Pyrazine derivatives and pharmaceutical use thereof

1. A compound of formula (I):

wherein

R 1 is

wherein

R 6 is hydrogen, or optionally substituted lower alkyl;

R 7 hydrogen or halogen;

R 8 is lower alkyl;

R 2 is hydrogen; hydroxy; halogen; cyano; acyl; or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, aryloxy, arylthio, aryl, heterocyclic group or amino, each of which is optionally substituted by substituent(s);

R 3 and R 4 are independently hydrogen, lower alkyl or acyl; and

R 5 is cyano; or lower alkenyl, lower alkynyl, aryl or heterocyclic group, each of which is optionally substituted by substituent(s);

or a salt thereof.

2. The compound of claim 1 , wherein

R 1 is

wherein

R 6 is hydrogen, lower alkyl, aryl(lower)alkyl, heteroaryl(lower)alkyl;

R 7 hydrogen or halogen;

R 2 is hydrogen, halogen, cyano, optionally substituted lower alkyl, optionally substituted lower alkynyl, lower alkoxy, aryloxy, arylthio, carbamoyl, carboxy, protected carboxy or optionally substituted amino;

R 3 and R 4 are independently hydrogen or lower alkyl; and

R 5 is aryl or heteroaryl each of which is optionally substituted by one or more substituent(s);

or a salt thereof.

3. The compound of claim 2 , wherein

R 2 is hydrogen, halogen, cyano, hydroxylated(lower)alkyl, lower alkynyl, lower alkoxy, aryloxy, arylthio, carboxy, esterified carboxy, carbamoyl, amidated carboxy, amino or mono- or di-(lower)alkylamino;

R 3 and R 4 are independently hydrogen;

R 5 is aryl or heteroaryl, each of which is optionally substituted by one or more substituent(s) selected from the group consisting of halogen and lower alkoxy;

R 6 is hydrogen or lower alkyl; and

R 7 is hydrogen;

or a salt thereof.

4. The compound of claim 3 , wherein

R 2 is hydrogen, bromo, cyano, hydroxymethyl, hydroxyethyl, hydroxypropyl, ethynyl, methoxy, ethoxy, propoxy, phenyloxy, phenylthio, carboxy, carbamoyl, mono- or di-methylaminocarbonyl, pyridylmethylaminocarbonyl, hydroxymethylaminocarbonyl or mono- or di-methylamino;

R 3 and R 4 are independently hydrogen;

R 5 is phenyl, pyridyl, furyl, thienyl, pyrrolyl or pyrazolyl, each of which is optionally substituted by one or more substituent(s) selected from the group consisting of fluoro, chloro and methoxy;

R 6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl; and

R 7 is hydrogen;

or a salt thereof.

5. The compound of claim 4 , wherein

R 2 is hydrogen, cyano, ethynyl, methoxy, phenyloxy, phenylthio, carboxy, carbamoyl or methylamino; and

R 5 is phenyl, furyl or thienyl, each of which is optionally substituted by one or more substituent(s) selected from the group consisting of fluoro, chloro and methoxy;

or a salt thereof.

6. The compound of claim 5 , wherein

R 2 is hydrogen, cyano, carboxy, carbamoyl or methylamino;

R 5 is phenyl which is optionally substituted by one or more fluoro; and

R 6 is hydrogen, methyl, ethyl or isopropyl;

or a salt thereof.

7. A process for preparing the pyrazine compound of the following formula (I):

wherein

R 1 is

wherein

R 6 is hydrogen, or optionally substituted lower alkyl;

R 7 is hydrogen or halogen;

R 8 is alkyl;

R 2 is hydrogen; hydroxy; halogen; cyano; acyl; or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, aryloxy, arylthio, aryl, heterocyclic group or amino, each of which is optionally substituted by substituent(s);

R 3 and R 4 are independently hydrogen, lower alkyl or acyl; and

R 5 is cyano; or lower alkenyl, lower alkynyl, aryl or heterocyclic group, each of which is optionally substituted by substituent(s); or a salt thereof;

which comprises

(1) reacting of a compound of the formula (II):

wherein R 1 , R 2 , R 3 and R 4 are each as defined above, and

Hal is a halogen atom;

or a salt thereof,

with a compound of the formula (III):

