Pyrido (2,3-B) pyrazine derivatives

• US 6,117,875 A
• Filed: 06/19/1998
• Issued: 09/12/2000
• Est. Priority Date: 12/27/1995
• Status: Expired due to Fees

• Current Assignee: Fujisawa Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Original Assignee: Fujisawa Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Inventors: Watanabe, Shinya, Sawada, Akihiko, Shimazaki, Norihiko
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Truong, Tamithom N.
• Application Number:
  US09/091,361
• Time in Patent Office: 816 Days
• Field of Search: 544/354, 544/255.01
• US Class Current: 514/255.01
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A compound of the formula: ##STR1## wherein R¹ is pyridyl(lower)alkyl, N-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl,

R² is aminophenyl, [protected amino]phenyl, [[[halophenyl](lower)alkenoyl]amino]phenyl, [[pyridyl(lower)alkenoyl]amino]phenyl, [[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protected aminopyridyl](lower)alkenoyl]amino]phenyl, [thiazolylcarbonylamino]phenyl which may have pyridyl, naphthyl having lower alkoxy and halogen, [dihalophenyl](lower)alkenyl, [N-oxidopyridyl](lower)alkenyl, [aminopyridyl](lower)alkenyl, [protected aminopyridyl](lower)alkenyl, [carboxypyridyl](lower)alkenyl, [protected carboxypyridyl](lower)alkenyl, [[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl, [[carboxy(lower)alkenyl]pyridyl](lower)alkenyl, [[protected carboxy(lower)alkenyl]pyridyl](lower)alkenyl, [pyridyl(lower)alkenyl]pyridyl, lower alkylbenzothiazolyl or [halopyridylcarbonyl]amino,

with proviso that when R² is [[4-pyridyl(lower)alkenoyl]amino]phenyl, aminophenyl, [lower alkanoylamino]phenyl or [dihalophenyl](lower)alkenyl, then

R¹ is N-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl,

and a pharmaceutically acceptable salt thereof, which is useful as a medicament.

Claims

1. A compound of the formula:

##STR5## wherein R¹ is pyridyl(lower)alkyl, N-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl,

R² is aminophenyl, [protected amino]phenyl, [[[halophenyl](lower)alkenoyl]amino]phenyl, [[pyridyl(lower)alkenoyl]amino]phenyl, [[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protected aminopyridyl](lower)alkenoyl]amino]phenyl, [thiazolylcarbonylamino]phenyl which may have pyridyl on thiazolyl, naphthyl having lower alkoxy and halogen, [dihalophenyl](lower)alkenyl, [N-oxidopyridyl](lower)alkenyl, [aminopyridyl](lower)alkenyl, [protected aminopyridyl](lower)alkenyl, [carboxypyridyl](lower)alkenyl, [protected carboxypyridyl](lower)alkenyl, [[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl, [[carboxy(lower)alkenyl]pyridyl](lower)alkenyl, [[protected carboxy(lower)alkenyl]pyridyl](lower)alkenyl, [pyridyl(lower)alkenyl]pyridyl, lower alkylbenzothiazolyl or [halopyridylcarbonyl]amino,

with proviso that when R² is [[4-pyridyl(lower)alkenoyl]amino]phenyl, aminophenyl, [lower alkanoylamino]phenyl or [dihalophenyl](lower)alkenyl, then

R¹ is N-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl, and a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein

R¹ is pridyl(lower)alkyl, N-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl,

R² is aminophenyl,

[lower alkanoylamino]phenyl,

[[[halophenyl](lower)alkenoyl]amino]phenyl,

[[pyridyl(lower)alkenoyl]amino]phenyl,

[[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl,

[[[acylaminopyridyl](lower)alkenoyl]amino]phenyl,

[[pyridylthiazolyl]carbonylamino]phenyl,

naphthyl having lower alkoxy and halogen,

[dihalophenyl](lower)alkenyl,

[N-oxidopyridyl](lower)alkenyl,

[aminopyridyl](lower)alkenyl,

[[acylamino]pyridyl](lower)alkenyl,

[carboxypyridyl](lower)alkenyl,

[esterified carboxypyridyl](lower)alkenyl,

[[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl,

[[carboxy(lower)alkenyl]pyridyl](lower)alkenyl,

[[esterified carboxy(lower)alkenyl]pyridyl](lower)alkenyl,

[pyridyl(lower)alkenyl]pyridyl,

lower alkylbenzothiazolyl or

halopyridylcarbonylamino,

with the proviso that when R² is [[4-pyridyl(lower)alkenoyl]amino]phenyl, aminophenyl, [lower alkanoylamino]phenyl or [dihalophenyl](lower)alkenyl, then R¹ is N-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl.

