KR840000056B1 - Process for preparation of glaucine lactate salt - Google Patents

Abstract

A lactate salt of l-glaucine, d,l-glaucine or their mixture is prepared by reacting isolated l-glaucine, or d,l-glaucine of an equal or excessive amount with a compd. selected from isolated salt-formed l-glaucine, d,l-glaucine, or their mixture. The reaction is easily conducted at the ambient or boiling temp. of glaucine in the presence of inert organic solvents, such as acetone, ethanol, chloroform, methanol, diethylether, or ethyl acetate. The produced crystals are filtered, recovered, recrystallized, and washed successively. The lactate salt is used effectively as an analgesic and a cough remedy.

Description

Method for preparing glaucine lactate salt

The present invention relates to a process for the preparation of lactate salts of l-glausin and d, l-glausin, useful as antitussive and analgesic agents. Glaucine has the following structural formula:

Glausine of the above formula has an asymmetric center designated as an asterisk in the formula. Thus two optical isomers are possible. Only one of the two, preferential form (d-glausin) is naturally occurring and can be isolated from the yellow poppy. The racemate, d, l-glausin is synthesized from papaverine according to the method described in Angewandte Chemie (Frank, Tierze, 1967) pp815-6 or according to the method described in the following document. Can be synthesized. [See: Chan and J. Chem. Of Maitland. Soc. (c) J. Org. 1966, 753 or Cava et al. Chem 35,175 (1970). Separation of these two colonies can be separated by conventional methods, for example diastereoisomeric salts formed using optically active acids such as d or l-tartaric acid followed by fractional crystallization.

It is known that d-glausin hydroamide and d-glausin hydrochloride have antitussive effects. See, Donev, Farmatsia (Sofia) 1962, 12, (4), p. 17, and Aleshinskaya, Khim. Farm. Zh. 10, (1), pp. 144-147 (1976) and Chemical Abstracts 84: 159725 w].

In addition, Aleshinskaya et al. Reported that glaucine obtained from thorny yellow poppies prolongs the sleep time of mice by Hellenal and tanrolal hydrates, and has analgesic effects and antiadrenergic doses when administered 50 to 100 mg / kg. It is described as having an effect.

Recent investigations have shown that the leprosy compounds and racemic isomers of glossine hydrobromide have better antitussive effects than prioritized compounds. [Belgium Patent No. 866,079].

As shown in the above structural formula, glausine is structurally similar to alkaloids of other plants such as codeine. Codeine and similar compounds such as hydrocodone are well known as antitussives and narcotic analgesics. See Merck Index, Ninth ed., Merck & Co., Rahway, N. J. (1976) monographs Nos. 2420-24 and 4672].

These compounds are the most effective and most widely used antitussive agents, despite their addiction and addiction. Antitussives are usually administered and are usually administered in the form of liquids such as elixis, suspensions or syrups, but may also be administered in the form of copedrops or solid lozenges that remain in the mouth until dissolved. In both cases, the bitter taste of alkaloids is a disadvantage of this reagent. Various formulations have been developed to eliminate the bad and aftertaste of codeine, but the technique is still not completely successful.

Glaucine is like codeine and has a bad taste. We have surprisingly found that l- and d, l-glausine lactates have analgesic effects superior to d-glausine in addition to the antitussive effect (better than d-glausin), with low habitability, particularly desirable solubility and safety, and unexpected taste. As such, it was found to be preferable for oral administration.

The novel lactate salts of the present invention are prepared by reacting base-type l-glausin or d, l-glausin (or mixtures thereof) with lactate silver under conditions suitable for preparing lactate salts of organic bases. It is a crystalline solid.

This compound is readily prepared by reacting the free glossine base with lactic acid and the reaction is easily carried out in the presence of an inert organic solvent such as acetone, ethanol, chloroform, methanol, diethyl ether or ethyl acetate. Lactate salts are typically formed in the form of precipitates which can be recovered by conventional methods, ie by filtration or decantation and purified by recrystallization and washing.

The reaction is carried out by dissolving free base glossine in an inert organic solvent at ambient temperature to the boiling point of the mixture and adding equimolar or excess lactic acid. Lactic acid is used in an amount of about 0.5 to about 1 to 2 to 3 times the molar excess, or more, but it is preferable to use an equimolar amount.

When excess lactic acid is used, excess lactic acid precipitated with the product can be removed by recrystallization.

