RU2002135620A

RU2002135620A - A2A ADENOSINE RECEPTOR ANTAGONISTS

Info

Publication number: RU2002135620A
Application number: RU2002135620/04A
Authority: RU
Inventors: Бернард Р. НОЙШТАДТ; Нил Э. ЛИНДО; Вильям Дж. ГРИНЛИ; Дин ТАЛШИАН; Лайза С. СИЛВЕРМАН; Ян КСИА; Крейг Д. БОЙЛ; Семюэл ЧАКАЛАМАННИЛ
Original assignee: Шеринг Корпорейшн
Priority date: 2000-05-26
Filing date: 2001-05-24
Publication date: 2004-12-10

Claims

1. Derivatives of 5-amino-pyrazolo- [4,3-e] -1,2,4-triazolo [1,5-c] pyrimidine of the General formula

where R is R ¹ -furanyl, R ¹ -thienyl, R ¹ -pyridyl, R ¹ -pyridyl-N-oxide, R ¹ -oxazolyl, R ¹⁰ -phenyl, R ¹ -pyrrolyl or (C ₄ -C ₆ ) - cycloalkenyl;

X is (C ₂ -C ₆ ) alkylene or —C (O) CH ₂ -;

Y is —N (R ² ) CH ₂ CH ₂ N (R ³ ) -, —OCH ₂ CH ₂ N (R ² ) -, —O—, —S—, —CH ₂ S—, - (CH ₂ ) _2- NH- or

Z is R ⁵ -phenyl, R ⁵ -phenyl- (C ₁ -C ₆ ) -alkyl, R ⁵ -heteroaryl, diphenylmethyl, R ⁶ -C (O) -, R ⁶ -SO ₂ -, R ⁶ -OC ( O) -, R ⁷ -N (R ⁸ ) -C (O) -, R ⁷ -N (R ⁸ ) -C (S) -,

phenyl-CH (OH) - or phenyl-C (= NOR ² ) -;

or if Q means

then Z also means a phenylamino or pyridylamino group;

or Z and Y together mean

R ¹ means from 1 to 3 substituents independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl, -CF ₃ , halogen, -NO ₂ , -NR ¹² R ¹³ , (C ₁ -C ₆ ) -alkoxyl, (C ₁ -C ₆ ) -alkylthioyl, (C ₁ -C ₆ ) -alkylsulfinyl and (C ₁ -C ₆ ) -alkylsulfonyl;

R ² and R ^{3 are} independently selected from the group consisting of hydrogen and (C ₁ -C ₆ ) -alkyl;

m and n are independently equal to 2-3;

Q means

R ⁴ means 1-2 substituents independently selected from the group consisting of hydrogen and (C ₁ -C ₆ ) -alkyl, or two R ⁴ substituents at one carbon atom can form a group = O;

R ⁵ means from 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) -alkyl, hydroxyl, (C ₁ -C ₆ ) -alkoxyl, -CN, di - ((C ₁ -C ₆ ) -alkyl) -amino, -CF ₃ , -OCF ₃ , acetyl, -NO ₂ , hydroxy- (C ₁ -C ₆ ) -alkoxyl, (C ₁ -C ₆ ) -alkoxy- (C ₁ - C ₆ ) alkoxy, di - ((C ₁ -C ₆ ) alkoxy) (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkoxy ( C ₁ -C ₆ ) -alkoxyl, carboxy- (C ₁ -C ₆ ) -alkoxyl, (C ₁ -C ₆ ) -alkoxycarbonyl- (C ₁ -C ₆ ) -alkoxyl, (C ₃ -C ₆ ) -cycloalkyl - (C ₁ -C ₆ ) -alkoxyl, di - ((C ₁ -C ₆ ) -alkyl) amino (C ₁ -C ₆ ) -alkoxyl, morpholinyl, (C ₁ -C ₆ ) -alkyl-SO ₂ - (C ₁ -C ₆₎ alkyl-SO- (C ₁ -C ₆₎ -alkoxy, tetra idropiraniloksil, (C ₁ -C ₆₎ -alkilkarbonil- (C ₁ -C ₆₎ -alkoxy, (C ₁ -C ₆₎ -alkoxycarbonyl, (C ₁ -C ₆₎ -alkilkarbo-niloksi- (C ₁ -C ₆ ) -alkoxyl, -SO ₂ NH ₂ , phenoxyl,

