Buprenophine derivatives and application thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula in which R1 represents C1-C10-alkyl with a straight or branched chain, optionally substituted by an aromatic ring, or -(CH2)nX(CH2)n- in which each n is equal to an integer from 0 to 2, X represents O, S, NH and where R2 represents H or C1-C6-alkyl with the straight or branched chain. Also, the invention refers to application of buprenophine derivative esters on a hydroxyl group of phenol for treating opiate dependences and/or moderate to strong pain, and to application as an agent releasing a therapeutic amount of buprenophine into a human body.

EFFECT: preparation of new buprenophine derivatives a hydroxyl group of phenol for treating opiate dependences and/or moderate to strong pain.

20 cl, 7 dwg, 1 tbl, 11 ex

 

The technical field to which the invention relates

The present invention relates to a derivative of buprenorphine and their applications.

The level of technology

Treatment for the abuse of opiates and opiate dependence by replacing the opiate used for abuse, safer, more long-acting opioid, is often a successful strategy of medical treatment. Heroin - opiate commonly used for abuse, acts as an agonist at the μ-opioid receptor (MOR). When heroin is often used intravenous injection, often leading to the sharing of needles by drug addicts, which is often the cause of the spread of life-threatening infections such as hepatitis C and HIV/AIDS. As a substitute of MOR agonist was applied methadone. Methadone is active in oral use and is of sufficient duration to ensure that such action with the introduction of a single daily dose. Recently for the medication was applied buprenorphine1, 21-(cyclopropyl-7α-[(S)-1-hydroxy-1,2,2-trimethylpropyl])-6,14-endoethano-6,7,8,14-tetrahydroazepine, partial agonist MOR, (see, for example, U.S. patent No. 4935428). As a partial agonist MOR it has a lower acceptable level of impact is of textbooks, mediated MOR than a full MOR agonist (e.g., methadone). As a result, the buprenorphine has a higher margin of safety than full agonists MOR. In addition, buprenorphine has a long duration of action. Increased safety of buprenorphine in combination with its extended duration of action provides a relatively long interval between doses of a medicinal product, usually every 24 hours, although it may be increased to every 72 hours or more.

The favorable safety profile of buprenorphine compared with methadone has allowed doctors to prescribe it as an outpatient, which significantly reduced the cost of treatment and increased the number of dependent people (drug addicts), undergoing medical treatment.

For the treatment of abuse of opiates and opiate dependence buprenorphine is available in tablet form designed for sublingual administration, and marketed under the brand name Subutex®. Daily maintenance dose of Subutex®is in the range of 4-16 mg Subutex®easily soluble in aqueous media, which creates an opportunity for addicts to abuse the drug by dissolving the tablets in water with subsequent injection of the obtained solution. To deal with this abuse, was developed with the feature of buprenorphine with naloxone - the MOR antagonist in the ratio 4:1 (Suboxone®).

Sublingual introduction of buprenorphine has several disadvantages, in particular the need to avoid swallowing pills due to the low bioavailability of buprenorphine (~5%) when administered orally. For comparison, with sublingual absorption bioavailability of buprenorphine is approximately fifty percent (see, for example, Jasinski and Preston,Buprenorphine, edited by A Cowan, Lewis JW, Wiley-Lis, NY pp. 189-211).

Several ester derivatives of buprenorphine described Stinchcomb and others in the publication ofPharm. Res(1995), 12, 1526-1529. Describes the physico-chemical properties of esters and compared with the properties of buprenorphine hydrochloride and free base. In publications Stinchcomb and otherBiol.Pharm.Bull.(1996), 19, 263-267 andPharm. Res.(1996), 13, 1519-1523 also described transdermal absorption of such esters. In published patent application U.S. No. 2005/0075361 (author Wang) also describes several derivatives of buprenorphine, which is obviously applicable to anesthesia with intramuscular or subcutaneous injection.

The invention

Described ester derivatives of buprenorphine1(structural formula above) on the phenolic hydroxyl group. Usually such derivatives include a fragment that is attached to the oxygen atom of the preceding phenol is a hydroxyl group. The fragment can include, for example, the end group in the form of a carboxylic acid, or a complex ester of carboxylic acid. As described herein, many of these derivatives, for example esters of dicarboxylic acids containing a suitable removable group, for example tosylate, iodide, bromide or chloride, can be obtained by the interaction of buprenorphine with a dicarboxylic acid corresponding to the anhydride or its equivalent. New esters, for example, solid dosage forms can be used to treat subjects who are physically dependent on opiates, or subjects suffering from pain, such as severe or chronic pain. Solid dosage forms can have excellent safety performance, increased duration of action and reduced opportunity for abuse.

In one aspect the invention relates to compounds of structural formulaIor their salts.

R1represents a

(1) C1-C10-alkyl straight or branched chain, optionally substituted aromatic ring,

(2) -(CH2)pCH=CH(CH2)p-in which each p is independently an integer from 0 to 4,

(3) -(CH2)nX(CH2)n-, where each n is an integer from 0 to 2, X represents O, S, NH, N(COOC 2Ph),

ring,with the substitution of 1,2-, 1,3 - or 1,4-positions, in which Y represents O, S or NH,

ring,with the substitution of 1,2-, 1,3 - or 1,4-positions, or

ring,in which m is an integer from 1 to 4;

R2represents H or C1-C6-alkyl straight or branched chain.

In another aspect the invention relates to compounds of structural formulaIAor their salts;

R1represents a

(1) C1-C10-alkylen straight chain,

(2) C1-C8-alkyl straight chain, substituted by 1-4 methyl groups or phenyl group,

(3) -(CH2)pCH=CH(CH2)p-in which each p is independently an integer from 0 to 3.

In another aspect the invention relates to a compound of structural formulaIA1or its salts:

In another aspect the invention relates to a compound of structural formulaIA2or its salts:

In another aspect the invention relates to compounds of structural formulaIIor their salts;

Each n is an integer from 0 to 2, X represents O, S, NH, N(COOCH2Ph),

to whom ICO ,with the substitution of 1,2-, 1,3 - or 1,4-positions, in which Y represents O, S or NH,

ring,with the substitution of 1,2-, 1,3 - or 1,4-positions, or

ring,in which m is an integer from 1 to 4.

Described in this description of the compounds and/or compositions include solid dosage forms that you can ingest, apply, sublingual and/or by transbukkalno introduction. Described in this description of the compounds and/or compositions can also be entered using other routes of administration such as intravenous, intramuscular or transdermal means.

In another aspect the invention relates to methods for treatment of opiate abuse and/or opiate dependency of the subject by introducing to the subject a therapeutically effective amount of one or more described in this description of the compounds and/or compositions.

In another aspect the invention relates to a method of pain relief or treatment of pain in the subject, for example humans, by introducing to the subject a therapeutically effective amount of one or more described in this description of the compounds and/or compositions.

The aspects or embodiments of the invention can have any of the following benefits or a combination of the following benefits Described in this description of the compounds and/or compositions suitable for treatment of opiate dependence. Some of the compounds and/or compositions may have reduced the opportunity for abuse, at least partly because of their low hydrophilicity and low solubility in water. The treatment is easy to use and less prone to being used in the wrong way. Compounds and/or compositions can be used for treatment outside the hospital (outpatient). Compounds and/or compositions are potent analgesics that can ease the pain, from mild to strong. Compounds and/or compositions can be entered using a variety of conventional routes of administration, including oral, sublingual, transbukkalno, intravenous, intramuscular or transdermal administration. Compounds and/or compositions can be obtained in various States, including solids and liquids. Compounds and/or compositions can be obtained in various traditional forms, including pills, powders and patches. Compounds and/or compositions can be converted to water-soluble or water-insoluble state. Compositions have increased bioavailability when administered orally and increased duration of action. Compounds and/or compositions compared with buprenorphine may have a slower onset of the beginning of the action.

If not is boreno otherwise, everything used in this description of the technical and scientific terms have the same meaning that is generally understood by the person skilled in the art to which this invention. The methods and materials described herein for use in the present invention; it is also possible to use other suitable methods and materials known in the field. Materials, methods and examples are intended for illustration only and are not intended to limit the invention. All publications, patent applications, patents, and others mentioned in this description of the link that is included in this description in full by reference. In case of contradiction the present description, including definitions, will be validated.

Other characteristics and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims.

Description of the DRAWINGS

In Fig. 1A is a graph showing the average plasma concentrations (ng/ml) of pradipta buprenorphine and buprenorphine, resulting from its hydrolysis, depending on time after oral administration (swallowing) dose 1 mg/kg of pradipta buprenorphine first group of dogs breed Beagle.

In Fig. 1B is a graph showing the average concentration of buprenorphine in plasma (ng/ml), depending on premenopause oral administration (swallowing) dose of 0.8 mg/kg of buprenorphine second group of dogs breed Beagle.

In Fig. 2A is a graph showing the average plasma concentrations (ng/ml) polyglutamate buprenorphine and buprenorphine, resulting from its hydrolysis, depending on time after oral administration (swallowing) dose 1 mg/kg polyglutamate buprenorphine first group of dogs breed Beagle.

In Fig. 2B is a graph showing the average concentration of buprenorphine in plasma (ng/ml) depending on time after oral administration (swallowing) dose of 0.8 mg/kg of buprenorphine second group of dogs breed Beagle.

In Fig. 3A is a graph showing the average plasma concentrations (ng/ml) of pradipta buprenorphine and buprenorphine, resulting from its hydrolysis, depending on time after oral administration (swallowing) dose of 63 mg/kg of pradipta buprenorphine first group of dogs breed Beagle.

In Fig. 3B is a graph showing the average concentration of buprenorphine in plasma (ng/ml) depending on time after oral administration (swallowing) dose of 50 mg/kg of buprenorphine second group of dogs breed Beagle.

In Fig. 4 shows a graph showing the pharmacokinetic profile of high daily doses of pradipta buprenorphine, administered orally for 28 days to breed Beagle.

DETAILED DESCRIPTION

Described new clonoey the major derivatives of buprenorphine on phenolic hydroxyl group. New esters can be used, for example, for the treatment of subjects who are physically dependent on opiates. You can get a variety of solid dosage forms, which include one or more esters. Solid dosage forms can, for example, to swallow or apply sublingual.

Derivatives of buprenorphine

Ester derivatives can usually be described as compounds of structural formulaIor salts of the compounds of structural formulaI.

In the structural formulaIR1represents (1) C1-C10is an alkyl fragment with a straight or branched chain, optionally substituted aromatic ring, for example, carbocyclic or heterocyclic aromatic ring; (2) fragment -(CH2)PCH=CH(CH2)P-in which each p is independently an integer from 0 to 4; or (3) the fragment -(CH2)nX(CH2)n-, where each n is an integer from 0 to 2, X represents O, S, NH, 5-membered ring represented by the structural formula2(below)that contains a substitution in the 1,2-positions (following structural formula2A), 1,3-positions (2Bor 1,4-positions (2C); in which Y represents O, S or NH, benzene ring, represented by strukturformel 3(below) containing a substitution in the 1,2-positions (3A), 1,3 - positions (3Bor 1,4-positions (3C), or

5-, 6-, 7 - or 8-membered alkyl ring, represented by the structural formula4(see below). In those cases, when X represents a 5-, 6-, 7 - or 8-membered alkyl ring, you can use all positional isomers of each of the respective ring systems, for example, substituted in positions 1,2 - and 1,3 - to 5-membered ring. In the structural formulaIR2represents H or C1-C6-alkyl straight or branched chain.

Some examples From1-C10-alkyl fragments with a straight or branched chain include, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2CH2and structural formulas5,6,7and8below.

Some examples From1-C10-alkyl fragments with a straight or branched chain, substituted aromatic ring, include structural formula9,10,11and12below.

The aromatic ring can represent, for example, a simple ring or a condensed ring. The aromatic ring can in order to represent a carbocyclic ring (e.g., benzene ring or naphthalene ring system, the heterocyclic ring (for example, a derivative of thiophene-derived furan or a derivative of pyrrole) or condensed carbocyclic and heterocyclic ring.

In specific embodiments of the invention R1represents-CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2OCH2-, -CH2SCH2-, -CH2NHCH2- or-CH2N(COOCH2Ph)CH2-.

In those cases where R2represents a C1-C6is an alkyl fragment with a straight or branched chain, R2can represent, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,Deut-butyl,t-butyl, amyl, isoamyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2,2-trimethylpropyl and 1,1,2-trimethylpropyl.

In some embodiments of the invention R2represents H, providing compounds of structural formulaIAor their salts.

In such cases, in the structural formulaIAR1represents (1) C1-C10-alkyl piece is straight chain; (2) C1-C8-alkalinity fragment with a straight chain, substituted by 1-4 methyl groups or carbocyclic aromatic ring, such as phenyl group; or (3) the fragment -(CH2)PCH=CH(CH2)P-, in which each p is independently an integer from 0 to 3.

In some embodiments of the invention the compound or salt of structural formulaIAare compounds in which R1represents a C2-C5-alkylen straight chain, for example-CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH(CH3)CH2- or-CH2C(CH3)2CH2-.

In specific embodiments of the invention the compound is a compound of structural formulaIAlorIA2or salt of one or the other.

In some embodiments of the invention R2represents H, and R1represents -(CH2)nX(CH2)n-providing compounds of structural formulaIIor their salts.

In such cases,- (CH2)nX(CH2)n- can be any of the above fragments. In specific embodiments the invention, n in each case is 1, and X before the hat is S, NH, N(COOCH2Ph) or O.

The method of obtaining derivatives of buprenorphine

Compounds of structural formulaIcan be obtained, for example, from acid free base (IA) by dissolving the acid/free base in alcohol, for example methanol or ethanol followed by treatment of the acid solution/free base required diazoalkanes (R2-H)N213R2. In some embodiments of the invention employ an excess of the diazoalkane. In some embodiments of the invention diazoalkane dissolve in a simple ester, for example a simple diethyl ether. In some embodiments of the invention diazoalkane add the acid to the free base at low temperature, for example less than 50°C, and after the addition the solution is allowed to warm to room temperature. The esterification of carboxylic acids using diazo compounds is discussed in the publication Furrow,J.Amer. Chem.Soc, 126, 12222-12223 (2004). Purification of ester can be performed by passing the crude reaction mixture through a chromatographic column containing an adsorbent, such as alumina or silicon dioxide, and subsequent recrystallization of the obtained material.

Typically, compounds of structural formulaIAcan be obtained, for example, is uprenorphine 1 or phenoxytoluene in the form of metal salts IA(for example, sodium salt) buprenorphine with dicarboxylic acid14or its anhydride15. For example, the dicarboxylic acid can be a malonic acid, succinic acid, glutaric acid, 3-methylglutaric acid, 3,3-dimethylglutaric acid, adipic acid, timelineview acid, diglycolic acid, thiodiglycolic acid, iminodiethanol acid, N-benzyloxycarbonylamino acid, terephthalic acid, isophthalic acid, 1,2-naphthaleneboronic acid, 1H-pyrrole-2,5-dicarboxylic acid, thiophene-2,5-dicarboxylic acid, and furan-2,5-dicarboxylic acid.

In particular, the compounds of structural formulaIget, for example, using one of three methods. In the first method, receive and allocate phenoxytoluene in the form of saltsIAsuch as sodium salt of buprenorphine. For example, the sodium salt of buprenorphine can be obtained by interaction of buprenorphine, which is dissolved in a solvent such as a mixture of ethanol/water, with sodium hydride. Then phenoxytoluene in the form of saltsIAsubjected to interaction with the desired anhydride. Resulting crude salt is converted into the hydrochloride by treatment with diluted, for example, 1 M hydrochloric acid. Acid/baseIyou can receive the diamonds from the hydrochloride by neutralization. The second method buprenorphine is subjected to interaction in a dry solvent, for example in a simple mixture of diethyl ether and acetonitrile, with the anhydride of the desired acid. Usually after maturation over night at room temperature produces the desired complex polyether. In the third method, complex palefire get, applying the desired dicarboxylic acid by combining dicarboxylic acid, taken in large excess, for example more than 5-molar excess, with buprenorphine in a dry solvent such as tetrahydrofuran, along with the excess bonding agent, such as NN'-dicyclohexylcarbodiimide (DCCI).

The nature of derivatives of buprenorphine

With no regard to any particular theory it is believed that described in this specification, compounds such as complex palefire and their salts, are prodrugs that release the active drug buprenorphine in the body (in vivo). The prodrug can be defined as the delivery system for the original medicinal product to which the prodrug is metabolically converted after his suction, for example, by biotransformation with the release of the active drug, for example, during the hydrolysis. Typically, the prodrug can protect the original drug from premature Jn is ctively and excretion before reaching the point of application of drug action. For example, heroin (3,6-diacetylmorphine) is a prodrug, although generally not for morphine, and 6-acetylmorphine. In this example, the group of 6-acetoxy usually more resistant to metabolism than group 3-acetoxy.

