FI68812B - EFFECTIVE EFFECTIVE FREQUENCY THERAPEUTIC L-OCH D, L-GLAUSINLACTATSALTER - Google Patents

Description

r, ANNOUNCEMENT

• ^ SFSt UTLAGGNI N GSSKRIFT ^ COI £ C (45) t.tl »yönnv l by 11 11 1935 (51) Kv.lk. * / Lnt.CI.4 C O7 D 221/18 FINLAND — FINLAND (21) Patent application - Patentansöknlng 792357 (22) Application date - Ansöknlngsdag 27.07.79 (23) Starting date —Giltighetsdag 27.07.79 (41) Become public - Blivit offentlig 22.02.80

National Board of Patents and Registration The date of publication and publication. -. , 0r

Patent- och registrstyrelsen '' Ansökan utlagd och utl.skriften publicerad 3 1 .U / .05 (32) (33) (31) Privilege claimed - Begärd priority 21.08.78 USA (US) 935220 (71) The Dow Chemical Company, Delaware, US; 929 East Main Street,

Midland, Michigan, USA (72) Samuel S.M. Wang, Indianapolis, Indiana, USA (US) (7 * 0 SA Munsterhielm (5 * 0 Process for the preparation of therapeutically effective 1- and d, 1-glausine1-lactate salts The invention relates to 1-glaucine and d, 1-glausine lactate salts, to a process for their preparation, to pharmaceutical compositions containing said salts and to a process for their use as antitussive and analgesic agents.

Glausine of the following formula OCH.

OCH ^

H.CO I

ΎΥΤΊ 3 1 H CH3 is the asymmetric center marked with an asterisk in the above formula. Thus, two optical isomers are possible. Only one of them, the dextrorotatory form (d-glausine) occurs in nature and can be isolated from the yellow poppy, The racemate, d, 1-glausine, can be synthesized from papaverine according to the method presented by 6881 2

Frank and Tietze, Angewandte Cheraie (1967) pp. 815-816, or by other methods, such as those described by Chan and Maitland, J. Chem. Soc. (C) 1966, 753 or Cava et al., J. Org. Chem. 17 5 (1970) · Separation of the two enantiomers can be carried out by conventional methods such as using an optically active acid, for example d- or 1-tartaric acid, to form diastereoisomeric salts which can be separated by fractional crystallization.

d-glausine hydrobromide and d-glausine hydrochloride are known to have antitussive activity (Donev, Pharmacy (Sofia) 1962, L2, (^ f), p. 17 and Aleshinskaya, Khim. Farm. Zh. 10, (1), p. 1M-M- -1-+ (7 (1976) and Chemical Abstracts: 159725 w). In addition, Aleshinskaya, supra, has shown that glausine derived from yellow hornbeam (d-glausine) prolongs the anesthetic time of hexenal and chloral hydrate in mice and has analgesic activity at doses of 50-100 mg / kg, as well as adrenolytic activity.

Recent studies have shown that the levorotatory isomer and racemic isomer of glausine hydrobromide have better antitussive properties than the previously known right-rotating form (BE Patent No. 866,079).

As can be seen from the above formula, glausine is structurally related to other plant alkaloids such as codeine. Codeine and similar compounds such as hydrocodone are well known as antitussive and narcotic analgesic agents. Merck Index, 9 · edition, Merck & Co., Rahway, N.J. (1976) monographs numbers 2 ^ + 20-2 ^ + and ^ 672. Although these compounds are known to have great potential for habituation or drug addiction, they remain the most effective and widely used antitussives. Anti-tusive agents are usually administered orally, most often in the form of a liquid composition such as an elixir, suspension or syrup, or a solid lozenge or cough drops which are kept in the mouth until dissolved. In both cases, the unpleasant bitter taste of the alkaloid is a disadvantage of such substances. Several compositions have been developed to mask the unpleasant taste and aftertaste of codeine with varying degrees of success. None of these methods have been completely successful.

Glausine, like codeine, has an unpleasant bitter taste. It has now surprisingly been found that 1- and d, 1-glausine lactates, in addition to having antitussive properties which are 6 8 81 2 better than d-glausine, have unexpectedly better analgesic activity than d-glausine. are associated with a very low potential for drug addiction, and have particularly desirable solubility and stability properties and are unexpectedly odorous and palatable, making them particularly useful for oral administration.

The novel lactate salts of the invention are crystalline solids prepared by reacting 1-glaucine or d, l-glaucine (or a mixture thereof) in the form of bases with a lactate ion under conditions suitable for the formation of lactate salts of organic bases. The salts can be obtained in crystalline solid form.

