Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-11
2002-10-29
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S238200
Reexamination Certificate
active
06472423
ABSTRACT:
This application is a 371 of PCT/SE 99/02176, filed Nov. 23, 1999.
FIELD OF THE INVENTION
The present invention relates to a composition which comprises a first component (a) which is (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide in the form of the free base, pharmaceutically acceptable salts and/or solvates thereof, and a second component (b) which is a monoamine oxidase (MAO) inhibitor. The present invention also relates to a process for the preparation of the composition of the invention, pharmaceutical formulations containing said composition and to the use of said composition either by concomitant administration or by separate administration as an improvement of the treatment of affective disorders such as depression, anxiety, obsessive compulsive disorder (OCD), etc.
BACKGROUND OF THE INVENTION
Today, it is generally considered that antidepressants take 2-4 weeks to reach full clinical effect. In contrast, the side effects occur immediately. Thus, slow onset of action of antidepressants leads to a vulnerable period for patients in which they experience the side effects, but not the therapeutic effects of drugs. There is often a heavy burden on the treating physician to persuade the patient to continue with the treatment during this period. Furthermore, in suicidal patients, as the onset of action is gradual, initiative may be regained without the experiencing of full reversal of symptoms, leaving a window of risk for suicide and a frequent requirement for hospitalization. An antidepressant with fast onset of action would not only be beneficial due to the faster symptom reduction, but would also be more acceptable to patients and physicians and reduce the need for and duration of hospitalization. The same long period to reach full clinical effect has been shown in the treatment of other affective disorders such as anxiety and OCD.
PRIOR ART
Effects of co-administration of a 5-HT
1A
receptor antagonist and a monoamine oxidase inhibitor has been reported in European Journal of Pharmacology 320 (1997), 15-19.
SUMMARY OF THE INVENTION
The present invention is directed to a new composition comprising of a first component (a) to which is (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide in the form of the free base, pharmaceutically acceptable salts and/or solvates thereof, and a second component (b) which is a monoamine oxidase (MAO) inhibitor. Said composition attains a faster onset of action and consequently results in a more efficacious treatment of the patients suffering from affective disorders, particularly depression.
The 5-HT transmission in the brain is negatively regulated by somatodrendritic 5-HT
1A
receptors (rate of cell firing) and the terminal h5-HT
1B
receptors (release of 5-HT). MAO inhibitors decrease the transmission of 5-HT by acting at both these sites. An antagonist of the somatodrendritic 5-HT
1A
receptors prevents the inhibition of the 5-HT release at the nerve terminals resulting in an elevated concentration of synaptic 5-HT showing that antagonists of 5-HT
1A
receptors may have a clinical potential to improve the efficacy of MAO inhibitors and offer a new rationale for rapid onset of effect in the treatment of affective disorders, for instance the antidepressant actions.
The compound (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5 carboxamide in the form of the free base, pharmaceutically acceptable salts and/or solvate thereof, as a selective 5-HT
1A
receptor antagonist, is known from WO 95/11891.
The specific salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5 carboxamide hydrogen (2R,3R)-tartrate monohydrate disclosed herein is described in the J. Pharmacol. Exp. Ther.,
283, 216-225
, (1997) as a selective 5-HT
1A
receptor antagonist. The (R)-3-N. N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide is in the form of the free base, a pharmaceutically acceptable salt and/or solvate thereof. Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, dibenzoyltartaric, diacetyltartaric, pamoic, ethanedisulfonic, sulfamic, succinic, propionic, glycollic; malic, gluconic, pyruvic, phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxvbenzoic, 3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic, naphthalenesulfonic, ascorbinic, cyclohexylsulfamic, fumaric, maleic and benzoic acids. These salts are readily prepared by methods known in the art. Illustrative solvates are hydrates such as monohydrate, dihydrate, trihydrate, sesquihydrate or alcoholates such as ethanolate, isopropanolate.
Preferably the active substance is (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H1-benzopyran-5-carboxamide hydrogen tartrate. The tartrate comprises the optical forms (2R,3R), (2R,3S) and (2S,3S). Of these forms (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate is preferred. The most preferred substance is (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate.
Suitable known monoamine oxidase inhibitors (MAOI:s) to be used are moclobemide, phenelzine, tranylcypramine and brofaromide, preferably moclobemide or phenelzine.
However, component (b) according to the invention is not limited only to these MAOI:s.
The definition and the chemical names of the above mentioned compounds (MAOI:s) can be found in the Merck Index, 12
th
Edition, S Budavari et al (ed.) and are incorporated herein by reference.
A preferred composition of the present invention is a composition wherein the first component (a) is (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and the second component (b) is pheneizine.
As well as including a monoamine oxidase inhibitor which is commercially available in a racemic form the invention also includes the corresponding optical isomeric forms of the compound having the same structure formula and possessing monoamine oxidase inhibitory activity. If the MAOI is in the form of an optical isomer, other isomers or the racemate of the same structural formula which possess monoamine oxidase inhibitory activity are also included in the invention.
The monoamine oxidase inhibitors may be used in the form of the free base, pharmaceutically acceptable salts and/or solvates thereof and all forms are included in the present invention. What is said above about salts and solvates regarding component (a) is also applicable to component (b).
The composition according to the present invention may exist in one pharmaceutical formulation comprising of (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide in the form of the free base, pharmaceutically acceptable salts and/or solvates thereof, and the monoamine oxidase (MAO) inhibitor, or in two different pharmaceutical formulations, one for (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro2-H-1-benzopyran-5-carboxamide in the form of the salts and/or solvates thereof and one for the monoamine oxidase inhibitor. The pharmaceutical formulation may be in the form of tablets or capsules, powders, mixtures, solutions or other suitable pharmaceutical formulation forms such as patches and nasal formulations.
The composition of the present invention can be prepared such that (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamid in the form of the free base, pharmaceutically acceptable salts and/or solvates thereof is incorporated into the same pharmaceutical formulation as the monoamine oxidase (MAO) inhibitor by e.g. mixing in a conventional way.
The present invention also includes a method of improving the ons
Ross Svante
Thorberg Seth-Olov
AstraZeneca AB
Krass Frederick
White & Case LLP
LandOfFree
Pharmaceutical composition does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical composition, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical composition will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2992054