Compound Having S1P Receptor Binding Potency and Use Thereof

• US 20080207584A1
• Filed: 06/22/2005
• Published: 08/28/2008
• Est. Priority Date: 06/23/2004
• Status: Active Grant

• Current Assignee: ONO Pharmaceutical Company Limited
• Original Assignee: ONO Pharmaceutical Company Limited
• Inventors: Nakade, Shinji, Habashita, Hiromu
• Granted Patent: US 8,039,674 B2
• Time in Patent Office: Days
• US Class Current: 514/210.01
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07C 217/60 : linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring

Abstract

Provided are: a compound represented by formula (I):

(wherein ring A and ring D each represent a cyclic group which may have a substituent(s); E and G each represent a bond or a spacer having 1 to 8 atoms in its main chain; L represents a hydrogen atom or a substituent; X represents amino which may have a substituent(s), or a heterocyclic group which contains at least one nitrogen atom and which may have a substituent(s); n represents 0 to 3, in which when n is 2 or more, a plurality of ring A'"'"'s may be the same or different from one another); a salt thereof; an N-oxide form thereof; a solvate thereof, a prodrug thereof; and a medicament which includes those. The compound represented by formula (I) is capable of binding S1P receptors (in particular, EDG-1 and/or EDG-6), and useful for preventing and/or treating rejection in transplantation, autoimmune diseases, allergic diseases, etc.

Claims

1. A compound represented by formula (I):

2. The compound according to claim 1, wherein ring A is a C3-10 monocyclic or bicyclic carbocyclic group which may have a substituent(s), or a 3- to 10-membered monocyclic or bicyclic heterocyclic group which contains 1 to 5 nitrogen atoms, one or two oxygen atoms, and/or one sulfur atom and which may have a substituent(s).

3. The compound according to claim 2, wherein ring A is benzene, oxadiazole, or cyclohexane ring which may have a substituent(s).

4. The compound according to claim 1, wherein ring D is a C3-15 monocyclic, bicyclic, or tricyclic carbocyclic group which may have a substituent(s), or a 3- to 15-membered monocyclic, bicyclic, or tricyclic heterocyclic group which contains 1 to 5 nitrogen atoms, one or two oxygen atoms, and/or one sulfur atom and which may have a substituent(s).

5. The compound according to claim 4, wherein ring D represents any one of the followings:

6. The compound according to claim 5, wherein ring D is benzene, dihydronaphthalene, or naphthalene ring which may have a substituent(s).

7. The compound according to claim 6, wherein ring D represents the following:

8. The compound according to claim 1, wherein E is a spacer having 1 to 8 atoms in its main chain which is 1 to 8 combinations selected from the group consisting of (1) C1-8 alkylene which may be substituted, (2) C2-8 alkenylene which may be substituted, (3) oxygen atom, (4) sulfur atom which may be oxidized, and (5) nitrogen atom which may be substituted.

9. The compound according to claim 8, wherein E is “

—

(C1-7 alkylene which may be substituted)-(oxygen atom)-”

in which the oxygen atom binds to ring D.

10. The compound according to claim 9, wherein E is “

—

(C1-3 alkylene which may be substituted)-(oxygen atom)-”

in which the oxygen atom binds to ring D and wherein n is 1.

11. The compound according to claim 10, wherein the “

—

(C1-3 alkylene which may be substituted)-(oxygen atom)-”

represented by E is any one of the followings;

12. The compound according to claim 11, wherein R⁶ represents methyl.

13. The compound according to claim 1, wherein G is a spacer having 1 to 4 atoms in its main chain.

14. The compound according to claim 13, wherein G is C1-3 alkylene which may be substituted, C2-3 alkenylene which may be substituted, or C2-3 alkynylene which may be substituted.

15. The compound according to claim 1, wherein X represents the following:

16. The compound according to claim 15, wherein R¹ represents the following:

17. The compound according to claim 1, wherein X represents a heterocyclic group which contains at least one nitrogen atom and which may have a substituent(s).

18. The compound according to claim 17, wherein X represents a 4- to 8-membered monocyclic heterocylic group which contains at least one nitrogen atom and which may have a substituent(s).

19. The compound according to claim 17, wherein a substituent for X represents the following:

20. The compound according to claim 1, which is a compound represented by formula (I-3-10):

21. The compound according to claim 20, wherein R represents a halogen atom, C1-8 alkyl which may have a substituent(s), or C1-8 alkoxy which may have a substituent(s).

22. The compound according to claim 20, wherein R⁵ represents a halogen atom, trifluoromethyl, a trifluoromethoxy, or C1-8 alkyl.

23. The compound according to claim 1, which is

N-({6-[3-(4-fluorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)ethanamine,

N-(3-{[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]amino}propanoyl)methanesulfonamide,

N-(3-{[(6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]amino}propanoyl)-3,5-dimethyl-4-isoxazolesulfonamide,

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

N-({6-[3-(4-fluorophenyl)-2-methylpropoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)ethanamine,

N-({1-[(1-chloro-6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinyl}carbonyl)methanesulfonamide,

N-({1-[(1-chloro-6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinyl}carbonyl)-2,6-difluorobenzensulfonamide,

N-({1-[(1-chloro-6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinyl}carbonyl)-3,5-dimethyl-4-isoxazolesulfonamide,

1-{6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}-N,N-dimethylmethanamine,

[1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinyl]methanol,

1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-4-(2-pyridinyl)piperazine,

2-[4-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-1-piperazinyl]pyrimidine, or

2-[4-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-1-piperazinyl]pyrazine.

24. A pharmaceutical composition which comprises the compound represented by formula (I) according to claim 1, a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier or diluent.

25. The pharmaceutical composition according to claim 24, which is an S1P receptor binding agent, an immunosuppressant agent, and/or an agent causing lymphopenia.

26. The pharmaceutical composition according to claim 25, wherein the S1P receptor binding agent is an EDG-1 agonist and/or an EDG-6 agonist.

27. The pharmaceutical composition according to claim 24, which is an agent for preventing and/or treating an EDG-1 and/or EDG-6-mediated disease.

28. The pharmaceutical composition according to claim 27, wherein the EDG-1 and/or EDG-6-mediated disease is rejection in transplantation of an organ, tissues, and/or cells, autoimmune disease, allergic disease, asthma, multiple organ failure, ischemia-reperfusion injury, malignant tumor, lung fibrosis, and/or liver fibrosis.

29. The pharmaceutical composition according to claim 28, wherein the rejection in transplantation of an organ, tissues, and/or cells is a rejection in transplantation of kidney, liver, heart, lung, dermal graft, cornea, vascular, chordae, bone, bone marrow cells, neuronal cells, and/or pancreatic islet cells, the autoimmune disease is systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, autoimmune diabetes, and/or collagen disease, and the allergic disease is atopic dermatitis, pollen disease, and/or food allergy.

30. A medicament comprising the compound represented by formula (I) according to claim 1, a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof in combination with one or at least two selected from the group consisting of an antimetabolite, an alkylating agent, a T cell activation inhibitor, a calcineurin inhibitor, a proliferation signal inhibitor, a steroid, an immunosuppressant agent, an antibody used in immune suppression, an agent for treating rejection, an antibiotic, an antiviral agent, and an antifungal agent.

31. A method for prevention and/or treatment of an EDG-1 and/or EDG-6-mediated disease, immunosuppression, and/or lymphopenia in a mammal, which comprises administering to the mammal an effective amount of the compound represented by formula (I) according to claim 1, a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof.

32. (canceled)