The compounds can be readily prepared by reacting the free glusI-ni base with lactic acid. The reaction is preferably carried out in the presence of an inert organic solvent such as acetone, ethanol, chloroform, methanol, diethyl ether or ethyl acetate. The lactate salt is usually formed as a precipitate which can be recovered by conventional methods such as filtration or decantation and purified by conventional methods such as recrystallization and washing.

The reaction is usually carried out by dissolving the free base, glausine, in an inert organic solvent at a temperature between ambient temperature and the boiling point of the mixture, and adding an equimolar amount or excess of lactic acid. Lactic acid may be used in an amount of about 0.5 to 1 mole, or a double or triple molar excess or more. Preferably an equimolar amount is used.

When excess lactic acid is used, the excess precipitates with the product, from which it can be removed by recrystallization. A mixture of 1- and d, 1-glausine lactates, 1-glausine lactate salts and a racemic salt are all useful as anti-tussives and analgesics, with similar desired properties. It is generally preferred to use a single lactate salt, such as d, 1-glausine lactate, or 1-glausine lactate, preferably the salt is d, 1-glausine lactate. Glausine lactate salts are highly effective, orally active, antitussive agents and also have analgesic activity when administered orally, combined with surprisingly good taste and the desired stability and solubility, in addition to being free of undesirable side effects such as drug addiction properties. They may be administered at doses of 4 to 6881 2 of about 0.1 to 40 mg or more / kg (mg / kg) for anti-inflammatory activity, and about 0.1 to 60 mg / kg for analgesic use, preferably orally. They are also active as antitussive and analgesic agents when administered parenterally, e.g. by intraperitoneal injection.

To test the method of the invention, an antitussive amount of one or more glausine lactates is administered internally to the animal, usually mammals. Administration can be performed either parenterally, such as intravenously, intraperitoneally or intramuscularly, by injection or by oral or rectal administration to the gastrointestinal tract, e.g. by oral administration of a solution of glausine lactate 1 in a throat spray form.

The antitussive amount of the compound, i.e. the amount of glaucine lactate suitable for preventing or alleviating cough depends on many factors, such as the size, species and age of the animal being treated, in particular the salt or mixture of salts used, the method and frequency of administration, the severity of the cough (if any) and the causative agent used; time of administration. Similar considerations influence the choice of analgesic amount of a compound, i. an amount of glaucine nilactate suitable for relieving pain symptoms. Glaucine nilactate salts are usually effective when administered orally as well as parenterally.

For example, in antitussive experiments in which different groups of hamsters were orally administered varying doses of test compounds or distilled water to a control group. One hour after oral dosing, hamsters were exposed to a 5% aerosol of citric acid for a 10 minute test period. The number of cough reactions elicited during the last five minutes of citric acid aerosol exposure was taken into account and the dose that relieved cough 50% of hamsters (ED 2 g) was calculated. The antitussive effect was recorded for the hamster when its total number of coughs over the 5-minute experimental period was at least two standard deviation units below the mean of the hamster coughs in the control group. In these experiments, an oral ED 50 value of 86.6 mg / kg was obtained for codeine phosphate; d-gauzine hydrobromide 11e EDg 89.0 mg / kg; and d, l-gluten for in-lactate ED 50 g 63.4 mg / kg.

In an experiment similar to that described above, test compounds were administered to hamsters intraperitoneally by injection of one group of hamsters with distilled water as a control.

6881 2 EDj-g values were calculated for antitussive activity in the citric acid aerosol assay as described above. Codeine phosphate gave an ED 2 Q value of 10.9 mg / kg; d-glaucine hydrobromic has an ED 2 of 10.0 mg / kg and d-glaucine lactate has an ED 2 of 7.9 mg / kg.

The dose to be administered in a given case can be ascertained using conventional methods for finding the amount of dosage, e.g., by detecting antitussive activity at various dosage ratios11a.

Good antitussive results can be obtained when the salts are administered orally in doses of about 0.1 to 0.2 to 0.5 to -1 to 10 to 20 to 30 to 40 to 80 mg of the glausine salt compound per kg of animal body and in doses of 0 , 1 to 40 mg / kg by intraperitoneal injection. In general, it is desirable to administer individual doses in the lowest amount that provides the desired cough arrest (suppression) on a permanent basis, with an appropriate dosing schedule. Oral administration is generally preferred for the administration of antitussives. The glausine lactates of this invention combine a high oral antitussive effect with good taste, which makes them particularly useful for oral administration.