3. The compound of claim 2, wherein

R¹ is pyridyl(lower)alkyl, and

R² is [[2-pyridyl(lower)alkenoyl]amino]phenyl, [[3-pyridyl(lower)alkenoyl]amino]phenyl, [[pyridylthiazolyl]carbonylamino]phenyl, [aminopyridyl](lower)alkenyl, [[lower alkanoylamino]pyridyl](lower)alkenyl, [[trihalo(lower)alkanoylaino]pyridyl](lower)alkenyl, [lower alkoxycarbonylpyridyl](lower)alkenyl, [[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl or lower alkylbenzothiazolyl.

4. The compound of claim 2, wherein

R¹ is imidazolyl(lower)alkyl, and

R² is naphthyl having lower alkoxy and halogen.

5. A process for preparing a compound of the formula:

##STR6## wherein R¹ and R² are each as defined in claim 1, or a salt thereof, which comprises

(1) reacting a compound of the formula;

##STR7## wherein R² is as defined above, or a salt thereof with a compound of the formula;

##STR8## wherein R¹ is as defined above, or a salt thereof to give a compound of the formula;

##STR9## wherein R¹ and R² are each as defined above, or a salt thereof, or

(2) subjecting a compound of the formula;

##STR10## wherein R¹ is as defined above, and R_a² is [aminopyridyl](lower)alkenyl, or its reactive derivative at the amino group, or a salt thereof to acylation reaction to give a compound of the formula;

##STR11## wherein R¹ is as defined above and R_b² is [acylaminopyridyl](lower)alkenyl, or a salt thereof, or

(3) subjecting a compound of the formula;

##STR12## wherein R¹ is as defined above,

R_c² is [lower alkanoylamino]phenyl, [[[halophenyl](lower)alkenoyl]amino]phenyl, [[pyridyl(lower)alkenoyl]amino]phenyl, [[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protected aminopyridyl](lower)alkenoyl]amino]phenyl, [thiazolylcarbonylamino]phenyl which may have pyridyl or [acylaminopyridyl](lower)alkenyl,

or a salt thereof to deacylation to give a compound of the formula;

##STR13## wherein R¹ is as defined above, and

R_d² is aminophenyl or [aminopyridyl](lower)alkenyl,

or a salt thereof, or

(4) reacting a compound of the formula;

##STR14## wherein R¹ is as defined above, and

R_e² is aminophenyl,

or its reactive derivative at the amino group, or a salt thereof with a compound of the formula;

space="preserve" listing-type="equation">R.sup.3 --OH

wherein

R³ is lower alkanoyl, [halophenyl](lower)alkenoyl, pyridyl(lower)alkenoyl, [N-oxidopyridyl](lower)alkenoyl, [protected aminopyridyl](lower)alkenoyl or thiazolylcarbonyl which may have pyridyl,

or its reactive derivative at the carboxy group,

or a salt thereof to give a compound of the formula;

##STR15## wherein R¹ is as defined above, and

R_f² is [lower alkanoylamino]phenyl, [[[halophenyl](lower)alkenoyl]amino]phenyl, [[pyridyl(lower)alkenoyl]amino]phenyl, [[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protected aminopyridyl](lower)alkenoyl]amino]phenyl or [thiazolylcarbonylamino]phenyl which may have pyridyl,

or a salt thereof,

(5) subjecting a compound of the formula;

##STR16## wherein R² is as defined above,

R⁵ is N-protective group,

A is lower alkylene, and

Y^- is halide,

or a salt thereof to elimination of N-protective group to give a compound of the formula;

##STR17## wherein R² and A are each as defined above, or a salt thereof.

6. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.

7. A method for the prophylactic or therapeutic treatment of phosphodiesterase IV (PDE-IV) and tumor necrosis factor (TNF) mediated diseases which comprises administering a compound of claim 1 or a pharmaceutically acceptable salts thereof to human or animals.

8. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

9. The compound of claim 2, wherein

[[[acylaminopyridyl](lower)alkenoyl]amino]phenyl is [[[[lower alkanoylamino]pyridyl](lower)alkenoyl]amino]phenyl);

[[acylamino]pyridyl](lower)alkenyl is [[lower alkanoylamino]pyridyl](lower)alkenyl or [[mono (or di or tri)halo (lower)alkanoylamino]pyridyl](lower)alkenyl;

[esterified carboxypyridyl](lower)alkenyl is [lower alkoxycarbonylpyridyl](lower)alkenyl; and

[[esterified carboxy(lower)alkenyl]pyridyl](lower)alkenyl is [[lower alkoxycarbonyl(lower)alkenyl]pyridyl](lower)alkenyl.