Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-31
2000-06-13
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 16, A61K 3144
Patent
active
060750332
DESCRIPTION:
BRIEF SUMMARY
The subject of the present invention is new, original derivatives of anthranilic acid which can be represented by the general formula (I) indicated below ##STR2## and in which the anthranilic acid aromatic ring may be mono- or di-substituted with the R.sub.1 group which can be selected independently from hydrogen, methyl and chloro, and in which the substituents at the chiral centre (marked with an asterisk in formula (I)) have the R (Rectus) configuration.
The anthranilic acid aromatic ring is preferably di-substituted with the methyl group in positions 3, 5 or with the chloro group in position 3 and the methyl group in position 5.
The compounds of the present invention have been found to be potent receptor antagonists of gastrin at the peripheral level, that is, at the level of the gastro-intestinal system, and potent receptor antagonists of cholecystokinin (CCK) at the level of the central nervous system (CCK-B-antagonists).
It can therefore be considered that they may be usable to advantage in the treatment of various diseases in man connected with imbalances in the physiological levels of gastrin and of CCK or of other bioactive polypeptides correlated therewith, both at the level of the gastro-intestinal system and at the level of the central nervous system (CNS), of the sense organs, or of other organs or systems in which these bioactive peptides play a physiological or pathological role. For example, advantageous use of these compounds can thus be predicted for the treatment, at the gastro-intestinal level, of diseases connected with disorders of motility and of trophism of the mucous membrane such as, for example, gastritis, peptic ulcers, colitis or certain gastro-intestinal tumours sustained by gastrin or polypeptide hormones correlated therewith and, at the level of the CNS, for the treatment of psychic disorders such as, for example, anxiety, panic attacks, psychosis, such as, for example, schizophrenia, depression, anorexia, etc. Pharmaceutical forms of the compounds of the invention such as, for example, tablets, capsules, suspensions, solutions, suppositories or patches, may be prepared in accordance with conventional techniques and may be administered by oral, parenteral, or rectal routes, through the skin or the mucous membrane, or by other means suitable for achieving the therapeutic effect such as, for example, solid preparations for oral use with delayed action which permit controlled release of the active substance over time.
The active ingredient is typically administered to the patient with a reference dose variable from 0.01 to 10 mg/kg of body weight per dose. For parenteral administration, the use of a water-soluble salt of the compounds of the invention such as the sodium salt or another non-toxic and pharmaceutically acceptable salt is preferable. Substances commonly used in pharmacology as excipients, binders, flavourings, dispersers, colourings, humectants, etc., may be used as inactive ingredients.
The method for the preparation of the derivatives of the invention is an enantio-selective method which enables the derivatives of formula (I) to be obtained in the optically active R (Rectus) form which is the pharmacologically active enantiometric form.
The method comprises the following steps: R.sub.1 has the meaning given above, with azaspiro[4.5]decane hydrochloride in the presence of a tertiary base such as triethylamine, in an inert anhydrous solvent at a temperature of between 20.degree. C. and the boiling point of the solvent, to give benzamides of formula (V), carbon atom with methanol, preferably in a slight excess, in an inert solvent, preferably toluene, at ambient temperature, for a period of between 8 and 24 hours, in the presence of a semi-catalytic quantity of an asymmetric tertiary base, preferably cinchonine or quinidine to give the monomethyl ester of (R)-3-(1-naphthyl) glutaric acid of formula (IV), boiling for a period of between 1 and 4 hours to give the corresponding chloride of formula (III), in the presence of two moles of a tertiary base, preferably trie
REFERENCES:
patent: 5500430 (1996-03-01), Makovec et al.
patent: 5587479 (1996-12-01), Makovec et al.
patent: 5723494 (1998-03-01), Makovec et al.
Makovec Francesco
Peris Walter
Rovati Lucio C.
Rovati Luigi A.
Owens Amelia
Rotta Research Laboratorium S.p.A
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