Conjugates of hydrocodone with benzoic acid, derivatives of benzoic acid and hetero-acryl-carbon acid, prodrugs, methods for their obtaining and application

FIELD: biotechnologies.

SUBSTANCE: conjugate represents benzoate-hydrocodone that has the following structure: benzoate-hydrocodone (Bz-HC). Invention also pertains to the application of pharmaceutical compound for obtaining the drug for curing the patient with illness, disease or condition mediated by opioid binding to the opioid receptors of the patient.

EFFECT: improvement of medical treatment efficiency or prevention of drug abuse, drug withdrawal symptoms or pain relief.

10 cl, 11 ex, 4 tbl, 20 dwg

 

Related applications

In this application claims the priority of provisional patent application U.S. serial No. 61/222718, filed on July 2, 2009, which in its entirety is included in this application by reference.

Research or development, subsidized from Federal sources

Data are not available.

Prerequisites to the creation of inventions

Opioids are highly effective analgesic agents, and they are usually prescribed for the relief of acute and chronic pain. They are usually also used as a remedy against cough. However, opioids cause euphoria and easily addictive. As a result they are often abused, resulting in far-reaching social consequences and has a serious impact on health.

Due to possible abuse, it is desirable to obtain any pharmaceutical composition comprising the agonist opioid, so that in practice it prevented the abuse or protected from the abuse of drug. People illegally using drugs often try to circumvent the properties of dosage forms with prolonged release of drugs by injection or other misuse of such dosage forms in order to achieve immediate release agony is the opioid.

Despite their ability to cause dependence and possible abuse, morphine-like drugs, in particular, codeine, hydrocodone and oxycodone, in recent decades, often prescribed for edema cruel acute and chronic pain. This is partly caused by the lack of alternatives to mitigate severe pain resistant to other less powerful analgesic tools such as nonsteroidal anti-inflammatory drugs (NSAID). In this regard, there remains a need to minimize the potential abuse. Unfortunately, undertaken so far, the attempts have not solved this problem.

Hydrocodone is an opioid analgesic agent, as well as antitussive agent and is a fine white crystals or crystalline powder. Hydrocodone is a semisynthetic narcotic analgetika, which is derived from codeine, and many of its effects qualitatively similar to the effects of codeine. It is mainly used to relieve moderate to moderately severe pain. In addition, subanalgesic doses (2.5-5 mg) it is used as an antitussive agent in medicines and tablets cough.

Patients taking opioid analgesic agents such as hydrocodone for pain, involuntarily m the gut to become dependent. With the development of tolerance to opioids, increasing the amount of medication required for pain relief and for good health, which originally could be achieved by taking the prescribed dose. This circumstance leads to an escalation of dose which, if not controlled, can quickly lead to addiction. In some cases, patients have become highly dependent only thirty days.

The invention

In the present invention is used in a complex covalent compounds (conjugates) of the opioid hydrocodone with certain arylcarbamoyl acids, to reduce its potential to cause an overdose or lead to abuse, due to the fact that in order to release the active hydrocodone is required in vivo destruction of conjugates under the action of enzymes or metabolism. In the present invention are also methods of delivery of hydrocodone in the form of conjugates, which release hydrocodone after oral administration and prevent the abuse of them by devious routes, such as intravenous injection ("introduction intravenous drug") or intranasal administration ("the administration of a dose of the powdered drug").

In accordance with at least one aspect of the present invention features a composition for Zam is Lenogo/extended/controlled release hydrocodone in the form of complex compounds, which allows slow/extended/controlled release hydrocodone and/or its active metabolite, hydromorphone, in the circulatory system of a person or animal within a safe therapeutic window, for example, by oral administration. At least some of the compositions/formulations of the present invention can reduce the possibility of addiction/abuse and/or reduce other common side effects associated with hydrocodone and similar compounds.

In accordance with one aspect of the present invention features a composition that contains at least one conjugate of hydrocodone and at least one benzoic acid or its derivative, its salt or their combinations, with benzoic acid or its derivative has the following formula I:

where X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-; R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10. In accordance with some aspects of benzoic Ki the lot or its derivative is aminobenzoate, hydroxybenzoate, aminohydroxylation, its derivative, or a combination of both.

In accordance with another aspect of the present invention features a composition that contains at least one conjugate of hydrocodone and at least one benzoic acid, its derivative, or combinations thereof.

In accordance with another aspect of the present invention include conjugates of hydrocodone to use in order to relieve the pain, preferably, from moderate to severe pain or for use to reduce or prevent the abuse of oral, intranasal or parenteral medicines. In accordance with some aspects conjugates give resistance to abuse in oral, intranasal or parenteral medicines.

In accordance with another aspect of the present invention features at least one conjugate of hydrocodone, which provides a lower rate of release over time and greater or equal to the value of the area under the curve (AUC) compared to an equivalent molar amount of unconjugated hydrocodone over the same time interval. In accordance with other aspects, the conjugate of hydrocodone shows less variability in pharmacokinetic about the île when administered orally compared to unconjugated hydrocodone. In accordance with another aspect of at least one conjugate produces fewer side effects compared to unconjugated hydrocodone, or prevents malicious use of medicines by both physical and chemical manipulation.

In accordance with another aspect of the features of at least one conjugate in an amount sufficient to provide a therapeutically bioequivalent AUC value, when compared to an equivalent molar amount of unconjugated hydrocodone. In accordance with further aspects of the proposed at least one conjugate in an amount sufficient to provide a therapeutically bioequivalent AUC value, when compared to an equivalent molar amount of unconjugated hydrocodone, and with the specified number does not lead to the appearance of the peak value of Cmaxor gives a smaller value of Cmaxthan therapeutically equivalent amount of unconjugated hydrocodone. In accordance with other aspects of the proposed at least one conjugate in an amount sufficient to provide a therapeutically bioequivalent AUC value, when compared to an equivalent molar amount of unconjugated hydrocodone, and that number does not drive the t to the emergence of equivalent peak value of C max. In accordance with some aspects, at least one conjugate gives the equivalent peak value of Cmaxwhen compared to unconjugated hydrocodone.

In accordance with another aspect of the present invention features a method of treating a patient having a disease, disorder or condition, which requires binding of opioid or which is mediated by the binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid or its derivative, its salt or their combinations, with benzoic acid or its derivative has the formula I:

where

X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-; R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10.

In accordance with another aspect of at least one conjugate binds irreversibly to receptors in the opioid the patient. The fit is accordance with another aspect of at least one conjugate binds irreversibly to receptors in the opioid the patient, without inhibitory effects on the Central nervous system.

In accordance with another aspect of the present invention features a method of treating a patient having a disease, disorder or condition that requires inhibition of binding of opioid or which is mediated by inhibition of binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid or its derivative, its salt or their combinations, with benzoic acid or its derivative has the formula I:

where

X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-; R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10.

In accordance with some aspects of the present invention features at least one conjugate, which reversibly inhibits the binding of an opioid to the opioid receptors of the patient. In accordance with other aspects the AMI at least one conjugate reversibly inhibits the binding of an opioid to the opioid receptors of the patient, without inhibitory effects on the Central nervous system.

In accordance with another aspect of the present invention features a method of treating a patient having a disease, disorder or condition (such as pain), which can be treated by binding with opioid receptors in the opioid the patient, and the method comprises oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid, its salts, its derivative, or combinations thereof.

In accordance with another aspect of the present invention features a method of treating a patient having a disease, disorder or condition (such as pain), which can be treated by inhibiting binding of an opioid to the opioid receptors of the patient, and the method comprises oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid, its salts, its derivative, or combinations thereof.

In accordance with another aspect of the present invention features a pharmaceutical kit comprising a certain number of individual doses in a package that contain a pharmaceutically effective amount of at least one what about the conjugate of hydrocodone and at least one benzoate, its salts, its derivative, or combinations thereof, with benzoate has the formula I:

where X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-; R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10. In accordance with some aspects of the specified set includes instructions for using a specified set of reagents in the method of treatment or prevention of withdrawal symptoms drugs or pain relief the patient-the person or patient is an animal.

In accordance with another aspect of the present invention features a pharmaceutical kit comprising a certain number of individual doses in a package that contain a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid, its salts, its derivative, or combinations thereof. In accordance with some aspects of the specified set further includes instructions for using the kit in a method of treatment or is the avoiding withdrawal symptoms drugs or pain relief the patient-the person or patient is an animal.

In accordance with another aspect of the present invention features a composition comprising at least one conjugate of hydrocodone and at least one heteroarylboronic acid, its derivative, or combinations thereof.

In accordance with another aspect of the present invention features at least one conjugate of hydrocodone and at least one heteroarylboronic acid, its derivative, or combinations thereof, where at least one heteroarylboronic acid selected from formula II, formula III and formula IV:

where X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-; R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10. In accordance with some aspects, at least one heteroarylboronic acid is a derivative of pyridine.

In accordance with some aspects of the present invention features at least one conjugate, which prevents malicious use of medicines by how physical the CSOs, and chemical manipulation.

In accordance with another aspect of the present invention features a method of treating a patient having a disease, disorder or condition, which requires binding of opioid or which is mediated by the binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one heteroarylboronic acid.

In accordance with another aspect of the present invention features a method of treating a patient having a disease, disorder or condition, which requires binding of opioid or which is mediated by the binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one heteroarylboronic acid, where heteroarylboronic acid selected from formula II, formula III and formula IV, where formula II, formula III and formula IV have the following structure:

where X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-; R1, R2and R3independently selected from the group which comprises H, alkyl, alcohol is si, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10.

In accordance with another aspect of the present invention features a method of treating a patient having a disease, disorder or condition, which requires binding of opioid or which is mediated by the binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one nicotinic acid, its derivative, or combinations thereof.

In accordance with another aspect of the present invention features a method of treating a patient having a disease, disorder or condition that requires inhibition of binding of opioid or which is mediated by inhibition of binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one heteroarylboronic acid. In accordance with some aspects heteroarylboronic acid selected from formula II, formula is III and formula IV, where formula II, formula III and formula IV have the following structure:

where X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-; R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10.

In accordance with another aspect of the present invention features a method of treating a patient having a disease, disorder or condition that requires inhibition of binding of opioid or which is mediated by inhibition of binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one nicotinic acid, its derivative, or combinations thereof.

In accordance with another aspect of the present invention features a pharmaceutical kit comprising a certain number of individual doses in a package that contain a pharmaceutically effective amount of at least one conjugate hydrocod is on and at least one heteroarylboronic acid, its derivative, or combinations thereof, where heteroarylboronic acid selected from formula II, formula III and formula IV, where formula II, formula III and formula IV have the following structure:

where X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-; R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10. In accordance with some aspects of the specified set further includes instructions for using the kit in a method of treatment or prevention of withdrawal symptoms drugs or pain relief the patient-the person or patient is an animal.

In accordance with another aspect of the present invention offers a prodrug comprising at least one conjugate of hydrocodone and at least one benzoic acid or a derivative of benzoic acid, its salts or combinations thereof, with benzoic acid or a derivative of benzoic acid has the following formula I:

where X, Y and Z are independently selected from the group including the surrounding H, O, S, NH, and -(CH2)X-; R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10.

In accordance with another aspect of the present invention offers a prodrug comprising at least one conjugate of hydrocodone and at least one benzoic acid, a derivative of benzoic acid or combinations thereof.

In accordance with another aspect of the present invention offers a prodrug comprising at least one conjugate of hydrocodone and at least one heteroarylboronic acid, its derivative, or combinations thereof. In accordance with some aspects of the prodrug comprises at least one heteroarylboronic acid selected from formula II, formula III and formula IV, where formula II, formula III and formula IV have the following structure:

where X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-; R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogenase the initial alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10.

In accordance with another aspect of the present invention offers a prodrug comprising at least one conjugate of hydrocodone and at least one nicotinic acid, its derivative, or combinations thereof.

In accordance with some aspects of the prodrug includes aminobenzoate, hydroxybenzoate, aminohydroxylation, its derivative, or combinations thereof.

In accordance with some aspects, at least one conjugate binds reversibly to receptors in the opioid the patient. In accordance with other aspects of at least one conjugate reversibly binds to the opioid receptors of the patient, without negative effects on the Central nervous system. In accordance with another aspect of at least one conjugate prevents or reduces at least one causing constipation side effect of unconjugated hydrocodone.

A brief description of several types of drawings

Figure 1. The chemical structure of hydroxybenzoic acids and derivatives of hydroxybenzoic acids, used for the purpose of obtaining conjugates of the present invention.