In particular, it is believed that the open complex palefire are prodrugs that release buprenorphine after hydrolysis in the body of the subject (as shown below).

The rate of hydrolysis can be controlled by varying the hydrophilicity of the complex Palmyra. Therefore compounds of structural formulaIwhen administered orally (by ingestion) the subject can produce higher concentrations of buprenorphine in the blood than are produced equivalent doses of buprenorphine. Such sign may also provide increased duration of action and a slower onset of the early steps in comparison with buprenorphine.

In the course of this work, with reference to figa, 1B, 2A and 2B on the breed Beagle carried out pharmacokinetic studies using tritium-labeled pradipat16and tritium-labeled polyglutamate17.

tritium-labeled in terms 15,16;2- polyglutamate labeled with tritium in the provisions 15,16;3- T=tritium (3H))

In Fig. 1A is a graph showing the average stake is entrale in plasma (ng/ml) of pradipta buprenorphine and buprenorphine, resulting from its hydrolysis, depending on time after oral administration (swallowing) dose 1 mg/kg of pradipta buprenorphine first group of dogs breed Beagle. For comparison in Fig. 1B is a graph showing the average concentration of buprenorphine in plasma (ng/ml) depending on time after oral administration (swallowing) dose of 0.8 mg/kg of buprenorphine second group of dogs breed Beagle. In Fig. 2B is a graph showing the average plasma concentrations (ng/ml) polyglutamate buprenorphine and buprenorphine, resulting from its hydrolysis, depending on time after oral administration (swallowing) dose 1 mg/kg polyglutamate buprenorphine first group of dogs breed Beagle. For comparison in Fig. 2B is a graph showing the average concentration of buprenorphine in plasma (ng/ml) depending on time after oral administration (swallowing) dose of 0.8 mg/kg of buprenorphine second group of dogs breed Beagle. These studies showed that when times up to 1 hour after administration of 1 mg/kg of complex Palmyra buprenorphine (or pradipta or polyglutamate) in plasma was attended by high initial concentration of ester. Received levels were higher than the levels released buprenorphine, although quickly fell, with 2 hours becoming b is more low, what levels of buprenorphine. In each study (figv and 2B) another group of animals received an equivalent dose neeterificirovannah buprenorphine. Buprenorphine levels in the plasma of dogs breed Beagle after oral administration of doses, equivalent doses of complex profirov, was significantly lower than the levels obtained with the introduction of complex profirov. Thus, each complex profirov provided 2-3 times higher levels of buprenorphine in the blood than the levels obtained using the original medicinal product.

The pharmaceutical composition

Typically, the pharmaceutical composition is a composition which, as an active ingredient includes at least one described in this description of complex polyether buprenorphine and/or at least one salt. Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. Used in this description, the phrase "pharmaceutically acceptable carrier" includes material, such as saline, solvents, dispersion media, covering layers, inert excipients for tablets, antibacterial and antifungal agents, isotonic means that slows the absorption, which is compatible with the introduction of pharmaceuticals is of rest. The composition can also include additional active compounds. Examples of additional active compounds are naloxone, naltrexone, nalmefene.

Pharmaceutical compositions typically are developed in accordance with the proposed route of administration. Examples of routes of administration include parenteral, for example intravenous, intradermal or subcutaneous; oral; transdermal (local) and transmucosal (e.g., sublingually, by inhalation and rectal) introduction.

How to create a suitable pharmaceutical compositions are described, for example, in editions of manuals and monographs:Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs(Dekker, NY). For example, solutions or suspensions used for parenteral, intradermal, or subcutaneous injection, can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; hepatoblastoma tools such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and means for regulating Tonino and, such as sodium chloride or dextrose. the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or vials for multiple injections, made of glass or plastic.

Pharmaceutical compositions suitable for injection may include sterile aqueous solutions (where water soluble compounds) or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersion. Suitable carriers for intravenous injection include physiological saline, antiseptic water, Cremophor EL(TM)(BASF, Parsippany, NJ) or phosphate-saline buffer (FSB). In all cases, the composition must be sterile and must be fluid enough to be able to easily pass through the syringe. It must be stable under conditions of manufacture and storage and must be protected from infective action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), and suitable mixtures. The proper fluidity can be maintained, for example, by applying the covering is of material, such as lecithin, by storing the required particle size in the case of dispersion and by using surfactants. Protection from the action of microorganisms can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, the composition will be preferable to include isotonic agents, such sugar, a polyalcohol, such as mannitol, sorbitol and/or sodium chloride. Prolonged absorption of injectable compositions can be performed, including in the composition an agent that slows the absorption such as aluminum monostearate and gelatin.

Sterile injectable solutions can be obtained by introducing the desired amount of active compound in a suitable solvent with one ingredient or combination of the above ingredients, if desired, followed by sterilization by filtration. Dispersion is usually obtained by introducing the active compound into a sterile filler that contains the basic dispersion medium and the other required ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are drying in vacuum and freeze drying, which Yes is t powder of the active ingredient plus any additional desired ingredient from its solution, pre-sterilized by filtration.

In some embodiments of the invention described compositions adapted for oral administration. The purpose of oral therapeutic introducing one or more active compounds - complex profirov (or their salts) can be entered with inert fillers and apply in the form of tablets, lozenges or capsules such as gelatin capsules; such compositions will generally include an inert diluent or edible carrier. Compositions for oral administration can be prepared for use in a liquid for rinsing the mouth, applying a carrier liquid. Pharmaceutically compatible binders and/or supporting materials may be included as part of the composition. Tablets, coated tablets, capsules, lozenges and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose, dezintegriruetsja agent, such as alginic acid or corn starch; a lubricant such as magnesium stearate; a substance promoting sliding, such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or a flavoring, such as arachna mint, methyl salicylate, or orange flavoring.

Systematic introduction described in this description of therapeutic compounds can also be transmucosal or transdermal means. For transmucosal or TRANS-dermal drug used wetting agents suitable to penetrate the border. Such wetting agents, for example, for transmucosal introduction include detergents, bile salts and derivatives of fuseboy acid. Transmucosally introduction can be accomplished through the use of nasal sprays or suppositories. For TRANS-dermal developed one or more active compounds - complex profirov (and/or their salts)used in ointments, salves, gels, or creams. For administration by inhalation developed one or more active compounds - complex profirov (and/or their salts) in the form of an aerosol spray from a pressurized container or device for sputtering, which contains a suitable propellant, for example a gas, such as carbon dioxide, or a nebulizer. You can also apply a material carriers normally used in dry powder preparations, for example mono - or disaccharides, such as glucose, lactose, lactose monohydrate, sucrose or trehalose, sugar Speer is s, such as mannitol or xylitol, polylactic acid or cyclodextrin, glucose, trehalose and, in particular, lactose monohydrate. In some embodiments of the invention, the preparations can also contain two or more material carrier. If you want, in addition to newdigate particles of the media product may also contain the relative amount of respirable particles of the medium; for example, in addition to the relatively large particles of carrier lactose monohydrate he can hold relative amount, for example, from 0.1 to 10 wt.% micronized monohydrate lactose particles which may have, for example, the size of diameter less than 10 μm, preferably not more than 5 μm, at least 50% of the particles. Dry powdered drugs, including those described in this description of the compounds can be applied in dry powder inhaler, which is known in this field, such as dry powder inhalers for repeated administration, which contain a reservoir for powder described in patent application WO 97/20589. A number of other methods and devices suitable for delivery of compounds through inhalation, as described, for example, in U.S. patent No. 6645466.

Pharmaceutical compositions can also be obtained in the form of suppositories (e.g., with the traditional bases for suppositories, such as cocoa butter and other is literaly) or retention enemas for rectal delivery.

In some embodiments of the invention, therapeutic compounds get with carriers that will protect therapeutic compound from the rapid removal from the body, such as drug controlled release, including implants and microencapsulated delivery systems. You can apply a biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, complex polyarteritis and polylactic acid. These drugs can be obtained using standard techniques. You can also get commercial materials, for example, from corporations Alza Corporation and Nova Pharmaceuticals, Inc.

Treatment

Described in this description, the methods include methods of treatment for the abuse of opiates and opiate dependence. In some embodiments of the invention opiate used for abuse, is a heroin. Usually described in the present description, the methods include the introduction of a therapeutically effective amount of a complex of Palmyra buprenorphine subject that needs such treatment, or the subject for which they identified the need to undergo such treatment. As used in this context, treatment of abuse of opiates and opiate dependence is aimed at the reduction is s or eliminating the correlation of the subject from zloupotrebljena drug removal of drugs from the body of the subject, drug abusers, and to some extent prevent the subject from recovering its dependence on this drug. Treatment is also aimed at preventing or minimizing the withdrawal symptoms experienced by the subject, or addictions to drug abuse, for example, by applying a maintenance regimen of medicines.

This description also describes methods of treating pain, such as severe or chronic pain. Typically, such methods include the introduction of therapeutically effective amounts described in this description of complex Palmyra buprenorphine subject that needs such treatment, or the subject for which they identified the need to undergo such treatment, for example to a subject suffering from pain, such as severe or chronic pain. As used in this context, treatment of pain intended to avoid, reduce or eliminate the perception of pain by the subject.

Dosage, toxicity and therapeutic efficacy of compounds can be determined, for example, using standard pharmaceutical procedures in cell cultures and/or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose terap whitesky effective for 50% of the population). The ratio between the doses corresponding to the toxic and therapeutic actions, represents therapeutic index and it can be expressed as the ratio LD50/ED50.

The data obtained in animal studies, can be used to determine the range of dosage for use in respect of the person. The dosage of such compounds is preferably in the range of circulating in the blood concentrations that include the ED50 dose, it is not toxic or low toxicity. The dosage may vary within this range depending upon the dosage form and used as a way of introduction. For any compound used in the here described method, therapeutically effective dose can be estimated at the initial stage of the tests on cell cultures. The dose can be installed on animal models to provide a range of concentrations, circulating in the plasma, which includes the index IC50 (concentration of the test compound, which provides half of the maximal inhibition of symptoms), determined by cell culture. Such information can be used for more accurate determination of doses applicable to humans. Levels in plasma may be measured, for example, by high performance liquid chromatography with the right detection systems and apply the data to determine the most appropriate doses and intervals between doses, to support buprenorphine at levels that prevent withdrawal effects and which are consistent with clinically acceptable levels, provided by the tablets of buprenorphine for sublingual administration.

"Effective amount" means a quantity sufficient for a positive effect or get the desired results. For example, a therapeutic amount means an amount that provides the desired therapeutic effect. An effective amount can be entered for one or more injections of applications or dosages. For example, the composition can be entered from one or several times a day, from one to several times per week; including once every other day. The person skilled in the art it will be clear that some factors may influence the dosage and the period of time required for effective treatment of a subject, including but not limited to, the seriousness of the disease or disorder, previous treatments, the General health and/or age of the subject and other present illness. Moreover, treatment of a subject with a therapeutically effective amount of compositions described herein can include a single treatment or can include a series of treatments. Usually for establishing the patient's treatment composition should be entered daily in what zmoznostjo to increase the period between doses, as soon as the patient's condition stabilizes. However, as the recommendations can be argued that to obtain a possible positive effect for the person undergoing drug treatment, required dosage of the compounds of structural formulaI,approximately 2-30 mg May be additional active compound, such as naltrexone or nalmefene. The weight ratio of the compound of structural formula I to the additional active compound, such as naloxone, naltrexone or nalmefene present in order to keep from drinking songs not on purpose, is in an appropriate range from 2:1 to 8:1, preferably from 2.5:1 to 6:1, preferably from 3:1 to 5:1, preferably from 3.5:1 to 4.5:1. The following examples are illustrative and should not be construed as limiting the invention.

EXAMPLES

Example a: Synthesis of polyacrylate buprenorphine

(complex buprenorphine of Palmyra succinic acid)

Nutritionally way

To a heated solution of sodium hydride (50% dispersion in oil, 0.24 g, 0,005 mol NaH) in a mixture of ethanol:H2O in the ratio 2:1 (9 ml) was added buprenorphine (2,35 g of 0.005 mol). After stirring for 30 minutes the solvent was removed by repeated azeotropic driving and with benzene. In addition the residue was dried over pjatiokisi phosphorus in vacuum. The crude sodium salt was dissolved in dry benzene (30 ml), then was added succinic anhydride (0.5 g, of 0.005 mol) and the mixture was stirred for 1.5 hours. After removal of the benzene, the residue was dissolved in 2 N. a solution of hydrochloric acid (50 ml) for 2 hours. Thus obtained salt (hydrochloride) was filtered, washed with water and dried. By recrystallization from isopropanol followed by washing the filtered product with hot methanol was obtained pure salt (1.0 g), TPL 214-216°C (decomposes). Found, %: C 64,95; H 7,6; N 2,2; Cl 6,25. For C33H43NO7(HCl)(1/2 H2O)requires C 64,84; H 7,4; N 2,3; Cl 5,8; 3480 (OH), 1757, and in 1735 cm-1.

Anhydrite way

Buprenorphine (1.7 g, 0,0036 mol) and succinic anhydride (1.1 g, to 0.011 mol) was dissolved in a heated mixture of simple dry ether: acetonitrile in the ratio 3:5 (40 ml). After maturation during the night the desired polosukhina (1.65 g) was filtered and dried, TPL 195-197°C (decomposes). Additional material (0.1 g) were obtained from mother solutions, when they were given the opportunity to stand for an additional 24 hours. Found, %: C To 69.9; H 7,8; N 2.4. For C33H49NO7requires C 70,0; H 7,65; N 2,5; 3460 (OH), 1760, and in 1733 cm-1.

Example B: Synthesis of polyglutamate buprenorphine

(complex buprenorphine of Palmyra glutaric acid)

The solution of buprenorphine (2.1 g, 0,0045 mol) and glutaric anhydride (1.6 g, 0.014 mol) in a mixture of dry simple ether: acetonitrile in the ratio 3:5 (50 ml) was stirred at room temperature for 5 days, during which precipitated salt polyglutamate buprenorphine and glutaric acid in the form of a dense solid white. The solid was filtered and washed simple dry ether (40 ml). When washing, getting salt in the form of a crystalline solid, white (1.4 g), melting point 160-161,5°C. the Salt was dissolved in minimum amount of cold methanol (12 ml) and then added an excess of simple dry ether (60 ml) followed by the addition of HCl solution in a simple ether. This led to the precipitation of a white solid, which was filtered and washed with dry simple ether. By recrystallization from methanol/simple broadcast received net polyglutamate buprenorphine in the form of the monohydrate hydrochloride (0.9 g), melting point of 214-215°C (decomposes). Found, %: C 63,85; H Of 7.75; N 2,08. For C34H47NO7(HCl)(H2O) requires C 64,18; H a 7.92; N 2,20; 3340 (OH), 1750 and in 1720 cm-1.

Example C: Synthesis of pradipta buprenorphine

(complex buprenorphine of Palmyra adipic acid)

Buprenorphine 96 g 0.2 mol) was dissolved in a recently dried tetrahydrofuran. To the solution was added adipic acid (to 129.2 g, 0.8 mol) and DCCI (100 g, 0.48 mol). The mixture was stirred for 6 days and then added an additional amount of adipic acid (30 g) and DECI (25 g). The resulting reaction mixture was stirred for three days. After this time the stirring was stopped and gave the mixture a chance to settle in for three days. The solids were filtered and then the solvent was removed from the dissolved material. When dissolved in a minimal amount of methanol and then adding a mixture of ethanol/HCl received solid hydrochloride of pradipta buprenorphine (86 g)which was purified by recrystallization from ethanol. The purified material had a melting point 270-272°C (decomposes). Found, %: C 66,49; H 8,12; N 2,23; Cl Of 5.53. For C35H50NO7Cl requires C 66,49; H of 7.97; N 2,22; Cl 5,61; 3440 (OH) 1762 and in 1739 cm-1.

An alternative way: To a solution of 4-dimethylaminopyridine (1.232 metric g 0,010 mol, the catalyst for the acylation) in tetrahydrofuran (1.5 l, THF) with stirring was added buprenorphine in the form of the free base (93,534 g, 0.20 mol) and then adipic acid (239,952 g of 1.64 mol). The suspension was stirred for 20 minutes and added dicyclohexylcarbodiimide (45,409 g, 0.22 mol) for about 30 minutes, at the same time with OSU cooling with cold water keeping the temperature in the range 16 to 21°C. Stirring was continued over night. Insoluble residue (mostly dicyclohexylphosphino) was removed by filtration under vacuum and optionally washed with THF. The solvent of the filtrate was removed in vacuum (extracted 960 ml). The precipitate (mainly adipic acid) was removed by filtration, optionally washed with a small amount of THF and dried in the air. The combined filtrates were stirred at room temperature and treated with concentrated hydrochloric acid (20,606 g, 0.20 mol). The precipitate was removed by filtration, washed with THF and dried in the air. The crude product was recrystallized from a mixture of ethanol/dichloromethane with hot filtration and removal of solvents in vacuum to concentrate the suspension. The solid was removed by filtration, washed with ethanol and dried to give the hydrochloride of pradipta buprenorphine (87,525 g). The identity of the material was confirmed by complete1H and13C NMR spectrum and by comparison of the obtained spectra with the NMR spectra of buprenorphine hydrochloride.

Example D: Synthesis of semi-3-methylglutaric buprenorphine

The solution of buprenorphine (6.8 g, 0,0146 mol) and 3-methylglutaryl anhydride (5,13G, 0.04 mol) was stirred with a mixture of simple dry ether:acetonitrile in the ratio 3:5 (160 ml) for two days at room is temperature, after which TLC (SiO2, methanol/ethyl acetate/880 ammonia, 25:74,5:0,5) showed the presence of a significant amount of remaining buprenorphine. Added additional amount of anhydride and continued stirring for an additional 24 hours. The reaction mixture was poured into a simple dry ether (600 ml) and then was added a solution of HCl in simple ether. The resulting precipitate was filtered and recrystallized from methanol/simple ether. When this was received hydrate hydrochloride semi-3-methylglutaric buprenorphine in the form of a crystalline solid, white (4.5 g). The solid is recrystallized three more times, thus obtaining 1.8 g of product, melting point 213-216°C (decomposes). Found (%) : C 63,73; H 8,16; N 2,10. For C35H47NO6(HCl)(H2O) requires C 64,65; H 8,6; N 2,15.

Example E: Synthesis of semi-3,3-dimethylglutaric buprenorphine

To a solution of buprenorphine (7,05 g, 0.015 mol) in a mixture of simple dry ether/benzene in the ratio of 1:3 (200 ml) was added sodium hydride (0,72 g, 0.015 mol, 50% dispersion in oil). After stirring at room temperature for 0.5 hours was added 3,3-dimethylglutaric anhydride (4.26 deaths g, 0.03 mol). Continued stirring for 7 hours, after which was added an additional amount of sodium hydride (0,72 g, 0.015 mol) and 3,3-dimethylglutaric anhydride (4,0g, 0,028 mol). After maturation for two days at room temperature the mixture was evaporated to dryness and added methanol (20 ml). The solution was suirable on a column of silica, using a mixture of ethyl acetate/0,5% 880 ammonia. The first three fractions contained pure buprenorphine; the other faction consisted of the desired complex Palmyra. Fractions were combined, dissolved in minimum amount of methanol (10 ml) was added an excess of simple ether followed by the addition of HCl solution in a simple ether. The solid, which precipitated, was filtered and recrystallized five times from a mixture of ethanol/simple ether to give the hydrochloride semi-3,3-dimethylglutaric buprenorphine in the form of a crystalline solid, white (1.5 g), melting point 216-219°C (decomposes). Found (%) : C 66,39; H 8,50; N 2,16. For C36H51NO7(HCl) requires C 66,91; H 8,11; N 2,17; 3300 (OH), 1730 and in 1720 cm-1.

Example F: Synthesis of prodigiosa buprenorphine

The solution of buprenorphine (6.8 g, 0,0146 mol) and diglycolic anhydride (5.1 g, 0,044 mol) in a mixture of dry simple ether: acetonitrile in the ratio 3:5 (100 ml) was stirred overnight at room temperature. Solution was added HCl in simple ether and then adding simple dry ether (500 ml), while receiving a dense white precipitate, which was filtered, the industry is Ali simple dry ether and dried. After two precrystallization from a mixture of ethanol/simple broadcast received paludicola buprenorphine in the form of the monohydrate hydrochloride (4.5 g), melting point 186-189°C (decomposes). Found (%) : C 62,04; H 7,73; N 2,10. For C33H45NO8(HCl)(H2O) requires C 62,10; H 7,78, N 2,19; 1780, 1760, and in 1720 cm-1.

Example G: Synthesis of politiologist buprenorphine

Thiodiglycolic anhydride was obtained by a method described in the publication Morril and others, J.Org.Chem., 26, 4103 (1961). Thiodiglycolic acid (32,4 g, 0,216 mol) and trichloride phosphorus (9.2 grams, 5.5 ml, 0,065 mol) was stirred at 55°C in chloroform (40 ml)until stopped the release of gaseous HCl. Then the mixture was heated under reflux for 1 hour, after which was added an additional amount (4.6 g, 2.9 ml, 0,033 mol) of trichloride phosphorus. After the addition was deposited oily substance, and the reflux was continued for additional 1 hour. Then with oily substances decantation hot solution of chloroform and set aside to cool. Has precipitated crystalline solid white, which was filtered and dried (24.6 g). TLC (SiO2, chloroform/methanol 4:1) showed one major component plus a very small amount of the original decollate. The solution of buprenorphine (6.8 g, 0,0146 mol) and thiodiglycolic anhydride is (11.6 g, 0,088 mol) in a mixture of dry simple ether:acetonitrile in the ratio 3:5 (160 ml) was stirred at room temperature for 6 hours. Deposited oily substance and stirring was stopped. The mixture was left to stand for 48 hours. Formed white solid, which was filtered and dissolved in hot methanol (25 ml). Added simple dry ether (500 ml) followed by the addition of HCl solution in a simple ether. Deposited white solid (6.4 g). A 2.5 g portion of the obtained substance was recrystallized from methanol/simple ether, thus obtaining the desired monohydrate hydrochloride of politiikasta buprenorphine (2.1 g), melting point 225-226°C (decomposes). Found (%) : C of 60.50; H 7,30; N 2,03. For C33H45NO7S(HCl)(H2O) requires C 60,57; H 7,39; N 2,14; 3300 (OH), 1745 and in 1710 cm-1.

Example H: Synthesis of polyaminoamide buprenorphine

Dicyclohexylamine salt of N-benzyloxycarbonylamino acid was mixed with a mixture of 10%citric acid and ethyl acetate and vigorously shook. Added solid citric acid up until two layer becoming transparent; an ethyl acetate layer was separated, washed with water and saturated salt solution, dried using MgSO4, and evaporated, thus obtaining a yellow oily substance. A portion of the substance-rayed and interaction at 0°C with an equimolar amount of N,N'-dicyclohexylcarbodiimide in methylene chloride for 1 hour and then at room temperature for 2 hours. Was filtered dicyclohexylphosphino and evaporated methylene chloride, thus obtaining the anhydride in the form of a white solid. By recrystallization from a mixture of ethyl acetate/petroleum ether there was obtained N-benzyloxycarbonyloxy anhydride in the form of a crystalline solid white; 1800, 1770, 1680 cm-1.

A solution of N-benzyloxycarbonylglycine anhydride (5.9 g, 0,025 mol) and buprenorphine (4.3 g, 0,009 mol) in a mixture of dry simple ether:acetonitrile in the ratio 3:5 (102 ml) was stirred at room temperature for 24 hours. Half-N-benzyloxycarbonylamino buprenorphine, which precipitated, was filtered and then washed with a simple ester (7.2 g), melting point 133-137°C; Found (%) : C 66,64; H 7,44; N 4,29. For C41H52N2O9(H2O) requires C 67,00; H 7,41; N 3,81), 3400 (OH), 1770 and 1700 cm-1.

Half-N-benzyloxycarbonylamino buprenorphine (2.0 g, 0,0028 mol) was dissolved in dry tetrahydrofuran (100 ml) was added 10% Pd on coal (0.25 g). The suspension was stirred at room temperature and was barbotirovany through her gaseous hydrogen. After 4 hours TLC showed that very small amounts of starting material. The catalyst Pd/C was filtered and to the filtrate was added a simple dry ether (600 ml). Solution was added HCl in simple ether and after scratching with the parties bulb in the sludge precipitated white solid. The solid was filtered and dried in vacuum over pjatiokisi phosphorus. Solid (1.2 g) relatively poorly dissolved in ethanol, although very good was dissolved in methanol. After washing with ethanol the product was dissolved in methanol (a small amount of insoluble solid was filtered and added a simple ether. It was obtained a crystalline solid is white, which was filtered (0.25 g). TLC (SiO2, CM20) showed one major product plus a small amount of impurity buprenorphine. After two more precrystallization from methanol/simple broadcast was received cleared dihydrochloride monohydrate of polyaminoamide buprenorphine (0.1 g), melting point 214°C; Found (%) : C 58,96; H to 7.59; N 3,17. For C33H46N2O7(HCl)(H2O) requires C 58,83; H of 7.48; N 4,16. 3450 (OH), 1770, and in 1630 cm-1.

