Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-23
2004-06-01
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S123000
Reexamination Certificate
active
06743802
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to compounds that are alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones. In particular, this invention is directed to phenyl substituted 1,8-naphthyridin-4(1H)-ones which are phosphodiesterase-4 inhibitors wherein the phenyl group is at the 1-position and contains a 2-alkyne substituent group further optionally substituted.
RELATED BACKGROUND
Hormones are compounds that variously affect cellular activity. In many respects, hormones act as messengers to trigger specific cellular responses and activities. Many effects produced by hormones, however, are not caused by the singular effect of just the hormone. Instead, the hormone first binds to a receptor, thereby triggering the release of a second compound that goes on to affect the cellular activity. In this scenario, the hormone is known as the first messenger while the second compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 3′,5′-cyclic monophosphate, “cAMP” or “cyclic AMP”) is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Thus, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.
Phosphodiesterases (“PDE”) are a family of enzymes that metabolize 3′,5′ cyclic nucleotides to 5′ nucleoside monophosphates, thereby terminating cAMP second messenger activity. A particular phosphodiesterase, phosphodiesterase-4 (“PDE4”, also known as “PDE-IV”), which is a high affinity, cAMP specific, type IV PDE, has generated interest as potential targets for the development of novel anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist as at lease four isoenzymes, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in allergic and/or inflammatory responses. Thus, it is believed that inhibition of PDE4, particularly the specific PDE4 isoforms that produce detrimental responses, can beneficially affect allergy and inflammation symptoms. It would be desirable to provide novel compounds and compositions that inhibit PDE4 activity.
A major concern with the use of PDE4 inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C. Burnouf et al., (“Burnouf”),
Ann. Rep. In Med. Chem
., 33:91-109(1998). B. Hughes et al.,
Br. J.Pharmacol
., 118:1183-1191(1996); M. J. Perry et al.,
Cell Biochem. Biophys
., 29:113-132(1998); S. B. Christensen et al.,
J.Med. Chem
., 41:821-835(1998); and Burnouf describe the wide variation of the severity of the undesirable side effects exhibited by various compounds. As described in M. D. Houslay et al.,
Adv. In Pharmacol
., 44:225-342(1998) and D. Spina et al.,
Adv. In Pharmacol
., 44:33-89(1998), there is great interest and research of therapeutic PDE4 inhibitors.
International Patent Publication WO9422852 describes quinolines as PDE4 inhibitors. International Patent Publication WO9907704 describes 1-aryl-1,8-naphthylidin-4-one derivatives as PDE4 inhibitors.
A.H. Cook, et al.,
J.Chem. Soc
., 413-417(1943) describes gamma-pyridylquinolines. Other quinoline compounds are described in Kei Manabe et al.,
J.Org. Chem
., 58(24):6692-6700(1993); Kei Manabe et al.,
J.Am. Chem. Soc
., 115(12):5324-5325(1993); and Kei Manabe et al.,
J.Am. Chem. Soc
., 114(17):6940-6941(1992).
Compounds that include ringed systems are described by various investigators as effective for a variety of therapies and utilities. For example, International Patent Publication No. WO 98/25883 describes ketobenzamides as calpain inhibitors, European Patent Publication No. EP 811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidine sodium channel blockers, U.S. Pat. No. 5,736,297 describes ring systems useful as a photosensitive composition.
U.S. Pat. Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, and International Patent Publication WO 95/35283 describe PDE4 inhibitors that are tri-substituted aryl or heteroaryl phenyl derivatives. U.S. Pat. No. 5,580,888 describes PDE4 inhibitors that are styryl derivatives. U.S. Pat. No. 5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl derivatives. U.S. Pat. No. 5,340,827 describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S. Pat. No. 5,780,478 describes PDE4 inhibitors that are tetra-substituted phenyl derivatives. International Patent Publication WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors. U.S. Pat. No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
However, there remains a need for novel compounds and compositions that therapeutically inhibit PDE4 with minimal side effects.
SUMMARY OF THE INVENTION
The present invention is directed to alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones represented by Formula (I):
or pharmaceutically acceptable salts thereof, which are phosphodiesterase-4 inhibitors.
This invention also provides a pharmaceutical composition which includes an effective amount of the novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones and a pharmaceutically acceptable carrier. This invention further provides a method of treatment in mammals of, for example, i) Pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, adult respiratory distress syndrome, and infant respiratory distress syndrome, ii) Gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and hypersecretion of gastric acid, iii) Infectious diseases such as bacterial, fungal or viral induced sepsis or septic shock, endotoxic shock (and associated conditions such as laminitis and colic in horses), and septic shock, iv) Neurological disorders such as spinal cord trauma, head injury, neurogenic inflammation, pain, and reperfusion injury of the brain, v) Inflammatory disorders such as psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, vi) Allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) Psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) Neurodegenerative disorders such as Parkinson disease, Alzheimer's disease, acute and chronic multiple sclerosis, ix) Dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) Oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissues, xi) Metabolic disorders such as diabetes insipidus, xii) Bone disorders such as osteoporosis, xiii) Cardiovascular disorders such as arterial restenosis, atherosclerosis, reperfusion injury of the myocardium, and xiv) Other disorders such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft versus host disease, and cachexia—maladies that are amenable to amelioration through inhibition of the PDE4 isoenzyme and the resulting elevated cAMP levels—by the administration of an effective amount of the novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones or a precursor compound which forms in vivo the novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones which are phosphodiesterase-4 inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
A compound of this invention is represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R is H, —C
1-6
alkyl or —C
3-6
cycloalkyl;
R
1
is H, or a —C
1-6
alkyl, —C
3-6
cycloalkyl, —C
1-6
alkoxy, —C
2-6
alkenyl, —C
3-6
alkynyl,
Friesen Richard
Girard Mario
Guay Daniel
Hamel Pierre
Laliberte Sebastien
Merck Frosst Canada & Co.
Morris Patricia L.
Panzer Curtis C.
Rose David L.
LandOfFree
Alkyne-aryl phosphodiesterase-4 inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Alkyne-aryl phosphodiesterase-4 inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Alkyne-aryl phosphodiesterase-4 inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3360837