Figure 2. The chemical structure of benzoic acids on what I use, for the purpose of obtaining conjugates of the present invention.

Figure 3. Chemical structure aminohydrocinnamic acids for use with the aim of obtaining conjugates of the present invention.

Figure 4. Figure 4A is a table of typical dosage forms hydrocodone and dose ranges, and figure 4B is a table of typical dosage forms of hydrocodone, which is used in cough syrups.

Figure 5. Schedule pharmacokinetic profile of concentrations in the plasma of hydrocodone released from Bz-HC (benzoate-hydrocodone), YYFFI-HC (Tyr-Tyr-Phe-Phe-Ile-hydrocodone) and diglycolate-HC, over time after oral administration to rats.

Figure 6. Schedule pharmacokinetic profile of concentrations in plasma active metabolite, hydromorphone, over time after oral administration of Bz-HC, YYFFI-HC and diglycolate-HC rats.

Figure 7. Schedule pharmacokinetic profile of concentrations in the plasma of hydrocodone released from Bz-HC and adipate-HC, over time after intranasal rats.

Figure 8. Schedule pharmacokinetic profile of concentrations in plasma active metabolite, hydromorphone, over time after intranasal Bz-HC and adipate-HC rats.

Figure 9. Schedule pharmacokinetic profile of concentrations in the plasma of hydrocodone released from Bz-HC, nicotinate-HC and hydrocodone·BT, with time on the Les oral administration to rats.

Figure 10. Schedule pharmacokinetic profile of concentrations in plasma active metabolite, hydromorphone, over time after oral administration of Bz-HC, nicotinate-HC and hydrocodone·BT rats.

Figure 11. Schedule pharmacokinetic profile of concentrations in the plasma of hydrocodone released from Bz-HC, 2-ABz-HC and hydrocodone·BT, over time after oral administration to rats.

Figure 12. Schedule pharmacokinetic profile of concentrations in plasma active metabolite of hydrocodone over time after oral administration of Bz-HC, 2-ABz-HC and hydrocodone·BT rats.

Figure 13. Chart of the synthesis of conjugates of hydrocodone. Figure 13A shows the synthesis of benzoate of hydrocodone. Figure 13B shows the synthesis of the nicotinate of hydrocodone (nicotinic acid). Figure 13C shows the synthesis of 2-aminobenzoate hydrocodone. Figure 13D shows the synthesis of salicylate of hydrocodone.

Figure 14. Schedule pharmacokinetic profile of concentrations in the plasma source Bz-HC, the active metabolite hydromorphone and hydrocodone released from Bz-HC, over time after oral administration to rats.

Figure 15. Schedule pharmacokinetic profile of concentrations in the plasma of hydrocodone released from Bz-HC and hydrocodone·BT, over time after oral administration to dogs.

Figure 16. Schedule pharmacokinetic p is ofile concentrations in plasma active metabolite, hydromorphone, over time after oral administration of Bz-HC and hydrocodone·BT dogs.

Figure 17. Schedule pharmacokinetic profile of concentrations in the plasma source Bz-HC and hydrocodone released from Bz-HC, over time after oral administration to dogs.

Figure 18. Schedule pharmacokinetic profile of concentrations in the plasma source Bz-HC, active metabolite, hydromorphone, and hydrocodone released from Bz-HC, over time after intravenous administration to rats in the amount of 0.30 mg/kg

Figure 19. Schedule pharmacokinetic profile of concentrations in the plasma of hydrocodone released from Bz-HC, over time after oral administration to rats for six different dosages.

Figure 20. Schedule pharmacokinetic profile of concentrations in plasma active metabolite, hydromorphone, over time after oral administration of Bz-HC rats for six different dosages.

Detailed description of the invention

The present invention provides compositions containing arylcarbamoyl acid, chemically related to hydrocodone (morphinan-6-he, 4,5-alpha-epoxy-3-methoxy-17-methyl), with new prodrugs and compositions of hydrocodone. In some embodiments, implementation of the present invention the chemical bond between these two fragments can be arr is implemented through the interaction of a C-6 enol tautomer hydrocodone with activated carboxyl group arylcarbamoyl acid to obtain the enol-ester conjugate.

It should be understood that the term "opioid" includes any drug that activates opioid receptors located in the brain, spinal cord and intestines. There are four broad classes of opioids: a naturally occurring alkaloids of opium, such as morphine (the prototype opioid, codeine and thebaine; endogenous opioid peptides such as endorphins; semi-synthetic opioids, such as heroin, oxycodone and hydrocodone, which are obtained by modification of natural alkaloids of opium and that have similar chemical structures; and pure synthetic substances such as fentanyl and methadone, which get not from opium and which may have a chemical structure which is completely different from alkaloids of opium. Additional examples of opioids are hydromorphone, Oxymorphone, methadone, Levorphanol, Dihydrocodeine, meperidine, Diphenoxylate, Sufentanil, Alfentanil, propoksifen, pentazocine, nalbuphine, butorphanol, buprenorphine, meptazinol, dezocine and their pharmaceutically acceptable salts.

It should be understood that the term "hydrocodone" includes semi-synthetic narcotic analgetic and antiphlogistic agent, which is derived from codeine and many whose actions qualitatively similar to the effect of codeine. It is usually used to relieve moderate to moderately severe pain. That is marketing names include Anexsia™, Hycodan™, Hycomine™, Lorcet™, Lortab™, Norco™, Tussionex™, Tylox™ and visual™. The present invention encompasses other salt forms of hydrocodone, such as hydrocodone bitartrate, and a polymer mixture of hydrocodone slow release of content.

In some embodiments, implementation of the present invention offers associated with hydrocodone carboxylic acid in which the carboxyl group is directly linked to the aryl fragment. Carboxylic acid, whose carboxyl group is directly linked to the aryl fragment include benzoate and heteroarylboronic acid.

In some embodiments, implementation of the present invention features at least one conjugate of hydrocodone and at least one benzoic acid or a derivative of benzoic acid, its salts or combinations thereof. Benzoate distributed in nature and include, for example, but not limited to, aminobenzoate (in particular, the analogues of Anthranilic acid, such as fenamate), aminohexanoate and hydroxybenzoate (for example, analogues of salicylic acid).

Benzoic acid and derivatives of benzoic acid according to the present invention have the following General structure:

where X, Y and Z can be independently any combination of H, O, S, NH, and -(CH2)X-; R1, Rsup> 2and R3independently can be any of the following groups: H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q can be independently denote either 0 or 1.

Appropriate hydroxybenzoic acid can be found in figure 1 and they include, but not limited to, benzoic acid, salicylic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 6-methylsalicylic acid, o,m,p-krestinov acid, anacardiaceae acid, 4,5-dimethylsilicone acid, o,m,p-hydroxy-parallelconvoy acid, diflunisal, o,m,p-anisic acid, 2,3-dihydrobenzoic acid (2,3-DHB), α,β,γ-resorcinol acid, protocatechuic acid, entityname acid, piperonylic acid, 3-metoxisalicilice acid, 4-metoxisalicilice acid, 5-metoxisalicilice acid, 6-metoxisalicilice acid, 3-hydroxy-2-methoxybenzoic acid, 4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid, vanillic acid, isovanillin acid, 5-hydroxy-3-methoxybenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratrole acid (3,4-di is ethoxybenzoyl acid), 3,5-dimethoxybenzoic acid, Gallic acid, 2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 3-O-metalalloy acid (3-OMGA), 4-O-metalalloy acid (4-OMGA), 3,4-O-dimethylallyl acid, lilac acid, 3,4,5-trimethoxybenzoic acid.

Suitable aminobenzene acid is shown in figure 2 and they include, but not limited to, Anthranilic acid, 3-aminobenzoic acid, 4,5-dimethylanthracene acid, N-methylanthranilic acid, N-acetylanthranilic acid, fanmovie acid (for example, tolfenamic acid, mefenamico acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA), 2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid, 2,4-diacetylbenzene acid.

Suitable aminohydroxylation acid include, but not limited to, 4-aminosalicylic acid, 3-hydroxyanthranilic acid and 3-methoxyestradiol acid.

In some embodiments, implementation of the present invention, the composition includes benzoate conjugate comprising at least one hydrocodone associated with at least one benzoic acid or a derivative of benzoic acid, its salt or their combination.

In some embodiments, implementation of the present invention benzoate clucalc many analogues of benzoic acid, benzoate derivative having a hydroxyl group or amino group, or a combination of both of these groups. Functional hydroxyl group and amino group may be present in their free form or they may be closed to other chemical fragment, preferably, but not limited to, methyl or acetyl groups. The phenyl group may have additional substituents, however, the total number of substituents may be equal to four or less, three or less, or two or less.

In another embodiment, the present invention prodrug or composition of the conjugate of the present invention is a benzoate-hydrocodone which has the structure:

benzoate-hydrocodone (Bz-HC)

In yet another embodiment, the present invention proposes a prodrug or composition comprising at least one conjugate of hydrocodone and at least one heteroarylboronic acid, its derivative, or combinations thereof. Heteroarylboronic acid may be selected from formula II, formula III and formula IV, where formula II, formula III and formula IV have the following structure:

In the above formulas, X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-; R1, R2 and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl; o, p, q are independently selected from 0 or 1; and x denotes an integer in the range from 1 to 10.

In some embodiments, implementation of the present invention carboxyl group arylcarboxylic acids can be attached directly to the aromatic nucleus. The present invention includes both aryl groups containing only carbon atoms and aryl groups with heteroatoms (heteroaryl group). Aryl or heteroaryl group that is directly attached to the carboxyl functional group, may be 6-membered cycle and does not contain or contains one heteroatom. In some embodiments, implementation of the present invention more substituted or unsubstituted aromatic or aliphatic cycles can be condensed with the specified 6-membered aryl or heteroaryl fragment. In some embodiments, implementation of the present invention arylcarbamoyl acid can have only one free carboxyl group, and the total number of phenyl substituents in the 6-membered cycle must be four or less, for example, 4, 3, 2 or 1.

is some embodiments, implementation of the present invention, depending on the individual arylcarbamoyl acid, which is associated with hydrocodone conjugate of hydrocodone may have a neutral form, the form of the free acid, free base or various pharmaceutically acceptable anionic or cationic salt form, or mixtures of salts with any relationship positively or negatively charged components. These salt forms include, but are not limited to: acetate, L-aspartate, besylate, bicarbonate, carbonate, D-kamilat, L-camsylate, citrate, Etisalat, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesilate, pamoate, phosphate, succinate, sulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isetionate, malonate, methyl sulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, acefylline, aceturate, aminosalitsilata, ascorbate, borate, butyrate, comfort, Campomarino, decanoate, hexanoate, Holt, cypionate, dichloroacetate, edentate, ethyl sulfate, Furat, fusidate, galactarate (mukat), galacturonic, gallate, gentisate, glutamate, glutarate, glycyrrhizinate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, malate, mandelate, methanesulfonate, monistat, napadisylate, oleate, oxalate, palmitate, picrate, pivalate, the PCC is ONAT, pyrophosphate, salicylate, salicicola, sulfosalicylate, tannat, terephthalate, thiosalicylate, tripotent, valerate, valproate, adipate, 4-acetamidobenzoate, Kamelot, octanoate, astolat, Eilat, glycolate, thiocyanate and undecylenate.

In the present invention is suitable conjugate of hydrocodone includes nicotinate-hydrocodone, which has the following structure:

nicotinate-hydrocodone (nicotinate-HC)

In some embodiments, implementation of the present invention features a conjugate of hydrocodone, which is destroyed in vivo either enzymatic or otherwise, releasing the active hydrocodone and the appropriate carboxylic acid or their metabolites. Arylcarbamoyl acid used in the conjugates of the present invention, is not toxic at these levels dosing and mainly represent the known medicines, natural products, metabolites or GRAS (generally recognized as safe) compounds (in particular, preservatives, colorings, flavorings and the like) or their non-toxic mimetics.

Compounds, compositions and methods of the present invention reduce the possibility of overdose, reduce the potential for abuse or addiction and/or improve the performance of hydrocodone, associated with high toxicity or suboptimal Professor who guides the release of the drug. Not wanting to limit themselves to the following theory, the authors present invention believe that the protection of overdose may occur due to the fact that oral conjugates are exposed to various enzymes and/or metabolic pathways, the effect on the conjugate will be provided in the gut, and he is subject to presystemic metabolism, in contrast to the effects of enzymes in the circulatory system and on the mucous membrane, which limits the ability of hydrocodone to be released from the conjugate. Thus, resistance to abuse is ensured by limiting "the initial manifestations of pleasant feelings" or "nervous rise, which occurs under the influence of active hydrocodone released from prodrugs, and by limiting the effectiveness of alternative routes of drug administration.

The compositions of the present invention preferably do not possess pharmacological activity or have significantly reduced pharmacological activity when administered by injection or intranasally. However, they are orally bioavailable. Again, not wishing to be bound to any specific theory, the authors present invention believe that the bioavailability can be the result of hydrolysis of chemical SV is zi (i.e., covalent bonds) after oral administration. In at least one embodiment of the present invention the release of the hydrocodone is reduced when the composition of the present invention deliver parenteral routes.

For example, in one embodiment of the present invention the composition according to the present invention retains its effectiveness and resistance to abuse after crushing the tablets, capsules or other oral dosage forms. On the contrary, from unconjugated (or "unpaired") parenteral hydrocodone indicated hydrocodone immediately released after crushing and allows you to use the content of crushed tablets by injection or allows you to take a dose of the powdered drug, causing the effect of the initial manifestations of pleasant feelings, which crave for drug addicts.

In some embodiments, implementation of the present invention, the conjugates of hydrocodone can oral to enter the patient is an animal or patient-man, and after they release the active hydrocodone due to hydrolysis of the conjugates in the body. Not wishing to be bound to any specific theory, the authors present invention believe that because arylcarbamoyl acids are naturally occurring metabolites Ilyich mimetics or are pharmaceutically active compounds, they are easily recognized physiological systems, which leads to their hydrolysis and release of hydrocodone. Themselves conjugates or do not possess pharmacological activity, or have limited pharmacological activity and, therefore, can move on metabolic pathways that are different from the metabolic pathways of the original medicinal product.

In some embodiments, implementation of the present invention the selection of the suitable arylcarboxylic acids ("ligands") for conjugation with hydrocodone determines the release of hydrocodone in the systemic circulation, and it can be controlled even when the conjugate is administered in a manner other than oral. In one embodiment of the present invention modified hydrocodone is capable of releasing hydrocodone similarly free or remotefilename the hydrocodone. In another embodiment of the present invention conjugated hydrocodone releases hydrocodone controlled or prolongirovanne. In some embodiments, implementation of the present invention specified controlled release can facilitate certain side effects and improve the security profile of the original medicinal product. These side effects may include, but atime limited to, anxiety, bleeding, constipation, decreased appetite, difficulty breathing, dizziness, drowsiness, soreness in the mouth, diarrhea, headache, nausea, stomach cramps, stomach pain, vomiting. In another embodiment of the present invention conjugated hydrocodone allows the metabolism to perform selective conversion of hydrocodone to hydromorphone. In another embodiment of the present invention these conjugates can be used for pain relief, such as moderate pain and severe pain.

Hydrocodone and other opioids have a strong ability to cause dependence and encourage abuse. Improper use of recreational drugs is a common problem and usually starts with oral doses that you take to experience euphoria (the"initial manifestation of pleasant feelings," "nerve up"). Over time, addicts often increases oral dosing to achieve a stronger nervous UPS" or to compensate for an increased tolerance to the opioid. This behavior escalates and leads to the search for other routes of administration, such as intranasal ("the dose of the powdered drug") and intravenous ("introduction intravenous drug").

In some embodiments, the OS is implement the present invention hydrocodone, which anywhereman with the appropriate ligand in the form of arylcarbamoyl acid after oral intake does not lead to rapid increase of its concentration in plasma, what people seek, which is able to abuse drugs. In some embodiments, implementation of the present invention released from these conjugates hydrocodone has lagged value of Tmaxand, perhaps, a smaller value of Cmaxthan unconjugated hydrocodone. Not wishing to be bound to any specific theory, the authors present invention believe that the conjugates of the present invention, when administered orally or other non-oral means, do not create a sense of "initial manifestations of pleasant feelings, even when they are administered in higher doses, but still able to reduce the pain.

In addition, in some embodiments, implementation of the present invention hydrocodone, conjugated with suitable ligands of the present invention, is not hydrolyzed efficiently in the case where it is administered by other than oral. The result of these conjugates, when administered as an injection or in the form of powder, do not create in the plasma or blood of larger concentrations of released hydrocodone compared with free hydrocodone that BBO is Yat specified path.

In some embodiments, implementation of the present invention, the conjugates of the present invention, since they include covalently linked hydrocodone, are not capable at physical manipulation to release the opioid hydrocodone from conjugated hydrocodone ways, as, for example, grinding or crushing of solid dosage forms. In addition, the conjugates of the present invention is stable to chemical hydrolysis under conditions that people are able to abuse drugs, can be used to extract the active portion of the molecule, for example, by boiling or by acid or alkaline treatment of the conjugate solution.

Composition and prodrugs of the present invention can be prepared in the form of oral dosage forms. These dosage forms include, but not limited to, a tablet, a capsule, a pill-shaped capsule, toffee, cake, powder, suspension, syrup, solution or oral thin-film form (OTF). Preferred oral forms are capsule, tablet, solution and OTF.

Solid dosage forms may include, but not limited to, the following types of auxiliary compounds: anti-adhesive substances, binders, coatings, leavening agents, fillers, flavorings and imenti, glidant, lubricants, preservatives, sorbents, and sweeteners.

Oral compositions of the present invention can also be incorporated into a solution or suspension in an aqueous liquid or non-aqueous liquid. The composition can be an emulsion, such as a liquid emulsion of oil in water or a liquid emulsion of water in oil. These oils can be entered by adding purified and sterile fluid to a prepared enteral composition, which is then placed in a feeding tube in a patient who cannot swallow.

Can be prepared capsules soft gel or soft gelatin capsules, for example, by dispersing the composition in a suitable carrier (usually use vegetable oil) with the formation of highly viscous mixture. This mixture then encapsulate in a film of gelatin, using methods and equipment well-known experts from the field of production of soft gels. Formed in this way individual drugs are then dried to a constant weight.

Chewable tablets can, for example, be prepared by mixing the compositions with inert fillers suitable for the formation of a relatively soft, flavored dosage forms as tablets, which is designed for grinding and not for swallowing. Can the use of conventional tablet press machines and conventional tabletting methods, for example, the direct extrusion or granulation, i.e. the aggregation of the grains of the granular material before pressing. Professionals who participate in the preparation of solid dosage forms, have experience with these methods and technological equipment, as designed for chewing dosage forms are very common drugs in the pharmaceutical industry.

Can be prepared, for example, a tablet with a film cover, forming on the tablet coating using techniques such as coating methods using a rotary evaporation apparatus or a coating of air-suspension method, to form the tablet continuous film layer.

Compressed tablets, for example, can be obtained by mixing the composition with an inert fillers, designed to give a mixture of binder properties or loosening properties. The mixture either directly pressed or granularit, and then pressed, using known industry methods and equipment. Received dosage forms as tablets then pack, depending on the needs of the market, for example, in the form of a single dosage form, rolls, cylinders, transparent at the of acook etc.

The present invention also covers the use of biologically acceptable carriers that can be obtained from a wide range of substances. Without limitation, such substances include solvents, binders and adhesives, lubricants, plasticizers, leavening agents, pigments, fillers, flavorings, sweeteners and various other substances, such as buffer additives and adsorbents in order to prepare the specific composition of the medicinal product.

Spanning connection, you can choose from a wide range of substances, such as hypromellose, ethylcellulose or other suitable cellulose derivatives, povidone, copolymers of acrylic and methacrylic acid, pharmaceutical glaze, gums, milk processing products, such as whey, starches and their derivatives, as well as other conventional binders known to the specialists from the field of technology. Non-limiting the present invention, examples of solvents are water, ethanol, isopropyl alcohol, methylene chloride or mixtures thereof and combinations. Non-limiting the present invention, examples of fillers are sugar, lactose, gelatin, starch and silicon dioxide.

It should be understood that in addition to those ingredients, which, in particular, noted above, compositions of the present invention can include other approach is Jamie agents, such as flavorings, preservatives and antioxidants. These antioxidants must be edible and can include vitamin E, carotene, BHT or other antioxidants.

Other compounds that can be incorporated by mixing, are, for example, inert from a medical point of view, the ingredients, in particular, solid and liquid diluents, such as lactose, dextrose, saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or etiloleat for soft capsules and water or vegetable oil for suspensions or emulsions; lubricants, such as silica, talc, stearic acid, magnesium stearate or calcium and/or polyethylene glycols; gelatinizers tools such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binders such as starches, gumarabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, Polysorbate or laurylsulfate; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffer additives and antioxidants, which are izvestnyakovye for these compositions.

For oral administration of micronized powders or granules, containing diluents, dispersing agents and/or surfactants, can be prepared in the form of a dose of liquid medication in the water or syrup, in capsules or sachets in the dry state, in the form of aqueous suspensions, which can be added suspendresume funds, or in the form of a suspension in water or syrup. If you want, you can add flavor enhancers, preservatives, suspendresume tools, thickeners or emulsifiers.

Liquid dispersions for oral administration can consist syrups, emulsions or suspensions. Syrups as the carrier may contain, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol. In particular, the syrup for diabetes patients may contain as carrier, only those substances such as sorbitol, which is not transformed with the metabolism of glucose, or that the metabolism constitute only a very small quantity of glucose. Suspensions and emulsions can contain the composition of the medium, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

Currently approved for use in the composition of hydrocodone are combined medicines hydrocodone, depending on the intended use, containing hydrocodone and one or more other inactive drug ingredients. Examples of these active pharmaceutical preparations include, but not limited to, acetaminophen, phenylpropanolamine, gomatropin, ibuprofen, aspirin, Pheniramine, chlorpheniramine, phenylephrine, pseudoephedrine, pyrilamine, guaifenesin. It is possible to prepare the composition of conjugated hydrocodone of the present invention with one of these active substances, or a combination of these or other active substances or to prepare the composition of the isolated active ingredient without additives of any other active ingredients.

Containing conjugate composition or prodrugs may be used in methods of treating a patient having a disease, disorder or condition requiring or mediated by binding or inhibition of binding of an opioid to the opioid receptors of the patient. Treatment includes oral administration to a patient pharmaceutically effective amount of at least one conjugate of hydrocodone, as specified in the present invention. The conjugate may exhibit a lower rate of release over time and lower AUC compared to an equivalent molar amount of unconjugated hydrocodone. In other embodiments, domestic the present invention at least one conjugate may exhibit less variability in the pharmacokinetic profile after oral administration compared to unconjugated hydrocodone.

In other embodiments, implementation of the present invention at least one conjugate is offered in a quantity sufficient to provide a therapeutically bioequivalent AUC value (area under the curve), compared to an equivalent molar amount of unconjugated hydrocodone. In other embodiments, implementation of the present invention at least one conjugate is offered in a quantity sufficient to provide a therapeutically bioequivalent AUC value, when compared to an equivalent molar amount of unconjugated hydrocodone, the conjugate has a lower value of Cmax(peak concentration) in plasma or does not show the equivalent value of Cmaxplasma concentrations. In accordance with some aspects, the conjugate is offered in a quantity sufficient to obtain a therapeutically bioequivalent value of Cmaxcompared to unconjugated hydrocodone.

Suitable diseases, disorders and conditions that can be treated using prodrugs or compositions of the present invention, are dependent on drugs or addicted to excessive use of drugs and/or acute or chronic pain.

The dosage of the conjugates of the present invention depend on the x molecular mass and corresponding mass percent of hydrocodone as part of the conjugate as a whole, and so they can be higher than the dosage free hydrocodone. The dose can be calculated based on the concentration of the dose of hydrocodone bitartrate, which varies in the range from 2.5 mg to 15 mg per dose. Conversion dose when switching from hydrocodone bitartrate to the prodrug hydrocodone can be done using the following formula:

dose(HC prodrug/enzyme conjugate) = [dose(HC bitartrate) × (molecular mass(HC prodrug/enzyme conjugate)/494,49)]/proportion of hydrocodone released from the prodrug/enzyme conjugate

HC: hydrocodone

Suitable dosages of conjugated hydrocodone of the present invention include, but are not limited to, compositions that contain from about 0.5 mg or more, or from about 2.5 mg or more, or from approximately 5.0 mg or more, or from about 7.5 mg or more, or from about 10 mg or more, or from approximately 20 mg or more, or from about 30 mg or more, or from approximately 40 mg or more, or from approximately 50 mg or more, or from about 60 mg or more, or from approximately 70 mg or more, or from about 80 mg or more, or from about 90 mg or more, or from about 100 mg or more, and include any more the positive increment for example, 0,1; 0,2; 0,25; 0,3; 0,4; 0,5; 0,6; 0,7; 0,75; 0,8; 0,9 or 1.0 mg, and multipliers (e.g., ×1; ×2; ×2,5; ×5; ×10; ×100 and so on). The present invention also includes compositions dose, including approved at the present time to the composition of hydrocodone (see figure 4), where the dosage can be calculated using the above formula, which determines the amount of hydrocodone bitartrate. In the present invention are available dosage forms prepared in the form of monotherapeutic money or drugs for combination therapy with another active pharmaceutical ingredient (figure 4).

Conjugates of hydrocodone derivative of benzoic acid or nicotinic acid according to the present invention have several advantages, including, but not limited to, a smaller variability of the concentrations of hydrocodone or hydromorphone in plasma compared with free hydrocodone, less potential for abuse of the drug, less risk of chemical or physical manipulation that leads to the selection of the dose of hydrocodone, improved dosage forms due to the formation of covalent bonds with carboxylic acid or its derivatives, increased or reduced metabolism of hydrocodone to hydromorphone and/or reduced side effects, in addition to drug abuse is redstem.

Hydrocodone is a narcotic analgesic agent, which acts as a weak agonist of the opioid receptor in the Central nervous system (CNS). It primarily acts on the μ (mu) receptor (OP3), but also has activity as an agonist δ (Delta) receptor (OP1) and κ (Kappa) receptors (OP2). In addition, the hydrocodone has antitussive properties, suppressing the cough reflex in the medullary cough center of the brain.

Side effects of opioid analgesic funds include gastrointestinal upset caused by binding of opioids with mu (μ) receptors present in the gastrointestinal tract. Side effects include stomach decreased secretion of hydrochloric acid, decrease in motor functions of the stomach, with lengthened time of gastric emptying, which can lead to gastroesophageal reflux. The time of passage of the contents of the stomach through the duodenum may increase by as much as 12 hours, and the absorbance of oral ingested drugs slows down. In the small intestine opioid analgesic tools reduce the secretion of bile, the secretion of pancreatic and intestinal secretion and delay the digestion in the small intestine. Propulsive peristaltic waves in the colon are reduced or terminated after the appointment of the of iaido, and the tone rises to the level of spasm. The resulting delay in the advancement of intestinal contents cause significant drying of faeces, which, in turn, slows their movement through the colon. These actions, combined with ignoring normal stimuli for reflex defecation caused by the Central action of the medicinal product, contribute to the development caused by opioid constipation.

Hydrocodone is used to relieve acute and moderately severe pains and a cough suppressant (in particular, a dry, nonproductive cough). Prodrugs of the present invention may be administered to alleviate pain, or cough suppressant, or for the treatment of any condition that may require blocking of opioid receptors.

The conjugates of the present invention can reduce the side effects of opioid analgesic funds, including the reduction or suppression effects, causing constipation.

In the present invention it is also proposed a method of synthesis, with the aim of obtaining conjugates of hydrocodone of the present invention. In one embodiment of the present invention the synthesis of the present invention includes the following stages:

1. Protection of the ligand, if necessary;

2. Activating the carboxyl group of the ligand, if it is not náchod is carried out in an activated form;

3. The addition of activated ligand to hydrocodone or Vice versa in the presence of a base; and

4. Removing the protective groups of the ligand, if they were used.

If arylcarbamoyl acid contains any additional reactive functional groups that can interfere with the reaction combination with hydrocodone, it may be necessary to first attach one or more protective groups. Can be used with any suitable protective group, depending on the type of functional groups and reaction conditions. Examples of protective groups are: acetyl (Ac), β-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyloxy ether (PMB), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDPS), three-ISOPROPYLCUMYL (TIPS), carbobenzoxy (Cbz), p-methoxybenzylamine (Moz), tert-butyloxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (MPM), tosyl (Ts). Appropriate is also a temporary formation of acetals or ketals of the carbonyl groups.

Carboxyl group of the ligands must be activated before it entered into interaction with hydrocodone and formed a noticeable amount of conjugate. The specified activation can be done in many ways using many of the condensing agents known is the shaft specialist. Examples of such condensing agents include: N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI), N,N'-diisopropylcarbodiimide (DBC), 1,1'-carbonyldiimidazole (CDI) or other carbodiimide; (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium hexaflurophosphate (BOP), patrimonialization hexaflurophosphate (PyBroP), (benzotriazol-1 yloxy)triprolidine hexaflurophosphate (PyBOP) or other postname reagents; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), fluoro-N,N,N',N'-tetramethylguanidine hexaflurophosphate (TFFH), N,N,N',N'-tetramethyl-O-(N-Succinimidyl)Urania tetrafluoroborate (TSTU) or other amenieties reagents. Arylcarbamoyl acid can also be converted into the corresponding allalone, acylated or mixed anhydride.

At any stage scheme of the synthesis of the conjugate of hydrocodone with arylcarbamoyl acid may be required basis. Suitable bases include, but are not limited to: 4-methylmorpholine (NMM), 4-(dimethylamino)pyridine (DMAP), N,N-diisopropylethylamine, bis(trimethylsilyl)amide lithium, diisopropylamide lithium (LDA), tert-piperonyl any alkali metal (for example, tert-piperonyl potassium), hydride of any of the alkali metal (e.g. sodium hydride), an alcoholate of any alkali metal (for example the EP, the sodium methoxide, triethylamine, or any other tertiary amine.

Suitable solvents that can be used in any of reaction schemes for the synthesis of the conjugate of hydrocodone with arylcarbamoyl acid include, but are not limited to: acetone, acetonitrile, butanol, chloroform, dichloromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane, methanol, methyl tert-butyl ether (MTBE), isopropanol, isopropylacetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.

In some embodiments, implementation of the present invention, the prodrug is hydrophobic and, thus, is poorly soluble in water. When the composition is mixed with water, this leads to the formation of a jelly-like consistency or education lumpy suspension. Examples of such prodrugs include, but not limited to, piperonylic-HC, 3-OH-4-MeO-Bz-HC, 3-OH-Bz-HC and gallate-HC. These prodrugs, you cannot enter the rats in the form of intranasal dosing, because they do not dissolve in water. Not wishing to be bound by any theory, the authors present invention is believed that these compounds harden or form lumps when the patient-the person tries to breathe through the nose ("the dose of the powdered drug"). The specified SV is istwo not only makes a nasty attempt to abuse the drug intranasally, but, apparently, also prevents the penetration of the prodrug through the mucous membrane of the nose. As a consequence, these compounds become ineffective for a given route of administration.

The present invention offers pharmaceutical kits for the treatment or prevention of withdrawal symptoms drugs or pain relief to the patient. The patient may be human or animal. Appropriate patients-people are patients-children, elderly patients and normal patients. The reagent kit includes the specific number of individual doses in a package containing a pharmaceutically effective amount of at least one conjugate of hydrocodone of the present invention. The reagent kit may also include instructions for using a specified set of reagents. The specific number of individual doses may contain from about 1 to about 100 individual doses, or from about 1 to about 60 individual doses, or from about 10 to about 30 individual doses, including about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 5, about 60, about 70, about 80, about 100, and to include any additional increment, for example, 1, 2, 5, 10, and multipliers (e.g., ×1; ×2; ×2,5; ×5; ×10; ×100 etc).

The described invention and its advantages will become clearer with reference to the following examples. These examples are provided to describe specific embodiments of the present invention. It should be understood that the specific examples do not limit the scope of the present invention and do not contradict the essence of the present invention. Professionals should be understood that the full scope of the described invention encompasses the subject matter of the invention, as defined described in this description, the claims, and any changes, modifications, and equivalents of the claims.

Examples

Example 1. Chemical stability benzoate and heteroarylboronic conjugates of hydrocodone

Examples of conjugates of hydrocodone of the present invention and test conjugates not according to the present invention have chemical stability under conditions similar to those potential abusers of drugs the patient may be used to "extract" the active part of the molecule dissolved in water, hydrochloric acid or bicarbonate intothree is at room temperature or at 100°C. The conjugates of one hour is placed in aqueous solution or at ambient temperature (approximately 20°C)or oil bath with a temperature of 100°C, and determine the amount of conjugate which has been subjected to hydrolysis under these conditions. The results are shown in table 1, and they show that the conjugates will not release hydrocodone when the ambient temperature or when heated in water up to a temperature of 100°C for one hour.

Table 1
Connectionwater
ambient temperature100°C
4-OH-Bz-HC0%0%
2-Abz-HC0%0%
4-MeO-Bz-HC0%0%

In addition, samples of conjugates of hydrocodone of the present invention are compared with samples of other conjugates of hydrocodone not according to the present invention (adipate-HC) on their ability to either hydrolyzed in hydrocodone after dilution in a 1N solution of hydrochloric sour is s (HCl) for 1 hour at ambient temperature (~20°C) or at an oil bath at 100°C. The percentage indicates how much of the original conjugate is hydrolyzed under these conditions. The results are shown in table 2.

Table 2
Connection% release in 1N HCl
ambient temperature100°C
4-OH-Bz-HC0%30%
2-Abz-HC0%16%
3-OH-4-MeO-Bz-HC0%35%
2-OH-Bz-HC3%27%
adipate-HC13%100%

Samples of each conjugate is dissolved in 5%solution of NaHCO3within one hour at ambient temperature (~20°C) or at an oil bath at 100°C. the Percentage indicates how much of the original conjugate is hydrolyzed under these conditions, the results are shown in table 3 for the conjugates of the present invention and conjugates for comparison, not according to the present invention (Tyr-Tyr-Phe-Phe-Ile-hydrocodone (YYFFI-HC) or adipate-HC).

Table 3
Connection% release of 5%NaHCO3
ambient temperature100°C
4-OH-Bz-HC1%23%
3-OH-4-MeO-Bz-HC0%36%
YYFFI-HC0%70%
adipate-HC3%100%

Example 2: Oral pharmacokinetic profile of conjugated hydrocodone of the present invention

Curves pharmacokinetic profile when administered orally to determine benzoate-hydrocodone (Bz-HC), the prodrugs of the present invention, in comparison with the two conjugates are not under the present invention: YYFFI-HC and diglycolate-HC. Rats orally administered number of conjugate equivalent to 2 mg/kg of hydrocodone in the form of free base, and the plasma concentration of released hydrocodone and active metabolite, hydromorphone, over time, determined by LC-MS/MS. Ka is shown in figure 5, curves pharmacokinetic profile when administered orally for the release of hydrocodone to a certain extent similar to Bz-HC and YYFFI-HC, however, plasma concentrations of hydrocodone released from Bz-HC, mostly much higher than the concentration of hydrocodone released from diglycolate-HC (AUC and Cmaxfor Bz-HC, respectively, by approximately 40% and 50% more). In addition, Bz-HC releases a higher concentration in the plasma is more effective active metabolite, hydromorphone (figure 6)than both YYFFI-HC (AUC and Cmaxfor hydromorphone, formed from Bz-HC, respectively, 60% and 80% more) and diglycolate-HC (AUC and Cmaxfor hydromorphone, formed from Bz-HC, respectively, 55% and 180% more). The specified observation suggests that all three compounds are choosing different ways of sharing and that Bz-HC potentially has a higher ability to stop pain than any of the exemplary compounds.

Example 3: Intranasal pharmacokinetic profiles of the conjugates of hydrocodone

Conjugate of hydrocodone of the present invention have the ability to prevent the abuse, exploring the efficiency of hydrolysis when assigning routes other than oral. Rats intranasally administered conjugate in an amount equivalent to 2 mg/kg of hydrocodone in the form of free on the establishment, the concentration in plasma of rats released hydrocodone and active metabolite, hydromorphone, over time, determined by LC-MS/MS. The concentration of hydrocodone in plasma were significantly lower for Bz-HC (AUC and Cmaxfor hydromorphone released from adipate-HC, approximately 280% and 60% higher, respectively), as shown in figure 7. In addition, Bz-HC give a very low concentration of hydromorphone in plasma compared to adipate-HC (AUC and Cmaxfor hydromorphone released from adipate-HC, approximately 750% and 660% more, respectively), as shown in figure 8.

Prodrugs of the present invention provide concentration of hydrocodone and hydromorphone in plasma, which is significantly lower than the corresponding plasma concentrations for unbound hydrocodone·BT or for other classes of prodrugs, when the introduction of a route.

Example 4: Sample intravenous pharmacokinetic profiles of the conjugates according to the present invention

Conjugates of hydrocodone of the present invention are hydrophobic, e.g., Bz-HC, nicotinate-HC, 4-MeO-Bz-HC, piperonylic-HC, 4-OH-Bz-HC, salicylate-HC, 3-OH-4-MeO-Bz-HC, 3-OH-Bz-HC and gallate-HC. Therefore, these compounds cannot be used intravenously in doses equivalent oral introduction, because they do not dissolve in acceptable in practice the amount of water, because SOS is ava for injection should be completely dissolved, since any solid particle can cause an embolism. The amount of water required for dissolving the required amount of conjugate, makes injection is impossible, and thus, the composition and prodrugs of the present invention have the potential to prevent drug abuse, unlike other conjugates of hydrocodone, which are soluble in water, such as adipate-HC and diglycolate-HC, and which can be administered intravenously in doses equivalent to oral administration.

Example 5: Comparison of oral pharmacokinetic profiles of the conjugates of hydrocodone

Plasma concentrations of hydrocodone released from Bz-HC and nicotinate-HC, compared with the concentrations in plasma of hydrocodone formed from unconjugated hydrocodone·BT after oral administration to rats. Rats injected conjugated or unconjugated drug in an amount equivalent to 2 mg/kg of hydrocodone in the form of free base, and the plasma concentration of hydrocodone and hydromorphone determined by LC-MS/MS, as shown in figures 9 and 10, respectively. Plasma concentration of hydrocodone released from Bz-HC, when administered orally, increases similar concentrations of hydrocodone in plasma observed for hydrocodone·BT, until then, until it reaches the values of C max(the value of Cmaxapproximately equal for both compounds). After Tmaxthe concentration of hydrocodone in plasma for Bz-HC decreases slower and more manageable than for unconjugated hydrocodone·BT (figure 9 and figure 10). Bz-HC has a larger value AUC (AUC approximately 25% more figure 9) compared hydrocodone·BT, and similar results were observed for concentrations in plasma active metabolite, hydromorphone (figure 10).

Nicotinate-HC forms a concentration of hydrocodone and hydromorphone in plasma, which are lower than those concentrations observed for conjugated hydrocodone·BT. However, the corresponding AUC values are in the range of bioequivalence for the same dose (in terms of hydrocodone in the form of free base).

2-ABz-HC shows a different release profile after oral administration to rats than Bz-HC or unconjugated hydrocodone·BT. Rats enter the amount equivalent to 2 mg/kg of hydrocodone in the form of free base, and the plasma concentration of hydrocodone or hydromorphone over time determined by LC-MS/MS, as shown in figure 11 and figure 12, respectively. 2-ABz-HC releases hydrocodone very slowly, as evidenced by the gradual increase in plasma concentrations with subsequent gradual decrease (figure 11). This Pref is the CIO to flatten the pharmacokinetic curve compared to the curve for hydrocodone·BT (T max2-ABz-HC is approximately four times larger value, AUC and Cmaxapproximately 35% and 60% less, respectively). In General, the pharmacokinetic curve for 2-ABz-HC is also flatter than for hydrocodone·BT (figure 12), however, shows a small initial burst (AUC and Cmax2-ABz-HC by approximately 25% and 50% less, respectively).

Example 6: Determination of changes of the concentrations in plasma benzoate hydrocodone

To determine the variability in plasma concentrations of hydrocodone (HC) and hydromorphone (HM), calculate the coefficient of variation (CV) for individual animals, which lead dose benzoate hydrocodone or unconjugated hydrocodone bitartrate (BT) in an amount equivalent to 2 mg/kg of hydrocodone in the form of free base, and plasma concentrations of hydrocodone or hydromorphone over time determined by LC-MS/MS. CV values calculated by dividing the value of the standard deviation of the concentrations in plasma for individual animals on the mean concentrations in the plasma of all animals, which were injected dose, for a given time point. "The average CV" indicates the average CV for all time points, as indicated in table 4.

Table 4
ConnectionThe average value of CV
HCHM
Bz-HC4641
hydrocodone·BT7564

The smaller the average value of CV for Bz-HC shows that this prodrug has a lower relative variability in plasma concentrations of hydrocodone and hydromorphone in all animals, which were injected dose, and at all time points, compared to the unconjugated drug, hydrocodone bitartrate.

Example 7: Synthesis of conjugates of hydrocodone

Synthesis of free base benzoate hydrocodone:

To a solution of free base hydrocodone (0,596 g, 1,99 mmol) in tetrahydrofuran (25 ml) is added 1M solution of LiN(SiMe3)2in tetrahydrofuran (5,98 ml). The obtained orange suspension was stirred at ambient temperature for 30 min, then add benzoate-succinic ester (1.25 g, 5,98 mmol). The resulting mixture is left to mix overnight at ambient temperature, and after 18 h the reaction is interrupted by adding 100 ml of saturated solution of ammonium chloride, and stirred for another 2 hours. To the mixture add this is latitat (100 ml) and washed with a saturated solution of ammonium chloride (3×100 ml) and water (1×100 ml). The organic extracts dried over anhydrous MgSO4the solvent is removed and the residue is dissolved in 2-propanol (50 ml). Add water until the formation of solids. The resulting mixture is cooled, filtered and dried, obtaining the free base benzoate-hydrocodone (of 0.333 g, 0,826 mmol, yield 42%) as a solid dark brown color. The above synthesis is depicted in figure 13A.

Synthesis of succinate 2-Boc-aminobenzoic acid:

2-Boc-aminobenzoic acid (2,56 g to 10.8 mmol) and N-hydroxysuccinimide (1,37 g, 11,88 mmol) dissolved in 25 ml of THF. At once add DCC (2,45 g, 11,88 mmol). The reaction mixture was allowed to mix overnight. The solid is filtered off and washed with acetone (2×10 ml). The filtrate is evaporated to dryness and the residue is dissolved in 100 ml of acetone. The precipitate (DCU) is filtered off and the filtrate is concentrated and receiving solid, which is collected, washed with methanol (3×4 ml) and receive 3,26 g (90%) of white product.

Synthesis of ester hydrocodone with 2-Boc-aminobenzoic acid:

The hydrocodone in the form of the free base (0,449 g, 1.5 mmol), dissolved in 20 ml of anhydrous THF, add a solution of LiHMDS in THF (1M, 4.5 ml, 4.5 mmol) for 20 minutes the Mixture is stirred for 30 min, and at once add succinate 2-Boc-aminobenzoic acid (1.50 g, 4.5 mmol). The reaction mixture is stirred in ECENA 4 hours, and then terminate the reaction by adding 100 ml of a saturated solution of NH4Cl. The mixture is stirred for 1 hour and extracted with 200 ml of ethyl acetate. The ethyl acetate layer was washed with a saturated solution of NaHCO3(2×80 ml) and 5%salt solution (80 ml), dried over anhydrous Na2SO4and concentrate. The residue is purified column chromatography on silica gel (7% MeOH/CH2Cl2and receive 449 mg (58%) of an amorphous solid.

Synthesis of hydrochloric salt of ester of hydrocodone with 2-Boc-aminobenzoic acid:

Ester hydrocodone and 2-Boc-aminobenzoic acid (259 mg, 0.5 mmol) is stirred in 4 ml of 4N HCl/dioxane for 4 hours. The solvent is evaporated to dryness and to the residue add 5 ml of ethyl acetate. The solid is collected and washed with ethyl acetate, getting 207 mg (84%) of product.

Synthesis of 2-IOM-salicyl succinate:

2-IOM-salicylic acid (3.2 g, 17.6 mmol) and N-hydroxysuccinimide (2,23 g, 19,36 mmol) dissolved in 40 ml of THF. At once add DCC (3,99 g, 19,36 mmol). The reaction mixture was allowed to mix overnight. Solids filtered and washed with acetone (2×10 ml). The filtrate is concentrated, and the residue is recrystallized from 10 ml of methanol, getting 2,60 g (53%) solid white color.

Synthesis of ester of hydrocodone and 2-MOM-salicylic acid:

The hydrocodone in the form of free founded the I (0,449 g, 1.5 mmol), dissolved in 20 ml of anhydrous THF, add a solution of LiHMDS in THF (1M, 4.5 ml, 4.5 mmol) for 20 minutes the Mixture is stirred for 30 min, and at once add succinate 2-MOM-salicylic acid (1.26 g, 4.5 mmol). The reaction mixture is stirred for 4 hours, and then terminate the reaction by adding 100 ml of a saturated solution of NH4Cl. The mixture is stirred for 1 hour and extracted with 200 ml of ethyl acetate. The ethyl acetate layer was washed with a saturated solution of NaHCO3(2×80 ml) and 5%salt solution (80 ml), dried over anhydrous Na2SO4and concentrate. The residue is purified column chromatography on silica gel (8% MeOH/CH2Cl2and receive 381 mg (58%) syrup-like substance.

Synthesis of hydrochloric salt of ester of hydrocodone with salicylic acid:

To complex ether hydrocodone and 2-MOM-salicylic acid (380 mg, 0.82 mmol) in 12 ml of methanol is added 0.5 ml of concentrated HCl (12N). The reaction mixture is stirred for 6 hours. The solution is concentrated, and the residual water is removed by joint evaporation with methanol (5×5 ml). The obtained solid substance was dissolved in 1 ml of methanol, and then add 20 ml of ethyl acetate. The obtained turbid mixture is concentrated to a volume of approximately 4 ml of the Resulting solid is collected and washed with ethyl acetate, getting 152 mg (41%) of product.

Example 8: Oral headlight is cokinetics profiles of conjugated hydrocodone, hydrocodone and hydromorphone in rats

After oral administration of benzoate-hydrocodone (Bz-HC) rats receive pharmacokinetic curves for the original Bz-HC, hydrocodone, and active metabolite, hydromorphone. Rats orally administered number of conjugate equivalent to 2 mg/kg of hydrocodone in the form of free base, and the concentration in the plasma source Bz-HC released hydrocodone and active metabolite, hydromorphone, over time, determined by LC-MS/MS. As shown in figure 14, the effect of the original prodrugs Bz-HC is much smaller than the effects of hydrocodone or hydromorphone (AUC for the original Bz-HC is approximately 10% and 3% of the AUC for hydrocodone and hydromorphone, respectively).

Example 9: Oral pharmacokinetic profile of conjugated hydrocodone, hydrocodone and hydromorphone in rats

After oral administration of benzoate-hydrocodone (Bz-HC) or hydrocodone·BT dogs get the pharmacokinetic curves for the original Bz-HC (only branch Bz-HC), hydrocodone and active metabolite, hydromorphone. Dogs orally administered amount of hydrocodone·BT or conjugate equivalent to 2 mg/kg of hydrocodone in the form of free base. Plasma concentrations of the original Bz-HC released hydrocodone and active metabolite, hydromorphone, over time determine metodami-MS/MS.

Comparison of the concentrations in plasma of hydrocodone released from Bz-HC and hydrocodone·BT, shown in figure 15. In General, plasma concentrations of hydrocodone generated both compounds are very similar. Systemic effects of hydrocodone slightly lower for Bz-HC compared to hydrocodone·BT (AUC value of hydrocodone for Bz-HC is approximately 72% of the AUC for hydrocodone·BT). The value of Cmaxhydrocodone for Bz-HC is approximately 92% of the value of Cmaxfor hydrocodone·BT.

Comparison of the concentrations in plasma active metabolite, hydromorphone, after oral administration of Bz-HC or hydrocodone·BT is shown in figure 16. System action and the maximum plasma concentration of hydromorphone is similar for both compounds. The AUC values of Cmaxhydrocodone for Bz-HC approximately 103% 109% from the corresponding values for hydrocodone·BT.

Comparison of the concentrations in plasma of the original Bz-HC and hydrocodone released from Bz-HC, shown in figure 17. Similar to the results observed in rats, plasma concentrations of the source prodrugs Bz-HC have lower values compared to the plasma concentration of hydrocodone (the value of the AUC for the original Bz-HC approximately 10% less than the value of the AUC for hydrocodone).

Example 10: Intravenous pharmacokinetic profiles conjug is checked hydrocodone, hydrocodone and hydromorphone in rats

Rats injected Bz-HC (0.30 mg/kg). Due to its poor solubility in water (solubility in phosphate buffered saline solution), 0.30 mg/kg close to the maximum dose that can be entered to rats intravenously. Determine the pharmacokinetic curves for the original Bz-HC, hydrocodone, and active metabolite, hydromorphone. Plasma concentrations of the original Bz-HC released hydrocodone and active metabolite, hydromorphone, over time, determined by LC-MS/MS. The obtained pharmacokinetic curves shown in figure 18.

Example 11: an Oral pharmacokinetic profiles of hydrocodone and hydromorphone after different doses of Bz-HC rats

Bz-HC orally administered to rats with doses of 0,25; 0,50; 1,00; 2,00; 3,00 or 4,00 mg/kg, plasma Concentrations of hydrocodone or hydromorphone determined by LC-MS/MS, as indicated in figure 19 and 20, respectively. Exposure (AUC) of hydrocodone and hydromorphone doses for Bz-HC in the range of 0.25 and 4,00 mg/kg practically linear. However, the corresponding values of Cmaxmore volatile, especially for hydromorphone. Maximum plasma concentrations of hydromorphone does not significantly change for doses of Bz-HC above 2,00 mg/kg

In this description the use of the singular implies, unless otherwise specified, use the use the plural.

Composition, prodrugs and methods described in the present description, can be illustrated by the following variants of implementation of the present invention are described below in numbered paragraphs.

1. A composition comprising at least one conjugate of hydrocodone and at least one benzoic acid or a derivative of benzoic acid, its salts or combinations thereof, and at least one benzoic acid or a derivative of benzoic acid has the following formula I:

where

X, Y and Z are independently selected from the group which includes H, O, S, NH, and -(CH2)X-;

R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl;

o, p, q are independently selected from 0 or 1; and

x denotes an integer in the range from 1 to 10.

2. A composition comprising at least one conjugate of hydrocodone and at least one benzoic acid or its derivative, or combinations thereof.

3. Composition containing benzoates conjugate, where benzoate conjugate includes at least one hydrocodone conjugated with at least one benzoic acid or manufacturer who dnim benzoic acid.

4. The composition according to claim 1 wherein the at least one benzoic acid or a derivative of benzoic acid is aminobenzoate, hydroxybenzoate, aminohydroxylation, derivative or combination thereof.

5. The composition according to paragraph 4, where aminobenzoate selected from the group which includes Anthranilic acid, 3-aminobenzoic acid, 4,5-dimethylanthracene acid, N-methylanthranilic acid, N-acetylanthranilic acid, fanmovie acid (for example, tolfenamic acid, mefenamico acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA), 2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid, 2,4-diacetylbenzene acid, derivatives thereof and combinations thereof.

6. The composition according to paragraph 4, where hydroxybenzoate selected from the group which includes salicylic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 6-methylsalicylic acid, o,m,p-krestinov acid, anacardiaceae acid, 4,5-dimethylsilicone acid, o,m,p-hydroxy-parallelconvoy acid, diflunisal, o,m,p-anisic acid, 2,3-dihydrobenzoic acid (2,3-DHB), α,β,γ-resorcinol acid, protocatechuic acid, entityname acid, piperonylic acid, 3-metoxisalicilice acid, 4-metoxisalicilice acid, 5-metoxisalicilice acid, 6-m is toxicology acid, 3-hydroxy-2-methoxybenzoic acid, 4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid, vanillic acid, isovanillin acid, 5-hydroxy-3-methoxybenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratrole acid (3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, Gallic acid, 2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 3-O-metalalloy acid (3-OMGA), 4-O-metalalloy acid (4-OMGA), 3,4-O-dimethylallyl acid, lilac acid, 3,4,5-trimethoxybenzoic acid, derivatives thereof and combinations thereof.

7. The composition according to paragraph 4, where aminohydroxylation selected from the group which consists of 4-aminosalicylic acid, 3-hydroxyanthranilic acid and 3-methoxyestradiol acid, derivatives thereof and combinations thereof.

8. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is a composition intended for the treatment or prevention of diseases, which is used for the treatment of drug abuse or opioid or to prevent withdrawal of the drug.

9. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate represents is the song, designed for pain relief.

10. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is a composition that is used to relieve moderate and severe pain.

11. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate reduces or prevents the abuse of drugs that are given orally, intranasally or intravenously.

12. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate provides resistance to abuse of oral, intranasal or parenteral drugs.

13. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate shows improved rate of release over time and the value of AUC compared to unconjugated hydrocodone over the same period of time.

14. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate shows less variability oral pharmacokinetic profile compared to unconjugated hydrocodone.

15. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate has less side effects compared to unconjugated hydrocodone.

16. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate prevents malicious use of medicinal cf the of funds by physical and chemical manipulation.

17. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is prepared in the form of a dosage form selected from the group which includes: tablet, capsule, pill-shaped capsule, suppository, toffee, cake, appointed by the oral powder, a solution, oral thin-film shape, a plate, suspension and suspension.

18. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value, compared to unconjugated hydrocodone.

19. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value and the value of Cmaxcompared to an equivalent molar amount of unconjugated hydrocodone.

20. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value and a smaller value of Cmaxcompared to an equivalent molar amount of unconjugated hydrocodone.

21. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of from about 0.5 mg or more.

22. To the position on paragraph 1, 2, 3, or 4, wherein at least one conjugate is present in an amount of from about 2.5 mg or more.

23. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of from about 5 mg or more.

24. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of from about 10 mg or more.

25. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of from about 20 mg or more.

26. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of from about 50 mg or more.

27. The composition according to item 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of about 100 mg or more.

28. A method of treating a patient having a disease, disorder or condition, which requires binding of opioid or which is mediated by the binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid or a derivative of benzoic acid, its salts or combinations thereof, with benzoic acid or a derivative of benzoic acid has the formula I:

where

X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-;

R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl;

o, p, q are independently selected from 0 or 1; and

x denotes an integer in the range from 1 to 10.

29. The method according to paragraph 28, where at least one conjugate shows a smaller rate of release over time and a higher AUC value when compared to an equivalent molar amount of unconjugated hydrocodone over the same period of time.

30. The method according to paragraph 28, where at least one conjugate shows less variability oral pharmacokinetic profile compared to unconjugated hydrocodone.

31. The method according to paragraph 28, where at least one conjugate has less side effects compared to unconjugated hydrocodone.

32. The method according to paragraph 28, where at least one conjugate is prepared in the form of a dosage form selected from the group which includes: tablet, capsule, pill-shaped capsule, suppository, toffee, cake, appointed by the oral powder, a solution, oral thin-film form, the layer of the GCC, suspension and suspension.

33. The method according to paragraph 28, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value, compared to unconjugated hydrocodone.

34. The method according to paragraph 28, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value and the value of Cmaxcompared to an equivalent molar amount of unconjugated hydrocodone.

35. The method according to paragraph 28, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value and a smaller value of Cmaxcompared to an equivalent molar amount of unconjugated hydrocodone.

36. The method according to paragraph 28, where at least one conjugate is present in an amount of from about 0.5 mg or more.

37. The method according to paragraph 28, where at least one conjugate is present in an amount of from about 2.5 mg or more.

38. The method according to paragraph 28, where at least one conjugate is present in an amount of from about 5 mg or more.

39. The method according to paragraph 28, where at least one conjugate is present in an amount of from about 10 mg or more.

40. The method according to paragraph 28, where at the ore one conjugate is present in an amount of from about 20 mg or more.

41. The method according to paragraph 28, where at least one conjugate is present in an amount of from about 50 mg or more.

42. The method according to paragraph 28, where at least one conjugate is present in an amount of about 100 mg or more.

43. The method according to paragraph 28, where at least one conjugate reversibly binds to the opioid receptors of the patient.

44. The method according to paragraph 28, where at least one conjugate reversibly binds to the opioid receptors of the patient, without negative effects on the Central nervous system.

45. The method according to paragraph 28, where at least one conjugate prevents or reduces at least one causing constipation side effect of unconjugated hydrocodone.

46. The method according to paragraph 28, where at least one conjugate reduces or prevents causing constipation side effects compared to unconjugated hydrocodone.

47. The method according to paragraph 28, where at least one conjugate binds irreversibly to receptors in the opioid the patient.

48. The method according to paragraph 28, where at least one conjugate binds irreversibly to receptors in the opioid the patient, without negative effects on the Central nervous system.

49. A method of treating a patient having a disease, disorder or condition that requires inhibition of binding of opioid or that TNA is raduetsa inhibition of binding of the opioid from the opioid receptors of the patient, includes oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid or a derivative of benzoic acid, its salts or combinations thereof, with benzoic acid or a derivative of benzoic acid has the formula I:

where

X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-;

R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl;

o, p, q are independently selected from 0 or 1; and

x denotes an integer in the range from 1 to 10.

50. The method according to paragraph 49, where at least one conjugate reversibly inhibits the binding of an opioid to the opioid receptors of the patient.

51. The method according to paragraph 49, where at least one conjugate reversibly inhibits the binding of an opioid to the opioid receptors of the patient, without negative effects on the Central nervous system.

52. The method according to paragraph 49, where at least one conjugate prevents or reduces at least one causing constipation side effect of the hydrocodone.

53. A method of treating a patient having a disease is s, disorder or condition, which requires binding of opioid or which is mediated by the binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid, its salts, its derivative, or combinations thereof.

54. The method according to item 53, where at least one conjugate shows a smaller rate of release over time and a higher AUC value when compared to an equivalent molar amount of unconjugated hydrocodone over the same period of time.

55. The method according to item 53, where at least one conjugate shows less variability oral pharmacokinetic profile as compared to hydrocodone.

56. The method according to item 53, where at least one conjugate has fewer side effects compared with the hydrocodone.

57. The method according to item 53, where at least one conjugate is prepared in the form of a dosage form selected from the group which includes: tablet, capsule, pill-shaped capsule, suppository, toffee, cake, appointed by the oral powder, a solution, oral thin-film shape, a plate, suspension and suspension.

58. The method according to item 53, where at least one conjug the t assign a number, enough to get a therapeutically bioequivalent AUC value, compared with the hydrocodone.

59. The method according to item 53, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value and the value of Cmaxcompared with the hydrocodone.

60. The method according to item 53, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value, as compared to hydrocodone, with the smaller value of Cmax.

61. The method according to item 53, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value, as compared to hydrocodone, but is not equivalent to the value of Cmax.

62. The method according to item 53, where at least one conjugate is present in an amount of from about 0.5 mg or more

63. The method according to item 53, where at least one conjugate is present in an amount of from about 2.5 mg or more

64. The method according to item 53, where at least one conjugate is present in an amount of from about 5 mg or more.

65. The method according to item 53, where at least one conjugate is present in an amount of from about 10 mg or more.

66. The way the paragraph is paragraph 53, where at least one conjugate is present in an amount of from about 20 mg or more.

67. The method according to item 53, where at least one conjugate is present in an amount of from about 50 mg or more.

68. The method according to item 53, where at least one conjugate is present in an amount of about 100 mg or more.

69. The method according to item 53, where at least one conjugate reversibly binds to the opioid receptors of the patient.

70. The method according to item 53, where at least one conjugate reversibly binds to the opioid receptors of the patient, without negative effects on the Central nervous system.

71. The method according to item 53, where at least one conjugate prevents or reduces at least one causing constipation side effect of the hydrocodone.

72. The method according to item 53, where at least one conjugate reduces or prevents causing constipation side effects.

73. The method according to item 53, where at least one long conjugate binds to the opioid receptors of the patient.

74. The method according to item 53, where at least one long conjugate binds to the opioid receptors of the patient, without negative effects on the Central nervous system.

75. A method of treating a patient having a disease, disorder or condition that requires inhibi the Finance associate opioid or which is mediated by inhibition of binding of an opioid to the opioid receptors of the patient, includes oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid, its salts, its derivative, or combinations thereof.

76. The method according to item 75, where at least one conjugate reversibly inhibits the binding of an opioid to the opioid receptors of the patient.

77. The method according to item 75, where at least one conjugate reversibly inhibits the binding of an opioid to the opioid receptors of the patient, without negative effects on the Central nervous system.

78. The method according to item 75, where at least one conjugate prevents or reduces at least one causing constipation side effect of the hydrocodone.

79. The pharmaceutical kit of reagents, including:

a certain amount of individual doses in a package that contain a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid or a derivative of benzoic acid, its salts or combinations thereof, with benzoic acid or a derivative of benzoic acid has the formula I:

where

X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-;

R1, R2and R3independently selected from the group which includes the t H alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl;

o, p, q are independently selected from 0 or 1; and

x denotes an integer in the range from 1 to 10.

80. The reagent kit according to item 79, where a specified set further includes:

(ii) instructions for using a specified set of reagents in the method of treatment or prevention of withdrawal symptoms drugs or pain relief the patient-the person or patient is an animal.

81. The reagent kit according to item 80, where the specified patient is patient is a child.

82. The reagent kit according to item 80, where the specified patient is an elderly patient.

83. The reagent kit according to item 80, where the specified patient is a regular patient.

84. The pharmaceutical kit of reagents, including:

a certain amount of individual doses in a package that contain a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid, its salts, its derivative, or combinations thereof.

85. The reagent kit according to paragraph 84, where the specified set further includes:

(ii) instructions for using a specified set of reagents in the method of treatment or prevention of symptoms mark the HN drugs or pain relief the patient-the person or patient is an animal.

86. The reagent kit according to item 85, where the specified patient is patient is a child.

87. The reagent kit according to item 85, where the specified patient is an elderly patient.

88. The reagent kit according to item 85, where the specified patient is a regular patient.

89. The reagent kit according to item 79, 80, 84 or 85, where the specified individual dose contains at least about 0.5 mg or more of at least one conjugate.

90. The reagent kit according to item 79, 80, 84 or 85, where the specified individual dose contains at least about 2.5 mg or more of at least one conjugate.

91. The reagent kit according to item 79, 80, 84 or 85, where the specified individual dose contains at least about 5.0 mg or more of at least one conjugate.

92. The reagent kit according to item 79, 80, 84 or 85, where the specified individual dose contains at least about 10 mg or more of at least one conjugate.

93. The reagent kit according to item 79, 80, 84 or 85, where the specified individual dose contains at least about 20 mg or more of at least one conjugate.

94. The reagent kit according to item 79, 80, 84 or 85, where these individual dosage containing at least about 50 mg or more of at least one conjugate.

95. The reagent kit according to item 79, 80, 84 or 85, where these individual dosage containing at least about 100 mg or more of at least one conjugate.

96. The reagent kit according to item 79, 80, 84 or 85, where the specified reagent kit contains from about 1 to about 60 individual dosages.

97. The reagent kit according to item 79, 80, 84 or 85, where the specified reagent kit contains from about 10 to about 30 individual dosages.

98. A composition comprising at least one conjugate of hydrocodone and at least one heteroarylboronic acid, its derivative, or combinations thereof.

99. The composition of paragraph 98, where at least one heteroarylboronic acid selected from formula II, formula III and formula IV, where formula II, formula III or formula IV have the following structure:

where

X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-;

R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl;

o, p, q are independently selected from 0 or 1; and

x denotes an integer in the range from 1 to 10.

100. The composition is tereasa at least one conjugate of hydrocodone and at least one nicotinic acid, its derivative, or combinations thereof.

101. The composition of paragraph 98, where at least one heteroarylboronic acid is a derivative of pyridine.

102. The composition of paragraph 98, where heteroarylboronic acid selected from the group which includes isonicotinoyl acid, Pikalyovo acid, 3-gidroksipropilovu acid, 6-hydroxynicotinic acid, carsinoma acid, 2,6-dihydroxyacetone acid, kynurenine acid, xanthurenate acid, 6-hydroxykynurenine acid, 8-methoxykynuramine acid, 7,8-dihydroxyquinoline acid, 7,8-dihydro-7,8-dihydroxyquinoline acid derivatives thereof, and combinations thereof.

103. The composition of paragraph 98, 99 or 100, where at least one conjugate is used in the treatment of abuse of drugs, narcotics, or opioids or to prevent withdrawal of the drug.

104. The composition of paragraph 98, 99 or 100, where at least one conjugate is used for pain relief.

105. The composition of paragraph 98, 99 or 100, where at least one conjugate is used to relieve moderate or severe pain.

106. The composition of paragraph 98, 99 or 100, where at least one conjugate reduces or prevents the abuse of oral, intranasal or intravenous drugs.

107. To the position on paragraph 98, 99 or 100, where at least one conjugate gives resistance to abuse of oral, intranasal or intravenous drugs.

108. The composition of paragraph 98, 99 or 100, where at least one conjugate prevents malicious use of medicines by both physical and chemical manipulation.

109. The composition of paragraph 98, 99 or 100, where at least one conjugate shows improved rate of release over time and the value of the AUC as compared to hydrocodone over the same period of time.

110. The composition of paragraph 98, 99 or 100, where at least one conjugate shows less variability oral pharmacokinetic profile compared to an equivalent molar amount of the hydrocodone.

111. The composition of paragraph 98, 99 or 100, where at least one conjugate has fewer side effects compared with the hydrocodone.

112. The composition of paragraph 98, 99 or 100, where the specified composition is prepared in the form of a dosage form selected from the group which includes: tablet, capsule, pill-shaped capsule, suppository, toffee, cake, appointed by the oral powder, a solution, oral thin-film shape, a plate, suspension and suspension.

113. The composition of paragraph 98, 99 or 100, where m is Nisha least one conjugate is administered in the amount enough to get a therapeutically bioequivalent AUC value, when compared to an equivalent molar amount of the unconjugated hydrocodone.

114. The composition of paragraph 98, 99 or 100, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value and the value of Cmaxcompared with the hydrocodone.

115. The composition of paragraph 98, 99 or 100, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value, as compared to hydrocodone, with the smaller value of Cmax.

116. The composition of paragraph 98, 99 or 100, where at least one conjugate is present in an amount of from about 0.5 mg or more.

117. The composition of paragraph 98, 99 or 100, where at least one conjugate is present in an amount of from about 2.5 mg or more.

118. The composition of paragraph 98, 99 or 100, where at least one conjugate is present in an amount of from about 5 mg or more.

119. The composition of paragraph 98, 99 or 100, where at least one conjugate is present in an amount of from about 10 mg or more.

120. The composition of paragraph 98, 99 or 100, where at least one conjugate is present in an amount of from about 20 the g or more.

121. The composition of paragraph 98, 99 or 100, where at least one conjugate is present in an amount of from about 50 mg or more.

122. The composition of paragraph 98, 99 or 100, where at least one conjugate is present in an amount of about 100 mg or more.

123. A method of treating a patient having a disease, disorder or condition, which requires binding of opioid or which is mediated by the binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one heteroarylboronic acid.

124. The method according to item 123, where at least one heteroarylboronic acid selected from formula II, formula III and formula IV, where formula II, formula III or formula IV have the following structure:

where

X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-;

R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl;

o, p, q are independently selected from 0 or 1; and

x denotes an integer in the range from 1 to 10.

125. A method of treating a patient having a disease, disorder or condition, which requires binding of opioid or which is mediated by the binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one nicotinic acid, its derivative, or combinations thereof.

126. The method according to item 123, 124 or 125, where at least one conjugate shows improved rate of release over time and the value of the AUC as compared to hydrocodone over the same period of time.

127. The method according to item 123, 124 or 125, where at least one conjugate shows less variability oral pharmacokinetic profile as compared to hydrocodone.

128. The method according to item 123, 124 or 125, where at least one conjugate has fewer side effects compared with the hydrocodone.

129. The method according to item 123, 124 or 125, where the specified composition is prepared in the form of a dosage form selected from the group which includes: tablet, capsule, pill-shaped capsule, suppository, toffee, cake, appointed by the oral powder, a solution, oral thin-film shape, a plate, suspension and suspension.

130. The method according to item 123, 124, or 12, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value, when compared to an equivalent molar amount of unconjugated hydrocodone.

131. The method according to item 123, 124 or 125, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value and the value of Cmaxcompared to an equivalent molar amount of unconjugated hydrocodone.

132. The method according to item 123, 124 or 125, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value and a smaller value of Cmaxcompared to an equivalent molar amount of unconjugated hydrocodone.

133. The method according to item 123, 124 or 125, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value, as compared to hydrocodone, but is not equivalent to the value of Cmax.

134. The method according to item 123, 124 or 125, where at least one conjugate is present in an amount of from about 0.5 mg or more.

135. The method according to item 123, 124 or 125, where at least one conjugate is present in an amount of from about 2.5 mg or more.

136. The method according to item 123, 124 or 125, where at least one conjugate is present in an amount of from about 5 mg or more.

137. The composition according to item 123, 124 or 125, where at least one conjugate is present in an amount of from about 10 mg or more.

138. The method according to item 123, 124 or 125, where at least one conjugate is present in an amount of from about 20 mg or more.

139. The method according to item 123, 124 or 125, where at least one conjugate is present in an amount of from about 50 mg or more.

140. The method according to item 123, 124 or 125, where at least one conjugate is present in an amount of about 100 mg or more.

141. The method according to item 123, 124 or 125, where at least one conjugate reversibly binds to the opioid receptors of the patient.

142. The method according to item 123, 124 or 125, where at least one conjugate reversibly binds to the opioid receptors of the patient, without negative effects on the Central nervous system.

143. The method according to item 123, 124 or 125, where at least one conjugate prevents side effect or reduces at least one side effect of the hydrocodone, which causes constipation.

144. The method according to item 123, 124 or 125, where at least one conjugate reduces or prevents causing constipation effects.

145. The way the paragraph is paragraph 123, 124 or 125, where at least one long conjugate binds to the opioid receptors of the patient.

146. The method according to item 123, 124 or 125, where at least one long conjugate binds to the opioid receptors of the patient, without negative effects on the Central nervous system.

147. A method of treating a patient having a disease, disorder or condition that requires inhibition of binding of opioid or which is mediated by inhibition of binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one heteroarylboronic acid.

148. The method according to paragraph 147, where at least one heteroarylboronic acid selected from formula II, formula III and formula IV, where formula II, formula III or formula IV have the following structure:

where

X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-;

R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl;

o, p, q are independently selected from 0 or 1; and

<> x denotes an integer in the range from 1 to 10.

149. A method of treating a patient having a disease, disorder or condition that requires inhibition of binding of opioid or which is mediated by inhibition of binding of an opioid to the opioid receptors of the patient, including oral administration of the indicated patient pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one nicotinic acid, its derivative, or combinations thereof.

150. The method according to paragraph 147, 148 or 149, where at least one conjugate reversibly inhibits the binding of an opioid to the opioid receptors of the patient.

151. The method according to paragraph 147, 148 or 149, where at least one conjugate reversibly inhibits the binding of an opioid to the opioid receptors of the patient, without negative effects on the Central nervous system.

152. The method according to paragraph 147, 148 or 149, where at least one conjugate prevents or reduces at least one causing constipation side effect of the hydrocodone.

153. The pharmaceutical kit of reagents, including:

a certain amount of individual doses in a package that contain a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one heteroarylboronic acid, its derivative or their combination : the tion, where at least one heteroarylboronic acid selected from formula II, formula III and formula IV, where formula II, formula III or formula IV have the following structure:

where

X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-;

R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl;

o, p, q are independently selected from 0 or 1; and

x denotes an integer in the range from 1 to 10.

154. The reagent kit according to paragraph 153, where the specified set further includes:

(ii) instructions for using a specified set of reagents in the method of treatment or prevention of withdrawal symptoms drugs or pain relief the patient-the person or patient is an animal.

155. The reagent kit according to paragraph 154, where the specified patient is patient is a child.

156. The reagent kit according to paragraph 154, where the specified patient is an elderly patient.

157. The reagent kit according to paragraph 154, where the specified patient is a regular patient.

158. The reagent kit according to paragraph 153 or 154, where the specified individual dose contains at least about 0.5 mg or Bo is the more of at least one conjugate.

159. The reagent kit according to paragraph 153 or 154, where the specified individual dose contains at least about 2.5 mg or more of at least one conjugate.

160. The reagent kit according to paragraph 153 or 154, where the specified individual dose contains at least about 5.0 mg or more of at least one conjugate.

161. The reagent kit according to paragraph 153 or 154, where the specified individual dose contains at least about 10 mg or more of at least one conjugate.

162. The reagent kit according to paragraph 153 or 154, where the specified individual dose contains at least about 20 mg or more of at least one conjugate.

163. The reagent kit according to paragraph 153 or 154, where the specified individual dose contains at least about 50 mg or more of at least one conjugate.

164. The reagent kit according to paragraph 153 or 154, where these individual dosage containing at least about 100 mg or more of at least one conjugate.

165. The reagent kit according to paragraph 153 or 154, where the specified reagent kit contains from about 1 to about 60 individual dosages.

166. The reagent kit according to paragraph 153 or 154, where the specified reagent kit contains from about 10 to about 30 indie is idealny dosages.

167. A prodrug comprising at least one conjugate of hydrocodone and at least one benzoic acid or a derivative of benzoic acid, its salts or combinations thereof, with benzoic acid or a derivative of benzoic acid has the following formula I:

where

X, Y and Z are independently selected from the group which includes H, O, S, NH, and -(CH2)X-;

R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl;

o, p, q are independently selected from 0 or 1; and

x denotes an integer in the range from 1 to 10.

168. A prodrug comprising at least one conjugate of hydrocodone and at least one benzoic acid, its derivative, or combinations thereof.

169. A prodrug comprising benzoate conjugate, where benzoate conjugate represents at least one hydrocodone conjugated with at least one benzoic acid or a derivative of benzoic acid.

170. A prodrug comprising at least one conjugate of hydrocodone and at least one heteroarylboronic acid, its derivative, or combinations thereof.

171. The prodrug according pun is the 170, where heteroarylboronic acid selected from formula II, formula III and formula IV, where formula II, formula III or formula IV have the following structure:

where

X, Y and Z are independently selected from the group including H, O, S, NH, and -(CH2)X-;

R1, R2and R3independently selected from the group which comprises H, alkyl, alkoxy, aryl, alkenyl, quinil, halogen atom, halogen-substituted alkyl, alkylaryl, arylalkyl, heterocycle, Allakaket, cycloalkyl, cycloalkenyl and cycloalkenyl;

o, p, q are independently selected from 0 or 1; and

x denotes an integer in the range from 1 to 10.

172. A prodrug comprising at least one conjugate of hydrocodone and at least one nicotinic acid, its derivative, or combinations thereof.

173. The prodrug according to paragraph 167, where a derivative of benzoic acid is aminobenzoate, hydroxybenzoate, aminohydroxylation, derivative or combination thereof.

174. The composition according to item 1 or 2, where at least one conjugate shows less variability intranasal pharmacokinetic profiles compared to unconjugated hydrocodone.

175. The composition according to item 1 or 2, where at least one conjugate, shows less variability parenteral pharmacokinetic profiles compared with unconjugated hydroco the hold.

176. The composition according to item 1 or 2, where at least one conjugate shows less variability intravenous pharmacokinetic profiles compared to unconjugated hydrocodone.

Described in this description of the invention considered in such a comprehensive, clear, concise and exact terms as to enable any person skilled in the art to carry out the present invention. It should be understood that the above preferred embodiments of the present invention and that they can be amended, which do not contradict the essence of the invention and are included in the scope of the present invention, as indicated in the following claims.

1. Pharmaceutical composition for treatment or prevention of abuse of the drug, withdrawal symptoms medicines or for pain relief, containing the conjugate and a biologically acceptable carrier, where the conjugate is a benzoate-hydrocodone, having the structure:

2. The composition according to claim 1, where the conjugate is used for the treatment of drug abuse or opioids; to prevent withdrawal of the drug or opioid; to relieve moderate or severe pain; to reduce or prevent drug abuse among the regular, which is given orally, intranasally or intravenously; or to impart resistance to abuse drugs that are given orally, intranasally or parenterally.

3. The composition according to claim 1, where the conjugate gives improved the AUC value and the best rate of release over time compared to unconjugated hydrocodone over the same period of time;
it shows less variability oral pharmacokinetic profile compared to unconjugated hydrocodone; or produces fewer side effects compared to unconjugated hydrocodone.

4. The composition according to claim 1, where the conjugate is prepared in the form of a dosage form selected from the group comprising: a tablet, a capsule, a pill in the form of a capsule, a suppository, toffee, cake, appointed by the oral powder, a solution, oral thin-film shape, a plate, suspension and suspension.

5. The composition according to claim 1, where the conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value, compared to unconjugated hydrocodone.

6. The composition according to claim 1, where the conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value and the value of Cmaxcompared to an equivalent molar amount of nekonya the new hydrocodone.

7. The composition according to claim 1, where at least one conjugate is administered in a quantity sufficient to obtain a therapeutically bioequivalent AUC value and a smaller value of Cmaxcompared to an equivalent molar amount of unconjugated hydrocodone.

8. The use of the pharmaceutical composition according to claim 1 for obtaining a medicinal product for the treatment of a patient having a disease, disorder or condition mediated by binding of an opioid to the opioid receptors of the patient.

9. The use of claim 8, where the conjugate reversibly binds to receptors in the opioid specified patient.

10. The use of claim 8, where the conjugate reversibly binds to receptors in the opioid specified patient, without negative effects on the Central nervous system.



 

Same patents:

The invention relates to organic chemistry and can find application in medicine

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention declares a compound of structural formula (I) or its pharmaceutically acceptable salt, solvate or hydrate wherein: X is phenol opiate wherein a hydrogen atom of a hydroxyl phenol group of substituted by a covalent bond with -C(O)-Y-(C(R1)(R2))n-N-C(R3)(R4);Y is -NR5-, R5 is (C1-6)alkyl; n is equal to 2 or 3, each of R1 and R2 is independently hydrogen, alkyl or substituted alkyl; R3 is hydrogen or methyl; R4 is a residue of L-amino acid or a residue of their N-acyl derivatives, as well as Hydromorphone 3-(N-methyl-N-(2-N'-acetylarginine amino)ethyl carbamate, or their pharmaceutically acceptable salt. What is also specified is a method for preparing the compound of formula (I) or its pharmaceutically acceptable salt.

EFFECT: what is declared is a pharmaceutical composition controlling phenol opiate release and a method of pain management in a patient in need thereof involving the introduction of an effective amount of the composition.

19 cl, 20 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly a method for making the oxymorphone derivative naltrexone being an opiate antagonist by naltrexone processing by diazomethane in the presence of palladium acetate.

EFFECT: method eliminates using hardly accessible and expensive parent compounds, and it is characterised by ease of implementation.

3 ex

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

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: chemistry.

SUBSTANCE: invention relates to substituted benzamides, which can be applied as antagonists of sphingonsine-1-phosphate receptors.

EFFECT: compounds are useful in treatment of wide series of disorders, associated with modulation of sphingonsine-1-phosphate receptors.

9 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry and represents a preparation possessing the anti-inflammatory action, stimulating the mucosa regeneration, and containing magnesium-chloride mineral bischofit brine 1.27±0.01 g/ml with normalised specific gravity, slastiline, menthol, thymol, and a stabilising agent differing by the fact that it contains magnesium-chloride mineral bischofit brine free from technogenic impurities, with the ingredients in the preparation are taken in specific proportions, g.

EFFECT: reducing acute daily oral toxicity in 1,7-1,9 times.

1 tbl

Jnk inhibitors // 2504545

FIELD: biotechnologies.

SUBSTANCE: in formula

each of R1 and R2 independently represents H or C1-6alkyl; or R1 and R2 together form C3-6cycloalkyl circle, which is optionally replaced with one or more R2'; R2' represents C1-6alkyl, hydroxy group, halogen, amino group, C1-6alkoxy group, C1-6hydroxyalkyl or C1-6haloalkyl; R3 represents H or N(R4)(R5); R4 represents H, C1-6alkyl or C(=O)OR4'; R4' and R5 represents H or C1-6alkyl; represents H or C1-6alkyl; or R2 and R3 together form 5-membered heterocycle containing 1 atom of N in the amount of heteroatom, which is optionally replaced with one or more R2'; Q represents CH or N; Z1 represents (CH2)u; u and v mean 1; Z2 represents (CH2)v; m, n, p, r, q mean 0; Y1 represents CH(Y1'); Y1' represents H or C1-6alkyl; Y2 represents H or represents C1-6alkyl. Invention also refers to compounds of structural formulae (II), (IV) and to pharmaceutical composition containing the above compounds.

EFFECT: improving inhibiting activity in relation to JNK kinase.

10 cl, 4 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to derivatives of oxazolopyrimidine in any of their stereoisomeric forms, or in the form of a mixture of stereoisomeric forms specified in Claim 1.

EFFECT: oxazolopyrimidine derivatives having agonistic activity in relation to Edg-1 receptor.

5 tbl, 319 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of novel pyrrolopyrazine derivatives of formula , where variables Q and R are as defined in the claim, which inhibit JAK and SYK.

EFFECT: high effectiveness when treating autoimmune and inflammatory diseases.

11 cl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to 7-benzoyl-8-hydroxy-6-phenyl-9-(3-phenyl-2-quinoxalinyl)-10H-pyrido[1,2-a]quinoxalin-10-one of formula (1)

EFFECT: obtaining a novel compound which can be used in medicine as a drug having analgesic activity.

3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphonamide derivatives of general formula:

where m equals 0, 1 or 2; n equals 1 or 2; o equals 0, 1 or 2; p equals 0, 1 or 2; q equals 0, 1, 2 or 3; r equals 0, 1 or 2, under the condition that q+r is not greater than 3; v equals 0 or 1; w equals 0 or 1; under the condition that if v equals 0, then w equals 0; An- denotes a halide anion; Q denotes a single bond, -O- or -CH2-; R1 denotes aryl; R2 and R3 have values given in (i) or (ii): (i) R2 denotes H, C1-6-alkyl, C3-8-cycloalkyl, a bicyclic 8-12-member carbocyclyl, CH(aryl)2 or aryl; or denotes a heteroaryl bonded through a C1-6-alkylene group, the heteroaryl being selected from pyridinyl; R3 denotes H, C1-6-alkyl or aryl; or (ii) R2 and R3, together with the -N-(CH-)- group bonding them, form a heterocycle which can be annelated with an aryl residue, where the heterocycle is 6-membered, saturated or at least monounsaturated but not aromatic, and together with the N heteroatom to which the residue R2 is bonded, can contain at least another O heteroatom; R4 denotes aryl or heteroaryl, selected from pyridinyl; R5 and R6 independently denote H or C1-6-alkyl, wherein R5 and R6 do not simultaneously denote H; or R5 and R6 together denote a substituted or unsubstituted 5- or 6-member heteroaryl which, together with an N atom to which R5 and R6 are bonded, can contain at least another N heteroatom; or R5 and R6 together denote a group selected from -(CH2)d- or -(CH2)e-X-(CH2)f, where d denotes 2, 3, 4, 5 or 6 and e and f are independently equal to 1, 2 or 3, under the condition that e+f is not greater than 5; and X denotes NR12, where R12 denotes H or C1-6-alkyl; R20 denotes C1-6-alkyl; and where said aryl and heteroaryl residues in case can be unsubstituted or monosubustituted or multi-substituted with the same or different residues selected from a group comprising F, Cl, Br, I, O-C1-6-alkyl, CF3 and C1-6-alkyl; and said C1-6-alkyl residues in each case can be branched or straight; in form of a separate enantiomer or separate diastereomer, racemate, enantiomers, diastereomers, mixtures of enantiomers and/or diastereomers, and in each case in form of bases and/or physiologically compatible salts thereof. The invention also relates to a method of producing the described compound, a drug having antagonistic action on B1R, based on compounds of formula I and use of said compound to produce a drug.

EFFECT: novel compounds which can be used in medicine are obtained and described.

15 cl, 131 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula

and a compound of general formula

,

where W is chlorine or fluorine, R1 is phenyl, optionally substituted with one or more halogen substitutes; and R4 is C1-C6alkyl, or pharmaceutically acceptable salts of said compounds. The invention also relates to a method of producing a compound of formula (II), use of compounds I and II to produce a drub for treating or preventing diseases such as asthma, allergic rhinitis and atopic dermatitis. Also described is a method of treating said diseases, as well as a pharmaceutical composition used to treat allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

EFFECT: novel compounds which can be used in treating allergic diseases such as asthma, allergic rhinitis and atopic dermatitis are obtained and described.

15 cl, 6 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to biologically active substances which are (Z)-2-[(3-carbamoyl-4,5,6,7-tetrahydrobenzo [b]thien-2-yl)amino]-4-(4-R-phenyl)-4-oxobut-2-enoic acids of general formula (1-3) . The acids (1-3) are obtained by reacting 4-(4-R-phenyl)-2,4-dioxobutanoic acid with an amide of 2-amino-4,5,6,7-tetrahydro[b]thiophene-3-carboxylic acid in a medium of ethyl alcohol at 60°C, followed by extraction of the end product using existing methods.

EFFECT: obtaining novel compounds with high output, having marked analgesic activity and low toxicity.

1 tbl, 4 ex

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