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Details for Patent: 6,407,236

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Details for Patent: 6,407,236

Title: Adenosine A3 receptor modulators
Abstract:The compounds of the following formula: ##STR1## wherein R, R.sup.1, R.sup.2 R.sup.3 and A have the meanings given in the specification, are endowed with selective A.sub.3 adenosine receptor agonist activity. These compounds can be used in a pharmaceutical composition to treat disorders caused by excessive activation of the A.sub.3 receptor, or can be used in a diagnostic application to determine the relative binding of other compounds to the A.sub.3 receptor. The compounds can be labeled, for example with fluorescent or radiolabels, and the labels used in vivo or in vitro to determine the presence of tumor cells which possess a high concentration of adenosine A.sub.3 receptors.
Inventor(s): Baraldi; Pier Giovanni (Ferrara, IT), Borea; Pier Andrea (Ferrara, IT)
Assignee: Medco Research, Inc. (Research Triangle Park, NC)
Filing Date:Aug 23, 1999
Application Number:09/379,300
Claims:1. A compound of the following formula: ##STR19##

wherein:

A is imidazole, pyrazole, or triazole;

R is --C(X)R.sup.1, --C(X)--N(R.sup.1).sub.2, --C(X)OR.sup.1, --C(X)SR.sup.1, --SO.sub.n R.sup.1, --SO.sub.n SR.sup.1, or SO.sub.n --N(R.sup.1).sub.2 ;

R.sup.1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, lower alkenyl, lower alkanoyl, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms;

R.sup.2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;

R.sup.3 is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with one or more substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, thioalkoxy, substituted thioalkoxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2 -alkyl, --SO.sub.2 -substituted alkyl, --SO.sub.2 -aryl, --SO.sub.2 -heteroaryl, and trihalomethyl;

X is O, S, or NR.sup.1 ; and

pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein R is --C(X)R.sup.1, --C(X)--N(R.sup.1).sub.2, --SO.sub.n R.sup.1 or SO.sub.n --N(R.sup.1).sub.2, wherein X is O or S.

3. The compound of claim 1 wherein R.sup.1 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.

4. The compound of claim 1 wherein R.sup.2 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.

5. The compound of claim 1 wherein R.sup.3 is furan.

6. The compound of claim 1 wherein X is O.

7. The compound of claim 1 wherein A is a triazolo ring.

8. The compound of claim 1 wherein A is a pyrazolo ring.

9. A radiolabeled compound of the following formula: ##STR20##

wherein:

A is imidazole, pyrazole, or triazole;

R is --C(X)R.sup.1, --C(X)--N(R.sup.1).sub.2, --C(X)OR.sup.1, --C(X)SR.sup.1, --SO.sub.n R.sup.1, --SO, SR.sup.1, or SO.sub.n --N(R.sup.1).sub.2 ;

R.sup.1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, lower alkenyl, lower alkanoyl, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms;

R.sup.2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;

R.sup.3 is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with one or more substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, thioalkoxy, substituted thioalkoxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2 -alkyl, --SO.sub.2 -substituted alkyl, --SO.sub.2 -aryl, --SO.sub.2 -heteroaryl, and trihalomethyl;

X is O, S, or NR.sup.1 ;

pharmaceutically acceptable salts thereof;

wherein one or more of the hydrogen atoms is a radioisotope.

10. The compound of claim 1 wherein, in the 5-6 membered heterocyclic ring containing one or more heteroatoms, the heteroatoms are N, O or S.

11. A radiolabeled compound of the following formula: ##STR21##

wherein:

A is imidazole, pyrazole, or triazole;

R is --C(X)R.sup.1, --C(X)--N(R.sup.1).sub.2, --C(X)OR.sup.1, --C(X)SR.sup.1, --SO.sub.n R.sup.1, --SO, SR.sup.1, or SO.sub.n --N(R.sup.1).sub.2 ;

R.sup.1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, lower alkenyl, lower alkanoyl, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms;

R.sup.2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;

R.sup.3 is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with one or more substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, thioalkoxy, substituted thioalkoxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2 -alkyl, --SO.sub.2 -substituted alkyl, --SO.sub.2 -aryl, --SO.sub.2 -heteroaryl, and trihalomethyl;

X is O, S, or NR.sup.1 ;

pharmaceutically acceptable salts thereof;

wherein .sup.14 C is a carbon radioisotope.

12. A fluorescent labeled compound of the following formula: ##STR22##

wherein:

A is imidazole, pyrazole, or triazole;

R is --C(X)R.sup.1, --C(X)--N(R.sup.1).sub.2, --C(X)OR.sup.1, --C(X)SR.sup.1, --SO.sub.n R.sup.1, --SO, SR.sup.1, or SO.sub.n --N(R.sup.1).sub.2 ;

R.sup.1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, lower alkenyl, lower alkanoyl, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms;

R.sup.2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;

R.sup.3 is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with one or more substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, thioalkoxy, substituted thioalkoxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2 -alkyl, --SO.sub.2 -substituted alkyl, --SO.sub.2 -aryl, --SO.sub.2 -heteroaryl, and trihalomethyl;

X is O, S, or NR.sup.1 ;

pharmaceutically acceptable salts thereof;

further comprising one or more fluorescent labels; wherein the fluorescent label is selected from the group of fluorescent labels consisting of fluorescein, 5,6-carboxymethyl fluorescein, Texas red, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose, coumarin, dansyl chloride and rhodamine.

13. A method of treating diseases mediated by adenosine A3 receptors, wherein said diseases are selected from the group consisting of hypertension, inflammation, mast cell degranulation, cardiac hypoxia, and protecting against cerebral ischemia, comprising administering to a patient in need of treatment thereof an effective amount of a compound of claim 1.