or adjacent R ⁵ substituents together are —O — CH ₂ —O—, —O — CH ₂ —CH ₂ —O—, —O — CF ₂ —O—, or —O — CF ₂ CF ₂ —O— and form a cycle together with the carbon atoms to which they are attached;

R ⁶ means (C ₁ -C ₆ ) -alkyl, R ⁵ -phenyl, R ⁵ -phenyl- (C ₁ -C ₆ ) -alkyl, thienyl, pyridyl, (C ₃ -C ₆ ) -cycloalkyl, (C ₁ -C ₆ ) -alkyl-OS (O) -NH- (C ₁ -C ₆ ) -alkyl-, di - ((C ₁ -C ₆ ) -alkyl) -aminomethyl or

R ⁷ means (C ₁ -C ₆ ) -alkyl, R ⁵ -phenyl or R ⁵ -phenyl- (C ₁ -C ₆ ) -alkyl;

R ⁸ means hydrogen or (C ₁ -C ₆ ) -alkyl, or R ⁷ and R ⁸ together represent - (CH ₂ ) pA- (CH ₂ ) q, where p and q are independently 2 or 3 and A represents a bond, —CH ₂ -, —S— or —O—, and form a ring together with the nitrogen atom to which they are attached;

R ⁹ means 1-2 groups independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl, hydroxyl, (C ₁ -C ₆ ) -alkoxyl, halogen, -CF ₃ and (C ₁ -C ₆ ) -alkoxy- (C ₁ -C ₆ ) -alkoxyl;

R ¹⁰ means from 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) -alkyl, hydroxyl, (C ₁ -C ₆ ) -alkoxyl, -CN, -NH ₂ , (C ₁ -C ₆ ) -alkylamino, di - ((C ₁ -C ₆ ) -alkyl) amino group, -CF ₃ , -OCF ₃ and -S (O) _0-2 (C ₁ -C ₆ ) -alkyl;

R ¹¹ means H, (C ₁ -C ₆ ) -alkyl, phenyl, benzyl, (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkoxy- (C ₁ -C ₆ ) -alkyl, di - ((C ₁ -C ₆ ) -alkyl) -amino (C ₁ -C ₆ ) -alkyl, pyrrolidinyl- (C ₁ -C ₆ ) -alkyl or piperidino (C ₁ -C ₆ ) -alkyl;

R ¹² is H or (C ₁ -C ₆ ) -alkyl;

R ¹³ means (C ₁ -C ₆ ) -alkyl-C (O) - or (C ₁ -C ₆ ) -alkyl-SO ₂ -,

and pharmaceutically acceptable salts thereof.

2. Derivatives of 5-amino-pyrazolo- [4,3-e] -1,2,4-triazolo [1,5-c] pyrimidine of the general formula according to claim 1, wherein R is R ¹ -furanyl.

3. Derivatives of 5-amino-pyrazolo- [4,3-e] -1,2,4-triazolo [1,5-c] pyrimidine of the general formula according to claim 1, where X means (C ₂ -C ₆ ) - alkylene.

4. Derivatives of 5-amino-pyrazolo- [4,3-e] -1,2,4-triazolo [1,5-c] pyrimidine of the general formula according to claim 1, where Y means

5. Derivatives of 5-amino-pyrazolo- [4,3-e] -1,2,4-triazolo [1,5-c] pyrimidine of the general formula according to claim 4, where Q means

m and n are 2, and R ⁴ means N.