To evaluate the pleasant taste of the compounds of the invention, various d, l-glausine salts were prepared and dissolved in distilled water to form various aqueous solutions, each solution containing a single salt of 0.2% (w / v). d, 1-glausine pamoate was not soluble and has not been tested in these tests. d, l-glaucine p-toluenesulfonate requires slight heating to obtain a 0.2% solution. The 0.2% solution contains 2 mg of test salt / ml. This concentration corresponds to 10 mg / 5 ml, which is a typical concentration of codeine phosphate in codeine-based syrups.

The pleasant taste of each solution was evaluated by putting a drop or two drops of the solution on the tongue for tasting. The mouth was rinsed with water to remove glausine solutions, followed by a pause to minimize the effect of aftertaste from sample to sample.

The results obtained with the various d, 1-Glucine salts 11a are as follows: 6 68812 hydrobromide bitter, sharp and metallic initial taste which increases with time, characterized as unpleasant sulphate, maleate, citrate bitter, metallic taste, same-taste, acetate- and p-toluene-like as with hydrochloride, sa- sulfonate salts in a racket-like unpleasant tartrate bitter, "acidic" taste and tooth-covering sensation; characterized as undesirable by salicylate bitter, pungent metallic taste, similar to hydrochloride 11a but more unpleasant succinate bitter, pungent metallic taste with mild nausea-like phosphate (2: 3) little or no taste; no significant bitterness of lactate similar to phosphate was observed, with no bitterness, slightly sweet.

The above method was performed on a "blind" basis, i. the taster was not told any information about the saline solution except that the preparations were glausine saline solutions.

Anyone familiar with the antitussives codeine and dexromethorpan and various attempts to disguise the characteristic bitter alkaloid taste of these and similar drugs can appreciate the importance of improving the taste of the antitussive. The fact is that antitussives are rarely administered orally in forms that pay attention to the good taste of the active substance. The predominant form of pharmaceutical antitussive preparations is a syrup containing a solution of the active ingredient.

The good taste of drugs is especially important in children and some adults who refuse drug treatment due to unpleasant taste. In situations that are not life-threatening, such as cough treatment, a pleasant taste is even more important.

These results are absolutely unforeseen and are further evidence of the unexpected properties of the compounds of this invention.

Dosage units suitable for oral administration are preferably, for example, tablets, capsules, lozenges, elixirs, syrups and the like, and the active glausin lactate compound may be combined with a conventional capsule or tablet released over time.

7 6881 2 When using the compounds of the invention, the active Glaucine lactate agent is preferably combined in a composition comprising a pharmaceutical carrier and about 0.001 to 95% by weight of a glucine lactate salt compound. The term "pharmaceutical carrier" means known pharmaceutical excipients which are useful in the preparation of pharmacologically active compounds for internal administration to animals and which are essentially non-toxic and non-sensitive under the conditions used. The compositions may be prepared by methods known in the art for preparing tablets, capsules, cough drops, lozenges, medicated buttons, suppositories, solutions, elixirs, syrups, emulsions, dispersions, wetting and effervescent powders, sterile injectable compositions, are known to be useful in preparing a composition of a particularly desired type.

The compounds may be co-administered with other active agents or other antitussive or analgesic agents. Other active ingredients may be, for example, antihistamines, decongestants, antitussives, mucusicides, bronchodilators and antibacterial agents or local anesthetics. Compositions of this type are generally useful in the treatment of cough or pain in conjunction with other symptoms.

Particularly desirable compositions are those prepared in unit dosage form, such as solid forms, including lozenges, lozenges, tablets, capsules, or measured volumes of liquid compositions containing from about 0.1 to about 20 mg / unit of glausine salt for oral use, and about 0.1 to 30-60 mg for analgesic use.

The composition of the cough syrup medium was prepared containing the following pharmaceutically acceptable excipients: excipient amount of sugar (cane) 1600 g sorbitol solution (U S P) 600 g ethanol (alcohol USP) 21 g water q.s. the total volume of 4 liters of d, 1-glausine hydrobromide was 0.3% soluble in this cough syrup medium, or about 15 mg in a 5 ml dosage unit. The solubility of d, l-glausine-lactate was found to be 2%, or about 100 8 6381 2 mg / 5 ml dosage unit.

The stability of d, l-glaucine-lactate was studied in a syrup medium as described above. After one month at ambient temperature, 40 ° C and 55 ° C, the syrup prepared to contain 0.6% d, l-glausine lactate contained 98.8, 100.6 and 96.7%, respectively. % of the initial glausine lactate concentration.

Syrups containing 0.2% codeine phosphate at the time of preparation contained 97.5, 104.5 or 100% after one month when stored at ambient temperature, 40 ° C or 55 ° C. Syrups containing 0.2% d, 1-glausine hydrobromide gave 99, 96 and 89.5% in the experiment, respectively, after one month of storage at ambient temperature, 40 ° C and 55 ° C.