Example I: Synthesis of 3-(3-carbomethoxybiphenyl)buprenorphine

Polosukhina buprenorphine (2.1 g) (see example A) was stirred in methanol (50 ml) and was treated with an excess of a solution of diazomethane simple ether (freshly). After removal of methanol, the residue was dissolved in ethyl acetate and filtered through a column of aluminum oxide (purity I; 9" x 1"). The filtrate was evaporated and the residue was recrystallized from a mixture of simple ether/light petroleum ether, the floor is th at this was 1.58 g of material, melting point 119,5-121°C; Found (%) : C is 70.3; H 7,8; N is 2.5. For C33H45NO7requires C 70,45; H 7,8; N 2.4. 3440 (OH), 1766, and in 1750 cm-1.

Salt is the hydrochloride was obtained using a solution of HCl/simple ether, melting point 254-254,5°C. Found (%) : C 66,0; H 7,8; N 2.4; Cl 5,9. For C34H45NO7(HCl) requires C to 66.3; H 7,5; N 2,3; Cl 5,57. 3450 (OH), 1763, 1735, and in 1618 cm-1.

Example J: Pharmacokineticsin-vitro

Measured the degree of hydrolysis ofin-vitrocomplex profirov buprenorphine in the plasma or blood of different animals (see results in table 1, below).

a)Radiochemical connection: Radiolabelled complex palefire buprenorphine was obtained from [15,16-3H]-buprenorphine18by applying the above-described methods of esterification, for example by interaction18with a suitable anhydride, while receiving the desired complex polyether. The specific activity was changed in the range of 20-800 µci/mg)

Structure [15,16-3H] buprenorphine18;T=tritium

b)Blood and plasma: Blood received from people who agreed to be tested, dog breed Beagle or baboons using puncture from Vienna and from all other animals by the terminal puncture of the heart. Blood was collected in heparinized plastic tubes, and plasma, if needed, were obtained using centrifuge the Finance (3000 g, 10 min). Plasma, if not used immediately, stored at -20°C.

c)Incubationin-vitro: The study was carried out at 37°C using a thermostatically controlled shaking water bath. Samples of plasma or blood (with the addition of a buffer or not) in a conical glass tube was allowed to warm to 37°C before incubation was initiated by adding appropriate aliquots (3-30 μl) of an aqueous solution of hydrochloride of complex Palmyra. Incubation was carried out at an initial concentration of 0.1-30 μg/ml.

After different time of incubation, aliquots of plasma or blood (100 μl) were placed in a plastic Eppendorf tubes, quickly frozen in a bath of acetone/ice was added methanol (100 ml). The tubes were shaken, then centrifuged in the Eppendorf centrifuge 3200 (1 minute) and held chromatography of the supernatant liquid, as described below.

d)Thin-layer chromatography: TLC was performed on plates from Merck silica gel 60 F254 (0.25 mm thick). Used the following solvent system:

i) a mixture of chloroform/methanol 20:1 (vol./vol.), containing 0.5% (vol./about.) NH4OH (density 0,88);

ii) a mixture of ethyl acetate/methanol 75:25 (vol./vol.), containing 1% (vol./about.) NH4OH (density 0,88).

Previously described methanolic supernatant was applied to the starting line of the plates 20×5 cm, dried and alwero the Lee, using a suitable solvent system. Conducted joint chromatography authentic labeled samples of ester and buprenorphine, then clearly seen under UV light wavelength range. After elution of silicon dioxide was removed in the form of 1 cm zones in scintillation vials and dissolved in 2 ml of water and 5 ml ES299 (Packard) or similar primary scintillation fluid. The vials were read for the3H (number of pulses per minute) in a scintillation spectrometer (Packard 2450 or Intertechnique SL 4221.

e)Treatment results: The results of the study radiochromatography were expressed as the percentage of remaining source of ester relative to the total extracted radioactivity. The results were presented graphically on semi-log paper, depending on the time and values of the half-life period in the first approximation, is obtained from the obtained straight lines.

f)Results: The results are shown in table 1.

Table 1
Values of half-life in the first approximationin-vitrofor pradipta buprenorphine plasma and buffered blood of various animals
IndividualsInitial concentration of ester (mg/ml plasma t½
(watch)
t½ buffered blood (hours)
People3,04,3-4,8of 7.5 to 9.6
0,253,3-4,8-
Dog3244,6
Baboon35-
Rat30,40,18
Guinea pig30,160,10
Rabbit30,070,03
Mouse30,030,02

The results show that pradipat buprenorphine remains in the plasma and releases buprenorphine over a long period of time.

Example K: Pharmacokineticsin-vivo

the distribution of levels of buprenorphine and complex profirov buprenorphine plasma were performed on dogs breed Beagle using gas chromatographic/mass spectrometric method of analysis (GC/MS) after oral administration pradipta buprenorphine and polyglutamate buprenorphine.

a.The introduction ofin-vivo: Dog breed Beagle chose to model the pharmacokinetic parameters esterase activity, which is responsible for the hydrolysis ofin-vivocomplex profirov to buprenorphine. The choice has been made as a result of extensive researchin-vitroseveral esters in whole blood and plasma of some species of animals in comparison with the blood and plasma of man. It was found that the blood specimens of rodents - rats, mice, Guinea pigs and rabbits, with high esterase activity rapidly hydrolyzed in complex palefire, whereas the higher animals - dogs and baboons, blood behaves like human blood with significantly more slowly leaking hydrolysis (see table 1). Thus, as the preferred experimental animal was the dog.

For complex Palmyra adipic acid (adipate) pharmacokinetic study was repeated at a much higher dose (63 mg/kg), administered orally to dogs breed Beagle, compared with the equivalent dose (50 mg/kg) source of buprenorphine.

b.Obtaining blood samples and their storage: Blood samples (2 ml) were taken by puncture of the vein at 0.5, 1, 2, 5, 8, and 24 hours after administration of the dose. To minimize any possibility of hydrolysis of complex floor the esters, immediately after obtaining blood samples were kept on ice, plasma, selected in a refrigerated centrifuge, was transferred to a flat tubes until analysis were stored at -20°C.

c.Analytical methods

To determine the free buprenorphine

All activities associated with the extraction and obtaining derivatives carried out in a glass container, silanizing by treatment with 5% trimethylchlorosilane (TMCS) in toluene.

Plasma (0.25 ml) in 15 ml conical centrifuge tube was mixed with 10 μl (1 μg) of the internal standard N-n-propylnorapomorphine in methanol. Added double-distilled analytical purity (AR) simple diethyl ether (5 ml), the contents of the tubes were mixed by shaking for 1 min and centrifuged at 2000 rpm./min for 10 minutes. The ether layer was transferred into a clean test tube and repeated the process with 4 ml of a simple ester. The combined ether layers were evaporated to dryness in a current of the N2and the tubes containing the extracted residues were placed in a desiccator over pjatiokisi phosphorus for 16-24 hours to remove traces of water. To the dried residues were added toluene (twice distilled, analytical purity (AR)) (20 μl), triethylamine in toluene (0.1 M, 20 ml) and heptacosane anhydride (HFBA, 10 ál). After thorough mixing for 1 minute, the solution was left with the Oyat for 15 minutes at room temperature. Added phosphate buffer (0.5 M, pH 6,0, 50 ml) to hydrolyze any unreacted HFBA and the contents of the tubes were mixed for 30 seconds. After centrifugation at 2000 rpm./min for 10 min took a portion (5 μl) of the upper organic phase for GC/MS analysis.

To determine the total buprenorphine

Plasma (0.25 ml) in 15 ml conical centrifuge tube was mixed with 10 μl (1 μg) of the internal standard solution and buffer on the basis of the glycine-sodium hydroxide (simple washed with ether, and 0.2 M, pH of 10.4, 0.25 ml). After stirring for 30 seconds, the tube was closed with a glass stopper and left to stand at room temperature for 18 hours, went to the hydrolysis of any unmodified adipate buprenorphine.

After hydrolysis of plasma sample was transferred into a test tube ClinElutTM(type CE 1003, Scietific Marketing Associates, London) and was allowed to adsorb onto the layer. Through the tube missed three servings double-distilled easy diethyl ether (3×5 ml) and collected into a clean conical centrifuge tube. A simple ether was evaporated in a stream of gaseous N2and the test tube was transferred into a desiccator with pjatiokisi phosphorus.

To the dried residue was added toluene (20 ml) and getattributelabel (HFBI, 20 ml), was stirred for 1 minute and left to stand at room temperature in them is giving 15 minutes. The reaction mixture was evaporated to dryness at room temperature under nitrogen atmosphere and the residue was treated with toluene (30 ml). A portion of the obtained extract was taken for GC/MS analysis.

The calibration curve

Every day during the day prior to analysis, all samples obtained from three dogs, prinimavshikh the same dose, was shot calibration curve obtained on the basis of mother solutions. For doses of 0.4 and 4.0 mg/kg range of values used in the calibration was 2-20 ng/0.25 ml plasma, and for a dose of 40 mg/kg 5-50 ng/0,25 ml of the same mark on the calibration curves were obtained during the hydrolysis procedure. Graphs of the relationship of the peak heights from the amount of added buprenorphine built on the results of the daily analysis and was used to obtain quantitative results obtained from samples processed during this day.

d)Instrumentation

The combined analysis using gas chromatography/mass spectroscopy (GC/MS) was carried out using gas chromatograph Pye 104 connected to a mass spectrometer LKB 2091 through a two-stage jet separator made of stainless steel. A glass column (1 m × 4 mm in diameter) was filled with 3% OV-1 on a solid carrier Gas-Chrom QTM(100-120 mesh)(JJ's Chromatography, Kings Lynn), aged overnight at 300°C. the flow Rate of the carrier gas is of men was 30 ml/min The working temperature of the chromatographic column, the separator and the ion source was 290°C, 280°C and 290°C, respectively. Applied ionizing voltage of 20 eV and the collector current of 50 µa.

Monitoring selected ions at m/e 562 (main peak of the internal standard derived HFB) were carried out by fast switching accelerating voltage with auxiliary device LKB 2091-710 M.I.D. At a voltage of 3.5 kV calibration factor for m/e 562 was 52620. Other operating parameters M.I.D. were as follows: the setting of the gain of pre - amplifier 3, the setting voltage of the electronic multiplier - 800, duration peak - 64 seconds and gain M.I.D. is in the range from 10 to 500. The signals from the monitored channels was recorded on an oscillographic recorder SE 3006 UV write speed chart 1 cm/min. For the quantitative determination of expected relationships of the peak heights of ions, referring to daily mark on the calibration curve.

e)Results

In Fig. 3A is a graph showing the average plasma concentrations (ng/ml) of pradipta buprenorphine and buprenorphine, resulting from hydrolysis, depending on time after oral administration (swallowing) dose of 63 mg/kg of pradipta buprenorphine first group of dogs portabil; and in Fig. 3B is a graph showing the average plasma concentrations (ng/ml) buprenorphine depending on time after oral administration (swallowing) dose of 50 mg/kg of buprenorphine second group of dogs breed Beagle. The graphs reproduced the results described above (see figa and 1B), only with the use of much higher doses (63 mg/kg, Fig. 3A), administered orally to dogs breed Beagle in comparison with almost equivalent dose (50 mg/kg, Fig. 3B) the source of buprenorphine. As in the case of lower dose levels the source of ester (non-hydrolyzed ether complex) in plasma were significantly higher than the levels of the release of buprenorphine, and the concentration in the plasma source of ester was maintained for 6 hours. The maximum level of buprenorphine obtained from a complex ether, was achieved after 1 hour, and was equal to approximately twice the maximum level reached with neeterificirovannah buprenorphine.

The pharmacokinetic profile of a high oral dose of pradipta buprenorphine, administered daily for 28 days to breed Beagle, shown in Fig. 4. On the 28th day levels of buprenorphine released from the complex ester in plasma was maintained for more than 24 hours, whereas the levels of the original complex ester was rapidly decreased after 2 hours. Although samco the dogs and female dogs such profiles are qualitatively different.

The obtained pharmacokinetic profiles show that pradipat buprenorphine when administered orally has a higher bioavailability than you can get from buprenorphine in pure form. At high doses, which are used in the treatment of opiate abuse, it is expected that the duration of the actions described in this description of complex profirov (or their salts) will be longer than can be provided by using equivalent doses of buprenorphine, which is reflected in the sustainable levels of pradipta plasma described above. In addition, it is expected that the maximum levels described here are complex profirov (or their salts) in the plasma will be achieved much later than the maximum levels achieved using an equivalent dose of buprenorphine.

OTHER embodiments of the INVENTION

It should be understood that although the invention is described on the basis of his detailed description, the foregoing description is intended to illustrate and not limit the scope of invention, which is defined by the scope of the attached claims. Other aspects, advantages, and modifications are included in the scope of the following claims.

1. Compounds of structural formula I or their salts:

in which R1represents a
(1) C1-C10-alkyl with p the pit or branched chain, optionally substituted aromatic ring, or
(2) -(CH2)nX(CH2)n-, where each n is an integer from 0 to 2, X represents O, S, NH
and where R2represents N or C1-C6-alkyl straight or branched chain.

2. Compounds according to claim 1, where R1selected from the group consisting of-CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2Och2-, -CH2SCH2- and-CH2NHCH2-.

3. Compounds according to claim 1 or 2, where R2represents N.

4. Compounds of structural formula IA or their salts:

where R1represents a
(1) C1-C10-alkyl straight chain, or
(2) C1-C8-alkylen straight chain, substituted by 1-4 methyl groups or phenyl group.

5. Compounds according to claim 4, where R1represents a C2-C5-alkylen with direct chain.

6. Compounds according to claim 5, where R1selected from the group consisting of-CH2CH2CH2-, -CH2CH2CH2CH2- and-CH2CH2CH2CH2CH2-.

7. The connection according to claim 6, where R1represents-CH2CH2CH2-.

8. The connection according to claim 6, where R1 represents-CH2CH2CH2CH2-.

9. Compounds according to claim 4, where R1represents-CH2CH(CH3)CH2- or-CH2C(CH3)2CH2-.

10. Compounds of structural formula II or their salts:

where each n is an integer from 0 to 2, and X represents O, S, NH.

11. Connection of claim 10, where each n is 1.

12. Compounds according to claim 11, in which X represents S, NH.

13. Connection to item 11, where X represents O.

14. Connection with structural formula IA1 or its salt:

15. The compound of structural formula IA2 or its salt:

16. Method for the treatment of opiate abuse and/or opiate addiction in a subject comprising administration to the subject a therapeutically effective amount of one or more compounds according to claims 1, 4, 10, 14, or 15.

17. The method according to clause 16, where one or more compounds are administered orally or sublingually.

18. The method of pain relief or treatment of pain from moderate to strong for a subject, comprising administration to the subject a therapeutically effective amount of one or more compounds according to claim 1, 4, 10, 14, or 15.

19. Derivatives of buprenorphine on the hydroxyl group of phenol, comprising the fragment attached to the oxygen atom before estoya phenolic hydroxyl group, where the specified portion includes an end group in the form of a carboxylic acid or a salt thereof.

20. The use of compounds of structural formulas I, IA, II, IA1 or IA2 as a means of releasing a therapeutic amount of buprenorphine in the body of the patient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: disclosed method of determining opium alkaloids involves extraction sample preparation carried out using a water-acetonitrile mixture with ratio of water to acetonitrile ranging from 38:12 to 42:8, as well as analysis of the obtained extract through high-performance liquid chromatography, carried out at wavelength 210 and 220 nm. The rate of extraction of alkaloids can be increased by adding mineral acid, for example orthophosphoric acid, to the extracting water-acetonitrile mixture.

EFFECT: shorter analysis time and fewer operations while preserving the degree of extraction of alkaloids.

