Controlled release of phenol opiate

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

 

The present invention claims the benefit of provisional patent application US No. 60/809082, registered on may 26, 2006, and provisional patent application US No. 60/901795, registered on February 16, 2007, the contents of which are incorporated here in full.

The technical field to which the invention relates.

The present invention relates to controlled release of phenolic opioids. More specifically it relates to a method of providing patients a controlled release of phenolic opiates using prodrugs with a certain Deputy phenolic hydrogen atom, phenol prodrugs of opioids and to pharmaceutical compositions comprising prodrugs.

The level of technology

Delivery systems are often important for the safe introduction of active agents such as drugs. Often, the delivery system can optimize bioavailability, improve the reproducibility of the dose and to improve the contact of the patient (for example, by reducing the frequency of doses). Solving problems of drug delivery and/or bioavailability of the pharmaceutical developments include the transformation of known drugs to prodrugs. Usually in the molecule prodrugs of the polar functional group of the active agent (e.g., carboxylic acid, amino group, phenol is the Rupp, sulfhydryl group, etc.) mask special group (progroups), labile under physiological conditions. Accordingly, prodrugs usually transferred through hydrophobic biological barriers such as membranes, and may have superior physical and chemical properties compared to the original drug. Prodrugs are typically non-toxic and ideally selectively broken down by the action of medicines. Preferably, the separation of progroup occurs rapidly and quantitatively with the formation of toxic by-products (for example, the hydrolyzed progroup).

Prodrugs, as described above, can provide patients with safe and effective treatment, if patients follow the instructions of the attending physician. Unfortunately, patients do not always follow the instructions that they receive. They may accidentally take an increased dose of the prodrug or intentionally abuse them, for example by receiving high doses by injection or inhalation, or through the application of readily available chemicals from household (for example, vinegar or baking soda) to get the active drug from the prodrug. The abuse is of particular importance in the case of prodrugs (predecessors) of opiates, which, when properly used used for the treatment of pain.

Antipatriot in prodrug opiate, which would have built-in control, so that it was difficult to apply the prodrug is not the purpose for which it is intended.

Disclosure of inventions

Now found a way to create this configuration, prodrugs phenolic opiate that provides controlled release of drugs.

Phenolic opiates form a subgroup of opiates and include commonly prescribed medication hydromorphone, Oxymorphone, and morphine.

In one aspect the present invention provides a method of providing patient phenolic opiate-activated after administration and controlled release, including the introduction of said patient corresponding compounds in which the phenolic hydrogen atom is substituted by dividing the outgoing group bearing a nucleophilic nitrogen, which is protected enzyme-otdalennym link configuration separating the waste group and the nucleophilic nitrogen such that enzymatic cleavage tsepliaeva part of nucleophilic nitrogen may form a cyclic urea, carbamate or THIOCARBAMATE, freeing up the connection from the separation of the departing group that provides the patient with controlled release of the phenolic opiate.

In another aspect the present invention provides a receiving medicines to provide is Alenia patient phenolic opiate, activated after administration and controlled release, where the active substance is the corresponding compound in which the phenolic hydrogen atom is substituted by dividing the outgoing group bearing a nucleophilic nitrogen, which is protected enzyme-otdalennym link configuration separating the waste group and the nucleophilic nitrogen such that enzymatic cleavage tsepliaeva part of nucleophilic nitrogen may form a cyclic urea, carbamate or THIOCARBAMATE, freeing up the connection from the separation of the departing group that provides the patient with controlled release of the phenolic opiate.

The corresponding compound (prodrug according to the present invention provides activated after the introduction of controlled release phenolic opiate, because it requires enzymatic cleavage to start releasing compounds and because the rate of release of the opiate dependent on the rate of enzymatic degradation and reaction rate of the cyclization. Accordingly, the prodrug has a reduced susceptibility to accidental overdose or abuse, whether through intentional overdose, introduction whether an inappropriate way, such as by injection, or by chemical modification using easy is available in the household chemicals. The prodrug is arranged so that it will not lead to excessively high concentrations in plasma active drug, if it is used incorrectly, and it is not easy to be decomposed to produce active substances other way in addition to enzymatic cleavage.

The enzyme is able to split enzymatic-detachable part of the molecule, can be peptidases, when enzyme-tsepliaeva part is connected with the nucleophilic nitrogen through amide bond (e.g., a peptide bond-NHCO-). In some implementations, the enzyme is a digestive enzyme, such as pepsin, trypsin, chymotrypsin, colipase, elastases, aminopeptidase N, aminopeptidase And, dipeptidylpeptidase IV, tripeptides or by enteropeptidase. Accordingly, in one implementation of the method corresponding compound administered to the patient orally.

Enzymatic-tsepliaeva part that is associated with the nucleophilic nitrogen through amide bond may be, for example, amino acid residue, or a peptide, or (α)N-acyl derivatives of amino acids or peptide (for example, N-acyl derivatives of pharmaceutically acceptable carboxylic acid, for example, N-acetyl derivative.). The peptide may contain, for example, up to 10 amino acid residues. For example, it may be a dipeptide or Tripeptide. Each amino acid can be preimushestvenno natural D - or L-amino acid (for example, L-amino acid). Examples of naturally occurring amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine, lysine and valine. Accordingly, examples of enzyme-tseplyaesh links include the remains of L-amino acids listed above, and their N-acetyl derivatives and dipeptides or tripeptides formed from two or three L-amino acids and their N-acetyl derivatives.

A cyclic group that is formed by the release of phenolic opiate, is pharmaceutically acceptable, in particular pharmaceutically acceptable cyclic urea, carbamate or THIOCARBAMATE. It is clear that cyclic urea, in particular, are very stable and have low toxicity.

In one particular implementation of the invention the separation of departing the group, bearing nucleophile that is protected otdalennym link is a group of the formula-C(O)-N(CH3)-(CH2)2-NH(R4), where R4is enzyme-otdalennym link associated with the NH group through an amide bond. When N-R4the amide bond is cleaved enzymatically, nucleophilic nitrogen (-NH2) is released and enters the cyclization reaction with carbonyl g is uppoi, forming a cyclic urea and releasing phenolic opiate.

Basically, dividing the group can be any group capable of forming a cyclic urea, carbamate or THIOCARBAMATE when phenolic opiate displaced by a nucleophilic nitrogen. Accordingly, dividing the group can be, for example, a group of the formula-C(O)-Y-L-N(R3)(R4), in which

Y is-NR5-, -O - or-S-;

L is unsubstituted or substituted by alkyl, alkenyl, quinil, carbocyclic or heterocyclic group or a combination of two or more such groups, linked together by a single bond, Spiro-bonded, single or double bond or via C=O, O, S, SO, SO2, CONH, NHCO, or NH bundle;

each of R3and R4independently is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;

R4is enzyme-otdalennym link associated with the nitrogen group NR through amide bond.

In one implementation of R4is a group of the formula

where:

each R6independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, replaced by arylalkyl, heteroalkyl, replaced by heteroalkyl, heteroaryl, replaced by heteroaryl, heteroallyl, replaced by heteroallyl, Il is in need of R 6and R7together with the atoms to which they are attached, form cyclogeranyl or substituted cyclogeranyl;

R7is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, replaced by alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted by arylalkyl;

p is an integer from 1 to 5;

each W is independently-NR8-, -O - or-S-;

each R8independently is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R6and R8independently together with the atoms to which they are attached, form cyclogeranyl or substituted cyclogeranyl.

It is clear that when W is NH and R7is H or acyl, R4is the remainder of the amino acid or peptide, or its N-acyl derivative. When W is NR8, R7is H or acyl, and R6and R8together with the atoms to which they are attached, form a ring pyrrolidine, R4is a Proline residue or its N-acyl derivative.

Accordingly, in another implementation of R4is a residue of D - or L-amino acids (for example, L-amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, is histidine, isoleucine, leucine, methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine, lysine and valine, residue of the dipeptide or Tripeptide, consisting of two or three D - or L-amino acid residues (for example, L-amino acid residues), independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine, lysine and valine residues or their N-acyl derivatives, for example, N-acetyl derivative.

In one implementation L is unsubstituted or substituted 1,2-phenylenebis group. For example, Y-L-NR3together can form a group of 1,2-diaminopentane, which is unsubstituted or substituted by venelinova cycle one or two substituents selected from halogen atoms, (1-4C)alkyl and (1-4C)alkoxy.

In another implementation, L is a divalent group of the formula

where

n is an integer from 1 to 10 and

each of R1and R2independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or R1and R2together with the carbon to which they are attached, form cycloalkyl or substituted cycloalkyl, or two R1or R2group on the cross border carbon atoms together with the carbon atoms, to which they are attached, can form cycloalkyl or substituted cycloalkyl.

Accordingly, in one implementation of waste separation group, bearing nucleophilic atom is protected with tsepliaeva link represented by the formula-C(O)-Y-(C(R1)(R2))n-N(R3)(R4); separating the waste group corresponds to the group-C(O)-Y-(C(R1)(R2))n-, nucleophilic nitrogen atom protected otdalennym link corresponds to a group-H-N(R3)(R4), and tsepliaeva link that corresponds to the group R4where

Y is-NR5-, -O - or-S-;

n is an integer from 1 to 10 and

each of R1, R2, R3and R5independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or R1and R2together with the carbon atom to which they are attached, form cycloalkyl or substituted cycloalkyl, or two R1or R2groups on adjacent carbon atoms together with the carbon atoms to which they are attached, can form cycloalkyl or substituted cycloalkyl;

R4is

;

each R6independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, replaced by arylalkyl, heteroalkyl, replaced by heteroalkyl, GE is eroarea, replaced by heteroaryl, heteroallyl, replaced by heteroallyl, or optionally, R6and R7together with the atoms to which they are attached, form cyclogeranyl or substituted cyclogeranyl;

R7is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, replaced by alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted by arylalkyl;

p is an integer from 1 to 5;

each W is independently-NR8-, -O - or-S-;

each R8independently is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R6and R8independently together with the atoms to which they are attached, form cyclogeranyl or substituted cyclogeranyl.

So, if HN is phenolic opiate that is emitted, the corresponding connection you can imagine the formula (I)

and cyclic urea, carbamate or thiocyanate can be represented by the formula

In one implementation, each of R1, R2, R3and R5independently is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl.

In another implementation of R6is lateral atom is whether the group of natural amino acids, for example, H (glycine), -CH2(CH2)NH2(leucine), CH2CH2CH2NHC(NH)NH2(from arginine), 4-hydroxybenzyl (tyrosine), CH2COOH (aspartic acid) or CH2CH2COOH (glutamic acid).

In another implementation of R7is a hydrogen atom or unsubstituted or substituted acyl group, for example (1-6C)alkanoyl, such as acetyl or tert-butanoyl; benzoyl, unsubstituted or substituted, methylenedioxy or one or two substituents selected from (1-4C)alkyl, (1-4C)alkoxy or halogen, such as benzoyl or piperonyl; CONRxRyin which Rxand Ryindependently are hydrogen or (1-4C)alkyl, for example CONH2or hemolysate or semifirm, for example CH2CH2COOH or CH2CH2COOEt. Unsubstituted or substituted group preferably is a remnant of the pharmaceutically acceptable carboxylic acid.

