Pyrano, piperidino, and thiopyrano compounds and methods of use

Details Pyrano, piperidino, and thiopyrano compounds and methods of use Pyrano, piperidino, and thiopyrano compounds and methods of use

1999-10-20

2001-02-20

Seaman, D. Margaret (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S211100, C514S211110, C514S215000, C514S222800, C514S291000, C514S293000, C540S578000, C540S580000, C544S034000, C546S081000, C546S082000, C546S083000, C546S089000, C546S090000, C546S093000, C546S102000

Reexamination Certificate

active

06191140

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)); (D. E. Nurse et al., Br. J. Urol., v. 68 pp. 27-31 (1991)); (B. B. Howe et al., J. Pharmacol. Exp. Ther., v. 274 pp. 884-890 (1995)); and (D. Spanswick et al., Nature, v. 390 pp. 521-25 (Dec. 4, 1997)). Such diseases or conditions include asthma, epilepsy, hypertension, male sexual dysfunction, female sexual dysfunction, 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.
Journal of Cardiovascular Pharmacology 8:1168-1175, (1986) Raven Press, New York, EP 0 059 291, EP 87051738, U.S. Pat. Nos. 4,321,384, 4,551,534, 4,596,873, and U.S. Pat No. 4,618,678 all disclose 4-(aryl)-4,5,6,7,8,-hexahydro-2-alkyl-5-oxo-1,7-naphthyridine-3-carboxylic esters as calcium entry blockers that may be useful as antihypertensive agents.
Compounds of the present Invention are novel, 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 of the present invention, compounds of the present invention have formula I
or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein
n is 0-1;
m is 1-2;
A is selected from the group consisting of NR
2
, O, and S;
A′ is selected from the group consisting of NR
3
, O, S and CR
4
R
5
;
D is selected from the group consisting of CH
2
and C(O);
D′ is selected from the group consisting of CH
2
, C(O), S(O), and S(O)
2
;
R
1
is selected from the group consisting of aryl and heterocycle;
R
2
and R
3
are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxy, hydroxyalkyl, —NZ
1
Z
2
, and (NZ
1
Z
2
)alkyl wherein Z
1
and Z
2
are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl;
R
4
and R
5
are independently selected from the group consisting of hydrogen and alkyl;
R
6
and R
7
are independently selected from the group consisting of hydrogen and alkyl;
with the proviso that when D is CH
2
then D′ is other than CH
2
; and
with the proviso that when D′ is S(O) or S(O)
2
then A′ is CR
4
R
5
.


REFERENCES:
patent: 4321384 (1982-03-01), Sulkowski et al.
patent: 4551534 (1985-11-01), Sulkowski et al.
patent: 4596873 (1986-06-01), Sulkowski et al.
patent: 4618678 (1986-10-01), Sulkowski et al.
patent: 0059291 (1982-09-01), None
patent: 0211584 (1987-02-01), None
patent: 0539153 (1993-04-01), None
patent: 0539154 (1993-04-01), None
patent: 9408966 (1994-04-01), None
patent: 9602547 (1996-02-01), None
patent: 9931059 (1999-06-01), None
Berge, S. M., et al., “Pharmaceutical Salts”,Journal of Pharma. Sci., 66(1):1-19 (1977).
Dodd, J. H., et al., “Synthesis of Novel Cyclic Sulfone Dihydropyridines Facilitated by a Selective Ethyl Diazoacetate Ring Expansion”,J. Heterocyclic Chem., 27:1453-1456 (1990).
Freedman, J.E., et al., “ATP-sensitive Potassium Channels: Diverse Functions in the Central Nervous System”,The Neuroscientist, 2(3):145-152 (1996).
Gehlert, D. R., et al., “ATP Sensitive Potassium Channels: Potential Drug Trgets in Neuropsychopharmacology”,Prog. Neuro-Psych. A. Biol. Psychiat., 18:1093-1102 (1994).
Gopalakrishnan, M., et al., “ATP_Sensitive K+ Channels: Pharmacologic Properties, Regulation, and Therapeutic Potential”,Drug Devel. Res., 28:95-127 (1993).
Howe, B. B., et al., “ZENECA AD6169: A Novel KATP Channel Opener with in Vivo Selectivity for Urinary Bladder”,The Journ. Of Pharmac.&Exp. Therap., 274():884-890 (1995).
Klockner. U., et al., Action potentials and net membrane currents of isolated smooth muscle cells (urinary bladder of the guinea-pig),Pflugers Archiv, 405:329-339 (1985).
Quast., U., et al., “Binding of the K+ Channel Opener {3H]P1075 in Rat Isolated Aorta: Relationship to Functional Effects of Openers and Blockers”,The Amer. Soc. For Pharma.&Exp. Terap., 43:474-481 (1993).
Lawson, K., “Potassium channel Activation: A Potential therapeutic Approach”,Pharmacol. Therap., 70(1):39-63 (1996).
Nurse, D. E., et al., “The Effect of Cromakallim on the Normal and Hyper-reflexic Human Detrusor Muscle”,British Journ. Of Urology68:27-31 (1991).
Silver, P. J., et al., “Wy-46,300 and Wy-46,531: Vascular Smooth Muscle Relaxant/Antihypertensive Agents with Combined CA2+ Antagonist/Myosin Phosphorylation Inhibitory Mechanism”,Journ of Cardio. Pharmacol., 8:1168-1175 (1986).
Spanswick, D., et al., “Leptin inhibits hypothalamic neurons by activation of ATP-sensitive postassium channels”,Letters to Nature, 390:521-525 (1997).
Terasawa, T., et al., “Novel Heterocyclic Synthons, Synthesis and Properties of Thia- and Oxacyclohexane-3,5-diones”,J. Org. Chem., 42(7):1163-1169 (1977).
Ziegler, F. E., et al., “The Claisen Rearrangement in Indole Alkaloid Synthesis. The Total Syntheis of (±)-Tabersomine1”,Journ of the Amer. Chem. Soc., 95(22):7458-7463 (1973).
Frank, C. A., et al., “Dihydropyridine KATP potassium channel openers”,Chemical Abstracts, 120(23):#289706—XP-002130833.
Jain, S. M., et al., “Synthesis and pharmacological screening of 1,8-dioxo-9-(substituted phenyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridines”,Chemical Abstracts, 116(9):#84026—XP-002130834.
Tamura, et al., “Studies on 3,5-dioxopiperidines: novel and facile synthetic routes tol 3-amino-5-hydroxypyridine derivatives”,Chemical Abstracts, 95(3):#24747—XP-002130835.

Affiliated with

Also associated with

Rating

Pyrano, piperidino, and thiopyrano compounds and methods of use does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Pyrano, piperidino, and thiopyrano compounds and methods of use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pyrano, piperidino, and thiopyrano compounds and methods of use will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2561447