The percentage of residual substance after three months is shown in the following table: Percentage after 3 months

Compound at ambient temperature 40 ° C at 55 ° C d, 1-Glau silyl lactate 1 04.1 97.0 97.4 Codeine phosphate 101.3 101.1 88.4 d, 1-glaucinei HBr 100 , 8 93.3 91, 4

In an experiment similar to the one described above, syrup compositions were prepared, placed in amber glass bottles and clear (silicon) glass bottles and kept exposed to light at ambient temperature conditions (approximately 21,520 lux combined with fluorescent and white incandescent light, 24 h a / day). ).

One month later, the d, 1-glazinin hydrobromide test in the brown bottles was 84%, with 74.5% remaining in the silicon wool. d, l-Glaucine lactate was 94% in the brown glass bottles and 80.6% in the silicon flasks. Codeine phosphate was stable in both types of vessels, 100% remaining.

In other experiments, crystalline d, l-glausine lactate was found to retain more than 99% of the original amount after two months of storage at 40 ° C.

I

6881 2

Physical dependence tendency was studied in mice by the method of Saelens et al., Arch. Int. Pharmacodynam, 19 0: 213-218, 1971. In this experiment, mice are administered increasing doses of a test compound from time to time for two consecutive days. After the last dose, on the second day, the mice are given an intraperitoneal injection of the morphine antagonist, naloxone, at a dose of 100 mg / kg, and the mice are observed to have characteristic jumping behavior due to opium drug withdrawal or morphine antagonism. In these experiments, morphine sulfate induced arousal and "Straub" tail in mice, resulting in five of the nine mice jumping (96 jumps in total) after naloxone treatment. Codeine phosphate induced 11 Straub "tails and agitation and naloxone-induced jumping in two of six mice (23 jumps in total). D, l-glausine lactate did not induce" Straub "tail at the highest dose (100 mg / kg) and did not jump in any of the ten mouse.

In other experiments, varying doses of d, l-glutenin-lactate were administered to groups of mice by oral or intraperitoneal injection, and the dose lethal to 50% of 11 mice (LD5q) was counted from deaths observed within 72 hours of dosing. The LDjjq i ntraper i tonal for injection was 178 mg / kg. The oral LDgg value was 383 mg / kg in these experiments.

Test compounds were tested for their analgesic activity in phenyl-β-quinone mice by twisting according to the experiment of Hendershot & Forsaith, J. Pharmacol. Exptl. Therap. 125 (3), 237 (1979). Test compounds were administered orally 30 minutes before the phenyl-p-quinone test. In these experiments, the oral ED 2 values for d-glausine hydrobromide, codeine phosphate and d, 1-glausine lactate were 34.0, 21.1 and 25.5 mg / kg, respectively.

Claims (1)

EXAMPLE 1 Preparation of 1, 1-glaucinyl lactate A. Two grams of d, 1-glaucine were dissolved in 40 ml of absolute alcohol (ethanol) at 50 ° C and the solution was added, with stirring, to a solution of 0, 57 g of 85% lactic acid diluted in 5 ml of ethanol. The resulting mixture was concentrated in vacuo, cooled and diethyl ether was added to the concentrated solution until a precipitate formed. The white crystalline solid precipitate was collected by filtration and washed with diethyl ether. The d, l-Glaucine 1 lactate product (yield 1.5 g) melted at 148.6-151 ° C. After re-implementation, the salt purified from ethanol-diethyl ether melted at 153.3 ° C. No optical rotation was observed with the product. ([μl = 0.0 ° in water-100 mg / 20 ml). B. 5.6 g (0.02 mol) of d, 1-Glucine was dissolved in 30 ml of alcohol (USP, 95% ethanol, 5% water). A solution of 2.5 g (0.02 mol) of 85% d, 1-lactic acid ([_; <, [q = 0) in 50 ml of alcohol (USP) was added to the glausin solution while stirring. The solution was concentrated under reduced pressure, cooled in a refrigerator, and dry diethyl ether was added until crystallization was complete. The crystalline product was filtered off, washed with diethyl ether and melted at 147-151 ° C. (Yield 7.3 g, 100%). The d, 1 -glucin-d, 1-1 lactate product was dissolved in 130 mL of alcohol (USP) at about 60 ° C, filtered and cooled. Diethyl ethers were added to precipitate the product and the purified d, l-glausine d, l-lactate melted at 153 ° C. (Yield 96%; purity obtained in the experiment 99.8%). C. d, l-Glucine Lactate Elemental Analysis: C, H, N calculated 64.70; 7.01; 3.14 C, H, N found 62.19; 7.17; 3.02.