Examples of particular values are:

for Y:-NR5-,

for R5: (1-4C)alkyl, for example-CH3,

for L: -CH2CH2-,

for R1and R2: hydrogen or (1-4C)alkyl, for example-CH3more specifically hydrogen,

for n: 2 or 3,

for R3: hydrogen or (1-4C)alkyl, for example-CH3,

for W: NH,

for R6: hydrogen, -CH2(CH2)3NH2C 2CH2CH2NHC(NH)NH2, 4-hydroxybenzyl, CH2COOH or CH2CH2COOH,

for R7: hydrogen, (1-6C)alkanoyl, for example acetyl or tert-butanol; optionally substituted benzoyl, for example benzoyl, unsubstituted or substituted, methylenedioxy or one or two substituents selected from (1-4C)alkyl, (1-4C)alkoxy or halogen, for example benzoyl or piperonyl, in particular hydrogen or acetyl;

for cyclogeranyl or substituted cyclogeranyl formed R6and R8together with the atoms to which they are attached: pyrrolidinyl,

for p: 1 or 2,

for R4: arginine, N-acetylamine, N-tert-mutanolysin, N-benzoylamino, N-piperacillin, N-glycinergic, lysine, glutamic acid, aspartic acid, tyrosine, Proline and N-lisiniprol.

Usually a corresponding compound (prodrug according to the invention) is administered orally. However, a particular implementation is provided by the possibility of another way of introduction.

Each corresponding connection can have a different release profile, where the rate of release of phenolic opiate dependent on the rate of detachment of tsepliaeva level and speed of reaction is intramolecular cyclization involving nucleophilic nitrogen, i.e. reactions release, thus representing f is Nonny opiate. Accordingly, one implementation of the method involves the introduction of a variety of appropriate compounds to a patient, where each of the corresponding connection has its own great dividing the waste group and/or its excellent tsepliaeva link so as to provide excellent patient from another controlled release of the phenolic opiate.

Specific examples of phenolic opioids include Oxymorphone, hydromorphone, morphine and derivatives thereof. It should be noted Oxymorphone, hydromorphone, and morphine. Other examples of phenolic opioids are buprenorphine, dihydroetorphine, diprenorphine, Etorphine and Levorphanol.

The prodrug can be entered by itself or it can be administered together with one or more other active agent. In one implementation they can be administered in conjunction with peripheral opiate antagonist, such as (R)-N-methylnaltrexone (N-MTX) or its prodrug. The person skilled in the art it is clear that (R)-N-methylnaltrexone is an antagonist of the actions of opioids, such as hydromorphone, Oxymorphone, and morphine, but cannot cross the blood-brain barrier. Therefore, it is an antagonist only their peripheral actions, which are undesirable, but not their actions on the Central nervous system, such as the pain, which is desirable. In one of the westline a prodrug of (R)-N-methylnaltrexone is a compound of formula (I), where X represents a phenolic residue (R)-N-methylnaltrexone, Y, R1, R2, R3n have any value from above, and R4is hydrogen or is any value from above. Such a prodrug can be entered orally. Compounds in which R4has any value from the above, it is preferable release (R)-N-methylnaltrexone in this way, a prodrug of releases opiate opiate, as antagonist which they are used. Such compounds can be included in the compositions for co-injection with the prodrug opiate according to the present invention, for example, a pharmaceutical composition including both compounds and a pharmaceutically acceptable carrier. It is clear that the original medicine, (R)-N-methylnaltrexone has poor bioavailability in oral introduction and usually require parenteral administration. Thus, prodrugs of (R)-N-methylnaltrexone according to the present invention is applicable in such a case, when the required therapy with oral introduction (R)-N-methylnaltrexone.

In another aspect the present invention provides a prodrug of Oxymorphone, hydromorphone or morphine, can provide Oxymorphone, hydromorphone or morphine activated after the introduction of controlled-release. Accordingly, nastoyascheevremya provides a compound of structural formula (I):

or its salt, hydrate or MES, where

X is Oxymorphone, hydromorphone or morphine, where the hydrogen atom of the hydroxyl group of the phenol is replaced by a covalent bond to-C(O)-Y-(C(R1)(R2))n-N(R3)(R4),

Y is-NR5-, -O - or-S-;

n is an integer from 1 to 4

each of R1, R2, R3and R5independently is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R1and R2together with the carbon to which they are attached, form cycloalkyl or substituted cycloalkyl, or two R1or R2groups on adjacent carbon atoms together with the carbon atoms to which they are attached, can form cycloalkyl or substituted cycloalkyl,

R4is

;

each R6independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, replaced by arylalkyl, heteroalkyl, replaced by heteroalkyl, heteroaryl, replaced by heteroaryl, heteroallyl, replaced by heteroallyl, or optionally, R6and R7together with the atoms to which they are attached, form cyclogeranyl or substituted cyclogeranyl;

R7is hydrogen, alkyl, substituted alkyl,acyl, substituted acyl, alkoxycarbonyl, replaced by alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted by arylalkyl;

p is an integer from 1 to 10;

each W is independently-NR8-, -O - or-S-;

each R8independently is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R6and R8independently together with the atoms to which they are linked, form cyclogeranyl or substituted cyclogeranyl.

For example, when X is a remnant of hydromorphone, the compound of formula (I) has the structure

In one implementation, X is hydromorphone go by Oxymorphone. In another implementation X is morphine.

In another aspect the present invention provides a compound of formula (I)

or its salt, hydrate or MES, where

X is (R)-N-methylnaltrexone, where the hydrogen atom of the hydroxyl group of the phenol is replaced by a covalent bond to-C(O)-Y-(C(R1)(R2))n-N(R3)(R4and Y, R1, R2n, R3and R4have the meanings as given above.

In another aspect, provided is a pharmaceutical composition, typically comprising one or more compound of formula (I), its salt, hydrate or MES, and pharmaceutically p is iamlive delivery, for example, a solvent, a carrier, filler or excipient. The choice of solvent, carrier, excipient and excipient depends among other factors on the desired method of administration.

In an additional aspect, the provided methods of treating or preventing various diseases or disorders. The methods typically include the introduction of a patient who is in need of treatment or prevention, a therapeutically effective amount of the compounds of formula (I) and/or includes pharmaceutical compositions.

Brief description of figures

Figure 1 shows the change over time in plasma concentrations of released N-MTX after oral administration (PO) dose in rats.

Figure 2 shows the change with time of the concentration in the plasma hydromorphone released and N-MTX after oral administration (PO) dose of the prodrug in rats.

The implementation of the invention

As used here, the term "alkyl" by itself or as part of another substituent refers to a saturated branched or unbranched monovalent hydrocarbon radical obtained by removing one hydrogen atom from a single carbon atom in the source alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, cuts, such as propan-1-yl or propan-2-yl, butyl, for example b is tan-1-yl, butane-2-yl, 2-methyl-propane-1-yl or 2-methyl-propane-2-yl.

In some implementations alkyl group contains from 1 to 20 carbon atoms. In other implementations alkyl group contains from 1 to 10 carbon atoms. In additional implementations alkyl group contains from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.

"Alkenyl" by itself or as part of another substituent refers to an unsaturated branched, unbranched or cyclic alkyl, the radical, having at least one double bond between carbon atoms obtained by removing one hydrogen atom from a single carbon atom in the original alkene. The group may have the CIS or TRANS conformation about dual relationships (links). Typical alkeneamine groups include, but are not limited to, ethynyl, propenyl, for example prop-1-EN-1-yl, prop-1-EN-2-yl, prop-2-EN-1-yl (allyl), prop-2-EN-2-yl, cycloprop-1-EN-1-yl, cycloprop-2-EN-1-yl, butenyl, such as but-1-EN-1-yl, but-1-EN-2-yl, 2-methyl-prop-1-EN-1-yl, but-2-EN-1-yl, but-2-EN-2-yl, buta-1,3-Dien-1-yl, buta-1,3-Dien-2-yl, cyclobuta-1-EN-1-yl, cyclobuta-1-EN-3-yl, cyclobuta-1,3-Dien-1-yl, etc. etc.

"Quinil" by itself or as part of another substituent refers to an unsaturated branched, unbranched or cyclic alkyl, the radical, having at least one stroynowski between carbon atoms, obtained by removing one hydrogen atom from a single carbon atom in the source alkyne. Typical alkyline groups include, but are not limited to, ethinyl, propinyl, for example prop-1-Jn-1-yl, prop-2-in-1-yl, etc., routinely, such as but-1-in-1-yl, but-1-in-3-yl, but-3-in-1-yl, etc. etc.

"Acyl" by itself or as part of another substituent refers to the radical - C(O)R30where R30is hydrogen, alkyl, cycloalkyl, cyclogeraniol, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroallyl, as defined above. Representative examples include, but are not limited to, formyl, acetyl, tert-butanol, cyclohexylcarbonyl, cyclohexylcarbonyl, benzoyl, piperonyl, benzylcarbamoyl etc.

"Alkoxy" by itself or as part of another substituent refers to a radical-OR31where R31represents alkyl or cycloalkyl group, as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy etc.

"Alkoxycarbonyl" by itself or as part of another substituent refers to the radical-C(O)R31where R31represents alkyl or cycloalkyl group, as defined above. Representative examples include, but are not limited to, methoxycarbonyl, etoxycarbonyl, propoxide is of IMT, butoxycarbonyl, cyclohexyloxycarbonyl etc.

"Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom in the original aromatic cycle. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, atrazine, azulene, benzene, chrysene, coronene, Fiorentina, florena, Exacta, hexagen, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octazen, octavina, octalene, evalena, Penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pesantren, rubeena, triphenylene, Trenitalia, etc. In a separate implementation aryl group includes from 6 to 20 carbon atoms. In other implementations aryl group contains from 6 to 12 carbon atoms. Examples of aryl groups are phenyl and naphthyl.

"Arylalkyl" by itself or as part of another substituent refers to an acyclic alkyl, the radical, in which one of the hydrogen atoms connected to carbon atom, typically with a limit or sp3carbon atom, a substituted aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-penile-1-yl, naftel the Tyl, 2-nattily-1-yl, naphthalenyl, 2-naphthenyl-1-yl, etc. In a separate implementation arylalkyl group is (C7-C30) arylalkyl, for example alkyl part arylalkyl group is a (C1-C10) and the aryl part is a (C6-C20). In other implementations arylalkyl group is a (C7-C20) arylalkyl, for example alkyl part arylalkyl troupe is (C1-C8) and the aryl part is a (C6-C12).

Compounds can be identified by their chemical structure and/or by their chemical name. Compounds described herein may contain one or more chiral center and/or double bond and can therefore exist as stereoisomers, such as isomers on double bond (for example, geometric isomeric), enantiomers or diastereomers. Accordingly, all possible enantiomers and stereoisomers of the compounds, including pure from the point of view of stereoisomeric forms (for example, pure geometric isomers, pure enantiomers or pure diastereomers and mixtures of enantiomers and stereoisomers, included in the description of the compounds according to the invention. Mixtures of enantiomers and stereoisomers can be divided into its component enantiomers or stereoisomers by using the splitting methods or ways of chiral synthesis well known to the person skilled in the art. Compounds can also be in several tautomeric forms including the enol form, the keto form and their mixture. Accordingly, the chemical structures presented here cover all possible tautomerase form of the considered compounds. Described compounds also include compounds labeled with isotopes, where one or more atoms have an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed here include, but are not limited to,2H,3H,11C,13C,15N18O,17O, etc. Connections can be either in resolutiony forms, and solvated forms, including hydrated forms. Individual compounds can be in multiple crystalline or amorphous form. Usually, all physical forms are equivalent for the application considered here, and covered by the scope of claims of the present invention.

