Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1988-05-16
1990-04-03
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546273, C07D40106, A61K 31435
Patent
active
049141147
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the new compound 3-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-butyl]-5-hydroxyindole methanesulfonate (I).
The underlying base (II) and the corresponding hydrochloride (III) are described in DE-OS 2,910,367.
It has been found that I has considerably more favourable pharmacokinetic properties than III. Thus, for example, 100 mg/kg of I administered orally to Cynomolgus monkeys already lead to a sedating reaction, whilst this effect can be achieved with III only with doses above 500 mg/kg. I also has a considerably better solubility in water (0.921 g in 100 ml) than III (0.035 g in 100 ml).
The invention accordingly relates to the new compound I and a process for its preparation, which comprises reacting the base II with methanesulfonic acid.
This reaction is advantageously carried out in an inert solvent, for example methanol or ethanol, at temperatures between 0.degree. and 80.degree., preferably between 15.degree. and 30.degree.. Stoichiometric amounts of the starting substances are preferably used.
The compound I can be used to prepare pharmaceutical formulations, in particular by a non-chemical route. For this, they can be brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary and if appropriate in combination with one or more other active compound(s).
The invention furthermore relates to pharmaceutical formulations contining the compound I. These formulations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral administration or topical application and do not react with the new compound, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc and vaseline. Tablets, coated tablets, capsules, syrups, elixirs, drops or suppositories are used, in particular, for enteral administration, solutions, preferably oily or aqueous solutions, and furthermore suspensions, emulsions or implants, are used for parenteral administration and ointments, creams or powders are used for topical application. The new compound can also be lyophilized and the resulting lyophilisates can be used, for example, to produce injection preparations. The formulations mentioned can be sterilized and/or contain auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyestuffs, flavouring substances and/or aroma substances. If desired, they can also contain one or more other active compounds, for example one or more vitamins.
The compound I can be administered to humans or animals, in particular mammals, such as monkeys, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and in combating diseases, in particular in the therapy of Parkinsonism, extrapyramidal disturbances in neuroleptic therapy, depression and/or psychoses and side effects in the treatment of hypertension (for example with .alpha.-methyldopa). The compound I can also be used in endocrinology and gynaecology, for example for the therapy of acromegaly, hypogonadism, secondary amenorrhoea, premenstrual syndrome, undesirable puerperal lactation and generally as a prolactin inhibitor, and furthermore for the therapy of cerebral disturbances (for example migraine), in particular in geriatrics in the same way as certain ergot alkaloids, and also for reducing blood pressure.
The compound I is as a rule thereby administered analogously to known commercially available preparations (for example bromocriptine and dihydroergocornine), preferably in dosages of between about 0.05 and 5 mg, in particular between 0.2 and 2 mg per dosage unit. The daily dosage is preferably between about 0.001 and 0.1 mg/kg of body weight. However, the specific dose for each particular patient depends on the most diverse factors, for example on the age, body w
REFERENCES:
patent: 4131680 (1978-12-01), Archibald et al.
patent: 4238215 (1966-03-01), Zenitz
patent: 4251538 (1981-02-01), Hausberg et al.
Bergmann Rolf
Bottcher Henning
Hausberg Hans-Heinrich
Seyfried Christoph
Merck Patent Gesellschaft Mit Breschrankter Haftung
Rotman Alan L.
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