Phenylalanine derivatives

• US 7,153,963 B2
• Filed: 11/21/2002
• Issued: 12/26/2006
• Est. Priority Date: 08/18/2000
• Status: Expired due to Term

• Current Assignee: EA Pharma Co., Ltd (Ajinomoto Co., Inc.)
• Original Assignee: Ajinomoto Co., Inc.
• Inventors: Nakanishi, Eiji, Satake, Yuko, Murata, Masahiro, Izawa, Hiroyuki, Tsuji, Takashi, Suzuki, Nobuyasu, Yoshimura, Toshihiko, Chiba, Akira, Sagi, Kazuyuki, Okuzumi, Tatsuya, Makino, Shingo
• Primary Examiner(s): Jiang, Shaojia A.
• Assistant Examiner(s): Krishnan, Ganapathy
• Application Number:
  US10/300,856
• Publication Number:
  US 20030220268A1
• Time in Patent Office: 1,496 Days
• Field of Search: 514/19, 514/266.21, 514/269, 544/284, 544/309, 544/285, 544/385, 546/141, 546/142
• US Class Current: 544/284
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• 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: C07D 239/22 with hetero atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/54 : as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 239/78 : with hetero atoms directly attached in position 2
• CPC Class Codes: C07D 239/80 : Oxygen atoms
• CPC Class Codes: C07D 239/91 : with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 239/95 : with hetero atoms directly attached in positions 2 and 4
• CPC Class Codes: C07D 239/96 : Two oxygen atoms
• CPC Class Codes: C07D 253/08 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 265/26 : Two oxygen atoms, e.g. isatoic anhydride
• CPC Class Codes: C07D 285/16 : Thiadiazines; Hydrogenated thiadiazines
• CPC Class Codes: C07D 285/24 : with oxygen atoms directly attached to the ring sulfur atom
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 475/02 : with an oxygen atom directly attached in position 4
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: Y02P 20/582 : Recycling of unreacted starting or intermediate materials

Abstract

Specified phenylalanine derivatives and analogues thereof have an antagonistic activity to α4 integrin. They are used as therapeutic agents for various diseases concerning α4 integrin

Claims

1. A phenylalanine compound of the following formula (1) or a pharmaceutically acceptable salt thereof:

2. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein A represents one of the groups indicated as the formula (2) or (3) and R1, R2, R3, R4, R5, R6 and R7 may be the same or different from one another, and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a cycloalkyl group which may contain a hetero atom(s) in the ring thereof, an aryl group, a heteroaryl group, a lower alkyl group substituted with a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, a lower alkyl group substituted with an aryl group(s), a lower alkyl group substituted with a heteroaryl group(s), a lower alkoxyl group, a lower alkylthio group, a lower alkoxyl group substituted with a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, a lower alkylthio group substituted with a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, a lower alkoxyl group substituted with an aryl group(s), a lower alkylthio group substituted with an aryl group(s), a lower alkoxyl group substituted with a heteroaryl group(s), a lower alkylthio group substituted with a heteroaryl group(s), a cycloalkyloxy group which may contain a hetero atom(s) in the ring thereof, an aryloxy group, a heteroaryloxy group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxyl group, a lower halogenoalkyl group, a lower halogenoalkoxyl group, a lower halogenoalkylthio group, a lower halogenoalkenyl group, a nitro group, a cyano group, a substituted or unsubstituted amino group, a carboxyl group, a lower alkyloxycarbonyl group, a substituted or unsubstituted carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylsulfonyl group or a substituted or unsubstituted sulfamoyl group, and R5 and R6 may be bonded together to form a ring which may contain one or two oxygen, nitrogen or sulfur atoms.

3. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 2, wherein, in formula (1), B represents a hydroxyl group or a lower alkoxyl group,

C represents a hydrogen atom or a lower alkyl group,

J and J′

represent a hydrogen atom, and

in formulae (2) and (3),

V and X represent any of C═

(O), S(═

O)₂ or C(—

R5)(—

R6), and

U represents any of C═

(O), S(═

O)₂, C(—

R5)(—

R6), C(═

C(R5)(R6)), C(═

S), S(═

O), P(═

O)(—

OH) and P(—

H)(═

O).

4. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 2, wherein, in formula (1), B represents a hydroxyl group or a lower alkoxyl group,

C represents a hydrogen atom or a lower alkyl group,

J and J′

represent a hydrogen atom, and

in formulae (2) and (3), Arm represents a benzene ring or an aromatic ring containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms.

5. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 2, wherein, in formula (1), B represents a hydroxyl group or a lower alkoxyl group,

C represents a hydrogen atom or a lower alkyl group,

J and J′

represent a hydrogen atom, and

in formulae (2) and (3), Arm represents a benzene ring or an aromatic ring containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms,

V and X represent any of C═

(O), S(═

O)₂ or C(—

R5)(—

R6), and

U represents any of C═

(O), S(═

O)₂, C(—

R5)(—

R6), C(═

C(R5)(R6)), C(═

S), S(═

O), P(═

O)(—

OH) and P(—

H)(═

O).

6. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein A represents the following formula (3-3):

7. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein A represents the following formulae (3-4) or (3-5):

8. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 7, wherein A represents the formula (3-4), Arm is a benzene ring, pyridine ring, pyrazole ring or cyclohexane ring, R1 is a lower alkyl group, R2, R3 and R4 may be the same or different from one another and each represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group which may contain a hetero atom(s) in the ring thereof, a lower alkyl group substituted with a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, a lower alkoxyl group, a lower alkylthio group, a lower halogenoalkyl group, a lower halogenoalkoxyl group, a lower halogenoalkylthio group, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group(s) or a trialkylammonium group.

9. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein, in formula (1), D represents the following formulae (4-1), (4-2), (4-3) or (4-4):

10. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 9, wherein, in formula (1), D represents the formula (4-1), and

in the formula (4-1), R13 and R8 represent a chlorine atom, and R9 represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group which may contain a hetero atom(s) in the ring thereof, a lower alkoxyl group, a lower alkylthio group, a lower halogenoalkyl group, a lower halogenoalkoxyl group, a lower halogenoalkylthio group, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group(s) or a trialkylammonium group.

11. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein, in formula (1), C represents a hydrogen atom and T is C(═

O).

12. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein, in formula (1), A represents the following formulae (3-4) or (3-5):

13. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 12, wherein, in formula (1), A represents the formula (3-4), Arm is a benzene ring, pyridine ring, pyrazole ring or cyclohexane ring, R1 is a lower alkyl group, R2, R3 and R4 may be the same or different from one another and each represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group which may contain a hetero atom(s) in the ring thereof, a lower alkyl group substituted with a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, a lower alkoxyl group, a lower alkylthio group, a lower halogenoalkyl group, a lower halogenoalkoxyl group, a lower halogenoalkylthio group, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group(s) or a trialkylammonium group,

D represents the following formula (4-1),

14. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 6, wherein, in formula (1), A represents the formula (3-3), and in the formula (3-3), U represents C(═

O) or C(═

S), R1 represents a lower alkyl group, R2, R3 and R4 may be the same or different from one another and each represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group which may contain a hetero atom(s) in the ring thereof, a lower alkyl group substituted with a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, a lower alkoxyl group, a lower alkylthio group, a lower halogenoalkyl group, a lower halogenoalkoxyl group, a lower halogenoalkylthio group, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group(s) or a trialkylammonium group,

C represents a hydrogen atom,

D represents the formula (4-1), (4-2), (4-3) or (4-4),

15. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 14, wherein, in formula (1), A represents the formula (3-3), and in the formula (3-3), U represents C(═

O) or C(═

S), R1 represents a methyl group or an ethyl group, R2, R3 and R4 may be the same or different from one another and each represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group which may contain a hetero atom(s) in the ring thereof, a lower alkoxyl group, a lower alkylthio group, a lower halogenoalkyl group, a lower halogenoalkoxyl group, a lower halogenoalkylthio group, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group(s) or a trialkylammonium group,

B represents a hydroxyl group or a lower alkoxyl group,

C represents a hydrogen atom,

D represents the formula (4-1), wherein R13 and R8 represent a chlorine atom, and R9 represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group which may contain a hetero atom(s) in the ring thereof, a lower alkoxyl group, a lower alkylthio group, a lower halogenoalkyl group, a lower halogenoalkoxyl group, a lower halogenoalkylthio group, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group(s) or a trialkylammonium group,

T is C(═

O) and

each of J and J′

is a hydrogen atom.

16. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1, which has the following formula:

17. A pharmaceutical composition comprising a phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

18. The phenylalanine compound according to claim 1, which has the following formula:

19. The phenylalanine compound according to claim 1, which has the following formula:

20. The phenylalanine compound according to claim 1, which has the following formula:

21. The phenylalanine compound according to claim 1, which has the following formula:

22. The phenylalanine compound according to claim 1, which has the following formula:

23. The phenylalanine compound according to claim 1, which has the following formula:

24. The phenylalanine compound according to claim 1, which has the following formula:

25. The phenylalanine compound according to claim 1, which has the following formula:

26. The phenylalanine compound according to claim 1, which has the following formula:

27. The phenylalanine compound according to claim 1, which has the following formula:

28. The phenylalanine compound according to claim 1, which has the following formula:

29. The phenylalanine compound according to claim 1, which has the following formula:

30. The phenylalanine compound according to claim 1, which has the following formula:

31. The phenylalanine compound according to claim 1, which has the following formula:

32. The phenylalanine compound according to claim 1, which has the following formula:

33. The phenylalanine compound according to claim 1, which has the following formula:

34. The phenylalanine compound according to claim 1, which has the following formula: