Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-12-04
2001-07-24
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S299000, C514S312000, C546S112000, C546S114000, C546S153000
Reexamination Certificate
active
06265417
ABSTRACT:
TECHNICAL FIELD
Novel dihydropyridine compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.
BACKGROUND OF INVENTION
Potassium channels play an important role in regulating cell membrane excitability. When the potassium channels open, changes in the electrical potential across the cell membrane occur and result in a more polarized state. A number of diseases or conditions can be treated with therapeutic agents that open potassium channels. See K. Lawson,
Pharmacol. Ther.,
v. 70, pp. 39-63 (1996); D. R. Gehlert et al.,
Prog. Neuro-Psychopharmacol
&
Biol. Psychiat.,
v. 18, pp. 1093-1102 (1994); M. Gopalakrishnan et al.,
Drug Development Research,
v. 28, pp. 95-127 (1993); J. E. Freedman et al.,
The Neuroscientist,
v. 2, pp. 145-152 (1996). Such diseases or conditions include asthma, epilepsy, hypertension, impotence, migraine, pain, urinary incontinence, stroke, Raynaud's Syndrome, eating disorders, functional bowel disorders, and neurodegeneration.
Potassium channel openers also act as smooth muscle relaxants. Because urinary incontinence can result from the spontaneous, uncontrolled contractions of the smooth muscle of the bladder, the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle provides a method to ameliorate or prevent urinary incontinence.
WO 9408966 and EP 0539154 A1 disclose a group of acridinedione and quinolone compounds that are claimed useful in the treatment of urinary incontinence. These compounds belong to the larger general chemical class of dihydropyridines. The compounds of the present invention are chemically distinct from those of WO94/08966 and EP 0539154 A1 since they have at least one sulfonyl group attached to the 3-position of the dihydropyridine ring.
Dihydropyridines of differing chemical structure may possess a variety of biological activities. For example, U.S. Pat. No. 4,879,384 discloses a group of thiacycloalkeno[3,2-b]pyridines that belong to the dihydropyridine class and are calcium channel antagonists. The compounds of the present invention are chemically distinct from those of U.S. Pat. No. 4,879,384 since they do not have a carboxylic acid derivative attached to the 3-position of the dihydropyridine ring.
Thus, the compounds of the present invention are chemically distinct from the prior art, hyperpolarize cell membranes, open potassium channels, relax smooth muscle cells, inhibit bladder contractions and are useful for treating diseases that can be ameliorated by opening potassium channels.
SUMMARY OF THE INVENTION
The present invention relates to, the invention discloses a compound having Formula I
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein
R
1
is alkyl;
R
2
is selected from the group consisting of aryl and heteroaryl;
the aryl or heteroaryl can be optionally substituted;
n is 0-2;
A is selected from the group consisting of hydrogen, alkyl, and —X—R
3
;
R
3
is alkyl or haloalkyl;
X is —C(O)— or —S(O)
p
— wherein p is 1-2;
R
4
and R
5
are independently selected from the group consisting of hydrogen, alkyl and haloalkyl; or
R
1
and R
5
together with the ring to which they are attached form a 5-, 6- or 7-membered sulfur-containing ring with 1-2 double bonds and 0-2 oxo substituents; or
A and R
4
together with the ring to which they are attached form a ring selected from the group consisting of a 5-, 6-, or 7-membered carbocyclic ring with 1-2 double bonds and 0-1 oxo substituents and a 5-, 6- or 7-membered sulfur-containing ring with 1-2 double bonds and 0-2 oxo substituents, provided that at least one of R
1
and R
5
or A and R
4
forms a ring.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the invention discloses a compound having Formula I
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof ereof wherein
R
1
is alkyl;
R
2
is selected from the group consisting of aryl and heteroaryl;
the aryl or heteroaryl can be optionally substituted;
n is 0-2;
A is selected from the group consisting of hydrogen, alkyl, and —X—R
3
;
R
3
is alkyl or haloalkyl;
X is —C(O)— or —S(O)
p
— wherein p is 1-2;
R
4
and R
5
are independently selected from the group consisting of hydrogen, alkyl and haloalkyl; or
R
1
and R
5
together with the ring to which they are attached form a 5-, 6- or 7-membered sulfur-containing ring with 1-2 double bonds and 0-2 oxo substituents; or
A and R
4
together with the ring to which they are attached form a ring selected from the group consisting of a 5-, 6-, or 7-membered carbocyclic ring with 1-2 double bonds and 0-1 oxo substituents and a 5-, 6- or 7-membered sulfur-containing ring with 1-2 double bonds and 0-2 oxo substituents, provided that at least one of R
1
and R
5
or A and R
4
forms a ring.
Another embodiment of the present invention includes a compound of formula II
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
R
2
is selected from the group consisting of aryl and heteroaryl;
the aryl or heteroaryl are optionally substituted;
n is 1 or 2;
X is selected from the group consisting of —CH
2
—, —C(O)—, —S(O)—, or —S(O)
2
—; and
n′ and n″ are independently 1-3.
Another embodiment of the invention discloses pharmaceutical compositions containing compounds having the Formula I and II.
Yet another embodiment of the invention discloses methods of treatment comprising administering an effective amount of compounds having Formula I and II.
Definition of Terms
The term “alkanoyl” as used herein refers to an alkyl group appended to the parent molecular moiety through a carbonyl (—C(O)—) group. Examples of alkanoyl include acetyl, propionyl, and the like.
The term “alkanoyloxy” as used herein refers to an alkanoyl group attached to the parent molecular group through an oxygen atom.
The terms “loweralkyl” or “alkyl” as used herein refer to straight or branched chain alkyl radicals containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1 -methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term “alkenyl” as used herein refers to a monovalent group derived from a hydrocarbon containing at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.
The term “alkylene” denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like.
The term “alkenylene” denotes a divalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. Examples of alkenylene include —CH═CH—, —CH
2
CH═CH—, —C(CH
3
)═CH—, —CH
2
CH═CHCH
2
—, and the like.
The term “alkylsulfinyl” as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfinyl (—S(O)) group. Examples of alkylsulfinyl include methylsulfinyl, ethylsulfinyl, isopropylsulfinyl and the like.
The term “alkylsulfonyl” as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonyl (—S(O)
2
) group. Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like.
The term “alkynylene” refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing a carbon-carbon triple bond. Examples of alkynylene include —CC—, —CC—CH
2
—, —CC—CH(CH
3
)— and the like.
The term “alkoxy” as used herein refers to R
41
O— wherein R
41
is a loweralkyl group, as defined above. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
The term “alkoxyalkoxy” as used herein refers to an alkoxy group at
Carroll William A.
Drizin Irene
Holladay Mark W.
Sullivan James P.
Zhang Henry Q.
Abbott Laboratories
Huang Evelyn Mei
Ward Michael J.
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