6. Derivatives of 5-amino-pyrazolo- [4,3-e] -1,2,4-triazolo [1,5-c] pyrimidine of the general formula according to claim 1, where Z is R ⁵ -phenyl, R ⁵ - heteroaryl, R ⁶ —C (O) —or R ⁶ —SO ₂ -.

7. Derivatives of 5-amino-pyrazolo- [4,3-e] -1,2,4-triazolo [1,5-c] pyrimidine of the general formula according to claim 6, where R ⁵ means H, halogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxyl, hydroxy- (C ₁ -C ₆ ) -alkoxyl or (C ₁ -C ₆ ) -alkoxy- (C ₁ -C ₆ ) -alkoxyl, and R ⁶ means R ^{5 is} phenyl.

8. Derivatives of 5-amino-pyrazolo- [4,3-e] -1,2,4-triazolo [1,5-c] pyrimidine of the general formula according to claim 1, where X is a group —CH ₂ —CH ₂ - , and R and ZY are as indicated in the table below:

9. A pharmaceutical composition having an adenosine A _2a receptor antagonist activity, comprising an active substance and a pharmaceutically acceptable carrier, wherein the active substance comprises the compound of claim 1 in a therapeutically effective amount.

10. The pharmaceutical composition according to claim 9, characterized in that it further comprises 1-3 other agents suitable for the treatment of Parkinson's disease.

11. A method of treating depression, cognitive diseases, neurodegenerative diseases or stroke by introducing an active substance, characterized in that the compound according to claim 1 is administered as an active substance.

12. The method according to claim 11, characterized in that in the case of the treatment of Parkinson's disease, 1-3 other agents suitable for the treatment of Parkinson's disease are additionally administered.

13. The method of obtaining the intermediate 5-amino-pyrazolo- [4,3-e] -1,2,4-triazolo [1,5-s] pyrimidine of the formula II

R ¹² is H or (C ₁ -C ₆ ) -alkyl;

R ¹³ means (C ₁ -C ₆ ) -alkyl-C (O) - or (C ₁ -C ₆ ) -alkyl-SO ₂ -,

characterized in that the compound of formula IX

where R has the above meaning, is subjected to dehydration rearrangement.

14. The method according to item 13, wherein the compound of formula IX is obtained by (1) reacting 2-amino-4,6-dihydroxypyrimidine of formula VI

with POCl ₃ in dimethylformamide, (2) reacting the resulting 2-amino-4,6-dichloropyrimidin-5-carboxaldehyde of formula VII

with a hydrazide of the formula H ₂ N-NH-C (O) -R, where R has the meaning indicated in paragraph 13, (3) and the interaction of the resulting product of the formula VIII

where R has the meaning indicated in paragraph 13, with hydrazine hydrate.

15. The method of obtaining the intermediate 7-bromoalkyl-5-amino-2- (R-substituted) -pyrazolo- [4,3th] -1,2,4-triazolo [1,5-c] pyrimidine of the formula IIIa

where R is R ¹ -furanyl, R ¹ -thienyl, R ¹ -pyridyl, R ¹ -pyridyl-N-oxide, R ¹ -oxazolyl, R ¹ -phenyl, R ¹ -pyrrolyl or (C ₄ -C ₆ ) - cycloalkenyl;

R ¹² is H or (C ₁ -C ₆ ) -alkyl;

R ¹³ means (C ₁ -C ₆ ) -alkyl-C (O) - or (C ₁ -C ₆ ) -alkyl-SO ₂ -,

characterized in that (1) a chloride of formula VIII

where R has the above meaning, is subjected to interaction with hydroxyalkylhydrazine of the formula HO-

(CH ₂ ) _r —NHNH ₂ , where r is 2-6, (2) the resulting compound of formula X,

subjected to dehydration rearrangement to obtain a tricyclic intermediate of formula XI

(3) which is converted to the bromide of formula IIIa.