Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-04-24
2004-04-27
Ramsuer, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S228800, C544S098000, C544S174000
Reexamination Certificate
active
06727244
ABSTRACT:
BACKGROUND OF THE INVENTION
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3), respectively.
Evidence has been reviewed for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Chrohn's disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyperreflexia.
It has furthermore been suggested that tachykinin receptor antagonists have utility in the following disorders: anxiety, depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorder related to immune enhancement or suppression such as systemic lupus erythmatosus, ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Attempts have been made to provide antagonists for the receptors of substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases. In particular, U.S. Pat. No. 5,719,147, Example 75, and U.S. Pat. No. 6,096,742 disclose the compound 2-(R)-(1-(R)-(3,5-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)-methylmorpholine which has the structure:
U.S. Pat. No. 5,719,147, Example 75 and U.S. Pat. No. 6,096,742 disclose methods for preparing this compound.
SUMMARY OF THE INVENTION
The present invention is directed to mammalian metabolites of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine and the process for the preparation of these compounds.
The present invention is also concerned with pharmaceutical formulations comprising these mammalian metabolites as an active ingredient and the use of these compounds and their formulations in the treatment of certain disorders and diseases.
The mammalian metabolites of this invention are tachykinin receptor antagonists useful in the treatment or prevention of inflammatory diseases, emesis, depresssion, anxiety, and other neuropsychiatric diseases, including bipolar disorder and schizophrenia.
DESCRIPTION OF THE INVENTION
The present invention is directed to mammalian metabolites of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine and processes for the preparation of these compounds.
The compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine has the structure:
and is a tachykinin receptor antagonist useful in the treatment of inflammatory diseases, emesis, depresssion, anxiety, and other neuropsychiatric diseases, including bipolar disorder and schizophrenia.
The compounds of the present invention are mammalian metabolites of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4fluoro)-phenyl-4-3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine.
The present invention is directed to a compound which is selected from the group consisting of:
and pharmaceutically acceptable salts and individual diasteromers thereof.
These compounds are among the mammalian metabolites of 2-(R)-(1-(R)-(3,5-bis(trifluoromethy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine.
The parent compound and some of these mammalian metabolites may be named alternatively as follows:
Parent Compound: 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one;
M-1: (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine;
M-2: (2R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-5,6-dihydro-2H-1,4-oxazine;
M-3: (5S,6R)-6-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-5-(4-fluorophenyl)-3-morpholinone;
M4: (6R)-6-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-5-(4-fluorophenyl)-5-hydroxy-3-morpholinone;
M-5: [(1R)-1-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-2-(4-fluorophenyl)-2-oxoethoxy]acetic acid;
M-6: [(1R)-1-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-2-(4-fluorophenyl)-2-hydroxyethoxy]acetic acid.
The present invention is also concerned with a process for the preparation of the mammalian metabolites of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine which comprises:
administering 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine to a mammal, such as a human. Optionally, the mammalian metabolites may be isolated from the urine or feces.
Preferably, the parent compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine is administered to the mammal orally.
The present invention is directed to the mammalian metabolites as they are formed in vivo upon administration of the parent compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxyl)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine to a mammalian species such as a human, as well as such mammalian metabolites as pure or partially purified compounds.
The specific pathways responsible for the mammalian metabolism of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine to some of the subject metabolites may be summarized as follows:
The primary metabolite (M-1) of 2-(R)-(1-(R)-(3,5-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine is the N-dealkylated derivative. The N-dealkylated metabolite (M-1) is present in incubates with liver microsomes from rats, dogs and humans. When (M-1) is incubated in the primary rat hepatocyte culture, several metabolites are obtained including the imine derivative of morpholine (M-2), the lactam derivative of morpholine (M-3), the hydroxy lactam (M-4), the morpholine-ring opened ketocarboxylic acid (M-5) and the corresponding hydroxycarboxylic acid (M-6). These metabolites result from at least 6 metabolic events on 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine: N-dealkylation to the des-triazolone derivative (M-1), oxidation at the benzylic carbon on the morpholine ring to form the imine derivative (M-2), oxidation alpha to the morpholine nitrogen to form a lactam (M-3), oxidation of the lactam to form a hydroxylated lacta
Chiu Shuet-Hing Lee
Huskey Su-er Wu
Merck & Co. , Inc.
Ramsuer Robert
Thies J. Eric
Winokur Melvin
LandOfFree
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