Mixtures of l- and d, l-glausin lactate, l-glausin lactate salts, and laccemic dyes are all effective as antitussives and analgesics and have similar desirable properties. Usually, it is preferable to use single lactate salts such as d, l-glausin lactate or l-glausin lactate salt, with d, l-glausin lactate being particularly preferred.

Glausine lactate salt is an active antitussive agent for oral administration, and also has an analgesic effect upon oral administration, and has an excellent umami taste, desirable safety and solubility, and no unnecessary side effects (eg, habituality). For the antitussive effect, about 0.1 to about 40 mg or more is administered per kg, and for the analgesic effect, 0.1 to 60 mg / kg is administered and oral administration is preferred. Parenteral administration such as intraperitoneal injection is also effective as an antitussive and analgesic agent.

In practicing the present invention, an antitussive effective amount of one or more glaucine lactates is internally administered to a mammal. The method of administration may be parenteral (eg, intravenous, intraperitoneal, intramuscular) or injected into the gastrointestinal tract by oral or rectal administration (eg, orally by spraying the glycine lactate solution on the neck).

The effective antitussive amount of the compound, i.e. the amount of glaucine lactate sufficient to suppress or relieve cough, depends on the size, type, age, type of salt or mixture of salts used, the route or frequency of administration, the extent of coughing, and the associated cause Depending on the causative agent, the time of administration, etc. Consideration should also be given to an effective analgesic amount of the compound, i.e. an amount of glaucine lactate sufficient to alleviate the pain. Glaucine lactate salts are effective when administered orally and parenterally. For example, in the antitussive effect, codeine phosphate has an ED ₅₀ of 10.9 mg / kg intraperitoneally and 86.6 mg / kg of ED _{50 in} oral administration, whereas d, l-glausin lactate is 7.9 mg. / kg and 63.4 mg / kg. In special cases, the dosage can be determined by measuring the antitussive effect obtained when using different dosage ratios.

가와 감칠맛이 있으므로 경구투여에 효과적이다.Preferred antitussive effects are oral administration of the glaucine salt at about 0.1 to about 0.2, about 0.5 to about 1 to about 10 to about 20 to 25 to 30 to 40 to about 80 mg, or intraperitoneally at 0.1 to 40 mg / kg. Appears when my injection. In general, it is preferable to administer the minimum amount that can suppress a desired cough according to a conventional administration schedule, and oral administration is a preferred method of administering an antitussive agent. Therefore, the glaucine lactate of the present invention is orally administered Jinhae

It is effective for oral administration because it has a rich flavor.

Preferred dosage units for oral administration are tablets, capsules, lozenges, elixis, syrups, etc. The active glossine lactate compounds may be formulated as capsules or tablets released after a certain time.

In using the compound of the present invention, it is preferable to add the active glossine lactate component in an amount of 0.01 to 95% by weight to the composition containing the pharmaceutical carrier. "Pharmaceutical carrier" means a pharmaceutical excipient that is useful for formulating a pharmaceutically effective compound for internal administration to an animal and which is nontoxic and insensitive under the conditions of use. The composition is prepared by known techniques used to prepare tablets, capsules, cope drops, lozenges, troches, suppositories, solvents, elixirs, syrups, emulsions, dispersants, hydrating agents, sterile injectable compositions, and the like. It may contain a known suitable excipient necessary to prepare the.

The compound may be administered with other active ingredients or with other antitussives or analgesics. Other active ingredients include antihistamines, decongestants, expectorants, mucolytic agents, dilators, antibacterial agents or local anesthetics. In general, mixtures with these are effective for treating cough or pain.

Particularly preferred compositions are prepared in the form of solids such as troches, lozenges, tablets, capsules, or liquids of constant volume, and as antitussives, contain about 0.1 to about 20 to 30 mg of the glossine salt per dosage unit, and about 0.1 to analgesics. To about 30 to about 60 mg of the glossine salt.

Example 1

preparation of d, l-glausin lactate,

A. 2 g of d, l-glausin are dissolved in 40 ml of anhydrous alcohol (ethanol) at 50 ° C. and this solution is added to 0.57 g of 85% lactic acid diluted with 5 ml of ethanol with stirring. The resulting mixture is concentrated in vacuo, cooled and diethyl ether is added to the concentrated solution until precipitation. When a white crystalline solid precipitate formed, it was collected by filtration and washed with diethyl ether to obtain 1.5 g of d, l-glausin lactate product having a melting point of 148.6 to 151 ° C. After recrystallization with ethanol-diethyl ether the melting point of the purified salt is 153.3 ° C. This product has no trace of light rotation.