R 5 -Z  (III)

wherein

R 5 is as defined above, and

Z is hydrogen, an alkali metal (e.g. lithium, sodium, potassium, etc.), SnBu 3 , BW 2 or Met-Hal;

wherein BW 2 is a part of organoboron compound; and

Met-Hal is a part of metalhalide compound;

or a salt thereof,

to give a compound of the formula (I):

wherein R 1 , R 2 , R 3 , R 4 and R 5 are each as defined above, or a salt thereof,

(2) hydrolyzing of a compound of the formula (Ia)

wherein R 3 , R 4 and R 5 are each as defined above, and

R 8 is as defined in claim 1 , or a salt thereof,

to give a compound of the formula (Iba):

wherein R 3 , R 4 and R 5 are each as defined above, and

R 9 is cyano, carbamoyl or carboxy;

or a salt thereof,

(3) alkylating to a nitrogen atom of a compound of the formula (Ib):

wherein R 2 , R 3 , R 4 and R 5 are each as defined above, or a salt thereof,

with a compound of the formula (IV):

R 10 —Y  (IV)

wherein R 10 is lower alkyl, aryl(lower)alkyl or heteroaryl(lower)alkyl, each of which is optionally substituted by one or more suitable substituent(s), and

Y is a leaving group;

or a salt thereof,

to give a compound of the formula (Ic):

wherein R 2 , R 3 , R 4 , R 5 and R 10 are each as defined above, or a salt thereof,

(4) hydrolyzing of a compound of the formula (Id):

wherein R 1 , R 3 , R 4 and R 5 are each as defined above, or a salt thereof,

to give a compound of the formula (Ie):

wherein R 1 , R 3 , R 4 and R 5 are each as defined above, or a salt thereof,

(5) decarboxylating of a compound (Ie) or a salt thereof above to give a compound of the formula (If):

wherein R 1 , R 3 , R 4 and R 5 are each as defined above, or a salt thereof,

(6) halogenating of a compound (If) or a salt thereof above to give a compound of the formula (Ih):

wherein R 1, R 3 , R 4 , R 5 and Hal are each as defined above, or a salt thereof,

(7) reacting of a compound (Ih) or a salt thereof above with a compound of the formula (V):

R 13 -Z  (V)

wherein Z is defined above, and

R 13 is lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, aryloxy, arylthio, acyl, aryl, heterocyclic group or amino, each of which is optionally substituted by substituent(s);

or a salt thereof,

to give a compound of the formula (Ij):

wherein R 1 , R 3 , R 4 , R 5 and R 13 are each as defined above, or a salt thereof,

(8) reacting of a compound of the formula (XI):

wherein R 1 is as defined above, or a salt thereof,

with aminomalonitrile, to give a compound of the formula (XII):

wherein R 1 and R 2 are each as defined above, or a salt thereof,

(9) halogenating of a compound of the formula (XV):

wherein R 1 , R 2 , R 3 and R 4 are each as defined above, or a salt thereof,

with a compound of the formula (XVI):

PO(Hal) 3   (XVI)

wherein Hal is as defined above,

to give a compound (II) or a salt thereof above.

8. The process of claim 7 , wherein BW 2 is a part of organoboron compound selected from the group consisting of B(OH) 2 , B(CHCH 3 CH(CH 3 ) 2 ) 2 , tetramethyl-1,3,2-dioxaborolan-2-yl, and 9-borabicyclo[3.3.1]nonanyl.

9. The process of claim 7 , wherein Met-Hal is a part of metalhalide selected from the group consisting of MgBr and ZnCl.

10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.

11. A method for treating a disease selected from the group consisting of depression, dementia, Parkinson's disease, anxiety, pain, and cerebral infarction, which comprises administering any of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.

12. A method for treating a disease selected from the group consisting of depression, dementia, Parkinson's disease and anxiety, which comprises administering any of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.

13. A method for treating Parkinson's disease, which comprises administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal in need thereof.

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