Compounds for the treatment of ischemia

Details Compounds for the treatment of ischemia Compounds for the treatment of ischemia

2000-08-17

2004-10-12

Crane, L. E. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S027220, C536S027230, C536S027630, C514S046000

Reexamination Certificate

active

06803457

ABSTRACT:

BACKGROUND OF INVENTION
This invention relates to adenosine A-3 receptor agonists, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat for example, ischemia particularly, perioperative myocardial ischemic injury in mammals, including humans.
Mycardial ischemic injury can occur in out-patient as well as in perioperative settings and can lead to the development of sudden death, myocardial infarction or congestive heart failure. There is an unmet medical need to prevent or minimize myocardial ischemic injury, particularly perioperative myocardial infarction. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
Pharmacological cardioprotection would reduce the incidence and progression of myocardial infarction and dysfunction occurring in these surgical settings (perioperatively). In addition to reducing myocardial damage and improving post-ischemic myocardial function in patients with ischemic heart disease, cardioprotection would also decrease the incidence of cardiac morbidity and mortality due to myocardial infarction and dysfunction in patients “at risk” (such as greater than 65 years, exercise intolerant, coronary artery disease, diabetes mellitus, hypertension) that require non-cardiac surgery.
U.S. Pat. No. 5,604,210 discloses the use of certain adenosine type compounds for the prevention or treatment of a brain edema, an intracranial hemorrhage and a cerebral infarction.
U.S. Pat. No. 5,688,774 discloses A
3
selective agonists, particularly, adenine compounds having selected substituents at the 2, 6 and 9 positions, and related substituted compounds, particularly those containing substituents on the benzyl and/or uronamide groups as agents which activate the A
3
receptor.
U.S. Pat. No. 5,773,423 discloses N
6
-benzyladenosine-5′-N-uronamide and related substituted compounds, particularly those containing substituents on the benzyl and/or uronamide groups, and modified xanthine ribosides for the activation of the A
3
adenosine receptor.
J. Med. Chem. 1994, 37, 636-646, “Structure-Activity Relationships of N
6
-Benzyladenosine-5′-uronamides as A
3
-Selective Agonists” discloses the synthesis of adenosine analogues modified at the 5′-position as uronamides and/or as N
6
-benzyl derivatives which are potentially useful as pharmacological and biochemical probes for A
3
receptors.
J. Med. Chem. 1995, 38, 1174-1188, “Search for New Purine- and Ribose-Modified Adenosine Analogues as Selective Agonists and Antagonists at Adenosine Receptors”, discloses that the binding affinities at rat A
1
, A
2a
, and A
3
adenosine receptors of a wide range of derivatives of adenosine have been determined. In particular, 3′-&bgr;-amino compounds were found to have no activity.
J. Med. Chem. 1995, 38, 1720-1735, “Structure-Activity Relationships of 9-Alkyladenine and Ribose-Modified Adenosine Derivatives at Rat A
3
Adenosine Receptors” discloses the synthesis of 9-alkyladenine derivatives and ribose-modified N-benzyladenosine derivatives as leads for the development of antagonists for the rat A
3
adenosine receptor.
U.S. Pat. No. 5,817,760 discloses recombinant human adenosine receptors A1, A2a, A2b, and A3 which were prepared by cDNA cloning and polymerase chain reaction techniques. The recombinant adenosine receptors can be utilized in an assay to identify and evaluate entities that bind to or enhance binding to adenosine receptors.
Thus, while there has been some progress in this field of art, there is clearly a need and a continuing search in this field of art for treatments for perioperative myocardial ischemia.
