Pyrrolidine derivatives having phospholipase A.sub.2 inhibitory activity

• US 6,147,100 A
• Filed: 07/22/1999
• Issued: 11/14/2000
• Est. Priority Date: 01/31/1997
• Status: Expired due to Fees

• Current Assignee: Shionogi & Co., Ltd.
• Original Assignee: Shionogi & Co., Ltd.
• Inventors: Seno, Kaoru, Ohtani, Mitsuaki, Watanabe, Fumihiko
• Primary Examiner(s): Gerstl, Robert
• Application Number:
  US09/355,008
• Time in Patent Office: 481 Days
• Field of Search: 548/183, 514/369
• US Class Current: 514/369
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

A compound represented by the formula (I): ##STR1## wherein, for example, R¹ is optionally substituted aralkyl, Z is nitrogen atom which optionally substituted with alkyl, X¹ is --CH₂ NHCO--, X² is phenylene, X³ is a bond, Y² is optionally substituted aryl, B is oxygen atom, its pharmaceutically acceptable salt, or hydrate thereof and a pharmaceutical composition which contains them as an active ingredient.

Claims

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

##STR353## wherein R¹ is hydrogen atom, lower alkyl, optionally substituted aryl, aryl fused with a non-aromatic hydrocarbon ring or a non-aromatic heterocyclic ring, optionally substituted aralkyl, optionally substituted arylcarbonyl, or optionally substituted heteroaryl;

Z is --S--, --SO--, --O--, --OCH₂ --, --CONH--, CONHCH_2--, --N(R¹⁶)-- (wherein R¹⁶ is hydrogen atom, alkyl, or aralkyl), or a bond;

X¹ is --(CH₂)_q --CO-- (wherein q is an integer of 0 to

     3), --(CH₂)_r --CO--N(R¹⁷)-- (wherein R¹⁷ is hydrogen atom or lower alkyl, and r is an integer of 0 to

     3), --CH₂ NSO₂ --, --(CH₂)_s --N(R¹⁸)--CO-- (wherein R¹⁸ is hydrogen atom or lower alkyl, s is an integer of 0 to

     3), --CH₂ NHCOCH₂ O--, --CH₂ N(R¹⁹)COCH═

CH-- (wherein R¹⁹ is hydrogen atom or lower alkyl), --CH₂ NHCS--, --CH₂ O--, --OCH₂ --, --CH₂ OCH₂ --, --CH₂ --N(R²⁰)--CH₂ -- (wherein R²⁰ is hydrogen atom, lower alkyl, or acyl), alkylene, alkenylene, or a bond;

X² is optionally substituted arylene, optionally substituted heteroarylene, heterocyclediyl, --C.tbd.C--, or a bond;

X³ is alkylene, alkenylene, or a bond;

A, B, and E are each independently oxygen atom or sulfur atom;

D is hydrogen atom or hydroxy lower alkyl;

Y¹ is --(CH₂)_m CO--, --(CH₂)_m CONH--, --(CH₂)_m CSNH--, --(CH₂)_m SO₂ --, --(CH₂)_m COO--, --(CH₂)_n NHCO--, --(CH₂)_n NHSO₂ --, or a bond;

m is an integer of 0 to 3;

n is an integer of 1 to 3;

Y² is a substituent represented by the formula;

##STR354## wherein R² and R³ are both hydrogen atom or one is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted cycloalkyl, and the other is hydrogen atom or lower alkyl;

R⁴, R⁵, G ring, J ring, and L ring are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or cycloalkenyl;

a broken line (-- -- --) represents the presence or absence of a bond; and

p is an integer of 0 to 2;

a broken line (-- -- --) represents the presence or absence of a bond;

a wavy line (˜

) represents cis or trans configuration of D to E;

provided that X¹ is alkylene and X² and X³ are both bonds when the carbon atom attached to D and the adjacent carbon atom in the ring is linked by a single bond, and Y¹ is not a bond when X¹ is --CH₂ O--, its pharmaceutically acceptable salt, or hydrate thereof.

