Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-21
2003-10-07
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S450000, C514S456000, C548S131000, C548S128000, C548S236000, C548S247000, C548S364400, C549S023000, C549S402000, C549S405000
Reexamination Certificate
active
06630506
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to bicyclic acyl guanidine compounds which are sodium/proton exchange (NHE) inhibitors and are useful as antianginal agents, and cardioprotective agents and for treating peripheral vascular disease including intermittent claudication.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, novel bicyclic acyl guanidines are provided which are sodium/proton exchange (NHE) inhibitors and have the structure I
including pharmaceutically acceptable salts thereof, all stereoisomers thereof, and prodrug esters thereof,
wherein
R
1
and R
2
are the same or different and are independently H, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, (alkyl or aryl)
3
Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, aryl, arylalkyl, aryloxy, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, heteroaryloxy, arylthio, arylsulfinyl, arylsulfonyl, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, hetero-arylsulfonyl, halogen, haloalkyl, polyhaloalkyl such as CF
3
and CF
3
CH
2
, polyhaloalkyloxy such as CF
3
O and CF
3
CH
2
O, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, acyl, carboxy, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, heteroarylcarbonyl, cyano, tetrazolyl, imidazole, oxazole or triazole, —PO(R
8
) (R
9
), S(O)
2
R
8
, R
9
(where R
1
and R
9
are the same or different and are independently hydrogen, alkyl, aryl, alkoxy, aryloxy, cycloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy);
Additionally R
1
and R
2
can be optionally joined together to form a non-aromatic substituted or unsubstituted carbocyclic ring (namely, a cycloalkyl or cycloalkenyl ring), or a cycloheteroalkyl ring (which includes one, two or three hetero atoms such as O, S and/or N), which ring contains 3 to 8 members.
X is a bond, O, S, SO, SO
2
, CO,
or NR
7
(wherein R
7
is H, lower alkyl, alkanoyl, or —SO
2
alkyl);
Y is a bond, O, S, SO, SO
2
, CO,
or NR
7′
(wherein R
7′
is H, lower alkyl, alkanoyl, or SO
2
alkyl);
n is an integer from 1 to 4;
n′ is an integer from 1 to 4; with the proviso that at least one of X and Y is other than a bond;
R
a
, R
b
, R
c
and R
d
may be the same or different and are any of the groups set out under the definition of R
1
and R
2
, and may be the same as or different from R
1
or R
2
;
where n is >1 and/or n′>1, then in the repeating
groups, R
a
and R
b
in repeating groups may be the same of different, and R
c
and R
d
in repeating groups may be the same or different.
R
3
, R
4
, R
5
and R
6
are the same or different and are independently selected from H, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, (alkyl or aryl)
3
Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, aryl, arylalkyl, aryloxy, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, heteroaryloxy, arylthio, arylsulfinyl, arylsulfonyl, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, hetero-arylsulfonyl, halogen, haloalkyl, polyhaloalkyl such as CF
3
and CF
3
CH
2
, polyhaloalkyloxy such as CF
3
O and CF
3
CH
2
O, acyl, carboxy, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, heteroarylcarbonyl, cyano, tetrazolyl, imidazole, oxazole or triazole, —PO(R
12
) (R
13
), S(O)
2
R
12
, R
13
(where R
12
and R
13
are the same or different and are independently hydrogen, alkyl, aryl, alkoxy, aryloxy, cycloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy), amino, alkylamino, alkenylamino, alkynylamino, arylalkylamino, arylamino, heteroarylamino, thio, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, hydroxy, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonyloxy, arylcarbonylamino, heteroarylcarbonyloxy, heteroarylcarbonylamino, nitro, alkenylcarbonylamino, alkynylcarbonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, alkynylaminocarbonylamino, arylaminocarbonylamino, heteroarylaminocarbonylamino, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aminocarbonylamino, alkylaminocarbonyloxy, 1,1-(alkoxyl or aryloxy)
2
alkyl (where the two aryl or alkyl substituents can be independently defined, or linked to one another to form a ring, such as 1,3-dioxane or 1,3-dioxolane), —NR
10
(C═NR
11
)alkyl, —NR
10
(C═NR
11
)alkenyl, —NR
10
(C═NR
11
)alkynyl, —NR
10
(C═NR
11
)heteroaryl, or —NR
10
(C═NCN)-amino;
R
10
and R
11
are the same or different and are independently hydrogen, alkyl, haloalkyl, aryl, alkoxy, aryloxy, cycloalkyl, heteroaryl, arylalkyl, or cycloheteroalkyl.
Additionally any two adjacent R
4
, R
5
and R
6
substituents can be joined together to form an aromatic or non-aromatic, substituted or unsubstituted ring (such as a cycloalkyl or cycloalkenyl ring), a cycloheteroalkyl ring or a heteroaryl ring, which ring contains 5 to 8 members.
Preferred are compounds of formula I of the invention wherein Y is a bond; that is
Preferably X is O or S; more preferably, X is O; preferably R
1
and R
2
are the same or different and are independently hydrogen, lower alkyl, perhaloalkyl, halogen, lower alkoxy, or aryl, at least one of R
1
and R
2
being other than hydrogen; more preferably R
1
and R
2
are the same or different and are independently hydrogen, lower alkyl, or perhaloalkyl, and R
3
is H; preferably R
4
, R
5
and R
6
are the same or different and are independently H, lower alkyl, lower alkoxy, aryl, perhaloalkyl, or halogen; more preferably R
4
, R
5
and R
6
are the same or different and are independently hydrogen, lower alkyl,lower alkoxy or halogen.
Preferred examples of R
1
and R
2
groups include methyl, ethyl, isopropyl, t-butyl, trifluoromethyl or phenyl. Preferred examples of R
4
, R
5
and R
6
groups include fluoro, chloro, methyl, trifluoromethyl or methoxy.
In addition, in accordance with the present invention, methods for preventing, inhibiting or treating angina (stable or unstable), cardiac dysfunction, myocardial necrosis, arrhythmia, peripheral vascular disease including intermittent claudication are provided, wherein a compound of formula I of the invention is administered in a therapeutically effective amount which inhibits sodium/proton exchange.
In addition, a method is provided for the relief of symptoms of pain, parethesia or discomfort in the lower limb and gluteal regions produced by arterial insufficiency where symptoms are initiated or worsened with ambulation, which includes the step of administering to a mammalian species in need of treatment a therapeutically effective amount of a compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, more preferably 1 to 12 carbons, in the normal chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various additional branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents which may be halo, for example F, Br, Cl or CF
3
, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, nitro, cyano, haloalkyl, polyhaloalkyl (or
Dugar Sundeep
O'Neil Steven V.
Bristol-Myers Squibb Co.
Davis Stephen B.
Gerstl Robert
Hermenau Ronald S.
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