Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-14
2002-09-03
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S317000, C514S318000, C544S298000, C544S333000, C544S335000, C546S194000, C546S208000
Reexamination Certificate
active
06444679
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to 4-phenyl-4-heteroaryl derivatives which have utility as ligands or opioid receptors.
In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds has been identified. In this effort, significant research has been focused on understanding the mechanism of opioid drug action, particularly as it relates to cellular and differentiated tissue opioid receptors.
Opioid drugs are typically classified by their binding selectivity in respect of the cellular and differentiated tissue receptors to which a specific drug species binds as a ligand. These receptors include mu (&mgr;), delta (&dgr;) and kappa (&kgr;) receptors.
At least three subtypes of opioid receptors (mu, delta and kappa) are described and documented in the scientific literature. All three receptors are present in the central and peripheral nervous systems of many species including man. Activation of delta receptors produces antinociception in rodents and can induce analgesia in man, in addition to influencing motility of the gastrointestinal tract. (See Burks, T. F. (1995) in “The pharmacology of Opioid Peptides”, edited by Tseng, L. F., Harwood Academic Publishers).
The well known narcotic opiates such as morphine and its analogs are selective for the opioid mu receptor. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal transit. Kappa receptors mediate analgesia and sedation.
The existence of the opioid delta receptor is a relatively recent discovery which followed the isolation and characterization of endogenous enkephalin peptides, which are ligands for the delta receptor. Research in the past decade has produced significant information about the delta receptor, but a clear picture of its function has not yet emerged. Delta receptors mediate analgesia, but do not appear to inhibit intestinal transit in the manner characteristic of mu receptors.
U.S. Pat. No. 4,816,586, which issued on Mar. 28, 1989 to P. S. Portoghese, refers to various delta opioid receptor antagonists. These compounds are described as possessing a unique opioid receptor antagonist profile, and include compounds that are highly selective for the delta opioid receptor.
U.S. Pat. No. 4,518,711, which issued May 21, 1985 to V. J. Hruby et al., describes cyclic, conformationally constrained analogs of enkephalins. These compounds include both agonists and antagonists for the delta receptor, and are said to induce pharmacological and therapeutic effects, such as analgesia in the case of agonist species of such compounds. The antagonist species of the disclosed compounds are suggested to be useful in the treatment of schizophrenia, Alzheimer's disease, and respiratory and cardiovascular functions.
S. Goenechea, et al, in “Investigation of the Biotransformation of Meclozine in the Human Body,”
J. Clin. Chem. Clin. Biochem
., 1988, 26(2), 105-15, describe the oral administration of a polyaryl piperazine compound in a study of meclozine metabolization in human subjects.
In “Plasma Levels, Biotransformation and Excretion of Oxatomide in Rats, Dogs, and Man,”
Xenobiotica
, 1984, 15(6), 445-62, Meuldermans, W., et al. refer to a metabolic study of plasma levels, biotransformation, and excretion of oxatomide.
T. Iwamoto, et al, in “Effects of KB-2796, A New Calcium Antagonist, and Other Diphenylpiperazines on [
3
H]nitrendipine Binding”,
Jpn. J. Pharmacol
., 1988, 48(2), 241-7, describe the effect of a polyaryl piperazine as a calcium antagonist.
K. Natsuka, et al, in “Synthesis and Structure-Activity Relationships of 1-Substituted 4-(1,2-Diphenylethyl)piperazine Derivatives Having Narcotic Agonist and Antagonist Activity,”
J. Med. Chem
., 1987, 30 (10), 1779-1787, refer to racemates and enantiomers of 1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives.
European Patent Application No. 458,160, published on Nov. 27, 1991, refers to certain substituted diphenylmethane derivatives as analgesic and antiinflammatory agents, including compounds wherein the methylene bridging group (linking the two phenyl moieties) is substituted on the methylene carbon with a piperidinyl or piperazinyl group.
South African Patent Application No. 8604522, which was published on Dec. 12, 1986, refers to certain N-substituted arylalkyl and aryl-alkylene substituted amino-heterocyclic compounds, including piperidine derivatives, as cardiovascular, antihistamine, and anti-secretory agents.
European Patent Application No. 133,323, published on Feb. 20, 1985, refers to certain diphenylmethyl piperazine compounds as non-sedative antihistamines.
United States Patent Application of Spiros Liras et al., entitled “3,3-Biarylpiperidine and 2,2-Biarylmorpholine Derivatives” and filed on Dec. 28, 1998, refers to 3,3-biarylpiperidine and 2,2-biarylmorpholine derivatives having the ability to bind to opioid receptors. U.S. patent application Ser. No. 60/099,565, filed on Sep. 9, 1998, refers to 4,4-biarylpiperidine derivatives having the ability to bind to opioid receptors.
There is a continuing need in the art for improved opioid compounds, particularly compounds which are free of addictive character and other adverse side effects of conventional opiates such as morphine and pethidine.
The present inventor has discovered a novel class of 4,4-biarylpiperidine derivatives that are potent and selective delta opioid ligands and are useful for treatment of rejection in organ transplants and skin grafts, epilepsy, chronic pain, neurogenic pain, nonsomatic pain, stroke, cerebral ischemica, shock, head trauma, spinal cord trauma, brain edema, Hodgkin's disease, Sjogren's disease, systemic lupus erythematosus, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhea, functional distention, nonulcerogenic dyspepsia and other disorders of motility or secretion, and emesis, acute pain, chronic pain, neurogenic pain, nonsomatic pain, allergies, respiratory disorders such as asthma, cough and apnea, inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and inflammatory bowel disease, urogenital tract disorders such as urinary incontinence, hypoxia (e.g., perinatal hypoxia), hypoglycemic neuronal damage, chemical dependencies and addictions (eq., a dependency on, or addiction to opiates, benzodiazepines, cocaine, nicotine or ethanol), drug or alcohol withdrawal symptoms, and cerebral deficits subsequent to cardiac bypass surgery and grafting.
SUMMARY OF THE INVENTION
This invention relates to compounds of the formula
wherein X and Y are selected, independently, from oxygen, nitrogen, sulfur and CH, with the proviso that the ring containing X and Y must be aromatic and with the proviso that X and Y cannot both be either oxygen or sulfur;
( )
n
means (CH
2
)
n
and n is zero or one;
R
1
is hydrogen, (C
0
-C
8
)alkoxy-(C
0
-C
8
)alkyl-, wherein the total number of carbon atoms is eight or less, aryl, aryl-(C
1
-C
8
)alkyl-, heteroaryl, heteroaryl-(C
1
-C
8
)alkyl-, heterocyclic, heterocyclic-(C
1
-C
8
)alkyl, (C
3
-C
7
)cycloalkyl-, or (C
3
-C
7
)cycloalkyl-(C
1
-C
8
)alkyl, wherein said aryl and the aryl moiety of said aryl-(C
1
-C
8
)alkyl- are selected, independently, from phenyl and naphthyl, and wherein said heteroaryl and the heteroaryl moiety of said heteroaryl-(C
1
-C
8
)alkyl- are selected, independently, from pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, 1,2,5-thiadiazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyt, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyridinyl, and pyrimidinyl; and wherein said heterocyclic and the heterocyclic moiety of sa
Liras Spiros
McHardy Stanton F.
Ginsburg Paul H.
Jacobs Seth H.
Pfizer Inc
Richardson Peter C.
Shah Mukund J.
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