Phenoxathin derivatives as inhibitors of monoamine oxidase

Details Phenoxathin derivatives as inhibitors of monoamine oxidase Phenoxathin derivatives as inhibitors of monoamine oxidase

1999-03-11

2000-08-29

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

549 16, A61K 31385, C07D32706

Patent

active

061109614

DESCRIPTION:

BRIEF SUMMARY
This invention relates to novel phenoxathiin derivatives, pharmaceutical formulations containing them, their use in medical therapy and processes for their preparation.
Monoamine oxidase (MAO) is the enzyme in the brain principally responsible for intraneuronal oxidation of biogenic amine neurotransmitters to inactive forms. It is understood to occur as two independent forms, normally designated MAO-A and MAO-B (White and Glassman, J. Neurochem., 28, 987-997, (1977) and Tipton et al, "Monoamine Oxidase and tis Selective Inhibitors", Beckmann and Riederer, Eds., Med. Probl. Pharmacopsychiat., 19 15-30, Karger, Basel (1983)). MAO inhibition has been found to elevate neurotransmitter concentrations in the brain.
MAO inhibitors are used therapeutically in the treatment of a wide variety of conditions, especially depression, particularly when characterized by anxiety, obsessional neuroses, or appetite disorders. However, a number of such compounds, for example isocarboxazid, phenelzine and tranylcypromine, are non-selective, irreversible inhibitors of the enzyme and are characterized by an undesirable side effect associated with ingestion of food or drink containing a high level of tyramine, for example, certain cheeses. When a patient receiving such a drug ingests such a product, then his blood pressure may be raised, sometimes to a dangerous level. Such patients are therefore instructed to avoid foods and beverages of this nature.
Prior art documents of interest area (A) EP 150 891; (B) WO 92 04897; (C) EP 419 157; and (D) U.S. Pat. No. 3,642,997. Patent publication (A) discloses the thioxanthen-9-ones represented by the formula ##STR1## wherein n is 0, 1 or 2, and physiologically acceptable salts thereof, and teaches that they are inhibitors of MAO-A and are useful in the prophylaxis and treatment of mental disorders such as depression. Unlike the present invention, the compounds of (A) do not contain a ring oxygen.
The phenoxathiin compounds of (B) and (C) are also directed to inhibiting MAO-A, but have an alkyl substituent and lack the alkoxy substituent included in the compounds of the present invention. Publication (D) is directed to anti-inflammatory tricyclic carboxylic acid compounds.
It has now been found that a class of novel phenoxathiin compounds, which are distance from these prior art compounds, are also useful in the prophylaxis and treatment of mental disorders, such as depression. Furthermore the compounds of the present invention are advantageous in that they accumulate in the brain quickly where they may remain for a relatively long time. Thus in the rat some of the compounds of the present invention could no longer be detected in plasma 3 hours after administration but in contrast were detected in the brain for more than 3 hrs. Inhibition of brain MAO-A was observed for greater than 8 hours, although it was reversed over a 24 hour period.
Accordingly, the present invention provides a compound of formula (I) and prodrugs and physiologically functional derivatives thereof. ##STR2## wherein n is C, 1 or 2; R.sup.2 is a branched or straight chain C1-5 alkyl or C3-6 cycloalkyl optionally; substituted with hydroxyl, or one or more halogens, especially fluorine; and X.sup.1, X.sup.2, X.sup.3, X.sup.4, and X.sup.5 are either all hydrogens or one or two of X.sup.1, X.sup.2, X.sup.3, X.sup.4 and X.sup.5 are halogen and the remainder are hydrogens.
Preferably n is 2. Thus, the phenoxathiin 10,10-dioxides are the most preferred. Compounds of the present invention wherein n is 0, may metabolize in vivo to compounds wherein n is 1 or 2. All such compounds are of course, encompassed within the present invention.
Preferably R.sup.1 is a branched or straight chain C1-3 alkyl such as methyl, ethyl, propyl and isopropyl substituted by one to four halogens, especially fluorine. When R.sup.1 is ethyl or propyl, 2,2,2-trifluoroethyl and 1,1,1-trifluoroprop-2-yl are the most preferred.
Most preferred are compounds of formula I where n is 0, 1 or 2 and R.sup.1 is a branched or straight chain C1-3 alkyl, and most

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Depoortere, Henri, "Pharmaceutical compositions containing a monoamine oxidase inhibitor as antidepressant", CA130:247053, 1999.

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