"Cycloalkyl" by itself or as part of another substituent refers to a saturated cyclic alkyl, the radical. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, etc. In a separate implementation cycloalkyl group is (C3 10) cycloalkyl. In other implementations of cycloalkene group is (C3-C7) cycloalkyl.

"Cyclogeranyl" by itself or as part of another substituent refers to a saturated cyclic alkyl, the radical, in which one or more carbon atoms (and any associated hydrogen atom) independently replaced with the same or different heteroatoms. Typical heteroatoms to replace the carbon atoms include, but not be limited to, N, P, O, S, Si, etc. Typical cyclogeranyl groups include, but are not limited to, groups derived from epoxides, azirines, tyranov, imidazolidine, research, piperazine, piperidine, pyrazolidine, pyrrolidine, hinoklidina etc.

"Heteroalkyl, heteroalkyl and heteroalkyl" by themselves or as part of another substituent refer to alkyl, alkenyl or alkynylaryl groups, respectively, in which one or more carbon atom (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups. Typical heteroatomic groups which can be included in these groups include, but are not limited to, -O-, -S-, -O-O-, -S -,- O-S-, NR37R38-, =N-N=, -N=N-, -N=N-NR39R40, -PR41-, -P(O)2-FOR42-, -O-P(O)2-, -SO-, SO2-, SnR43R44- and the like, where R37, R38, R39 , R40, R41, R42, R43and R44independently are hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, replaced by arylalkyl, cycloalkyl, replaced by cycloalkyl, cyclogeraniol, replaced by cyclogeraniol, heteroalkyl, replaced by heteroalkyl, heteroaryl, replaced by heteroaryl, heteroallyl or substituted by heteroallyl.

"Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic the radical obtained by removing one hydrogen atom from a single atom in the source heteroaromatic cyclic system. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsehole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochroman, isoindole, isoindoline, isoquinoline, isothiazole, isoxazol, naphthiridine, oxadiazole, oxazole, pyrimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, Piran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, heatline, quinoline, hemolysin, cinoxacin, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthine, etc. In a separate implementation heteroaryl g is the SCP is a 5-20-membered heteroaryl. In other implementations heteroaryl group is a 5-10 membered heteroaryl. In additional implementations heteroaryl group is a derivative of thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

"Heteroaromatic" by itself or as part of another substituent refers to an acyclic alkyl, the radical, in which one of the hydrogen atoms connected to carbon atom, typically with a limit or sp3carbon atom, a substituted heteroaryl group. In some implementations heteroallyl group is 6-30-membered heteroallyl, for example alkyl part of heteroallyl is 1 to 10-membered and the heteroaryl portion is a 5-20-membered heteroaryl. In other implementations heteroallyl group is 6 to 20-membered heteroallyl, for example alkyl part of heteroallyl is 1-8-membered and the heteroaryl portion is a 5-12-membered heteroaryl.

"Opiate" refers to a chemical substance exhibiting its pharmacological effect by interacting with opiate receptors, giving patients pain relief. "Phenolic opiate" refers to the group of opiate-containing phenolic group. Examples of phenolic opioids include buprenorphine, dihydroetorphine, diprenorphine, Etorphine, hydromorphone, Levorphanol, morphine and Oxymorphone. "The opiate antagonist" is a compound exhibiting antagonism in relation to the pharmacological action of the opiate. The term includes antagonists phenolic opiates. Examples of antagonists of phenolic opioids include naltrexone, naloxone and (R)-N-methylnaltrexone. "Peripheral opiate antagonist" is a compound, unable to penetrate the blood-brain barrier and therefore is able to show an antagonistic effect only in respect of (unwanted) actions of opiates outside the Central nervous system. An example of peripheral opiate antagonist is (R)-N-methylnaltrexone.

"The original aromatic cyclic system" by itself or as part of another substituent refers to an unsaturated cyclic or polycyclic system with the conjugated system of π-electrons. Specifically included in the definition of "original aromatic cyclic system" the system of interconnected rings in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated, for example Floren, indan, inden, finale etc. Typical source of aromatic cyclic system include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysin, corona, Florentine is, Floren, hexagen, hexalen, as-indocin, s-indocin, indan, inden, naphthalene, octazen, octave, octalene, oval, Penta-2,4-diene, pentacene, pentalene, Pentagon, fixed, finale, phenanthrene, pizen, Pleiades, pyrene, pesantren, rubison, triphenylene, triathalon etc.

Source heteroaromatic cyclic system" by itself or as part of another substituent refers to the original aromatic cyclic system, in which one or more carbon atoms (and any associated hydrogen atom) independently replaced with the same or different heteroatoms. Typical heteroatoms to replace the carbon atoms include, but not be limited to, N, P, O, S, Si, etc. Specifically included in the definition of "source heteroaromatic cyclic system" is the system of interconnected rings in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated, such as Arsenal, benzodioxan, benzofuran, chroman, chrome, indole, indoline, xanthine, etc. Typical source heteroaromatic cyclic systems include, but are not limited to, Arendal, carbazole, β-carboline, chroman, chrome, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochroman, isoindole, isoindoline, isoquinoline, isothiazol, isoxazol, naphthiridine, oxadiazol, oxazol, perimede is, phenanthridine, phenanthroline, fenesin, phthalazine, peridin, purine, Piran, pyrazin, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, hinzelin, quinoline, hemolysin, cinoxacin, tetrazol, thiadiazole, thiazole, thiophene, triazole, xanthine, etc.

"Pharmaceutical composition" refers to at least one compound and pharmaceutically acceptable delivery vehicle with which the compound is administered to the patient.

"Pharmaceutically acceptable carrier" refers to salts of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) additional salt acids, formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxide the sulfonic acid, benzolsulfonat acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonate acid, 4-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionate acid, trimethylhexane acid, tertbutylamine acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and the like; or (2) salts formed when replacing the acidic proton in the initial connection of a metal ion such as alkali metal ion, an alkaline earth ion metal or aluminum ion, or in the formation of a complex with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like

"Pharmaceutically acceptable delivery vehicle" refers to the solvent, auxiliary substance, excipient or carrier with which a compound is administered.

"Patient" includes mammals, namely people. The terms "man" and "patient" are used here interchangeably.

"Prevention" refers to the reduction of risk of onset of diseases or disorders (e.g., bringing to nerazviti at least one disease symptom in a patient who may be exposed to or predisposed to the disease, but still n the feels or does not show symptoms of the disease).

"Prodrug" refers to a derivative of an active agent that you want be turning in the body to release the active agent. The prodrug is often, though not necessarily, is pharmacologically inactive to become active agent.

"Programa" refers to the shape of the protective group, which when applied to mask a functional group of the active agent turns the active agent in the prodrug. Usually, progroup can praedicat to the medication through the connection (connection), split enzymatic or nonenzymatic method in vivo.

"Protective group" refers to a grouping of atoms that when joining the reactive functional group of a molecule masks, reduces or prevents that reactivity of functional groups. Examples of protective groups can be found in Green et al., "Protective Groups in Organic Chemistry, (Wiley, 2<nd>ed. 1991) and Harrison et al., "Compendium of Synthetic Organic Methods," Vols.1-8 (John Wiley and Sons, 1971-1996). Representative protective groups for amines include, but are not limited to, formyl, acetyl, TRIFLUOROACETYL, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethynyl ("SES"), trityl and substituted triteleia group, allyloxycarbonyl, 9-fertilityscore ("FMOC"), nitroferricyanide ("NVOC") and other Representative the protective groups for hydroxyl include, not limited to, those where the hydroxyl group is acylated or alkilirovanny, for example, benzyl and triteleia esters, and alkyl ethers, tetrahydropyranyl esters, trialkylsilyl ethers and allyl ethers.

"Substituted" refers to a group in which one or more hydrogen atom is independently substituted by identical or different substituents. Typical substituents include, but are not limited to, alkylenedioxy (for example, methylenedioxy), -M, -R60, -O-, =O, -OR60, -SR60, -S-, =S, -NR60R61, =NR60, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2O-, -S(O)2OH, -S(O)2R60, -OS(O)2O; -OS(O)2R60, -P(O)(O-)2, -P(O)(OR60)(O-), -OP(O)(OR60)(OR61), -C(O)R60, -C(S)R60, -C(O)OR60, -C(O)NR60R61, -C(O)O-, -C(S)OR60, -NR62C(O)NR60R61, -NR62C(S)NR60R61, -NR62C(NR63)NR60R61and-C(NR62)NR60R61where M is halogen; R60, R61, R62and R63independently are hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, replaced by cycloalkyl, cyclogeraniol, replaced by cyclogeraniol, aryl, substituted aryl, heteroaryl or substituted by heteroaryl, or if it is Timoti R 60and R61together with the nitrogen atom to which they are bound, form cyclogeranyl or substituted cyclogeranyl, and R64and R65independently are hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, replaced by cycloalkyl, cyclogeraniol, replaced by cyclogeraniol, aryl, substituted aryl, heteroaryl or substituted by heteroaryl, or optionally, R64and R65together with the nitrogen atom to which they are bound, form cyclogeranyl or substituted cyclogeranyl. In some implementations, the substituents include-M, -R60, =O, -OR60, -SR60-S-, =S, -NR60R61, =NR60, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2R60, -OS(O)2O-, -OS(O)2R60, -P(O)(O-)2, -P(O)(OR60)(O-), -OP(O)(OR60)(OR61), -C(O)R60, -C(S)R60, -C(O)OR60, -C(O)NR60R61, -C(O)O-, -NR62C(O)NR60R61. In other implementations, the substituents include-M, -R60, =O, -OR60, -SR60, -NR60R61, -CF3, -CN, -NO2, -S(O)2R60, -P(O)(OR60)(O-), -OP(O)(OR60)(OR61), -C(O)R60, -C(O)OR60, -C(O)NR60R61, -C(O)O-. In additional implementations, the substituents include-M, -R60, =O, -OR60, -SR60, -NR60R61, -CF3 , -CN, -NO2, -S(O)2R60, -OP(O)(OR60))(OR61), -C(O)R60, -C(O)OR60, -C(O)O-where R60, R61and R62as defined above. For example, the substituted group can carry methylendioxy Deputy or one, two or three substituent selected from a halogen atom, (1-4C) alkyl group and (1-4C)alkoxy group.

Treatment of disease or disorders in a separate implementation refers to the weakening of the diseases or disorders (eg, to stop or slow development of the disease or at least one clinical symptom). In other implementations "treatment" refers to the weakening of the at least one physical parameter, which may be unnoticed by the patient. In other implementations "treatment" refers to the suppression of diseases or disorders on the physical level (for example, stabilization of the visible symptom), at the physiological level (e.g., stabilization of a physical parameter), or both. In other implementations "treatment" refers to the slow onset of diseases or disorders.

"Therapeutically effective amount" means an amount of compound that when administered to a patient for treatment of the disease is sufficient to achieve the effect of such a treatment of the disease. "Therapeutically effective amount" will vary depending on the connection, Zabol the cation and its severity and the age, weight, etc. of the patient to the treatment.

Further detail different implementation. It should be understood that the invention is not limited to these implementations. On the contrary, it embraces alternatives, modifications and equivalents that may be included in the scope of claims of the claims.

In the present invention discloses prodrugs of phenolic opioids. Programa prodrugs includes dividing the group and tsepliaeva link, where dividing the group inter alia physically separates the molecule drugs tsepliaeva link. Accordingly, a prodrug, disclosed here includes phenol, attached via the oxygen atom of the phenol to the separation group, which is optionally attached to tsepliaeva link. Cleavage tsepliaeva link opens a nucleophilic nitrogen, which leads to activation of prodrugs. Controlled release of the original medications can be oposredovanie nucleophilic nitrogen undergoes an intramolecular cyclization reaction and release.

Tsepliaeva link may include amide. Usually, tsepliaeva link can be chipped off under physiological conditions. Tsepliaeva link cleaved enzymatically.

In certain implementations provided a compound of structural formula (I) or its salt, solvate or hydrate

where

X is a phenolic opiate, in which the hydrogen atom of the hydroxyl group replaced by a covalent bond to-C(O)-Y-(C(R1)(R2))n-N(R3R4),

Y is-NR5-, -O - or-S-;

n is an integer from 1 to 4

each of R1, R2, R3and R5independently is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R1and R2together with the carbon to which they are attached, form cycloalkyl or substituted cycloalkyl,

R4is

Each R6independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, replaced by arylalkyl, heteroalkyl, replaced by heteroalkyl, heteroaryl, replaced by heteroaryl, heteroallyl, replaced by heteroepitaxial or optionally, R6and R7together with the atoms to which they are linked, form cyclogeranyl or substituted cyclogeranyl;

R7is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, replaced by alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted by arylalkyl;

p is an integer from 1 to 10;

each W is independently-NR8-, -O - or-S-;

each R8independent is what I hydrogen, the alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R6and R8independently together with the atoms to which they are linked, form cyclogeranyl or substituted cyclogeranyl.

In some implementations, each of R1, R2, R3and R5independently is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl.

In a separate realizations X is hydromorphone, morphine or Oxymorphone. In other implementations X is buprenorphine, dihydroetorphine, diprenorphine, Etorphine or Levorphanol.

In some implementations, R7is hydrogen, alkyl, acyl or alkoxycarbonyl. In other implementations, R7is,

where R9is hydrogen or alkyl and x is an integer from 1 to 2000. In other implementations, R7is a commercially available derivative of PEG, such as PEG-200, PEG-400, PEG-1550, PEG-3350, PEG-6000, PEG-20000 or PEG-40000.

In a separate realizations Y is-NR5and R5is hydrogen or alkyl. In other implementations, n is 1. In other implementations, R1, R2, R3, R5and R8independently are hydrogen or alkyl.

In some implementations, each R6independently is hydrogen, what Kilom, substituted by alkyl, aryl, arylalkyl, cycloalkyl, replaced by cycloalkyl, replaced by arylalkyl or heteroallyl, or optionally, R6and R7together with the atoms to which they are attached, form cyclogeranyl or substituted cyclogeranyl. In other implementations, R6independently is hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, replaced by arylalkyl, heteroalkyl, heteroallyl, replaced by heteroallyl, or optionally, R6and R7together with the atoms to which they are attached, form cyclogeranyl or substituted cyclogeranyl. In other implementations, each R6independently is hydrogen, stands, isopropyl, isobutyl, second-bootrom, tert-bootrom, cyclopentyl, cyclohexyl, -CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2CH2SCH3, -CH2SH, -CH2(CH2)3NH2, -CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, gooberzilla, 4-hydroxybenzyl, 4-brombenzene, 4-imidazolinium, 3-indolylmethane, 3-(5-hydroxyindole)-stands, 9-anthranilamide, 3-benzothiazolethiol, cyclohexylmethyl, diphenylmethyl, 2-furylmethyl, jameila, 1-naphthylmethyl, 2-naphthylmethyl, 2-what piridiletilen, 3-pyridylmethyl, 4-pyridylmethyl, 3-sterilsation, 2-thienylmethyl, vinylmation, cyclohexyl, acetalization, 2-cryptomaterial, 2-chlorbenzyl, 2-cyanobenzyl, 2-Formentera, 2-methylbenzyl, 3-cryptomaterial, 3-chlorbenzyl, 3-cyanobenzyl, 3-Formentera, 3-methylbenzyl, 4-benzoylbenzene, 3,5-dibromo-4-hydroxybenzyl, 3-cryptomaterial, 4-chlorbenzyl, 4-cyanobenzyl, 4-Formentera, 4-identicom, 4-methylbenzyl, 4-nitrobenzyl, 3,4-dihydroxybenzene, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-differentiam, 3,5-dead-4-hydroxybenzyl, 3-nitro-4-hydroxybenzyl, aminomethyl,

,,

or

or optionally, R6and R7together with the atoms to which they are attached, form azetidin, pyrrolidine or piperidine.

In some implementations W is-NR8and each R7independently is hydrogen or alkyl, aryl or arylalkyl.

In some implementations, R7is hydrogen, alkyl, acyl or alkoxycarbonyl.

In other implementations, each R6independently is-CH2(CH2)3NH2or-CH2CH2CH2NHC(NH)NH2. In additional implementations p is avno 1 and R 6is-CH2(CH2)3NH2or-CH2CH2CH2NHC(NH)NH2. In other implementations, each W is-NR8-, each R8is hydrogen and R7is hydrogen, acyl, substituted acyl, alkoxycarbonyl or substituted by alkoxycarbonyl.

In some implementations, each R6independently is a phenyl, a benzyl, 4-hydroxybenzyl, 4-brombenzene, 4-imidazolinium, 3-indolylmethane, isobutyl, -CH2CH2SCH3, -CH2CH2CONH2-CH2CH2CONH2or-CH2CO2H. In other implementations, each R6independently is a benzyl, 4-hydroxybenzyl, 4-brombenzene or 3-indolylmethane. In other implementations, n is 1 and R6is a phenyl, a benzyl, 4-hydroxybenzyl, 4-brombenzene, 4-imidazolinium, 3-indolylmethane, isobutyl, -CH2CH2SCH3, -CH2CH2CONH2, -CH2CH2CONH2or-CH2CO2H. In other implementations, n is 1 and R6is benzyl, 4-hydroxybenzyl, 4-brombenzene or 3-indolylmethane. Separate from any among the above realizations W is-NR8-, each R8is hydrogen and R7is acyl, substituted acyl, alkoxycarbonyl or substituted by alkoxycarbonyl.

In a separate realizations of p is greater than 1 and R 7is hydrogen. In any of the above implementations, each W is-NR8-, each R8is hydrogen and R7is acyl, substituted acyl, alkoxycarbonyl or substituted by alkoxycarbonyl.

In some realizations of p is 3 and R7is hydrogen. In other implementations, each W is-NR8and each R8is hydrogen.

In some implementations, each R7independently is hydrogen, stands, isopropyl, isobutyl, sec-bootrom, -CH2OH or-CH2SH. In other realizations of p is 1 and R6is hydrogen, stands, isopropyl, isobutyl or sec-bootrom, each W is-NR8-, each R8is hydrogen and R7is acyl, substituted acyl, alkoxycarbonyl or substituted by alkoxycarbonyl.

In some implementations, each R6independently is hydrogen, stands, isopropyl, isobutyl, sec-bootrom, tert-bootrom, cyclopentyl, cyclohexyl, -CH2OH, -CH(OH)CH3, -CH2CONH2, -CH2CH2SCH3, -CH2SH, phenyl, benzyl, 4-hydroxybenzyl, 4-brombenzene or 3-indolylmethane. In other implementations, each R6independently is hydrogen, stands, isopropyl, isobutyl, sec-bootrom, tert-bootrom, cyclopentyl, cyclohexyl, f is'neil, a benzyl, 4-brombenzene, 3-indolylmethane, or optionally, R6and R7together with the atoms to which they are attached, form azetidin, pyrrolidine or piperidine. In some of the above implementations, each W is-NR8each R8is hydrogen or optionally, each R6and R8independently together with the atoms to which they are attached, form azetidin, pyrrolidine or piperidine and R7is acyl, substituted acyl, alkoxycarbonyl or substituted by alkoxycarbonyl.

In some implementations, each R6independently is a benzyl, 4-hydroxybenzyl or isobutyl. In other implementations, each W is-NR8-, each R8is hydrogen and R7is acyl, substituted acyl, alkoxycarbonyl or substituted by alkoxycarbonyl.

In some implementations, each R6independently is-CH2CO2H or-CH2CH2CO2H. In other implementations, each W is-NR8-, each R8is hydrogen and R7is acyl, substituted acyl, alkoxycarbonyl or substituted by alkoxycarbonyl.

In other realizations of p is 2 and R6group adjacent to the N-terminal nitrogen atom, independently, is hydrogen, stands, isopropyl, isobutyl, sec-bootrom, the pet-bootrom, cyclopentyl, cyclohexyl, -CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2CH2SCH3, -CH2SH, -CH2(CH2)3NH2, -CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, gooberzilla (Venetian), 4-hydroxybenzyl, 4-brombenzene, 4-imidazolinium, 3-indolylmethane, 3-(5-hydroxyindole)-stands, 9-anthranilamide, 3-benzothiazolethiol, cyclohexylmethyl, diphenylmethyl, 2-furylmethyl, jameila, 1-naphthylmethyl, 2-naphthylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 3-sterilsation, 2-thienylmethyl, vinylmation, cyclohexyl, acetalization, 2-cryptomaterial, 2-chlorbenzyl, 2-cyanobenzyl, 2-Formentera, 2-methylbenzyl, 3-cryptomaterial, 3-chlorbenzyl, 3-cyanobenzyl, 3-Formentera, 3-methylbenzyl, 4-benzoylbenzene, 3,5-dibromo-4-hydroxybenzyl, 3-cryptomaterial, 4-chlorbenzyl, 4-cyanobenzyl, 4-Formentera, 4-identicom, 4-methylbenzyl, 4-nitrobenzyl, 3,4-dihydroxybenzene, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl 3,4-differentiam, 3,5-dead-4-hydroxybenzyl, 3-nitro-4-hydroxybenzyl, aminomethyl,

,,

or

or if necessary, each R6and R8independently together with the atoms to which they are attached, form azetidin, pyrrolidine or piperidine, and the other R6the group is stands, or R6and R8independently together with the atoms to which they are attached, form pyrrolidin. In other implementations, each W is-NR8-, each R8is hydrogen or optionally, each R6and R8independently together with the atoms to which they are attached, form pyrrolidin and R7is acyl, substituted acyl, alkoxycarbonyl or substituted by alkoxycarbonyl.

In other separate these realizations of p is 1 and R6is hydrogen. In some of the above realizations of p is 1, R6is hydrogen and W is NH. In some of the above realizations of p is 1, R6is hydrogen, W is NH and R7is hydrogen. In other implementations, each R6is hydrogen and W is NH. In other implementations, each R6is hydrogen, W is NH and R7is hydrogen.

In a separate realizations Y is NR5, n is 2 or 3, p is 1 or 2, R1R2, R3, R5and R7independently are hydrogen or alkyl, each R6regardless of who is hydrogen, the alkyl, substituted alkyl, aryl, arylalkyl, replaced by arylalkyl, heteroalkyl, heteroallyl, replaced by heteroallyl, or optionally, R6and R7together with the atoms to which they are linked, form cyclogeranyl or substituted cyclogeranyl. In other implementations Y is NR5, n is 2, p is 1, R1and R2are hydrogen, R3and R5are the stands or hydrogen and R6independently is hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, replaced by arylalkyl, heteroalkyl, heteroallyl, replaced by heteroallyl, or optionally, R6and R7together with the atoms to which they are attached, form cyclogeranyl or substituted cyclogeranyl, or optionally, R7is hydrogen. Additional accomplishments Y is NR5, n is 2, R1and R2are hydrogen, R3and R5are the stands or hydrogen, R7is hydrogen and R6is-CH2(CH2)3NH2or-CH2CH2CH2NHC(NH)NH2. In separate these realizations X is Oxymorphone or hydromorphone.

