Antitussive and mucus regulating agent, a process for the prepar

Details Antitussive and mucus regulating agent, a process for the prepar Antitussive and mucus regulating agent, a process for the prepar

1992-11-23

1994-10-04

Kumar, Shailendra

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

514849, 514850, 564184, 564183, 564182, A61K 31165, C07C23366

Patent

active

053527038

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to 2-benzoylamino-3,5-dibromo-N-(4-hydroxycyclohexyl)benzylamine of formula (I) ##STR2## and to the salts thereof with pharmaceutically acceptable acids.
A particularly preferred salt is the hydrochloride salt, which has been used for the pharmacological tests and will be named hereinafter YS 912.
2-Amino-3,5-dibromo-N-(4-hydroxycyclohexyl)benzylamine is a known medicament which has been used for a long time in human therapy. The compound of the present invention is an Ambroxol benzoyl derivative, having improved pharmacological and pharmacokinetic features in comparison with the parent compound.
Compound (I) or a salt thereof (for example YS 912), for the envisaged therapeutical uses as an antitussive and/or mucus regulating agent, will suitably be formulated, according to conventional techniques and excipients, in pharmaceutical compositions for the oral, parenteral or rectal administrations, such as capsules, tablets, syrups, granulates, vials or ampoules, suppositories. The amount of the active ingredient will depend on a number of factors, such as weight and age of the patient and severity of the disease to be treated, but generally it will range from 5 to 100 mg daily, in one or more administrations. The compositions of the present invention are particularly suited for the treatment of bronchitis, tracheobronchitis, emphysema, sinusitis, otitis, pneumonia of both acute and chronic nature.
Compound (I) is prepared by reacting a benzoic acid reactive derivative (chloride, mixed anhydride, imidazolide etc.) with Ambroxol in suitable solvents and using appropriate reaction conditions.
In fact, acylation also takes place on the secondary amine group, which is more basic: however, the resulting acylated product can rearrange to compound (I) by treatment with HCl gas under heating. The chloride is particularly preferred as the benzoic acid reactive derivative: in this instance the reaction is preferably carried out in the presence of pyridine.
The obtained compound is then treated with HCl gas at a temperature ranging from 30.degree. to 70.degree. C. in a solvent such as ethanol or acetone.
The following Example further illustrates the present invention.


EXAMPLE

Benzoyl chloride (9.2 ml, 0.079 mole) is added to a solution of 3,5-dibromo-N-(4'-cyclohexanol)benzylamine (30 g, 0.079 mole) in toluene (150 ml). Pyridine (6.5 ml, 0.079 mole) is dropped therein, keeping temperature below 20.degree. C. The reaction mixture is left at room temperature for 3 hours, then is washed with 150 ml of water. The organic phase is dried over MgSO.sub.4, then evaporated to obtain a residue which is crystallized from ethanol, then dissolved in acetone and added with HCl-saturated acetone to acid pH. The mixture is left at room temperature for 2 hours, then the resulting solid is filtered and washed with acetone.
m.p. 278.degree.-280.degree. C.
NMR (90 MHz; DM50-D.sub.2 O): .delta. 1.7, 1.8, 2.7, 3.8, 4.5, 7.1, 7.5.
Pharmacological tests.


ANTITUSSIVE ACTIVITY

1. Citric acid induced cough in Guinea pig.
The procedure described by R.A. Turner in "Screening methods in pharmacology-Antitussive agents" -Academic Press. New York-chapt. 23-page 219, 1965, with the changes reported by S. Malandrino et al. (Arzneim. Forsch. Drug. REs, 38, 1141, 1988), was used, comparing YS 912 with Ambroxol.
The results are reported in the following Table I, from which a remarkable antitussive activity is evidenced for YS 912, said activity being higher than that of Ambroxol, at the different used doses.


__________________________________________________________________________ Antitussive activity-Citric acid cough in Guinea pig. Means .+-. S. E. of cough strokes before and after treatment (n = 10). Cough strokes % Body weight After inhibition Treatment Dose mg/kg ip. (g) Basal treatment vs. basal __________________________________________________________________________ Controls -- 265.60 .+-. 11.38 7.90 .+-. 1.31 7.10 .+-. 1.12 10.13 12.5 270.00 .+-. 12.11 9.20 .+-. 1.41 7.40 .+-.

REFERENCES:
patent: 4191780 (1980-03-01), Tosi

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