Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-18
2002-12-10
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S406000, C548S255000, C548S362500, C548S306100, C546S165000, C546S145000, C546S175000
Reexamination Certificate
active
06492401
ABSTRACT:
BACKGROUND OF INVENTION
This invention relates to sodium-hydrogen exchanger type 1 (NHE-1) inhibitors, 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.
The mechanism(s) responsible for the myocardial injury observed after ischemia and reperfusion is not fully understood.
A variety of publications have disclosed the use of guanidine derivatives as useful for the treatment of, for example arrhythmias.
U.S. Pat. No. 5,698,581, granted Dec. 16, 1997 (EP 676395 A2 published 1995), discloses certain substituted N-heteroarylguanidines as inhibitors of the (Na+/H+) exchange transport system useful for the treatment of, for example, arrhythmias.
EP 803 501 A1, published Oct. 10, 1997, discloses substituted guanidine derivatives useful as (Na+/H+) exchange inhibitors.
WO 94/26709 discloses guanidine derivatives as inhibitors of (Na+/H+) exchange in cells.
PCT/JP97/04650 application published on Jun. 25, 1998 discloses N-[(substituted five-membered heteroaryl)carbonyl]guanidine compounds which are stated to be useful as inhibitors of Na
+
/H
+
exchange and consequently effective for the treatment of various diseases such as hypertension, arrhythmia, angina pectoris, myocardial infarct, arteriosclerosis, and complications of diabetes.
Thus, 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 a compound of Formula I
a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug wherein
Z is carbon connected and is a five-membered, diaza, diunsaturated ring having two contiguous nitrogens, said ring optionally mono-, di-, or tri-substituted with up to three substituents independently selected from R
1
, R
2
and R
3
;
or
Z is carbon connected and is a five-membered, triaza, diunsaturated ring, said ring optionally mono- or di-substituted with up to two substituents independently selected from R
4
and R
5
;
wherein R
1
, R
2
, R
3
, R
4
and R
5
are each independently hydrogen, hydroxy(C
1
-C
4
)alkyl, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkylthio, (C
3
-C
4
)cycloalkyl, (C
3
-C
7
)cycloalkyl(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkoxy(C
1
-C
4
) alkyl, mono-N-— or di-N,N—(C
1
-C
4
)alkylcarbamoyl, M or M(C
1
-C
4
)alkyl, any of said previous (C
1
-C
4
)alkyl moieties optionally having from one to nine fluorines; said (C
1
-C
4
)alkyl or (C
3
-C
4
)cycloalkyl optionally mono- or di-substituted independently with hydroxy, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alklthio, (C
1
-C
4
)alkylsulfinyl, (C
1
-C
4
)alkylsulfonyl, (C
1
-C
4
)alkyl, mono-N- or di-N,N—(C
1
-C
4
)alkylcarbamoyl or mono-N— or di-N,N—(C
1
-C
4
)alkylaminosulfonyl; and said (C
3
-C
4
)cycloalkyl optionally having from one to seven fluorines;
wherein M 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;
said M is optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon or nitrogen with up to three substituents independently selected from R
6
, R
7
and R
8
, wherein one of R
6
, R
7
and R
8
is optionally a partially saturated, fully saturated, or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen optionally substituted with (C
1
-C
4
)alkyl and additionally R
6
, R
7
and R
8
are optionally hydroxy, nitro, halo, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkoxycarbonyl, (C