2. A compound represented by the formula (II):

##STR355## wherein R¹, Z, X¹, X², X³, Y¹, Y², and B are as defined in claim 1, a wavy line represents cis or trans configuration of hydrogen atom to sulfur atom, provided that Y¹ is not a bond when X¹ is --CH₂ O--, its pharmaceutically acceptable salt, or hydrate thereof.

3. A compound represented by the formula (III):

##STR356## wherein R¹, Z, X¹, X², X³, Y², B, and a wavy line are as defined in claim 1, its pharmaceutically acceptable salt, or hydrate thereof.

4. A compound represented by the formula (IV):

##STR357## wherein R¹, Z, X¹, X², X³, Y², B, and a wavy line are as defined in claim 1, its pharmaceutically acceptable salt, or hydrate thereof.

5. A compound represented by the formula (V):

##STR358## wherein R¹, Z, R¹⁸, X³, Y², B, and a wavy line are as defined in claim 1, its pharmaceutically acceptable salt, or hydrate thereof.

6. A compound represented by the formula (VI):

##STR359## wherein R¹, Z, R¹⁸, X³, Y², B, and a wavy line are as defined in claim 1, it pharmaceutically acceptable salt, or hydrate thereof.

7. A compound represented by the formula (VII):

##STR360## wherein R¹, Z, R¹⁹, X³, Y², B, and a wavy line are as defined in claim 1, its pharmaceutically acceptable salt, or hydrate thereof.

8. A compound represented by the formula (VIII):

##STR361## wherein R¹, Z, Y², B, and a wavy line are as defined in claim 1, its pharmaceutically acceptable salt, or hydrate thereof.

9. A compound represented by the formula (IX):

##STR362## wherein R¹, Z, Y², B, and a wavy line are as defined in claim 1, its pharmaceutically acceptable salt, or hydrate thereof.

10. A compound represented by the formula (X):

##STR363## wherein R¹, Z, Y², B, and a wavy line are as defined in claim 1, its pharmaceutically acceptable salt, or hydrate thereof.

11. A compound represented by the formula (XI):

##STR364## wherein R¹, Z, Y², B, and a wavy line are as defined in claim 1, its pharmaceutically acceptable salt, or hydrate thereof.

12. The compound of claim 1, wherein Z is --N(R¹⁶)--, its pharmaceutically acceptable salt, or hydrate thereof.

13. The compound of claim 5, wherein R¹⁸ is hydrogen atoms and X³ is a bond, its pharmaceutically acceptable salt, or hydrate thereof.

14. The compound of claim 1, wherein R¹ is optionally substituted aryl, aryl fused with a non-aromatic hydrocarbon ring or a non-aromatic heterocyclic ring, optionally substituted aralkyl, its pharmaceutically acceptable salt, or hydrate thereof.

15. The compound of claim 1, wherein Y² is a substituent represented by the formula:

##STR365## wherein R⁵ is optionally substituted aryl, its pharmaceutically acceptable salt, or hydrate thereof.

16. A compound represented by the formula (I'"'"'):

##STR366## wherein Z is --N(R¹⁶)--, Y² '"'"' is optionally substituted aryl, and R¹, X¹, X², X³, Y¹, A, B, a wavy line, and a broken line are as defined in claim 1, its pharmaceutically acceptable salt, or hydrate thereof.

17. A pharmaceutical composition which contains a compound of claim claim 1 as an active ingredient.

18. A composition for inhibiting phospholipase A₂ which contains a compound of claim 1 as an active ingredient.

19. A composition for inhibiting the production of arachidonic acid which contains a compound of claim 1 as an active ingredient.

20. A composition for inhibiting the production of prostaglandin E₂ which contains a compound of claim 1 as an active ingredient.

21. A composition for inhibiting the production of leukotriene C₄ which contains a compound of claim 1 as an active ingredient.

22. A method for the prevention or treatment of an inflammatory disease, comprising administering to a patient in need thereof an effective amount of a compound according to claim 1.

23. A method according to claim 22, wherein said inflammatory disease is rheumatoid arthritis, asthma, inflammatory bowel diseases, injury due to ischemic reperfusion, allergic rhinitis or psoriasis.