Compounds described herein can be obtained by methods mainly illustrated in schemes 1-4.

Progroup described here you can obtain and attach to drugs containing phenols, according to methods known to a person skilled in the art (see, for example, Green et al, "Protective Groups in Organic Chemistry" (Wiley, 2<nd>ed. 1991); Harrison et al, "Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996); "Beilstein Handbook of Organic Chemistry", Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al., "Reagents for Organic Synthesis, Volumes 1-17, (Wiley Interscience); Trost et al., "Comprehensive Organic Synthesis", (Pergamon Press, 1991); "Theilheimer''s Synthetic Methods of Organic Chemistry", Volumes 1-45 (Karger, 1991); March, "Advanced Organic Chemistry" (Wiley Interscience), 1991; Larock "Comprehensive Organic Transformations" (VCH Publishers, 1989); Paquette, "Encyclopedia of Reagents for Organic Synthesis" (John Wiley & Sons, 1995); Bodanzsky, "Principles of Peptide Synthesis (Springer Verlag, 1984). Additionally, the source material can be obtained from commercial sources by well-known methods of synthesis, supra.

In scheme 1 and in formula I, supra, where for illustrative purposes T is-O-, -S - or-NR3, Y is NR5, -O - or-S-, W is NR8, -O - or-S-, n is 2, R1and R2are hydrogen, p, R3, R5, R6, R7and R8is as defined above, X is a phenolic opiate, P is a protecting group and M is an outgoing group, compound 1 can be allievate with a suitable carboxylic acid or equivalent carboxylic acid to obtain compound 2, which you can then remove the protection from the connection 3. Connected to the e 3 then reacts with the carbon equivalent of carbonic acid 4 to obtain the desired compound 5.

In scheme 2 and in formula I, supra, where for illustrative purposes T is-O-, -S - or-NR3, Y is NCH3W is NR8, -O - or-S-, n is 2, R1and R2are hydrogen, p, R3, R5, R6, R7and R8is as defined above, X is a phenolic opiate, P is a protecting group and M is an outgoing group, compound 6 acelerou with a suitable carboxylic acid or equivalent carboxylic acid to obtain compound 7. With compound 7 then remove protection and result in interaction with active equivalent of carbonic acid 4 to obtain the desired compound (9).

In scheme 3 and in formula I, supra, where for illustrative purposes T is NCH3, Y is NR5, -O - or-S-, W is NR8, -O - or-S-, n is 2, R1and R2are hydrogen, p, R3, R5, R6, R7and R8is as defined above, X is a phenolic opiate, P is a protecting group and M is an outgoing group, compound 10 acelerou with a suitable carboxylic acid or equivalent carboxylic acid to obtain the compound (11), which after removal of the protection and internal restructuring, functional groups, if necessary, make the connection 12. Interaction of soy is inane 12 carbon equivalent of carbonic acid 4 gives the desired compound 13.

In figure 4 and in the formula I, supra, where for illustrative purposes T and Y are NCH3W is NR8, -O - or-S-, n is 2, R1and R2are hydrogen, p, R3, R5, R6, R7and R8is as defined above, X is a phenolic opiate, P is a protecting group and M is an outgoing group, compound 14 acelerou with a suitable carboxylic acid or equivalent carboxylic acid to obtain compound 15. The interaction of compounds 15 carbon equivalent of carbonic acid 4 gives the desired compound 16.

The compound of formula (I)obtained by this method, in which R7represents a hydrogen atom, can then be allievate to obtain the corresponding compound of formula (I), in which the p value is increased or in which R7represents an acyl group.

Therefore, according to another aspect of the present invention provides a method for obtaining compounds of formula (I) or its pharmaceutically acceptable salt which comprises the reaction of compounds of formula (III)

or its derivative with the protection with the compound of the formula (IV)

where M represents the departing atom or group, such as activated aryloxychromones group, for example p-nor is openexternal,

with the subsequent removal of the protective group and, if necessary, by acylation of compounds of formula (I)in which R7(in the group R4by the above definition) represents a hydrogen atom and/or the formation of pharmaceutically acceptable salts.

The compounds of formula (I)in which X represents the residue of (R)-N-methylnaltrexone, can also be obtained by methylation of the corresponding compounds of formula (I)in which X is the residue of naltrexone or its derivatives with added protection.

The choice of suitable protective groups, reagents and reaction conditions for any stage of the above schemes is within the range of specialist knowledge in the art. Other methods of synthesis of the prodrugs described herein are easily understandable to the expert and can be used for the synthesis of the above compounds. Accordingly, the methods presented in the diagrams are illustrative and not exhaustive.

The invention further presents the all-new intermediates described here.

Basically, prodrugs disclosed here can be used to treat and/or prevent those diseases or conditions as the original medication, it is well known in the art (see, for example, Physicians Desk Reference, 2000 54th Edition and the Merck Index, 13th Edition). Phenolic opioids used in the treatment of pain.

Example is, the prodrug phenolic opiate, such as hydromorphone, can be applied inter alia, for the treatment or prevention of pain, including, but not limited to, acute pain, chronic pain, neuropathic pain, acute traumatic pain, arthritis pain, pain in osteoarthritis, pain, rheumatoid arthritis, musculoskeletal pain, pain after dental surgery, dental pain, muscular-paspaley pain, pain and cancer pain, pain in the bowels, pain in diabetes, muscle pain, nerve pain after herpes, chronic pelvic pain, pain with endometriosis, pelvic inflammatory pain and the pain associated with childbirth. Acute pain includes, but is not limited to, acute traumatic pain and pain after surgery. Chronic pain includes, but is not limited to, neuropathic pain, arthritis pain, pain in osteoarthritis, pain, rheumatoid arthritis, musculoskeletal pain, toothache, muscular-fascial pain, pain and cancer pain, pain caused by diabetes, pain in the bowels, muscle pain, nerve pain after herpes, chronic pelvic pain, pain with endometriosis, pelvic inflammatory pain and back pain.

The pharmaceutical compositions disclosed here include the prodrug, revealed here, with the appropriate amount of pharmaceutically acceptable vehicle, so you have forms is for a proper introduction to the subject.

Suitable pharmaceutical vehicle include fillers, such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerylmonostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like, the Pharmaceutical compositions of the present invention optionally may also include a small amount of moisturizer or emulsifying agents, or pH buffering agents. Additionally, you can apply auxiliary agents, thickeners, lubricants and dyes.

The pharmaceutical compositions can be obtained by any method using conventional mixing, dissolving, granulating, get pills, grinding into powder, emulsifying, concluding in capsules, capture (in the shell) and lyophilization. The pharmaceutical compositions can be conventional manner using one or more physiologically acceptable medium, thinner, fillers or excipients that facilitate processing of the compounds disclosed here, in the medicines that can be applied in the pharmaceutical industry. Proper selection of the composition depends on the chosen way of introduction.

The pharmaceutical compositions according to the present invention may take the form of solutions, suspensions, emulsions, is Ableton, pills, powders, capsules containing lipid capsules, powders, compositions with delayed release, suppositories, emulsions, aerosols, sprays, suspensions, or any other usable forms known to the person skilled in the art. In some implementations pharmaceutically acceptable delivery vehicle is a capsule (see, e.g., Grosswald et ah, US patent No. 5698155). Other examples of suitable pharmaceutical vehicles are described in the art (see Remington's Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, 19th Edition, 1995).

Pharmaceutical compositions for oral administration can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, viscous syrups, suspensions or elixirs, for example. Compositions for oral administration can contain one or more additional components, for example, sweetening agents such as fructose, aspartame or saccharin, flavoring, such as peppermint and spearmint or oil simalube, or Vishneva dyes and preservatives to obtain palatable pharmaceutical agents. Additionally, upon receipt of the tablets or pills of the composition can be coated shell to delay disintegration and absorption in the gastrointestinal tract, thus providing a delayed action for an extended PE the iodine-time. Oral compositions can include standard features such as lures, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate, sucrose, sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, resin tragakant, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium and/or polyvinylpyrrolidone (PVP), granulating agents, binding agents and dezintegriruetsja agents, such as cross-linked polyvinylpyrrolidone, agar or elganowo acid or its salt, for example alginate sodium, etc.

In some implementations, the pharmaceutical compositions are in the form of lozenges or candies, where dissolution and release of the active ingredients occurs in the oral cavity, mainly involving the mucous membranes of the mouth. In the case of such implementations can also be applied buffer agents to obtain an optimal environment for the delivery of agents or compositions. Additional components may include, for example, sweeteners, binding agents, solvents, dezintegriruetsja agents, lubricants, etc.

In other implementations, the pharmaceutical composition is soluble sublingual tablet when the dissolution and release of the active ingredient takes place under the tongue and compositions and/or compounds disclosed here, absorbed through the mucous membrane of the mouth. In the case of such implementations can also be applied buffer agents to obtain an optimal environment for the delivery of each agent. Additional components may include, for example, sweeteners, binding agents, solvents, dezintegriruetsja agents etc.

Ways, including oral introduction of the compounds disclosed here can also be applied with different dosage form providing delayed release.

In some implementations dosage form mastoid balls, which at the dissolution or diffusion release compositions and/or compounds disclosed here within the span at the clock time period, preferably over a period of at least 6 hours, for a period of at least 8 hours, more preferably for a period of at least 12 hours and, most preferably, over a period of at least 24 hours. Beads can include a composition located in the center or in the nucleus, including the compounds disclosed here, and pharmaceutically acceptable means, including, if necessary, lubricants, antioxidants and buffer agents. The balls can be drug in diameter from approximately 1 to approximately 2 mm, some balls may include doses of the compounds disclosed is here. In some implementations, the balls get out of unstitched materials to enhance their destruction in the gastrointestinal tract. The beads may be coated with a polymer to control the speed of release, which provides a release profile over time.

Balls to release in time (delayed or prolonged release) can be obtained in the form of tablets for therapeutically effective introduction. Beads can be incorporated into the matrix tablets by direct compression set of balls, covered with, for example, acrylic film and mixed with a filler, such as hydroxypropylmethylcellulose. Ways to get balls disclosed in the art (Lu, Int. J. Pharm. 1994, 112, 117-124; Pharmaceutical Sciences, by Remington, 14th ed, pp 1626-1628 (1970); Fincher, J Pharm. Sci. 1968, 57, 1825-1835; Benedikt, United States Patent No. 4,083,949) as well as the reception of tablets (Pharmaceutical Sciences, by Remington, 17th Ed, Ch. 90, pp 1603-1625 (1985).

In other implementations, you can use the pump to slow oral administration (Langer, supra; Sefton, 1987, CRC Crit RefBiomed. Eng. 14: 201; Saudek et al, 1989, JV. Engl. J Med. 321: 574).