1
-C
4
)alkyl, formyl, (C
1
-C
4
)alkanoyl, (C
1
-C
4
)alkanoyloxy, (C
1
-C
4
)alkanoylamino, (C
1
-C
4
)alkoxycarbonylamino, sulfonamido, (C
1
-C
4
)alkylsulfonamido, amino, mono-N— or di-N,N—(C
1
-C
4
)alkylamino, carbamoyl, mono N— or di-N,N—(C
1
-C
4
)alkylcarbamoyl, cyano, thiol, (C
1
-C
4
)alkylthio, (C
1
-C
4
)alkylsulfinyl, (C
1
-C
4
)alkylsulfonyl, mono-N— or di-N,N—(C
1
-C
4
)alkylaminosulfonyl, (C
2
-C
4
)alkenyl, (C
2
-C
4
)alkynyl or (C
5
-C
7
)cycloalkenyl,
wherein said (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl, (C
1
-C
7
)alkanoyl, (C
1
-C
4
)alkylthio, mono-N— or di-N,N—(C
1
-C
4
)alkylamino or (C
3
-C
7
)cycloalkyl R
6
, R
7
and R
8
substituents are optionally mono-substituted independently with hydroxy, (C
1
-C
4
)alkoxycarbonyl, (C
3
-C
7
)cycloalkyl, (C
1
-C
4
)alkanoyl, (C
1
-C
4
)alkanoylamino, (C
1
-C
4
)alkanoyloxy, (C
1
-C
4
)alkoxycarbonylamino, sulfonamido; (C
1
-C
4
)alkylsulfonamido, amino, mono-N— or di-N,N—(C
1
-C
4
) alkylamino, carbamoyl, mono-N— or di-N,N—(C
1
-C
4
)alkylcarbamoyl, cyano, thiol, nitro, (C
1
-C
4
)alkylthio, (C
1
-C
4
)alkylsulfinyl, (C
1
-C
4
)alkylsulfonyl or mono-N— or di-N,N—(C
1
-C
4
)alkylaminosulfonyl or optionally substituted with one to nine fluorines.
A preferred group of compounds, designated the A group, contains those compounds having the Formula I as shown above wherein Z is
R
1
and R
3
are each independently hydrogen, (C
1
-C
4
)alkyl, (C
3
-C
7
)cycloalkyl, phenyl or phenyl(C
1
-C
4
)alkyl, said (C
1
-C
4
)alkyl optionally substituted with from one to nine fluorines, said R
1
and R
3
substituents optionally mono- or di-subtituted independently with hydroxy, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkylthio, (C
1
-C
4
)alkylsulfinyl or (C
1
-C
4
)alkylsulfonyl; and
R
2
is unsubstituted (C
1
-C
4
)alkyl or (C
3
-C
7
)cycloalkyl; or R
2
is phenyl, phenyl(C
1
-C
4
)alkyl, pyridyl or pyrimidinyl or a bicyclic ring consisting of two fused five and/or six membered rings taken independently optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said R
2
substituent optionally mono-, di- or tri-substituted independently with halo, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, hydroxy, (C
1
-C
4
)alkoxycarbonyl, mono-N— or di-N,N—(C
1
-C
4
)alkylcarbamoyl, mono-N— or di-N,N—(C
1
-C
4
)alkylamino, (C
1
-C
4
)alkylsulfonyl or sulfonamido, said (C
1
-C
4
)alkyl or (C
1
-C
4
)alkoxy optionally substituted with from one to nine fluorines or the pharmaceutically acceptable salts thereof.
A group of compounds which is preferred among the A Group of compounds designated the B Group, contains those compounds wherein
R
1
is (C
1
-C
4
)alkyl or (C
3
-C
7
)cycloalkyl;
R
2
is phenyl, optionally mono- or di-substituted; and
R
3
is hydrogen or the pharmaceutically acceptable salts thereof.
Especially preferred compounds of Formula I are the compounds
[1-(2-chlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidine;
[5-methyl-1-(2-
Guzman-Perez Angel
Hamanaka Ernest S.
Mularski Christian J.
Ruggeri Roger B.
Webster Ronald T.
Benson Gregg C.
Olson A. Dean
Pfizer Inc.
Richard Peter C.
Robinson Binta
LandOfFree
N-[(substituted five-membered di- or triaza... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with N-[(substituted five-membered di- or triaza..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and N-[(substituted five-membered di- or triaza... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2995137