Triazolo(4,5-d)pyrimidine compounds

• US 6,525,060 B1
• Filed: 03/08/2000
• Issued: 02/25/2003
• Est. Priority Date: 12/04/1998
• Status: Expired

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Inventors: Willis, Paul, Guile, Simon, Ingall, Anthony, Hardern, David, Springthorpe, Brian
• Primary Examiner(s): Ford, John M.
• Application Number:
  US09/508,195
• Time in Patent Office: 1,084 Days
• Field of Search: 514/258, 544/254
• US Class Current: 514/261.1
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 211/40 containing only non-condensed rings
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Triazolo[4,5-d]pyrimidine compounds, their use as medicaments, compositions containing them and processes for their preparation. The compounds of the invention have the formula (I) as follows:

wherein R, X and R¹ through R³ are as defined in the specification.

Claims

1. A compound of formula (I)

wherein:

R¹ is C_3-5 alkyl optionally substituted by one or more halogen atoms;

R² is a phenyl group, optionally substituted by one or more fluorine atoms;

R³ and R⁴ are both hydroxy;

R is XOH, where X is CH₂, OCH₂CH₂ or a bond;

or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt provided that;

when X is CH₂ or a bond, R¹ is not propyl;

when X is CH₂ and R¹ is CH₂CH₂CF₃, butyl or pentyl, the phenyl group at R² must be substituted by fluorine;

when X is OCH₂CH₂ and R¹ is propyl, the phenyl group at R² must be substituted by fluorine.

2. A compound according to claim 1 in which R¹ is 3,3,3,-trifluoropropyl, butyl or propyl.

3. A compound according to claim 1 in which R² is phenyl or 4-fluorophenyl or 3,4-difluorophenyl.

4. A compound according to claim 1 in which R is CH₂OH or OCH₂CH₂OH.

5. A compound according to claim 1 which is:

[1R-[1α

,2α

,3β

(1R*,2S*),5β

]]-3-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;

[1R-[1α

,2α

,3β

(1R*,2S*),5β

]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;

[1S-(1α

,2α

,3β

(1S*,2R*),5β

]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;

1R-[1α

,2α

,3β

(1R*,2S*),5β

]]-3-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo [4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;

[1S-[1α

,2β

,3β

,4α

(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(4-flurophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol;

[1S-(1α

,2α

,3β

(1S*,2R*),5β

]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;

[1S-[1α

,2α

,3β

,5β

(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol [1S-[1α

,2β

,3β

,4α

(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol;

[1S-[1α

,2α

,3β

(1S*,2R*),5β

]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diol;

or pharmaceutically acceptable salts or solvates thereof, or solvates of such salts.

6. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable diluent, adjuvent and/or carrier.

7. A method of treatment of post-myocardial infarction which comprises administering to a patient suffering therefrom a therapeutically effective amount of a compound according to claim 1.

8. A process for the preparation of a compound of formula (I) which comprises reacting a compound of formula (II):

where R, R¹, R³ and R⁴ are as defined in claim 1, or are protected derivatives thereof, or R³ and R⁴ together form a bond in the 5-membered ring, or R is CH₂CH₂OR′

where R′

is C_1-6 alkyl or benzyl, and L is a leaving group, with a compound of formula (III);

where R² is defined in claim 1 or is a protected derivative thereof, in the presence of a base in an inert solvent at ambient or elevated temperature, and optionally thereafter and in any order;

converting one or more functional groups into further functional groups;

removing any protecting groups;

forming a pharmaceutically acceptable salt or solvate, or a solvate of such a salt.

14. A method of treatment of stroke which comprises administering to a person suffering therefrom a therapeutically effective amount of the compound according to claim 1.

9. The compounds:

[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;

[[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropy)lthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;

[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]-6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;

[3aR-(3aα

,4α

,6α

,6aα

)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;

[3aR-(3aα

,4α

,6α

,6aα

)]-[[6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]acetic acid, methyl ester;

[3aR-(3aα

,4α

,6α

,6aα

)]-[[6-[7-Bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]acetic acid, methyl ester.

10. The compounds:

[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]]-[[6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]acetic acid, methyl ester;

[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]]-6-[[7-[2-(3,4-Difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol;

[3aR-(3aα

,4α

,6α

,6aα

)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;

[3aR-(3aα

,4α

,6aα

)]-6-[7-Amino-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;

11. The compounds:

[3aR-(3aα

,4α

,6α

,6aα

)]-6-[7-Amino-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;

[3aR-(3aα

,4α

,6α

,6aα

)]-6-[7-Amino-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol, acetate;

[3aR-(3aα

,4α

,6α

,6aα

)]-6-[7-Bromo-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol, acetate;

[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]]-6-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol, acetate;

[3aR-[3aα

,4α

,6α

,6aα

(1S*,2R*)]]-6-[7-[[(4-Fluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimdin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;

[3aR-[3aα

,4α

,6α

,6aα

(1S*,2R*)]]-6-[[7-[(4-Fluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;

12. The compounds:

[3aR-[3aα

,4α

,6α

,6aα

(1S*,2R*)]]-6-[7-[[(4-Fluorophenyl)cyclopropyl]amino]-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;

[1S-(1α

,2α

,3β

(1S*,2R*),5β

)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;

(1S-cis) 2-[[4-[7-Chloro-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl ester;

[1S-(cis)] 2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl ester;

[1S-(cis)] 2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-1-ethanol;

13. The compounds:

[3aR-(3aα

,4α

,6α

,6aα

)]-2-[6-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol;

[3aR-(3aα

,4α

,6α

,6aα

)]-2-[6-[7-Bromo-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol;

[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]-2-[6-(7-Phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-1,3-dioxol-4-yloxy]ethanol;

[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]-6-[[7-[(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;

[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]]-6-[[7-[(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;

[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]]-6-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;

[3aR-[3aα

,4α

,6α

(1R*,2S*),6aα

]]-2-[6-[[5-(Butylthio)-7-chloro-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol;

[3aR-[3aα

,4α

,6aα

(1R*,2S*),6aα

]]-2-[6-[[5-(Butylthio)-7-[2-phenylcyclopropyl]amino-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol;