Ways to get 14-hydroxymorphinone, the intermediate

 

(57) Abstract:

Describes how to obtain 14-hydroxymorphinone, including oxycodone, noroxymorphone, naltrexone by oxidation of dianol allatom of normorphine using aqueous medium in the presence of a weak acid, which simplifies the process. Noroxymorphone is a key intermediate product to obtain the number of analgesics and antagonists drugs. Describes new intermediate compounds. 3 S. and 21 C.p. f-crystals.

BACKGROUND OF THE INVENTION

1. The scope of the invention

The present invention relates to a method of conversion of normorphine and its derivatives that can be synthesized from morphine, a corresponding 14-hydroxymorphinan and its derivatives, including oxycodone, Oxymorphone, noroxymorphone and naltrexone. Noroxymorphone is a key intermediate compound for the manufacture of important narcotic painkillers and antagonistic funds. In addition, the present invention relates to the creation of new intermediate compounds.

2. Art

14-Hydroxy-substituted morphine derivatives are important narcotic analgesic and/or and the and nalmefene. They are easily synthesized from thebaine, which is a minor component of opium resin (gum). Because stocks of thebaine is limited, and the demand for it grows, the cost of thebaine high. As a result, was taken many conflicting attempts, which were intended to obtain 14-hydroxymorphinone derivatives. These attempts to obtain such drugs, with its basis in the 14-hydroxy group of easily accessible and abundant source materials of morphine and codeine (a minor component of opium resin, which can also be synthesized by methylation of morphine) in total are as follows:

(1) the conversion of codeine in thebaine by dihydrocodeinone (yield of 5.4%, , Rappoport and others, "journal of the American Chemical Society", T. 89, 1967 , page 1942, Rapoport and others, "Journal of Organic Chemistry", T. 15, 1950 , page 1103), codeinone (yield 20%, I. Seki, "Chemical and Pharmaceutical Bulletin", T. 18, 1970, page 671, and G. Rapoport and others, "journal of the American Chemical Society", I. 77, 1955, page 490)or 6-methyl ester of codeine (using manganese dioxide, yield 67%, R. B. Barber and others, "Journal of medicinal Chemistry", T. 18, 1975, page 1074);

(3) direct allyl oxidation of codeine in the corresponding 14-hydroxy derivative by means of chromic acid (H. L. Helms and others, "journal of the American Chemical Society", I. 69, 1947, p. 1966), manganese dioxide (I. brown and others, "Journal of Chemical Society, 1960, page 4139), and selenium dioxide plus t-butyl hydrogen peroxide (M. A. Schwartz and others, "Journal of medicinal Chemistry", T. 24, 1981, page 1525); and

(4) six-step transformation of codeine noroxycodone (yield 52%) and in noroxymorphone (yield 43%) using formed by photochemical method of singlet oxygen (M. A. Schwartz, and others, "Journal of medicinal Chemistry", T. 24, 1981, page 1525); and

(5) obtaining noroxymorphone from morphine through an intermediate connection with carbamato protected on the nitrogen atom (position 17), or carbamato protection in position 3 and carbamato protection in position 17 normorphine Diana acetate with MSRV with substantial absence of water (yield 37%, Valleys, U.S. patent 5112975). These processes inherent disadvantages, limited or low outputs, long stages, do not give to a gradual increase of outputs, or to the necessity of the use of heavy metals that are harmful to the surrounding derivatives in the corresponding 14-hydroxymorphinan and its derivatives. Another objective of the present invention is to provide ways to obtain relatively high outputs indicated the desired product. Another objective of the present invention is the development of methods that would be safe for the environment and would eliminate the use of heavy metals.

Another objective of the present invention is to create ways in which the quality of the source material instead of rare could be used morphine or codeine. Codeine is a component of opium resin (gum) and can also be obtained by methylation of morphine, carried out using known methods.

Another objective of the present invention is to condition the use of the water system at the stage of oxidation for the formation of 14-hydroxymorphinone that is not only beneficial to the environment, but also desirable when carrying out the subsequent reaction hydrogenative, eliminating the need for isolation of intermediate compounds 14-hydroxymorphinone.

Another objective of the present invention is the obtaining of certain intermediate compounds, which are new compounds.

the products, such as oxycodone, Oxymorphone, naltrexone and noroxymorphone.

These and other objectives will become apparent to the person skilled in the art in light of the following disclosure of the present invention.

THE INVENTION

In a broader sense, the present invention relates to methods of producing 14-hydroxymorphinone formula

< / BR>
and certain derivatives as described below. In the above formula R is selected from the group consisting of lower alkyl with 1-7 carbon atoms, cycloalkenyl with 3-6 ring carbon atoms, benzyl and substituted benzyl of the formula

< / BR>
where Q and Q' are selected individually from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino, cyan;

R is preferably methyl (when the desired products are oxycodone and Oxymorphone), cyclopropylmethyl (when the desired products are required naltrexone, nalmefene), cyclobutylmethyl (when as a desirable product requires nalbuphine) and benzyl (when the desired products are required naloxone, naltrexone, nalbuphine or nalmefene);

R' is methyl, ethyl, 2-(4-morpholinyl)ethyl, benzyl, substituted benzyl (as defined;

R' is preferably methyl (when the desired product is required oxycodone), benzyl (when the desired products are required Oxymorphone and 14-hydroxyl normorphine), or acyl (when the desired product is required Oxymorphone) and R" are methyl;

of the respective normorphine formula

< / BR>
where R and R' have the meanings given above;

by interacting normorphine (as defined above) by any of the following methods (1) or (2):

(1) directly from the oxidizing agent is hydrogen peroxide, at a temperature of from about 15oWith up to 70oWith, preferably in the range 40oWith up to 50oIn the presence of acid, such as formic acid, tartaric acid, acetic acid or other inorganic acids, preferably formic acid, in a suitable non reactive solvent, such as water, acetic acid, THF, DMSO or a mixture of solvents, such as Etoac/BUT suitable for solution or suspension of the reactants, preferably water, over a time period of 1 to 24 hours, depending on the scale of the reaction; or

(2) by a two-stage initial acylhalides connection fo doctitle Cl;

or with acetic anhydride of the formula

[R"C(O)2]O

where R" has the meaning defined above;

and at the second stage - with the corresponding acid salt of the formula

R"COOM,

where R" has the meaning given above,

M is an atom of sodium or potassium, preferably sodium atom;

with or without co-solvent, such as toluene, DMF or DMAC, preferably toluene;

with heating at a temperature of from about 60oWith approximately 150oC, preferably 110oWith over a time period of 1 to 24 hours, depending on the lot size, to obtain dianol of acylate formula

< / BR>
where R, R' and R" have the meanings given above;

with the subsequent interaction of the specified Diana of acylate or oxidizing agent under the conditions described in relation to method (1) or peroxide acid, such as 3-chloroperoxybenzoic acid (MSRA) in a weak acid such as acetic acid or formic acid, with water or without it and with Sortavala or without him to assist in the dissolution of the specified acid and peroxide specified reactant.

THE DISCLOSURE OF THE PREFERRED EMBODIMENTS

Embodiments of the present invention are discussed with reference to RA is roxanemartino. These R, R' and R" have the meanings given above.

The key characteristic properties is made possible by connecting several essential new concepts and methods, consisting in

(a) converting the 17(N) 3(O)-substituted of normorphine formula

< / BR>
in the corresponding 14-hydroxy-17(N) 3(O)-substituted, normorphine formula

< / BR>
with hydrogen peroxide in an aqueous system in the presence of an acid;

(b) converting the 17(N) 3(O)-substituted-normorphine formula

< / BR>
in the corresponding 14-hydroxy-17(N) 3(O)-substituted, normorphine formula

< / BR>
with an oxidizing agent selected from aqueous hydrogen peroxide or precisionmodel acid in the aqueous system in the presence of a weak organic acid;

(C) oxidizing the reaction for the formation of 14-hydroxy-17(N) 3(O)-substituted-normorphine formula

< / BR>
in acetic water system that is highly desirable for the subsequent stage catalytic hydrogenative;

(g) 14-hydroxy 3(O)-substituted and/or 17(N) substituted normorphine formula

< / BR>
can interact in a special way for the formation of oxycodone, Oxymorphone, naltrexone and noroxymorphone. Last aerpostale group substitution depends on the class of the desired product to this choice helped to facilitate the process and rational consumption of solvent and reagent.

The advantages of this method is the subject of the present invention, intended to get oxycodone, includes, among others, the following:

(a) widespread use at the present time the source material is codeine, which is a minor component of opium gum and which can also be obtained by methylation of morphine using known techniques. This method does not require demethylation of the N-methyl group at position 17 of codeine, protection of nitrogen-17 norcodeine and norcodeine using carbamate and subsequent creation of insecurity 14-hydroxy-N-ethoxycarbonylmethylene, and, finally, re-methylation of the nitrogen as described in U.S. patent 4472253; 4639520 and 4795813;

(b) the use of the water system in the oxidation normorphine or normorphine Diana azelate not only beneficial to the environment, but is also desirable for the subsequent reaction hydrogenative because there is no need to allocate intermediate 14 hydroxycodone. The main nitrogen at position 17 is protonated in acidic aq is from a new way of synthesizing ensures high outputs, adequate reliability and direct loop and control at each stage of the synthesis, as well as significant cost reduction for the synthesis of oxycodone, Oxymorphone, noroxymorphone, naltrexone and nalbufina.

So, for the synthesis of oxycodone from codeine, according to the present invention, the source material of the formula

< / BR>
converted in codeine formula

< / BR>
by means of the method known from the sources of prior knowledge, such as Collapse oxidation (SO/acid halide or acid anhydride). In accordance with the first method of the present invention, codeine interacts with hydrogen peroxide in water in the presence of acid at a temperature of from about 15oWith up to 70oWith over a time period, depending on the reaction scale, to ensure a good outputs 14-hydroxycotinine. Thus obtained 14 hydroxycodone hydrogenized in the same reaction medium with a catalyst to ensure good release oxycodone. Preferably, the temperature was in the range between approximately 40oWith and approximately the 50oWith, and acid was formic acid.

The sequence of this is Ana scheme 1, listed at the end of the description.

In the above case and in the subsequent reaction transformations, which are listed below, written over dash two-digit number that appears under each formula corresponds to the same pointer that appears after the name of each of such examples. Accordingly, solvents, reactants, temperature, time periods, and outputs the examples in relation to each stage of the overall reaction. By the present invention it was found that the outputs of intermediate products has increased substantially through the initial acylation normorphine in the respective Diana utility and subsequent oxidation of these allatom in the corresponding 14-hydroxymorphinone in contrast to the direct oxidation normorphine in the corresponding 14-hydroxymorphinone.

Although such a method, and includes an additional step, however, indicated a higher output is more than it justifies. For example, the oxidation of codeine Diana acetate in 14 hydroxycodone gives the output of the order of 70-80% after chromatography, while the direct oxidation of codeinone 14-hydroxycodone provides about 40% of the output.

Accordingly, the techniques, described in the sources of prior knowledge (DE 902257, 1957, and M-S Brown, JCS, 1960. p. 4139), and then codeine Diana acetate interacts with hydrogen peroxide under the conditions specified in the binding to the initial process of obtaining 14-hydroxycotinine that hydrogenesised in oxycodone highest outputs.

Alternatively, codeine Diana acetate interacts with peroxidization oxidizing agent in water or no water system with a weak acid at room temperature for education 14-hydroxycotinine with the highest output.

On the other hand, the specified product-14-hydroxycotinine in its reaction mixture suitable for the next reaction, catalyst hydrogenative, without allocation 14-hydroxycotinine by adding a catalyst and hydrogenative mixture, followed by separation of oxycodone.

Preferably peroxidization oxidizing agent is 3-chloroperbenzoic acid, derbentina acid, peroxidasa acid; although the preferred 3-chloroperbenzoic acid.

For dissolution specified oxidizing means is used not interact a co-solvent, such as EA or formic acid, which also serves as a solvent.

Carrying out the reaction with water or without water, or oxalic acid does not affect the output.

The sequence of steps for the second method, in which codeine into codeine Diana acetate during the synthesis of oxycodone from morphine, can be illustrated by figure 2, is provided at the end of the description.

For synthesizing Oxymorphone of morphine according to the present invention

(a) the first stage is reduced to the protection of the phenolic hydroxy at position-3 of morphine for education 3(O)-protected-morphine formula

< / BR>
where P= P1or P2P is a suitable protecting group which is stable under the reaction conditions and can be easily removed by a moderate hydrolysis with acid or base (for P1or in terms of catalytic gidrogenizirovanii (P2). P1includes acyl, benzoyl and alkoxycarbonyl. P2includes benzyl, substituted benzyl and benzyloxycarbonyl.

(b) the second stage is reduced to the oxidation of 3(O)-protected-morphine 3(O)-protected-morphinan formula

< / BR>
by any known method such as oxidation Collapse (DMSO/acid halide or acid anhydride).

(lisovanim techniques according to the present invention as specified in the conversion of codeinone 14-hydroxycodone when synthesizing oxycodone.

Intermediate substance -3(O)-protected codeine Diana Atzilut is a new compound of the formula

< / BR>
where R and R" have the meanings defined above; preferably P1- acetyl and P2- benzyl.

(g) depending on the particular protective group, R1or R2the fourth stage is either

(i) to obtain first 7,8-double bond at the 3-(O)-R2-secure morphinone and subsequent removal of the protective group by acid or basic hydrolysis to obtain Oxymorphone or

(ii) to hydrogenation 7,8-double bond and at the same time to eliminate the protection of 3-(O)-R-secure morphinone to get Oxymorphone.

This synthetic Oxymorphone from morphine, where R1- acetyl can be illustrated by scheme 3, shown at the end of the description.

Written through the dash two-digit number, which is indicated under each formula, identifies appropriate the examples below. Synthesis of Oxymorphone from morphine, where P2-benzyl can be illustrated by figure 4, is given at the end of the description.

For synthesizing noroxymorphone from morphine, in accordance with another embodiment of the present R>< / BR>
6-acetyl include 3-benzylmorphine-N-dimethylurea 1-chloroethyl chloride salt of formic acid or CYANOGEN bromide followed by acid hydrolysis of 3-benzylmorphine. 3-benzylmorphine interacts with benzyl halide in the presence of a base, such as sodium or potassium bicarbonate to obtain 3,17-dibenzoylmorphine, new compounds through oxidation Swery.

Applying the above conditions according to the present invention 3,17-dibenzoylmorphine oxidized in 3.17-dibenzyl-14-hydroxymorphinan either by direct interaction with hydrogen peroxide in formic acid or by initial conversion to 3,17-dibenzoylmorphine Diana Atzilut, new connection, and the subsequent interaction of the latter with hydrogen peroxide in formic acid or peroxynitrite as listed in the synthesis of oxycodone. Without resorting to the selection 3,17-dibenzyl-14-hydroxymorphinone from its reaction mixture, this connection hydrogenperoxide to remove the two benzyl groups and the simultaneous recovery of the 7,8-double bond and get good outputs noroxymorphone.

Specified synthesizing noroxymorphone of morphine can be prodeine last, according to the present invention, is converted to 6-acetylcodeine that N-demetiliruetsa 6-acetylcisteine hydrochloride, followed by alkylation of the nitrogen for the formation of 17-cyclopropanemethylamine. The latter is oxidized to 17-cyclopropanemethylamine. As indicated, when synthesizing oxycodone, according to the present invention, 17-cyclopropanemethylamine converted to 14-hydroxy-17-cyclopropanemethylamine either through oxidation with hydrogen peroxide in formic acid or the initial conversion to 17-cyclopropanemethylamine Diana acetate, a new compound, with subsequent oxidation by hydropredict or MSRV.

14-hydroxy-17-cyclopropanemethylamine hydrogenesised 3-methylnaltrexone. 3 methylnaltrexone can be demetrious in naltrexone by BBr - previously known method.

This reaction can be illustrated by scheme 6, provided at the end of the description.

For the synthesis of naltrexone from morphine in this invention, morphine is converted to 3-benzylmorphine as described above, in the process of synthesizing noroxymorphone.

3-benzylmorphine interacts with halide is implemented in 3-benzyl-17-cyclopropanemethylamine, a new connection through oxidation Collapse. In accordance with the terms stipulated in this yobretenie, 3-benzyl-17-cyclopropanemethylamine is oxidized to 3-benzyl-17-cyclopropylmethyl-14-hydroxymorphinan either by direct interaction with hydrogen peroxide in formic acid or by initial conversion to 3-benzyl-17-cyclopropanemethylamine Diana Atzilut, a new connection with the subsequent interaction of the latter with hydrogen peroxide in formic acid or peroxynitrite, as indicated in the case of the synthesis of oxycodone. Without resorting to the separation of 3-benzyl-17-cyclopropylmethyl-14-hydroxymorphinone from its reaction mixture is hydrogenation this connection in order to remove the benzyl group and the simultaneous recovery of the 7,8-double bond to obtain a good output of naltrexone.

Synthesis of naltrexone is illustrated in scheme 7, provided at the end of the description.

The General scheme (8) for the synthesis of noroxymorphone and morphine, where P, Q, Q, and R have the meanings stated above, the circuit 8 is provided in the end of the description.

As mentioned above, certain intermediate compounds detected during sintezirovany in the points of claim.

Examples illustrating the present invention, is shown at the end of the text.

1. The way to obtain 14-hydroxymorphinone General formula

< / BR>
where R is selected from the group consisting of lower alkyl with 1-7 carbon atoms, cycloalkyl-methyl with 3-6 ring carbon atoms, benzyl;

R' is chosen from the group consisting of benzyl, R"C(O), where R" is lower alkyl with 1-4 carbon atoms,

including the interaction of normorphine dienal allatom General formula

< / BR>
where R and R' have the above values,

with an oxidizing agent at a temperature of from about 15 to about 70oSince, in the presence of weak acid and water or an organic solvent for dissolving the above reagents in a period of time sufficient for the formation of 14-hydroxymorphinone.

2. The method according to p. 1 in which the oxidizing agent is hydrogen peroxide, the temperature is in the range from about 40 to about 50oWith, a weak acid is concentrated formic acid, water is the solvent in a ratio sufficient to dissolve the above reagents.

3. The method according to p. 1 in which the oxidizing agent is metachlorobenzoic acid, the temperature is ora is also a solvent.

4. The method according to p. 1 in which the oxidizing agent is metachlorobenzoic acid, the temperature is in the range from about 15 to about 30oWith, a weak acid is acetic acid, which is also a solvent.

5. The way to obtain 14-hydroxymorphinone General formula

< / BR>
where R is selected from the group consisting of lower alkyl with 1-7 carbon atoms, cycloalkenyl with 3-6 ring carbon atoms, benzyl;

R' is chosen from the group consisting of benzyl, R"C(O), where R" is lower alkyl with 1-4 carbon atoms,

including interaction normorphine General formula

< / BR>
where R' and R" have the above values,

with hydrogen peroxide at a temperature of from about 15 to about 70oIn the presence of acid, and an aqueous solvent to dissolve the specified reagent for a time sufficient for the formation of 14-hydroxymorphinone.

6. The method according to p. 5, in which the acid used formic acid.

7. The method according to p. 5, in which the solvent used water.

8. The method according to p. 5, in which the solvent used water and ethyl acetate.

9. The method according to p. 5, to the P>With, as the acid is concentrated formic acid as solvent - water ratio, sufficient for dissolution specified reagents.

10. The method according to p. 5, where R and R' are the stands.

11. The method according to p. 5, where R is the stands, and R' is benzyl.

12. The method according to p. 5, where R and R' each is benzyl.

13. Normorfin, normorphine, normorphine dienal Atzilut compounds selected from the group consisting of formulas I

< / BR>
where R' is chosen from the group consisting of substituted and unsubstituted benzyl groups of the formula

< / BR>
where Q and Q1independently selected from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino and CYANOGEN;

R is chosen from the group consisting of R', and cycloalkyl - lower alkyl with 3-6 ring carbon atoms of the formula

< / BR>
where R' is chosen from the group consisting of alkyl with 1 to 7 carbon atoms and substituted and unsubstituted benzyl formula

< / BR>
where Q and Q' independently are selected from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino, cyan;

R' is alkyl with from 1 to 4 carbon atoms

< / BR>
where R is selected from the group consisting of alkyl with 1 to 7 carbon atoms, /BR>< / BR>
where Q and Q' independently are selected from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino, cyan;

R' is chosen from the group consisting of substituted and unsubstituted benzyl, as defined above, and R"C(O)-, where R" is alkyl with 1-4 carbon atoms, and under the conditions that (1) both R and R' cannot simultaneously be the stands, (2) when R is methyl, R' cannot be benzyl, and (3) when R' is methyl, R may not be cyclopropylmethyl;

< / BR>
where R is selected from the group consisting of alkyl with 1 to 7 carbon atoms, cycloalkyl - lower alkyl with 3-6 ring carbon atoms and substituted and unsubstituted benzyl formula

< / BR>
where Q and Q' independently are selected from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino, cyan;

R' is chosen from the group consisting of R and R"C(O)-, where R" is alkyl with 1-4 carbon atoms, provided that R, R' and R" are not all at the same time lower alkyl,

< / BR>
where R is selected from the group consisting of substituted of unsubstituted benzyl formula

< / BR>
where Q and Q' is separately selected from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino, cyanide and cycloalkyl - lower alkyl with 3-6 ring carbon atoms;

R/P> 14. Connection on p. 13 of the formula I

< / BR>
where R' is chosen from the group consisting of substituted and unsubstituted benzyl formula

< / BR>
where Q and Q' independently are selected from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino, cyan;

R is chosen from the group consisting of R' and cycloalkyl - lower alkyl with 3-6 ring carbon atoms:

15. Connection on p. 13 formula II

< / BR>
where R' is chosen from the group consisting of alkyl with 1 to 7 carbon atoms and substituted and unsubstituted benzyl formula

< / BR>
where Q and Q' is separately selected from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino, cyan;

R" is alkyl with 1-4 carbon atoms.