3 cl, 9 dwg, 1 ex

The invention relates to a method for producing derivatives of morphinan, which are intermediate compounds for obtaining derivatives of 14-hydroxymorphinone, which, in turn, are used to obtain opiate antagonists derived Oxymorphone

The invention relates to organic chemistry, specifically to a method for producing esters of N-substituted 14-hydroxymorphinone that are important narcotic analgesic and/or antagonistic means - opiate receptor blockers prolonged action

The invention relates to organic chemistry, particularly to esters of N-substituted 14-hydroxymorphinone that are important narcotic analgesic and/or antagonistic means - opiate receptor blockers prolonged action and to methods for their preparation

The invention relates to an improved process for the preparation of thebaine known derived oripavine General formula

< / BR>
possessing pharmacological activity and is used in medicine as a strong analgesic with low potential for addiction and shock tools

The invention relates to optically active pornobeastiality connection, which is an important intermediate in the synthesis of optically active derivative of pianolessons - azole, useful in the treatment of hypertension (hypertension) and asthma, and to methods of optical time - division pornoencaricaturas connection in the form of a racemic modification

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are dosed forms of guanfacine for per oral application, suitable for single intake per day, which has acceptable general size of pills.

EFFECT: dosed form by invention ensures satisfactory pharmacological profile for prolonged delivery of guanfacine during period of time up to 24 hours with regulated total weight of dosed form.

79 cl, 1 dwg, 2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and its application for prevention and treatment of abuse with psychoactive substances and dependence on psychoactive substances, which contains compound of formula (R)-2-{3-[1-(acenaphthene-1-yl)pyperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl} -N-methyl acetamide or its pharmaceutically acceptable salt as active ingredient.

EFFECT: compound, which is agonist and has highly selective affinity to ORL-1 receptors, possesses effects of reduction of intensity of alcohol abstinence symptoms and suppression of surplus intake of alcohol and other psychoactive substances.

18 cl, 1 tbl, 8 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: compounds are suitable for use as kinase 1β-adrenergic receptor (βARK-1) inhibitors. The invention also relates to compositions containing such compounds and to use of compounds of formula to treat and prevent chronic heart failure, hypertension myocardial ischemia and hepatitis C viral infections (HCV) and for preventing opiate addiction. The invention also pertains to methods of producing formula (I) compounds.

EFFECT: more effective use of the compounds.

11 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to bioorganic chemistry and specifically to synthesis of peptides which inhibit attraction to morphine in the period for quitting narcotic drugs. This compound can be used as a medicinal agent which inhibits attraction to morphine during a prolonged period for quitting a narcotic drug, which facilitates achieving prolonged remission of one form of opium addiction - morphine addiction and prevent disease recurrence.

EFFECT: wide range of agents which inhibit attraction to morphine during a period for quitting narcotic drugs, which is achieved through use of the chlorohydrate of tetrapeptide Trp-Nle-Asp-PheNH-CH(CH3)2.

4 dwg, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to therapeutic agents and concerns a therapeutic agents used for treatment of the patients suffering from diseases caused by monoaminooxidase overactivity and representing polyprenols of formula (1). The content of polyprenols of formula (1) where n=8-20 in the specified agent is 0.1 to 80%. Also there is disclosed method for treatment of the patients suffering from diseases caused by monoaminooxidase overactivity, characterised that a patient takes one or more doses of polyprenols of formula (1) in amount 1 to 150 mg a day (1).

EFFECT: invention allows extending range of therapeutic agents for treatment of the patients suffering from diseases caused by monoaminooxidase overactivity.

4 cl, 8 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to study of narcotic addiction and psychotherapy and can be used for treatment of the patients suffering from addiction, mainly opium-containing substances. Treatment involves sessions of individual psychotherapy and reflexotherapy. The therapeutic course starts for 5-7 day after reduction of abstinence syndrome. Psychotherapy is combined with individual pharmacotherapy including opiate antagonists depending on amount of taken narcotics and rate of symptomatology change. Sessions of individual psychotherapy are systematic by cognitive psychotherapy as a dialogue on the preset subject with using guiding and key questions, and suggestive psychotherapy in Erickson hypnotherapy by influencing the patient's emotional component. Reflexotherapy is carried out within first two weeks in number 7-10 sessions in the miraculous meridians points R 9 chu-bin, TR 5 vaj-guan, then in the points intensifying somatic and mental balance E 36 chu-san-li, GI 4 he-gu, GI 11 tsuj-chi, V 15 sin-shu, V 59 fu-jan, MC 6 ney-uan, VG 20 baj-huej, VG 14 da-chuj, VC 15 tszju-vej, VB 38 jan-fu. And action of the mental balance points of V 15 sin-shu from both sides, while VG 14 da-chuj is additionally intensified with action on the point VG 20 baj-huej.

EFFECT: method allows involving various representative data input channels, mobilising personal resources of the patient.

3 cl, 3 ex

FIELD: medicine; addictology.

SUBSTANCE: for heroine addiction treatment, 2-3 drops of naloxone hydrochloride are administered into each nasal meatus, i.e. 80-120 mcg 3 times a day during the whole course of treatment.

EFFECT: efficient treatment due to increasing naloxone hydrochloride dosage, reduced affective disorders in post-abstinent period using smaller average effective doses of key psychotropic medicines.

1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical composition is used for treatment of by-effects and idiphatic syndromes caused by opioids, contains a matrix and a pharmaceutically active substance, and the matrix is executed from ethyl cellulose or polymer on a basis of ethyl cellulose and at least one acyclic spirit; thereat the matrix is diffused and practically not bulking up, and contains naloxone as a pharmaceutically active substance, released from the matrix invariant and prolonged, in amount of 1-50 mg, 5-30 mg preferably, and the most preferably in amount of 5-20 mg.

EFFECT: composition is tolerant at storage.

19 dwg, 16 ex, 2 cl

FIELD: medicine; pharmacology.

SUBSTANCE: inventions refer to: substance for ethyl alcohol and/or narcotic addiction treatment, psychosomatic and neurological complication treatment, as well as to pharmaceutical compositions containing this substance, and to method of psychosomatic and neurological complication treatment using this substance. Stated invention implies production of new medicinal agent with minimum by-effect, which is to-date actual problem for such diseases. Substance used for ethyl alcohol and/or narcotic addiction treatment is polyprenols of formula (1), where n=8-20.

EFFECT: high efficiency and non-toxicity.

5 cl, 4 ex, 9 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical compositions are invented, which decrease the abstinent syndrome manifestations in narcotic opioid drug withdrawal. The compositions contain the optimal proportions of tiapride and clofelin (8000÷1000:1). These compositions, which contain less amount of each drug, demonstrate the potentiation of analgesic activity (which significantly exceeds that in monotherapy with tiapride and clofelin). Also, toxic effect of the compositions is less than that when tiapride and clofelin are administered separately, in mice.

EFFECT: compositions terminate the opiate abstinent syndrome with minimal toxic effect.

3 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and deals with simultaneous, separate or separated in time therapeutic application of, at least, one botulic neurotoxin and, at least, one opiate derivative. Essence of invention includes application of subactive dose of botulinic neurotoxin with subactive dose of opiate derivative for obtaining medication, intended for treatment or prevention of pain.

EFFECT: advantage of invention lies in application of subactive doses of both partners, which themselves alone do not produce therapeutic effect, but produce it when introduced in combination.

10 cl, 3 ex, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, and deals with medical form and method for delivery of medical substances, in particular, dependence habit-forming medical substances, which are characterised by stability to solvent extraction, compression, crushing and milling.

EFFECT: ensuring initial fast release of medicinal substance with following continuous period of controlled release of medicinal substance.

42 cl, 9 ex, 34 tbl, 22 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof:

,

where A is a single bond or oxygen; R1 is selected from a group comprising hydrogen; -C(O)OC1-10alkyl and -C(O)OC1-10alkyl-phenyl; and R2 is selected from a group comprising C1-10alkyl, (CH2)n-phenyl, adamantinyl, adamantinyl, C1-10alkyl substituted with C3-10carbocycle, and C3-10carbocycle, where n assumes values from 0 to 4.

EFFECT: novel compounds and salts thereof which can be used in preventing or treating Parkinson's disease are obtained and described.

6 cl, 105 ex, 3 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention relates to drug form for treatment pain in patients suffering from diarrhea using medications, simultaneously containing opioid analgesic and opioid antagonist, which includes from 10 to 40 mg of oxycodon and/or its pharmaceutically acceptable salt and from 5 to 20 mg of naloxon and/or its pharmaceutically acceptable salt, present in ratio 2:1 by weight.

EFFECT: providing drug form for treatment of pain in patients suffering from diarrhea using medications, simultaneously containing opioid analgesic and opioid antagonist.

9 cl, 51 dwg, 38 tbl, 6 ex

Up!