Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-26
2002-08-13
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S132000
Reexamination Certificate
active
06432952
ABSTRACT:
SUMMARY OF THE INVENTION
This invention is concerned with novel polymorphic forms of the compound: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethyl-amino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine hydrochloride. The present invention is also concerned with pharmaceutical formulations comprising the novel polymorphic forms of the compound as an active ingredient and the use of the compound and its formulations in the treatment of certain disorders.
The novel polymorphic forms of this invention are tachykinin receptor antagonists useful in the in the treatment or prevention of inflammatory diseases, emesis, depresssion, anxiety, and other neuropsychiatric diseases, including bipolar disorder and schizophrenia.
These polymorphic forms have advantages over the other known forms of 2-(R)-(1-(R)-(3,5-bis(tiifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylanino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine hydrochloride in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.
BACKGROUND OF THE INVENTION
The neuropeptide receptors for substance P (neurokinin-1; NK-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition. Substance P (also called “SP” herein) 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. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nonmenclature designates the receptors for SP, neurokinin A, and neurokinin B as NK-1, NK-2, and NK-3, respectively.
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. 5,612,337, Example 12, Method B, discloses the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-4-(5-(dimethyl-amino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluoro-phenyl)morpholine hydrochloride which has the structure:
Morphological forms of pharmaceutical compounds may be of interest to those involved in the development of a suitable dosage form because if the morphological form is not held constant during clinical and stability studies, the exact dosage used or measured may not be comparable from one lot to the next. Once a pharmaceutical compound is produces for use, it is important to recognize the morphological form delivered in each dosage form to assure that the production process use the same form and that the same amount of drug is included in each dosage. Therefore, it is imperative to assure that either a single morphological form or some known combination of morphological forms is present. In addition, certain morphological forms may exhibit enhanced thermodynamic stability and may be more suitable than other morphological forms for inclusion in pharmaceutical formulations. As used herein, a polymorphic form of a chemical compound is the same chemical entity, but in a different crystalline arrangement.
REFERENCES:
patent: 5612337 (1997-03-01), Baker et al.
patent: WO 99 01444 (1999-01-01), None
Cai Dongwei
Crocker Louis
Wang Jiang
Merck & Co. , Inc.
Ramsuer Robert W.
Thies J. Eric
Winokur Melvin
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