SUMMARY OF THE INVENTION
This invention is directed to compounds of Formula I
prodrugs thereof and pharmaceutically acceptable salts of said compounds and of said prodrug, wherein
X is oxy, methylene or thio;
Y is CH or N;
Z is H, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkyloxy, trifluoromethyl or halo;
R
1
is hydroxymethyl, (C
1
-C
3
)alkoxymethyl, (C
3
-C
5
)cycloalkoxymethyl, carboxy, (C
1
-C
3
)alkoxycarbonyl, (C
3
-C
5
)cycloalkoxycarbonyl, 1,1-aminoiminomethyl, 1,1-(mono-N- or di-N,N-(C
1
-C
4
)alkylamino)iminomethyl, 1,1-(mono-N- or di-N,N-(C
3
-C
5
)cycloalkylamino)iminomethyl, carbamoyl, mono-N- or di-N,N-(C
1
-C
4
)alkylaminocarbonyl, mono-N- or di-N,N-(C
3
-C
5
)cycloalkylaminocarbonyl or N-(C
1
-C
4
)alkyl-N-(C
3
-C
5
)cycloalkylaminocarbonyl;
R
2
is H, (C
1
-C
3
)alkyl or (C
3
-C
5
)cycloalkyl;
R
3
is halo, trifluoromethyl, cyano, (C
1
-C
3
)alkyl, (C
1
-C
3
)alkyloxy, ethenyl or ethynyl;
D is oxy, thio, NH, (C
1
-C
6
)alkyloxy, (C
1
-C
6
)alkylthio or (C
1
-C
6
)alkylamino;
G is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said G is optionally mono-, di- or tri-substituted independently with halo, (C
1
-C
3
)alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, (C
3
-C
6
)cycloalkyl, hydroxy or (C
1
-C
3
)alkoxy or
G is cyano, (C
1
-C
4
)alkoxycarbonyl, (C
3
-C
5
)cycloalkoxycarbonyl, C(O)NR
4
R
5
, C(S)NR
4
R
5
, C(NH)NR
4
R
5
, C(N(C
1
-C
3
)alkyl)NR
4
R
5
or C(N(C
3
-C
10
)cycloalkyl)NR
4
R
5
;
R
4
is a bond, H, (C
1
-C
10
)alkyl, hydroxy, (C
1
-C
10
)alkoxy, (C
3
-C
10
)cycloalkoxy or a partially saturated, fully saturated or fully unsaturated five to eight membered ring, optionally linked through (C
1
-C
3
)alkyl, optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring or a bicyclic ring with optional (C
1
-C
3
) bridge (e.g., adamantane) optionally linked through (C
1
-C
3
)alkyl, said bicyclic ring or bridged bicyclic ring optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen wherein said (C
1
-C
10
)alkyl, (C
1
-C
10
)alkoxy, (C
3
-C
10
)cycloalkoxy or R
4
ring(s) is optionally mono-, di- or tri-substituted independently with halo, (C
1
-C
3
)alkyl, trifluoromethyl, nitro, cyano, (C
3
-C
5
)cycloalkyl, hydroxy or (C
1
-C
3
)alkoxy;
R
5
is a bond, H, (C
1
-C
10
)alkyl or (C
1
-C
10
)cycloalkyl; or
R
4
and R
5
taken together with the nitrogen to which they are attached form a fully saturated or partially unsaturated four to nine membered ring, said ring optionally bridged, optionally having one to three additional heteroatoms selected independently from oxygen, sulfur and nitrogen, said ring optionally mono- or di-substituted independently with oxo, hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
8
)alkyl, amino, mono-N- or di-N,N-(C
1
-C
4
)alkylaminocarbonyl, mono-N- or di-N,N-(C
3
-C
5
)cycloalkylaminocarbonyl, N-(C
1
-C
4
)alkyl-N-(C
3
-C
5
)cycloalkylaminocarbonyl, mono-N- or di-N,N-(C
1
-C
4
)alkylamino, mono-N- or di-N,N-(C
3
-C
5
)cycloalkylamino, N-(C
1
-C
4
)alkyl-N-(C
3
-C
5
)cycloalkylamino, formylamino, (C
1
-C
4
)alkylcarbonylamino, (C
3
-C
5
)cycloalkylcarbonylamino, (C
1
-C
4
)alkoxycarbonylamino, N-(C
1
-C
4
)alkoxycarbonyl-N-(C
1
-C
4
)alkylamino, (C
1
-C
4
)sulfamoyl, (C
1
-C
4
)alkylsulfonylamino, (C
3
-C
5
)cycloalkylsulfonylamino or a partially saturated, fully saturated or fully unsaturated five to eight membered ring, optionally linked through (C
1
-C
3
)alkyl, optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally linked through (C
1
-C
3
)alkyl, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, optionally mono or di-substituted with halo, trifluoromethyl, trifluoromethoxy (C
1
-C
3
)alkyl or (C
1
-C
3
)alkoxy.
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