B. Dissolve 5.6 g (0.02 mole) of d, l-glausin in 30 ml of alcohol USP (95% ethanol, 5% water). A solution of 2.5 g (0.02 mol) of 85% d, l-lactic acid ([α] _D = 0) in 50 ml of alcohol USP was added to the glossine solution with stirring. The solution is concentrated under reduced pressure, cooled in a freezer and anhydrous diethyl ether is added until crystallization is complete. The crystalline product was filtered off and washed with diethyl ether to give the product (7.3 g, 100%) with a melting point of 147-151 占 폚. The d, l-glausin-d, l-lactate product is dissolved in 130 ml of alcohol USP at 60 ° C., filtered and then cooled. The addition of diethyl ether precipitates the product and the melting point of the purified d, l-glausin-d, l-lactate is 153 ° C. (Yield: 96% Analysis: 99.8% Purity)

c. Elemental Analysis of d, l-Glausine Lactate:

Calculated Value: C 64.70 H 7.01 N 3.14

Found: 62.19 7.17 3.02

Example 2

Different doses of test compound are orally administered to different groups of molarmots and distilled water is administered to the control group. After 1 hour of oral administration, the molmot is exposed to 5% citric acid aerosol for 10 minutes. Record the cough water that occurs during the last 5 minutes of exposure to the satyr aerosol and calculate the effective dose (ED ₅₀ ) to suppress coughing at 50% of molar.

Record the antitussive effect if the total number of coughs for 5 minutes is at least 2 standard deviations less than the average number of coughs per molar in the control group. In this operation, codeine phosphate was 86.6 mg / kg ED ₅₀ in oral administration, d-glausin hydrobromide was 89.0 mg / kg ED ₅₀ and d, l-glausin lactate was 63.4 mg / kg ED ₅₀ . Appeared.

Example 3

In a similar operation as in Example 2, test compounds are administered intraperitoneally to molemot and one group is administered distilled water as a control. To determine antitussive activity, ED ₅₀ is calculated by citric acid aerosol test as described in Example 2. Codeine phosphate had an ED ₅₀ value of 10.9 mg / kg, d-glausin hydrobromide had an ED ₅₀ of 10.0 mg / kg, and d-glausin lactate had an ED ₅₀ of 7.9 mg / kg.

Example 4

Coff syrup vehicle formulations are prepared to contain the following pharmaceutically toxic excipients:

The solubility of dL-glausin hydrobromide in this Coff syrup vehicle was 15, or 15 mg per 5 ml dose unit. The solubility of dL-glausin lactate was 2%, or 100 mg per 5 ml dose unit.

Example 5

The stability of d, l-glausin lactate was investigated in the syrup vehicle of Example 4. Syrup formulated to contain 0.6% d, l-glausin lactate maintains 98.8%, 100.6% and 96.7% (55 ° C) of the original glossine concentration after one month at ambient temperature, 40 ° C and 55 ° C, respectively. appear. Syrup containing 0.2% codeine phosphate was 97.5%, 104.5% or 100% after one month at ambient temperature, 40 ° C or 50 ° C, respectively. Syrup containing 0.2% of dℓ-glausin hydrobromide After one month at 40 ° C and 55 ° C it was analyzed as 99.96% and 89.5%, respectively. The amount of antitussive remaining after 3 months is as follows.

Example 6

In a manner similar to Example 5, the syrup is formulated and placed in amber and transparent vials and left at ambient temperature while still being exposed to light. (Mixed fluorescent and incandescent light at approximately 21.520 lux for 24 hours / day)

One month later, the amber, vi, d, l-glausin hydrobromide assay was 84% and the compound in the vial was 74.5%. D, l-Glausin lactate analysis in amber vial was 94%, 80.6% in the clear glass bottle. Codeine phosphate was found to be stable as a 100% assay in both containers. In another operation, crystalline d, l-glausin lactate was found to retain more than 99% of the original assay after two months storage at 40 ° C.