16. Connection on p. 13 formula III

< / BR>
where R is selected from the group consisting of alkyl with 1 to 7 carbon atoms, cycloalkyl - lower alkyl with 3-6 ring carbon atoms and substituted and unsubstituted benzyl formula

< / BR>
where Q and Q' independently are selected from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino and CYANOGEN,

R' is chosen from the group consisting of R"C(O)-, where R" is alkyl with 1-4 carbon atoms and, under the conditions that (1) both R and R' cannot simultaneously be the stands; (2P> 17. Connection on p. 13 formula IV

< / BR>
where R is selected from the group consisting of alkyl with 1 to 7 carbon atoms, cycloalkyl - lower alkyl with 3-6 ring carbon atoms and substituted and unsubstituted benzyl formula

< / BR>
where Q and Q' independently are selected from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino and CYANOGEN;

R' is chosen from the group consisting of R and R"C(O)-, where R" is alkyl with 1-4 carbon atoms, provided that R, R' and R" may not be all at the same time lower alkyl.

18. Connection on p. 13 formulas V

< / BR>
where R is selected from the group consisting of substituted and unsubstituted benzyl formula

< / BR>
where Q and Q' independently are selected from the group consisting of hydrogen, lower alkyl, trifloromethyl, nitro, dialkylamino, cyanide and cycloalkenes of alkyl with 3-6 ring carbon atoms;

and R' - substituted and unsubstituted benzyl, as defined above.

19. Connection on p. 17 formula, which is a 3-acetylmorphine.

20. Connection on p. 18 formula, which is 3-acetylmorphine dienal acetate.

21. Connection on p. 18 formula, which is 3-benzylmorphine dienal acetate.

22. Connection on p. 15 formula, zelnormonline.

24. Connection on p. 18 formula, which is 3,17-dibenzoylmorphine dienal acetate.

 

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11 cl, 1 tbl, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes analgesic compositions containing buprenorphine in the level of subclinic analgesic doses in combination with naloxone, naltrexone or nalmephene. The mass ratio buprenorphine to naloxone is in the range from 12.5:1 to 27.5:1, and the mass ratio buprenorphine to naltrexone or to nalmephene is in the range from 12.5:1 to 22.5:1. Compositions are prepared as the parenteral or sublingual medicinal formulation or as a medicinal formulation that can be delivered through mucosa. Analgesic effect of buprenorphine is enhanced by low dose of naloxone, naltrexone or nalmephene.

EFFECT: enhanced effectiveness of compositions, valuable medicinal properties.

7 cl, 3 dwg, 21 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an agent possessing anti-coughing and expectorative effects. Agent possessing anti-coughing and expectorative effects comprises codeine, sodium hydrocarbonate, terpin hydrate, potato starch, stearic acid, nutritive gelatin and medicinal talc in the following ratio of components, g per a tablet of mass 0.6 g: codeine, 0.008; sodium hydrocarbonate, 0.3; terpin hydrate, 0.2; potato starch, 0.0617; stearic acid, 0.0053; nutritive gelatin, 0.01, and medicinal talc, 0.015. Invention provides safety in prolonged intake of the agent that shows less expressed irritant effect on stomach mucosa.

EFFECT: improved and valuable medicinal and pharmaceutical properties of agent.

5 tbl

FIELD: medicine, narcology, biochemistry, pharmacy.

SUBSTANCE: invention proposes using the combination of dextromethorphan and the second medicine (quinidine, yohimbin, haloperdol, adjmaline, lobeline, pipamperon, fluoxetine, labetalol, chlorpromazine, domperidone, nortryptiline, quinine, oxyprenolol, propranolol, timolol, methaprolol, diphenhydramine, papaverine, mexiletine or their salts or isomers) for removing addiction to opiates, opioids or synthetic narcotics with exception cocaine and barbiturates (help in refusal in their using) or in case of chronic using antidepressant and corresponding treatment methods. The proposed combination of drugs reduces pain and relieves the withdrawal syndrome on the background of reducing morphine dose (antidepressant) up to the complete removing their intake.

EFFECT: enhanced effectiveness and valuable medicinal properties of medicine combinations.

54 cl, 2 ex

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