In other implementations can be applied polymeric materials (see "Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press., Boca Raton, Florida (1974); Controlled Drug Bioavailability", Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Langer et al, 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; Levy et al., 1985, Science 228:190; During et al, 1989, Ann. Neurol. 25:351; Howard et al, 1989, J Neurosurg. 71:105). In the part of the implementation of polymeric materials can be used for oral administration of sustained-release. Such polymers include, for example, carboxymethylcellulose sodium, hydroxypropylcellulose, hypromellose and hydroxyethyl cellulose (most preferably, hypromellose). Other cellulose ethers are also described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984, 5(3) 1-9). Factors affecting the release of drugs are well known to the expert and described in the art (Bamba et al, Int. J. Pharm. 1979, 2, 307).

In other implementations abdominal drugs in the shell (enteric-coated) can be used for oral administration of sustained-release. The materials for the shell include, for example, polymers with pH-dependent solubility (i.e. controlled pH release), polymers with a slow or pH-dependent rate of swelling, dissolution or destruction (i.e. controlled time release), polymers, collapsing under the action of enzymes (i.e. enzyme-controlled release), polymers, forming dense layers, decaying with increasing pressure (controlled pressure release).

In other implementations for oral administration of sustained-release can be applied lipid matrix, releasing the drug. For example, solid particles of the compositions and/or compounds disclosed here, can be covered with a thin layer of lipid controlled visual is to testify (for example, glycerinate and/or glycerylmonostearate), as disclosed in Farah et al, U.S. patent No. 6375987 and Joachim et al, U.S. patent No. 6379700. Covered with lipid particles can optionally be compressed into a tablet. Other material matrix lipid based controlled release formulation suitable for oral administration of sustained-release includes poliglecaprone glycerides, as disclosed in Roussin et al., the U.S. patent No. 6171615.

In other implementations, you can apply the wax for oral administration of sustained-release. Examples of waxes suitable for slow release, disclosed in Cain et al, U.S. patent No. 3402240 (Carnauba wax, beeswax candelilla, Esparto wax and wax ouricuri), Shtohryn et al, U.S. patent No. 4820523 (hydrogenomonas vegetable oil, beeswax, Carnauba wax, paraffin wax candelilla, ozokerite and their mixture) and Walters, U.S. patent No. 4421736 (a mixture of paraffin and castor oil).

In other implementations use an osmotic delivery system for oral maintenance with a slow release (Verma et al, DrugDev. Ind. Pharm. 2000, 26: 695-708). In some implementations apply the OROS® system production Alza Corporation, Mountain View, CA in the means of delivery for oral administration of sustained-release (Theeuwes et al, U.S. patent No. 3845770; Theeuwes et al, U.S. patent No. 3916899).

In other implementations of the system for controlled, visual the statement can be placed close to the target compositions and/or compounds disclosed here, it only requires a fraction of the systemic dose (see, e.g., Goodson, in "Medical Applications of Controlled Release, supra, vol.2, pp.115-138 (1984)). Other systems controlled release discussed in Langer, 1990, Science 249:1527-1533, can also be used.

In other implementations dosage forms include compounds disclosed here, covered with a polymer substrate. The polymer can be degradiruem or degradiruem polymer. The coated substrate can be folded into itself to provide a double-layer forms of medication. For example, the compounds disclosed here can be applied to the polymer layer from a polypeptide, collagen, gelatin, polyvinyl alcohol, polyarteritis, Polyacetal or preordainment, and covered with the polymer can be folded into itself to get a two-layer dosage forms. When used biodegrability dosage form is destroyed with a controlled speed, release the compounds for a long period of time. Representative biodegradable polymers include selected from the group consisting of biodegradable polyamides, polyaminoacid, polyesters, poly(lactic acid), poly(glycolic acid), poly(carbohydrate), poly(arteparon), poly(orthocarbonate), poly(acetyl), poly(anhydrides), biodegradable poly(dihydropyrano) and poly(dioc the ins), known in the art (Rosoff, Controlled Release of Drugs, Chap.2, pp.53-95 (1989); Heller et al, U.S. patent No. 3811444; Michaels, U.S. patent No. 3962414; Capozza, U.S. patent No. 4066747; Schmitt, U.S. patent No. 4070347; Choi et al, U.S. patent No. 4079038; Choi et al, U.S. patent No. 4093709).

In other implementations dosage form includes a compound disclosed here, placed in a polymer that releases the drug by diffusion through the polymer, or by flow through the pores, or by destruction of the polymer matrix. The polymeric form of drug delivery include the amount from 10 to 2500 mg, evenly distributed on or in the polymer. Dosage form includes at least one accessible surface at the beginning of the dose delivered. Available surface, if there is one, is covered with a pharmaceutically acceptable material, impervious to drugs (medicines). Dosage form can be obtained by methods known in the art. Example of getting the dosage form comprises blending pharmaceutically acceptable carrier, such as polyethylene glycol, with a known dose of the composition and/or compounds disclosed here, at elevated temperature (for example, 37°C) and add it to the silicone elastomer medical quality with cross-linking agent, for example, to octanoate, followed by fill in the form. Stage I repeat if necessary for each of the placenta the subsequent layer. System leave be balanced for about 1 hour to obtain a dosage form. Representative polymers to obtain the dosage forms include selected from the group consisting of olefins, vinyl polymers, additional polymers, condensed polymers, carbohydrate polymers and silicone polymers represented by polyethylene, polypropylene, polyvinyl acetate, polymethylacrylate, polyisobutylcyanoacrylate, polyalkenes, polyamide and polysilicon. Polymers and methods for their preparation are described in the art (Coleman et al. Polymers 1990, 31, 1187-1231; Roerdink et al. Drug Carrier Systems, 1989, 9, 57-10; Leong et al. Adv. Drug Delivery Rev. 1987, 1, 25, 199-233; Roff et al. Handbook of Common Polymers 1971, CRC Press; Chien et al, U.S. patent No. 3992518).

In other implementations dosage form includes a lot of small pills. Small pill for slow release provides a set of individual doses to provide different doses over time to achieve the profile of a delayed release of the drug over a period of time up to 24 hours. The matrix comprises a hydrophilic polymer selected from the group consisting of a polysaccharide, agar, agarose, natural resins (gum), the alkaline alginate, including alginate sodium, Cartagena, fucoidan, furcellaran, laminaran, hypnea, gum Arabic, resin Ghati, resin karaya, resin tragakant, smo is s seeds Ceratonia, pectin, amylopectin, gelatin and hydrophilic colloid. Hydrophilic matrix comprises multiple (4 to 50) small pills, each small pill contains a dose of the population from 10 ng, 0.5 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 5.0 mg, etc. Small pills include wall, controlling the rate of release, of a thickness of from 0.001 mm to 10 mm to provide stretched in time release drugs. Representative materials for the formation of walls include a triglyceride ester selected from the group consisting of glycerylmonostearate, glycerylmonostearate, glyceryltrinitrate, literallayout, glyceryltrinitrate and glyceryltrinitrate. Other materials for the formation of walls include polyvinyl acetate, phthalate, methylcellulose phthalate and microporous olefins. Methods of obtaining small pills disclosed in Urquhart et ah, U.S. patent No. 4434153; Urquhart et ah, U.S. patent No. 4721613; Theeuwes, U.S. patent No. 4853229; Barry, U.S. patent No. 2996431; Neville, U.S. patent No. 3139383; Mehta, U.S. patent No. 4752470.

In other implementations dosage form comprises an osmotic dosage form comprising a semipermeable wall that surrounds a therapeutic composition comprising compounds disclosed here. When used in the body of the subject of the osmotic dosage form comprising a homogeneous composition absorbs the liquid through a semipermeable membrane inside the drug is the result of form under the influence of the concentration gradient across a semi-permeable membrane. A therapeutic composition in dosage form creates a difference in osmotic pressure, which causes the introduction of a therapeutic composition by withdrawal from the dosage form over an extended period of time up to 24 hours (or in some cases up to 30 hours) to provide a controlled slow release. This delivery method can provide essentially zero order profile delivery in contrast to the profile with the peak of the formulations with immediate-release.

In other implementations dosage form comprises another osmotic dosage form comprising a wall surrounding a compartment, the wall includes a semipermeable polymeric composition permeable to the passage of fluid and almost impervious to the passage of the compounds disclosed in the present invention and located in the compartment, a layer of a composition containing the drug in the compartment, a layer of the composition eject hydrogel in the compartment, including osmotically active compound for absorption and absorption of the fluid to increase in size and ejection of the composition of the drug from the dosage form, and at least one hole in the wall for releasing composition. According to this method, the delivery of the compounds disclosed here, occurs by absorption of liquid through polipropileno the wall with the speed of the fluid is absorbed determined by the permeability of the semipermeable wall and the osmotic pressure on the semi-permeable wall, which causes the push layer to swell, while delivery of the compounds disclosed here, from the dosage form through the outlet to a subject over an extended period of time (up to 24 or even 30 hours). The composition of the hydrogel layer may include from 10 mg to 100 mg of a hydrogel selected from the group consisting of polyalkyleneglycol with an average molecular weight in the range of from 1000000 to 8000000 selected from the group consisting of polyethylene oxide with average molecular weight of 1,000,000, of polyethylene oxide with average molecular weight 2000000, of polyethylene oxide with average molecular weight 4000000, of polyethylene oxide with average molecular weight 5000000, of polyethylene oxide with average molecular weight 7000000 and polypropyleneoxide with an average molecular weight of from 1000000 to 8000000; or from 10 mg to 1000 mg of an alkali carboxymethylcellulose with an average molecular weight from 10,000 to 6000000, for example carboxymethylcellulose sodium or potassium carboxymethylcellulose. Growing a layer of hydrogel comprises from 0.0 to 350 mg, this product; from 0.1 mg to 250 mg hydroxyethylcellulose average molecular weight of 7500 to 450000 (for example, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxybutanal is wlosy or hydroxyethylcellulose) in this product; from 1 mg to 50 mg of an osmotically active agent selected from the group consisting of sodium chloride, potassium chloride, one-deputizing potassium phosphate, tartaric acid, citric acid, raffinose, magnesium sulfate, magnesium chloride, urea, Inositol, sucrose, glucose and sorbitol; from 0 to 5 mg of a colorant such as iron oxide; from 0 to 30 mg this product, from 0.1 to 30 mg hydroxypropylmethylcellulose average molecular weight of 9,000 to 225,000 selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose; 0 up to 1.5 mg of an antioxidant selected from the group consisting of ascorbic acid, butylated of hydroxyanisole, bottled hydrochinone, butylhydroxyanisole, hydroxycoumarin, bottled hydroxytoluene, cefaly, Etisalat, propylgallate, octisalate, laurilsulfate, propylhydroxybenzoate, trihydroxyacetophenone, dimethylphenol, dibutylphtalate, vitamin E, lecithin and ethanolamine and from 0 to 7 mg of a lubricant selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, magnesium oleate, calcium palmitate, suberate sodium, laurate potassium salts of fatty acids, salts of alicyclic acids, salts of aromatic acids, stearic acid, oleic acid, palmic the new acid, a mixture of salts of a fatty, alicyclic or aromatic acid, and a fatty, alicyclic or aromatic acid.

In one osmochescu dosage form a semi-permeable wall comprises a composition that is permeable to fluid and impermeable to compounds disclosed here. The wall is non-toxic and includes a polymer selected from the group consisting of acylate cellulose, diallate cellulose, triacetate cellulose, cellulose acetate, cellulose diacetate and cellulose triacetate. The wall includes 75-100 wt.% pulp stankoosnastka polymer, or the wall may also include from 0.01 to 80 wt.% poly (ethylene glycol) or 1-25 wt.% cellulose ether selected from the group consisting of hydroxypropylcellulose or hydroxypropylmethylcellulose, such as hydroxypropylmethylcellulose. The sum of the weight percent of all components of the wall 100. Inner compartment comprises a composition comprising the drug by itself or applied to the layer of composition capable of swelling of the hydrogel. The composition is capable of swelling of the hydrogel in the compartment increases in size by soaking liquid through a semipermeable wall that leads to swelling of the hydrogel and the occupation space of the compartment, resulting in the composition of the medicine is ejected from the dosage form. Layer with therapeutic component is izia and layer capable of swelling, work together in the functioning of the dosage form with the release of the compounds disclosed here, in the body of the subject over time. Dosage form includes an outlet opening in the wall that connects the environment with the internal compartment of the dosage form. The dosage form, driven by osmosis, can be obtained for delivery of the drug from the dosage form to a subject with a speed of zero order release over a period of time up to about 24 hours.

The expression "the hole", as used here, includes the methods and approaches that are applicable for the dosed release of the compounds disclosed here, from the compartment of the dosage form. Exits include at least one channel including a hole, a hole, a crack, pore, porous element, hollow fiber, capillary tube, a channel, a porous lid or porous element that provides controlled by osmosis release compounds disclosed here. Output channel includes material destroyed or washed out from the wall in a liquid medium in the application receiving at least one dimension of the outlet for controlled release. Representative materials for the formation of the outlet or multiple outlets include the destructible (corroded) polymers polyglycolic acid or polylactic acid composition of the wall, gelatinous filament, polyvinly alcohol, destructible polysaccharides, salts and oxides. Output time or many pores can be obtained by corrosive destroying compounds, for example sorbitol, in the wall. The hole has dimensions of supervised release, for example, is round, triangular, square or elliptical for the dosed release of the composition and/or drugs from dosage forms. Dosage form can be constructed with one or more output openings spaced from each other on one surface or more than one surface of the wall. The expression "liquid medium" refers to aqueous fluids in a patient person, including the gastrointestinal tract. Outlets and equipment for their formation are described in Theeuwes et al, U.S. patent No. 3845770; Theeuwes et al, U.S. patent No. 3916899; Saunders et al, U.S. patent No. 4063064; Theeuwes et al, U.S. patent No. 4088864 and Ayer et al, U.S. patent No. 4816263. Weekend openings formed by destruction (leaching) described in Ayer et al, U.S. patent No. 4200098 and Ayer et al, U.S. patent No. 4285987.

To reduce the frequency of injection dosage forms and increasing convenience to the subject and increase approval subject dosage form for oral administration of sustained-release (regardless of the specific dosage forms with delayed released the eat) preferably provides therapeutic concentrations of the compounds, disclosed here in the bloodstream of a patient over a period of at least about 6 hours, more preferably over a period of time of at least about 8 hours, more preferably over a period of time of at least about 12 hours, and most preferably within a time period of at least 24 hours.

In the case of oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients and solvents include water, saline, alkalophile (e.g., propylene glycol), polyalkylene glycols (e.g. polyethylene glycol), oils, alcohols, slightly acidic buffer solutions with pH from 4 to 6 (for example, acetate, citrate, ascorbate at a concentration of from about 5 mm to about 50 mm), etc. Optionally, you can add aromatic agents, preservatives, dyes, salts of bile acids, acylcarnitine etc.

Liquid drug formulations suitable for use with nebulizers and accessories for liquid sprays and devices for EHD (electrohydrodynamic) aerosols typically include compounds disclosed here, together with a pharmaceutically acceptable carrier, for example a liquid (e.g., alcohol, water, polyethylene glycol or perfluorocarbons). If necessary, you can add another material to change aerosol properties rastv the RA or suspension compositions and/or compounds disclosed here. In some implementations, the material is liquid, such as alcohol, glycol, polyglycol or fatty acid. Other methods of preparation of liquid solutions or suspensions of drugs for use with aerosol devices known to the person skilled in the art (Biesalski, U.S. patent No. 5112598; Biesalski, U.S. patent No. 5556611).

For topical injection of the compounds disclosed here, can be included in the composition in the form of solutions, gels, ointments, creams, suspensions, etc. as are well known in the art.

For buccal injection of the compounds disclosed herein may also be in the form of tablets, lozenges, candies, etc. prepared by known methods.

Compounds disclosed here may also be included in compositions of the rectal or vaginal compositions such as suppositories or held enemas, e.g. containing conventional basis of suppositories, for example cocoa butter or other glycerides.

Systemic formulations include those designed for injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration. Systemic compounds can be made in combination with an additional active agent, improve the criterion mucociliary clearance of the mucous membrane of the respiratory tract or reducing the viscosity of sputum. Such active agents include, but are not limited to, blockers of sodium channels, antibiotics, N-acetylcysteine, homocysteine and phospholipids.

For injection, the compounds disclosed here, can be included in compositions with aqueous solutions, such as physiologically compatible buffers such as Hanks solution, ringer's solution, physiological saline buffer or in Association with a surface-active agent (or wetting agent or surface-active agent), or get in the form of emulsions (for example, emulsions of the type water-in-oil or oil-in-water). Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitan (e.g., Tween™ 20, 40, 60, 80 or 85) and other sorbitan (for example, Span™ 20, 40, 60, 80 or 85). Compositions with surface-active agent may include from 0.05 to 5% surface-active agent or from 0.1% to 2.5% surface-active agent. The solution can contain, for example, suspendida, stabilizing and/or dispersing agents. Alternatively, compounds disclosed herein may be in powder form for mixing with a suitable vehicle before use, for example sterile water free of pyrogens.

Suitable emulsions can be obtained by using commercially available fat emulsions. Combination (or individual compounds can be dissolved in a pre-made emulsion, or alternatively they can be dissolved in oil (for example, soy oil, oil of safflower, cottonseed oil, sesame oil, grain oil, or almond oil) and to obtain an emulsion by mixing with phospholipids (e.g., phospholipids eggs, soybean phospholipids and lecithin from soy) and water. It is clear that you can add other ingredients such as glycerol or glucose, to bring toychest emulsion. Suitable emulsions usually contain 20% of oil, for example from 5 to 20%. In some implementations add EDTA as preservative.

In addition to the formulations described previously, the compounds disclosed here may also be included in the compositions of the deposited products. Such compositions with prolonged action can be administered by implantation (for example, subcutaneous or intramuscular) or by intramuscular injection. So, for example, the compounds disclosed here, can be included in compositions with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or applied in the form of poorly soluble derivatives, for example in the form of a soluble salt.

When applying for treatment and/or prevention of diseases of the compounds disclosed here, and/or including their pharmaceutical compositions can be entered by themselves or in combination with other pharmaceutical agents, including the organisations, disclosed here and/or including their pharmaceutical compositions. Compounds disclosed here, you can enter or cause themselves or in the form of pharmaceutical compositions. Specific pharmaceutical composition depends on the desired method of administration, as is well known to a person skilled in the technical field.

Compounds disclosed here, and/or including their pharmaceutical compositions can be entered to the subject by intravenous bolus injection, continuous intravenous infusion, oral tablets, oral capsules, oral solution, im injection, subcutaneous injection, percutaneous absorption, buccal absorption, intranasal absorption, inhalation, sublingual, intracerebral, intrawaginalno, rectal, topicaine, in particular through the ears, nose, eyes, or skin, or any other suitable method known to the person skilled in the art. In some implementations, the compounds disclosed here, and/or pharmaceutical composition is delivered using dosage forms with delayed release, including oral dosage forms with delayed release. The administration can be systemic or local. There are various delivery systems (e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, systems drug delivery "controlled the Aya patient analgesia" and so on), you can apply for delivery of the compounds disclosed here, and/or including their pharmaceutical compositions.

Compounds disclosed here, and/or including their pharmaceutical compositions can also be entered directly into the lungs by inhalation. For administration by inhalation the compounds disclosed here, and/or including their pharmaceutical compositions can enter into the lungs with the help of various devices. For example, you can use the inhaler with dispenser (MDI), which applies vessel containing a suitable boiling propellant, for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or you can apply other suitable gases for delivery of the compounds disclosed here, and/or including their pharmaceutical compositions.

Alternatively, you can use the inhaler dry powder (DPI) for administration of the compounds disclosed here, and/or including their pharmaceutical compositions (see, e.g., Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40, 397). Fixtures DPI usually use this mechanism as a gas kick, to create a cloud of dry powder inside a container, which the patient can breathe. A popular variation is the multiple doses (MDDPI), allowing the delivery of more than one therapeutic dose. For example, gelatin capsules, catridge on what I use in inhaler or insufflator can make it, to contain the powder mixture compositions and/or compounds disclosed here, and a suitable powder base, such as lactose or starch.

Another type of device that can be used to deliver the compounds disclosed here, and/or including pharmaceutical compositions, is a device for liquid sprays, which is produced, for example, Aradigm Corporation, Hayward, CA. System for liquid sprays are used very small nozzle for the conversion of the liquid dosage compositions in aerosol that can be inhaled.

In some implementations use a nebulizer for delivery of the compounds disclosed here, and/or including their pharmaceutical compositions. The nebulizers create aerosols from liquid dosage formulations, using, for example, ultrasound energy for the formation of very small particles that are easily inhaled (for example, Verschoyle et al, British J. Cancer, 1999, 80, Suppl. 2, 96; Armer et al, 15, U.S. patent No. 5954047; van der Linden et al, U.S. patent No. 5950619; van der Linden et al., the U.S. patent No. 5970974).

In other implementations use electrohydrodynamic aerosol device ("EHD") for delivery of the compounds disclosed here, and/or including their pharmaceutical compositions. Aerosol device EHD apply electrical energy to be transformed into aerosols of liquid medicinal solutions Il the suspensions (see, for example, Noakes et al., the U.S. patent No. 4765539; Coffee, U.S. patent No. 4962885; Coffee, international publication WO No. 94/12285; Coffee, international publication WO No. 94/14543; Coffee, international publication WO No. 95/26234; Coffee, international publication WO No. 95/26235; Coffee, international publication WO No. 95/32807). Other ways intrapulmonary delivery of the compounds disclosed here, and/or including their pharmaceutical compositions are known to the person skilled in the art and are within the scope of claims of the present disclosure.

Transdermal devices can also be used for compounds disclosed here, and/or including their pharmaceutical compositions. In some implementations, the device for transdermal delivery is the transdermal device of the matrix type (Miller et al., international publication WO No. 302004/041324). In other implementations, the device for transdermal delivery is multilaminate transdermal device (Miller, U.S. patent application 2005/0037059).

A number of compounds according to the invention and/or including pharmaceutical compositions, which will be effective for the treatment or prevention of disease in the patient, depends on the specific nature of the condition and can be determined by standard clinical approaches known in the art. The number of input connections according to izaberete the Oia and/or including their pharmaceutical compositions of course, among other factors, depends on the subject treated, the route of administration and the judgment of the treating physician.

In a particular implementation of the compounds according to the invention and/or including their pharmaceutical compositions can be used in combination therapy together with at least one other therapeutic agent. Compounds according to the invention and/or including their pharmaceutical compositions and therapeutic agent can act additively or, more preferably, a synergistic way. In some implementations, the compounds according to the invention and/or enclosing the pharmaceutical composition is administered simultaneously with the introduction of another therapeutic agent. For example, the compounds according to the invention and/or including their pharmaceutical compositions can be entered together with another therapeutic agent (e.g., including, but not limited to, together with peripheral opiate antagonist, laxative, neopytnym analgesic and so on). In other implementations, the compounds according to the invention and/or enclosing the pharmaceutical composition is administered before or after administration of other therapeutic agents.