Example 7

Physical dependence is assessed using the mouse with the procedure described in the following document. [See: Arch of Saelens et al. Int. Pharmacodynam, 190: 213-218. 1971.] In this procedure, the dose of test compound is administered to the mice in increasing intervals of two days at intervals. After administration of the last dose of day 2, the morphine antagonist naroxone was injected intraperitoneally at a dose of 100 mg / kg and the characteristic jump behavior or morphine antagonism that occurred when opiate administration was stopped in mice was observed. In these manipulations, morphine sulphate exhibited excitability and straub tail in mice, and five of nine mice (total 96 jumps) jumped after narroxone treatment. Codeine phosphate showed straubottail and excitability, and jumps induced by narroxone were seen in two out of six mice. (23 jumps in total). d, l-Glausine lactate did not show a straub tail at high doses (100 mg / kg), and none of the 10 mice treated showed a jump response.

Example 8

Various d, l-glausin salts are prepared as 0.2% (w / v) solutions dissolved in distilled water. Various salt solutions are dipped into the tongue to evaluate taste. In these operations involving the blindness of experienced taste testers who are familiar with the taste of preparations containing agents such as codeine and dextromemethorpan, hydrobromide is unpleasant with a bitter, irritating and metallic initial taste that increases over time. One taste. Sulfate, maleate, citrate, acetate, pamoate, and p-toluenesulfonate salts are similar to hydrobromide and have a similarly unpleasant taste.

Salicylate and succinate salts have been shown to have a more unpleasant taste than hydrobromide. d, l-Glausin lactate did not appear to have a pungent metallic taste and was not unpleasant.

Example 9

A. Aromatic cosphorus preparations are prepared to contain as follows:

The syrup contains 0.6% (w / v) of d, l-glausin lactate and the 5 ml dose unit (1 teaspoon) contains 30 mg of active lactate salt. The syrup is sealed in a 5 ml gold engraved plastic container and can be filled in a regular glass jar. Dosage units of 15 mg and 20 mg per 5 ml may be made using 300 or 400 mg of d, l-glausin lactate or l-glausin lactate or mixtures thereof in the formulation.

B. Tablets are prepared as follows: Granules are prepared by mixing 40 g l-glausin lactate and 150 g modified starch (Sta-Rex 1500) and granulating with a sufficient amount of aqueous alcohol (75% water, 25% ethanol). . The granules are dried and mixed with 15 g of starch usp, 1.5 g of stearic acid (40 mesh), 0.5 g of hydrogenated vegetable oil (40 mesh), 3 g of colloidal silicon oxide and an appropriate amount of microcrystalline cellulose to make a total of 300 g. The ingredients are mixed and compressed into 300 mg tablets using an 11/32 inch (= 8.7 mm) tablet. The tablets each contain 40 mg of l-glausin lactate.

C. Capsules are prepared by mixing 10 g d, l-glausin lactate, 3 g colloidal silica, 2 g stearic acid and 285 g lactose, and admixing the mixture to No. 2 gelatin capsules at 300 mg per capsule. The capsules thus prepared contain 10 mg of glaucine lactate per capsule. Larger unit doses such as 15, 20 or 25 mg can be prepared at 300 g by adding 15, 20 or 25 g of glaucine lactate and a suitable amount of lactose. Smaller doses are similarly prepared.

D. The troches are mixed with 30 g of d, l-glausin lactate, 435 g of powdered sugar and 35 g of powdered acacia, added with sufficient water to form a flexible mass, pushing the ingot into the columnar and dividing it into 0.5 g size.

Example 10

In another operation, various doses of d, l-glausin lactate are administered to the mouse group by oral or intraperitoneal injection, with the 50% lethal dose (LD ₅₀ ) of the mice calculated from the mortality observed within 72 hours after administration. The LD ₅₀ by intraperitoneal injection was 178 mg / kg. Oral LD ₅₀ was 383 mg / kg in this operation.

Example 11

The analgesic action of the test compounds is shown in Hendershot & Forsaith, J. Pharmacol. Exptl. Therap. 125 (3), 237 (1979)] by the phenyl-p-quinone mouse torsion test. Test compounds are administered orally 30 minutes prior to phenyl-p-quinone administration. In this operation, oral ED ₅₀ values with d-glausin hydrobromide, codeine phosphate and d, l-glausin lactate were 34.0, 21.1 and 25.5 mg / kg, respectively.

Claims (1)

A compound selected from l-glausin, d, l-glausin and mixtures thereof in freebase form is reacted with an equimolar or excess of lactic acid to give a compound selected from l-glausin, d, l-glausin and mixtures thereof. Process for preparing lactate salts.