Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-04
2003-02-11
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S079000
Reexamination Certificate
active
06518279
ABSTRACT:
TECHNICAL FIELD
Novel, water soluble 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. NeuroPsychopharmacol
&
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.
DE 2003148 discloses acridinedione and quinolone compounds claimed to possess spasmolytic action on the smooth muscle of the gastrointestinal tract, the urogenital tract and the respiratory system. Compunds disclosed in DE 2003148 are also claimed to have antihypertensive properties. These compounds belong to the larger general chemical class of dihydropyridines. The examples described in DE 2003148 all possess a cyclohexanone ring fused to the dihydropyridine nucleus and as a result have the disadvantage of possessing very low water solubility. This low solubility limits the utility of these agents as pharmaceuticals. Low water solubility can result in erratic patterns of absorption when drugs are administered orally. This can result in wide variability in drug absorption from patient to patient and potentially to toxic side-effects. The compounds of the present invention are chemically distinct from the examples described in DE 2003148 since they must have a cyclopentanone ring fused to the dihydropyridine ring, a structural feature that confers upon the compounds of the present invention the surprising and unexpected property of vastly superior water solubility, on average 55 times higher solubility in water than comparable analogs from DE 2003148.
WO 9408966, EP 0539153 A1 and EP 0539154 A1 disclose 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 examples described in WO 9408966, EP 0539153 A1 and EP 0539154 A1 all possess a cyclohexanone ring fused to the dihydropyridine nucleus and as a result have the disadvantage of possessing very low water solubility. This low solubility limits the utility of these agents as pharmaceuticals. Low water solubility can result in erratic patterns of absorption when drugs are administered orally. This can result in wide variability in drug absorption from patient to patient and potentially to toxic side-effects. The compounds of the present invention are chemically distinct from those of WO94/08966, EP 0539153 A1 and EP 0539154 A1 since they must have a cyclopentanone ring fused to the dihydropyridine ring, a structural feature that confers upon the compounds of the present invention the surprising and unexpected property of vastly superior water solubility, on average 55 times higher solubility in water than comparable analogs from the above inventions.
Dihydropyridines of differing chemical structure may possess a variety of biological activities. Dimmock et al (
Eur. J. Med. Chem.
1988, 23, 111-117) describe a N-methyldihydropyridine containing two cyclopentanone rings fused to the dihydropyridine nucleus. The only biological activity indicated was that it was inactive against murine P388 lymphocytic leukemia. The compounds of the present invention are distinct from this compound since they must be unsubstituted at the dihydropyridine nitrogen.
EP 622366 A1 describes dihydropyridines substituted with quinolines as cardiovascular agents.
EP 299727 describes 4-aryl-(5,6-bicyclo)-2-(imidazol-1-ylalkoxymethyl)dihydropyridines as platelet activating factor (PAF) antagonists.
WO 9012015-A describes dihydropyridines that are claimed to be PAF antagonists. EP 173943-A describes dihydropyridines that are modifiers of enzymes involved in arachidonic acid metabolism. EP 186027-A describes dihydropyridines that have vasodilating properties. All of these patents describe dihydropyridines that generically claim a cyclopentanone fused on one side of the dihydropyridine with carboxylic esters on the other side.
Thus, the compounds of the present invention are chemically distinct from the prior art, are water soluble, 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
In its principle embodiment, the present invention discloses compounds having formula I:
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, a broken line represents the presence of an optional double bond;
R
1
is selected from the group consisting of aryl and heteroaryl;
A is selected from the group consisting of hydrogen, alkyl, cyano, haloalkyl, heteroaryl, nitro, and —C(O)R
2
, wherein, R
2
is selected from the group consisting of alkyl, haloalkyl, and hydroxy;
R
3
is selected from the group consisting of hydrogen, alkyl, and haloalkyl; and
A and R
3
taken together with the ring to which they are attached can form a 5- or 6-membered carbocyclic ring, said 5- or 6-membered carbocyclic ring can contain 1 or 2 double bonds, and can be substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo, and —NR
4
R
5
wherein, R
4
and R
5
are independently selected from the group consisting of hydrogen and lower alkyl.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Yet another embodiment of the invention relates to a method of treating asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, compounds of the present invention have formula I:
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, a broken line represents the presence of an optional double bond;
R
1
is selected from the group consisting of aryl and heteroaryl;
A is selected from the group consisting of hydrogen, alkyl, cyano, haloalkyl, heteroaryl, nitro, and —C(O)R
2
, wherein, R
2
is selected from the group consisting of alkyl, haloalkyl, and hydroxy;
R
3
is selected from the group consisting of hydrogen, alkyl, and haloalkyl; and
A and R
3
taken together with the ring to which they are attached can form a 5- or 6-membered carbocyclic ring, said 5- or 6-membered carbocyclic ring can contain 1 or 2 double bonds, and can be substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyal
Carroll William A.
Chen Yiyuan
Drizin Irene
Kerwin James F.
Moore Jimmie L.
Abbott Laboratories
Chen Portia
Morris Patricia L.
Ward Michael J.
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