Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-05-09
1999-10-05
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514217, 514357, A61K 3135, A61K 3140
Patent
active
059625147
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a combination of a 5-HT reuptake inhibitor and a selective 5-HT.sub.1A antagonist, more specific (R)-5-carbamoyl-8-fluoro-3-N,N-disubstituted-amino-3,4-dihydro-2H-1-benzop yrans in the form of free base or pharmaceutically acceptable salts thereof, process for the preparation of the combination, pharmaceutical formulation containing said combination and to the use of said combination either by coadministration or by individual administration for 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, including Selective 5-HT Reuptake Inhibitors (SSRIs), take 2-4 weeks to reach full clinical effect. In contrast, the side effects occur immediately, and even reduce during this period. Thus, slow onset of action of antidepressants lead 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, they may regain initiative without experiencing full reversal symptoms, leading a window of risk for suicide and a frequent requirement for hospitalisation. An antidepressant with fast onset of action would not only be benificial due to the faster symptom reduction, but would also be more acceptable to patients and physicians and reduce the need for and duration of hospitalisation. 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
In Arch. Gen. Psychiatry, vol. 51. Mar.1994 is described that a beta blocker such as pindolol which also has high affinity to 5-HT receptors and antagonize 5-HT.sub.1A mediated responses induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors.
SUMMARY OF THE INVENTION
turnover by selective 5HT.sub.1A antagonists
Selective 5-HT reuptake inhibitors (SSRIs) decrease the impulse propagation in 5-HT neurons via a negative feed-back reaction probably mediated by collateral 5-HT axons releasing 5-HT in raphe nuclei. By inhibiting the somatodendritic 5-HT.sub.1A autoreceptors the selective antagonists counteract the decrease in 5-HT turnover caused by 5-HT reuptake inhibitors. This indicates that a selective blockade of somatodendritic autoreceptor i.e. 5-HT.sub.1A antagonist may have a clinical potential to improve the efficacy of 5-HT reuptake inhibitors (SSRIs) and offer a new rational for rapid onset of affective actions, for instance the antidepressant actions.
Thus, by combining a first component (a) which is a 5-HT reuptake inhibitor with a second component (b) which is a selective 5-HT.sub.1A antagonist of the formula ##STR2## wherein R.sub.1 is n-propyl or cyclobutyl; cyclohexyl; said components (a) and (b) being in the form of free base or pharmaceutically acceptable salts thereof, a faster onset of action will occur and consequently, a more efficacious treatment of the patients.
The following 5-HT.sub.1A antagonists may be included as component (b) in the combination of the invention: o-2H-1-benzopyran enzopyran benzopyran an nzopyran -benzopyran -benzopyran benzopyran -1-benzopyran
The (R)-5-carbamoyl-8-fluoro-3-N,N-disubstituted-amino-3,4-dihydro-2H-1-benzop yrans disclosed herein are described in WO 95/11891 (PCT/SE94/01010).
The (R)-5-carbamoyl-8-fluoro-3-N,N-disubstituted-amino-3,4-dihydro-2H-1-benzop yrans are in the form of free base or pharmaceutically acceptable salt 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, diacetylta
REFERENCES:
patent: 4698342 (1987-10-01), Crosby
patent: 5616610 (1997-04-01), Evenden et al.
Artigas, et al., Arch. Gen. Psychiatry 51, 248-251 (1994).
Evenden John
Thorberg Seth-Olov
Astra Aktiebolag
Krass Frederick
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