PGD2 receptor antagonistic pharmaceutical compositions

• US 6,933,317 B2
• Filed: 10/26/2001
• Issued: 08/23/2005
• Est. Priority Date: 11/01/2000
• Status: Expired due to Fees

• Current Assignee: Shionogi & Co., Ltd.
• Original Assignee: Shionogi & Co., Ltd.
• Inventors: Hiramatsu, Yoshiharu, Inagaki, Masanao, Honma, Tsunetoshi, Tanimoto, Norihiko
• Primary Examiner(s): Solola, Taofiq
• Assistant Examiner(s): WALLER, ROBIN REGINA
• Application Number:
  US10/399,605
• Publication Number:
  US 20040054003A1
• Time in Patent Office: 1,397 Days
• Field of Search: 549/57, 549/467, 514/448, 514/469, 514/443
• US Class Current: 514/443
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• 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: C07D 307/79 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 307/85 attached in position 2
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/54 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 333/64 Oxygen atoms
• CPC Class Codes: C07D 333/70 attached in position 2
• CPC Class Codes: C07D 333/76 Dibenzothiophenes
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

Compounds of the general formula (I) which are metabolically stable and have an antagonistic activity against PGD₂ receptor:

 
wherein Y is bicyclic ring; R¹ is optionally substituted heteroaryl; R² is hydrogen, etc.; R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—COOR⁴; R⁴ is hydrogen, etc.; X¹ is —O—, etc.

Claims

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

2. A compound as described in claim 1, wherein

3. A compound as described in claim 1, wherein R¹ is heteroaryl which may be substituted with a group of the formula:

-Z¹-Z² wherein Z¹ is a bond, —

O—

, —

S—

, —

NH—

, —

NH—

C(═

O)—

, —

NH—

C(═

O)—

O—

, —

NH—

SO₂—

, —

O—

C(═

O)—

, —

C(═

O)—

O—

, —

SO₂—

, —

CH₂—

O—

, —

CH₂—

NH—

C(═

O)—

, —

CH₂—

NH—

C(═

O)—

O—

, —

CH₂—

NH—

SO₂—

or —

CH₂—

C(O)— and

Z² is alkyl or optionally substituted amino;

carboxy;

halogen;

hydroxy;

or nitro, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

4. A compound as described in claim 1, wherein R³ is —

CH₂—

CH₂—

CH₂—

CH₂—

CH═

CH—

COOR⁴, —

CH₂—

CH₂—

CH₂—

CH₂—

X¹—

CH₂—

COOR⁴, —

CH₂—

CH═

CH—

CH₂—

X¹—

CH₂—

COOR⁴ or —

CH₂—

CH₂—

CH₂—

CH₂—

COOR⁴;

R⁴ is hydrogen; and

X¹ is —

O—

or —

S—

, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

5. A compound as described in claim 4, wherein R³ is —

CH₂—

CH₂—

CH₂—

CH₂—

CH═

CH—

COOR⁴ or —

CH₂—

CH₂—

CH₂—

CH₂—

X¹—

CH₂—

COOR⁴;

R⁴ is hydrogen; and

X¹ is —

O—

or —

S—

, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

8. A method of making a pharmaceutical composition for treating nasal blockage, allergic conjunctivitis or allergic rhinitis, comprising introducing to an auxiliary component a compound of claim 1.

6. A pharmaceutical composition comprising an auxiliary component and a compound of Formula (I):

9. A pharmaceutical composition of claim 6, wherein

10. A pharmaceutical composition of claim 6, wherein R¹ is heteroaryl which may be substituted with a group of the formula:

-Z¹-Z² wherein Z¹ is a bond, —

O—

, —

S—

, —

NH—

, —

NH—

C(═

O)—

, —

NH—

C(═

O)—

O—

, —

NH—

SO₂—

, —

C(═

O)—

, —

O—

C(═

O)—

, —

C(═

O)—

O—

, —

SO₂—

, —

CH₂—

O—

, —

CH₂—

NH—

C(═

O)—

, —

CH₂—

NH—

C(═

O)—

O—

, —

CH₂—

NH—

SO₂—

or —

CH₂—

C(O)— and

Z² is alkyl or optionally substituted amino;

carboxy;

halogen;

hydroxy;

or nitro, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

11. A pharmaceutical composition of claim 6, wherein R³ is —

CH₂—

CH₂—

CH₂—

CH₂—

CH═

CH—

COOR⁴, —

CH₂—

CH₂—

CH₂—

CH₂—

X¹—

CH₂—

COOR⁴, —

CH₂—

CH═

CH—

CH₂—

X¹—

CH₂—

COOR⁴ or —

CH₂—

CH₂—

CH₂—

CH₂—

COOR⁴;

R⁴ hydrogen; and

X¹ is —

O—

or —

S—

, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

12. A pharmaceutical composition of claim 11, wherein R³ is —

CH₂—

CH₂—

CH₂—

CH₂—

CH═

CH—

COOR⁴ or —

CH₂—

CH₂—

CH₂—

CH₂—

X¹—

CH₂—

COOR⁴;

R⁴ is hydrogen; and

X¹ is —

O—

or —

S—

, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

7. A method for treating nasal blockage, allergic conjunctivitis or allergic rhinitis, which comprises administrating a compound of Formula (I):

13. A method of claim 7, wherein

14. A method of claim 7, wherein R¹ is heteroaryl which may be substituted with a group of the formula:

-Z¹-Z² wherein Z¹ is a bond, —

O—

, —

S—

, —

NH—

, —

NH—

C(═

O)—

, —

NH—

C(═

O)—

O—

, —

NH—

SO₂—

, —

C(═

O)—

, —

O—

C(═

O)—

, —

C(═

O)—

O—

, —

SO₂—

, —

CH₂—

O—

, —

CH₂—

NH—

C(═

O)—

, —

CH₂—

NH—

C(═

O)—

O—

, —

CH₂—

NH—

SO₂—

or —

CH₂—

C(O)— and

Z² is alkyl or optionally substituted amino;

carboxy;

halogen;

hydroxy;

or nitro, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

15. A method of claim 7, wherein R³ is —

CH₂—

CH₂—

CH₂—

CH₂—

CH═

CH—

COOR⁴, —

CH₂—

CH₂—

CH₂—

CH₂—

X¹—

CH₂—

COOR⁴, —

CH₂—

CH═

CH—

CH₂—

X¹—

CH₂—

COOR⁴ or —

CH₂—

CH₂—

CH₂—

CH₂—

COOR⁴;

R⁴ is hydrogen; and

X¹ is —

O—

or —

S—

, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

16. A method of claim 15, wherein R³ is —

CH₂—

CH₂—

CH₂—

CH₂—

CH═

CH—

COOR⁴ or —

CH₂—

CH₂—

CH₂—

CH₂—

X¹—

CH₂—

COOR⁴;

R⁴ is hydrogen; and

X¹ is —

O—

or —

S—

, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.