcineurin inhibitor, proliferation signal inhibitor, steroid, immunosuppressant, antibody used for immunosuppression, rejection medication, antibiotic, antiviral agent and antifungal agent. 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 § 38, which is an agent 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 of formula (I) according to claim 1, a salt thereof, a solvate thereof or a prodrug thereof. 41. A method of providing immunosuppression and / or lymphopenia in a mammal, which comprises administering to the mammal an effective amount of a compound of formula (I) according to claim 1, a salt thereof, a solvate thereof, or a prodrug thereof. 42. The use of a compound of formula (I) according to claim 1, a salt thereof, a solvate thereof or a prodrug thereof for the manufacture of a medicament for the prophylaxis and / or treatment of a disease associated with EDG-1 and / or EDG-6. 43. The use of a compound of formula (I) according to claim 1, a salt thereof, a solvate thereof or a prodrug thereof for the preparation of an immunosuppressant and / or an agent causing lymphopenia.