14. The method of claim 13 wherein R is --C(X)R1, --C(X)--N(R.sup.1).sub.2, --SO.sub.n R.sup.1 or --SO.sub.n --N(R.sup.1).sub.2, wherein X is O or S.

15. The method of claim 13 wherein R.sup.1 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.

16. The method of claim 13 wherein R.sup.2 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.

17. The method of claim 13 wherein X is O.

18. The method of claim 13 wherein A is a pyrazolo ring.

19. The method of claim 13 wherein A is a triazolo ring.

20. The method of claim 13 wherein the disorder to be treated is selected from the group consisting of cardiac hypoxia and cerebral ischemia.

21. A method for determining the presence of tumor cells which possess a high concentration of adenosine A.sub.3 receptors in a patient comprising:

a) administering to the patient a compound of claim 9 which includes a radiolabel which can be detected following binding of the compound to tumor cells,

b) allowing the compound to bind to the tumor cells; and

c) detecting the radiolabel.

22. A method for determining the presence of tumor cells which possess a high concentration of adenosine A.sub.3 receptors in a cell sample comprising:

a) preparing a suspension of the cells in a cell culture media,

b) administering to the cells a compound of claim 9 which includes a radiolabel which can be detected following binding of the compound to tumor cells,

c) allowing the compound to bind to the tumor cells; and

d) detecting the radiolabel.

23. A method for determining the presence of residual tumor cells which possess a high concentration of adenosine A3 receptors following surgical removal of a tumor, comprising:

a) administering to the patient, before, after or during surgical removal of a tumor, a compound of claim 9 which includes a radiolabel which can be detected following binding of the compound to residual tumor cells,

b) allowing the compound to bind to the residual tumor cells, and

c) detecting the radiolabel.

24. A method of treating allergic disease, comprising administering to a patient in need of treatment thereof an effective amount of a compound of claim 1 wherein the allergic disease is selected from the group consisting of allergic rhinitis, allergic pollinosis, poison ivy induced responses, urticaria, scleroderma, arthritis, inflammatory bowel disease and asthma.

25. The method of claim 24 wherein R is --C(X)R.sup.1, --C(X)--N(R.sup.1).sub.2, --SO.sub.n R.sup.1, or SO.sub.n --N(R.sup.1).sub.2, wherein X is O or S.

26. The method of claim 24 wherein R.sup.1 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.

27. The method of claim 24 wherein R.sup.2 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.

28. The method of claim 24 wherein X is O.

29. The method of claim 24 wherein A is a pyrazolo ring.

30. The method of claim 24 wherein A is a triazolo ring.

31. A method of treating cancer disease with high concentrations of adenosine A.sub.3 receptors, comprising administering to a patient in need of treatment thereof an effective amount of a compound of claim 1 wherein the cancer disease is selected from the group consisting of leukemia and lymphoma.

32. The method of claim 31 wherein R is --C(X)R.sup.1, --C(X)--N(R.sup.1).sub.2, --SO.sub.n R.sup.1, or SO.sub.n --N(R.sup.1).sub.2, wherein X is O or S.

33. The method of claim 31 wherein R.sup.1 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.

34. The method of claim 31 wherein R is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.

35. The method of claim 31 wherein X is O.

36. The method of claim 31 wherein A is a pyrazolo ring.

37. The method of claim 31 wherein A is a triazolo ring.

38. A method for determining the presence of tumor cells which possess a high concentration of adenosine A.sub.3 receptors in a patient comprising:

a) administering to the patient a compound of claim 11 which includes a radiolabel which can be detected following binding of the compound to tumor cells,

b) allowing the compound to bind to the tumor cells; and

c) detecting the radiolabel.

39. A method for determining the presence of tumor cells which possess a high concentration of adenosine A.sub.3 receptors in a cell sample comprising:

a) preparing a suspension of the cells in a cell culture media,

b) administering to the cells a compound of claim 11 which includes a radiolabel which can be detected following binding of the compound to tumor cells,

c) allowing the compound to bind to the tumor cells; and

d) detecting the radiolabel.

40. A method for determining the presence of residual tumor cells which possess a high concentration of adenosine A3 receptors following surgical removal of a tumor, comprising:

a) administering to the patient, before, after or during surgical removal of a tumor, a compound of claim 11 which includes a radiolabel which can be detected following binding of the compound to residual tumor cells,

b) allowing the compound to bind to the residual tumor cells, and

c) detecting the radiolabel.

41. A method for determining the presence of tumor cells which possess a high concentration of adenosine A.sub.3 receptors in a patient comprising:

a) administering to the patient a compound of claim 12 which includes a fluorescent label which can be detected following binding of the compound to tumor cells,

b) allowing the compound to bind to the tumor cells; and

c) detecting the fluorescent label.

42. A method for determining the presence of tumor cells which possess a high concentration of adenosine A.sub.3 receptors in a cell sample comprising:

a) preparing a suspension of the cells in a cell culture media,

b) administering to the cells a compound of claim 12 which includes a fluorescent label which can be detected following binding of the compound to tumor cells,

c) allowing the compound to bind to the tumor cells; and

d) detecting the fluorescent label.

43. A method for determining the presence of residual tumor cells which possess a high concentration of adenosine A3 receptors following surgical removal of a tumor, comprising:

a) administering to the patient, before, after or during surgical removal of a tumor, a compound of claim 12 which includes a fluorescent label which can be detected following binding of the compound to residual tumor cells,

b) allowing the compound to bind to the residual tumor cells, and

c) detecting the fluorescent label.
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