In one implementation of the present invention is a pharmaceutical composition comprising a compound of formula (I) or its salt, hydrate or MES, what oterom X is (R)-N-methylnaltrexone, and the compound of formula (I) or its salt, hydrate or MES, in which X is a phenolic opiate, such as Oxymorphone, hydromorphone or morphine, and a pharmaceutically acceptable carrier.

Specialist in the art will understand that you can apply many modifications, both of materials and methods, without departing from the scope of claims of the present invention. Accordingly, the present implementation should be considered as illustrative and not restrictive, and the invention should not be limited to the details shown here, but can be modified within the scope of the claims specified in the enclosed claims or equivalent.

All publications and patents cited herein, are incorporated fully by reference.

The following examples illustrate the invention.

In the examples the following abbreviations are used:

HOBt: 1-hydroxybenzotriazole; PyBOP: benzotriazol-1-yl-oxy-Tris-pyrrolidinone hexaphosphate; DIEA: diisopropylethylamine and BocGlyOSu: N-(N-α-glycidyloxy)succinimide.

The drug 1

BocArg(diBoc) - OH (Bachem, of 0.47 g, 1.0 mmol) dissolved in dimethylformamide (5 ml) and mixed with HOBt (0.15 g, 1.15 mmol) and PyBOP (0.6 g, 1.15 mmol). Diisopropylethylamine (0.4 ml, 2.3 mmol) is added to the mixture, then the resulting solution is stirred for 10 min and added to the Astaro H 2NCH2CH2N(CH3)CBz (0.28 g, 1.15 mmol) in dimethylformamide (3 ml). Zamalchivaut by adding DIEA (0.4 ml, 2.3 mmol). The mixture is stirred for 2 hours and then poured into 40 ml of 5% aqueous citric acid. The product is extracted with 20 ml of a mixture of ethyl ether with ethyl acetate (5:1). The organic layer is washed with water, twice with 10 ml of 1 M aqueous solution of sodium carbonate, water and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is removed by evaporation to obtain 0.65 g (98%) of the depicted product.

The product 2

Drug (product) 1 (0.65 g, 0.98 mmol) dissolved in ethanol (10 ml). Then add the catalyst Perlman (0.32 g) and the mixture subjected to hydrogenation (1 ATM, 24 hours). The resulting mixture is filtered off from the catalyst and the solvent is removed by evaporation. The residue is then dried under vacuum for 2 hours to obtain 0,525 g (99%) of the depicted product.

Drug 3

Hydromorphone (0.21 g, of 0.74 mmol) suspended in dichloromethane (3 ml). Then added dropwise a solution of p-nitrophenylphosphate (0.16 g, of 0.79 mmol) in dichloromethane (3 ml) for 5 minutes the Reaction mixture was then voiced for 2 hours to obtain a stock solution of the depicted product, which is used in the next step.

P is apart 4

Drug (product) 2 (0.21 g, 0.38 mmol) is added to the drug 3 (mother solution, 3 ml, 0.38 mmol). Then bring the pH by the addition of triethylamine (0,056 ml, 0.4 mmol). The reaction mixture is then stirred for 6 hours. The solvent is then evaporated under vacuum and the residue dissolved in a mixture of diethyl ether with ethyl acetate (3:1, 10 ml) and washed four times with 5 ml of 1 M aqueous solution of sodium carbonate. The organic layer is washed three times with water (10 ml) and once with saturated NaCl solution (10 ml), then dried over magnesium sulfate. Solvent then removed by evaporation to obtain 0.28 g of the depicted product (87,5%).

Example 1

Hydromorphone-3-(N-methyl-N-(2-Argireline))ethylcarbamate

Drug (product) 4 (0.28 g, 0.33 mmol) dissolved in a mixture of dichloromethane and triperoxonane acid (1:1) (6 ml). The reaction mixture is then stirred for 6 hours. The solvent is then removed by evaporation under vacuum and the residue is subjected to trituration acylovir ether (10 ml). Precipitation is formed, it is filtered off, washed with diethyl ether (10 ml) four times and dried in a stream of dry nitrogen to obtain a coarse product (0.26 g). Part of the gross product (0.14 g) and purified using preparative chromatography HPLC (liquid chromatography high resolution is) with reversed phase (gradient acetonitrile) to obtain the depicted compounds (0,031 g, 29%). Mass spectrum: calculated to 541.3 observed 542,4.

The drug 5

BocGlyOSu (0.037 g, 0,136 mmol) is added under stirring to a solution of the product obtained according to example 1 (0.12 g, 0,136 mmol) in dimethylformamide (3 ml). Then the reaction mixture is added triethylamine (0,048 ml, 0,272 mmol) and the resulting solution is stirred for 2 hours. The solvent is then removed by evaporation under high vacuum and the residue is subjected to trituration diethyl ether (3 ml) to obtain the depicted compound (0.125 g, 100%).

Example 2

Hydromorphone-3-(N-methyl-N-(2-N'-glycylamino))ethylcarbamate

The drug (product) 5 remove the protection by the method of example 1 to obtain a coarse product, which was purified using preparative chromatography HPLC with reversed phase with obtaining the depicted product (0.015 g, 16%). Mass spectrum: calculated 598,3 observed 599,1.

Example 3

Hydromorphone-3-(N-methyl-N-(2-N'-acetilsalicilico))ethylcarbamate

Connection receive according to the method applied to obtain preparation 5 and example 2, but using acetic anhydride instead of BocGlyOSu. Mass spectrum: calculated 583,3 observed 584,4.

Example 4

Hydromorphone-3-(N-methyl-N-(2-N'-tert-bouteillerie))ethylcarbamate

Connection receive according to the method applied to obtain preparation 5 and example 2, but using tert-butanolate instead BocGlyOSu. Mass spectrum: calculated 625,4 observed 626,8.

Example 5

Hydromorphone-3-(N-methyl-N-(2-N'-benzoylamino))ethylcarbamate

Connection receive according to the method applied to obtain preparation 5 and example 2, but using benzoyl chloride instead BocGlyOSu. Mass spectrum: calculated kzt645.3 observed 646,7.

Example 6

Hydromorphone-3-(N-methyl-N-(N'-piperonyl-2-Argireline))ethylcarbamate

Connection receive according to the method applied to obtain preparation 5 and example 2, but using piperonylic instead BocGlyOSu. Mass spectrum: calculated 689,3 observed 690,4.

Example 7

Hydromorphone-3-(N-methyl-N-(2-isinline))ethylcarbamate

Connection receive according to the method used to obtain preparations 1-4 in example 1, but with the use of BocLys(Boc) - OH instead of BocArg(diBoc)OH.. mass Spectrum: calculated was 513.3 observed 514,2.

Example 8

Hydromorphone-3-(N-methyl-N-(2-leinil(methyl) amino)ethylcarbamate

Connection receive according to the method used in example 7, but using CH3NHCH2CH2N(CH3)CBz instead of H2NCH2CH2N(CH3 )CBz. Mass spectrum: calculated 527,3 observed 528,2.

Example 9

Hydromorphone-3-(N-methyl-N-(2-N'-arginyl(methyl)amino)ethylcarbamate

Connection receive according to the method used to obtain preparations 1-4 in example 1, but with the use of CH3NHCH2CH2N(CH3)CBz instead of H2NCH2CH2N(CH3)CBz. Mass spectrum: calculated 555,3; observed 556,3.

Example 10

Hydromorphone-3-(N-methyl-N-(2-glutamylation))ethylcarbamate

Connection receive according to the method used to obtain preparations 1-4 in example 1, but using BocGlu(OButHE instead BocArg(diBoc) - OH. Mass spectrum: calculated 514,2 observed 515,3.

Example 11

Hydromorphone-3-(N-methyl-N-(2-aspartamine))ethylcarbamate

Connection receive according to the method used to obtain preparations 1-4 in example 1, but using BocAsp(OtBu)OSu instead BocArg(diBoc) - OH. Mass spectrum: calculated 500,23 observed 501,5.

Example 12

Hydromorphone-3-(N-methyl-N-(2-tyrosinemia))ethylcarbamate

Connection receive according to the method used to obtain preparations 1-4 in example 1, but using BocTyr(OtBu) - OH instead of BocArg(diBoc) - OH. Mass spectrum: calculated 548,26 observed 549,3.

Comparative example 1

Connect the get out the way used to obtain preparations 1-4 in example 1, but using cyclopentenopyridine instead of H2NCH2CH2N(CH3)CBz. Mass spectrum: calculated 553,3 observed 554,5.

The drug 6

Oxymorphone (0.15 g, 0.5 mmol) suspended in dichloromethane (3 ml). Then added dropwise p-nitrophenylphosphate (0,105 g, 0.52 mmol) in dichloromethane (5 ml) for 5 minutes the Reaction mixture was then voiced for 2 hours to obtain stock solution shows the connection, which is used in the next step.

Preparation 7

Drug (product) 2, previously described, (0,265 g, 0.5 mmol) is added to the drug 6 (mother solution, 8 ml, 0.5 mmol). Then bring the pH by the addition of triethylamine (of 0.14 ml, 1.0 mmol). The reaction mixture is then stirred for 4 hours. The solvent is then evaporated under vacuum and the residue dissolved in a mixture of diethyl ether with ethyl acetate (3:1, 10 ml) and washed 4 times with 5 ml of 1 M aqueous solution of sodium carbonate. The organic layer is then washed three times with water (10 ml) and once with saturated sodium chloride solution (10 ml), then dried over magnesium sulfate. The solvent is then removed by evaporation under vacuum to obtain 0.39 g of the depicted product (90%).

Example 13

Oxymorphone-3-(N-methyl-N-(2-Argireline))eTalk Ramat

Drug (product) 7 (0.39 g, 0.46 mmol) dissolved in a mixture of dichloromethane with triperoxonane acid (6 ml). The reaction mixture is then stirred for 6 hours. The solvent is then removed by evaporation under vacuum and the residue is subjected to trituration ethyl ether (10 ml). Precipitation is formed, it is filtered off, washed with diethyl ether (10 ml) four times and dried in a stream of dry nitrogen to obtain a coarse product (0,46 g). Part of the gross product (0.06 g) and purified using preparative chromatography HPLC with reversed phase (gradient acetonitrile) to obtain the depicted compound (0.035 g, 90%). Mass spectrum: calculated 557,3 observed 558,0.

Preparation 8

BocGlyOSu (0,065 g, 0.24 mmol) is added under stirring to the solution of the coarse product from example 13 (0.2 g, 0.22 mmol) in dimethylformamide (3 ml). Then the reaction mixture is added triethylamine (of 0.066 ml, 0.48 mmol) and the resulting solution is stirred for 2 hours. The solvent is then removed by evaporation under high vacuum and the residue is subjected to trituration diethyl ether (3 x 3 ml) to obtain the depicted compounds (0,164 g, 79%).

Example 14

Oxymorphone-3-(N-methyl-N-(2-N'-glycylamino))ethylcarbamate

The drug (product) 8 remove protections the method according to example 13 to obtain a coarse product, which purify using preparative chromatography HPLC with reversed phase with obtaining the depicted product (by 0.055 g, 44%). Mass spectrum: calculated 614,3 observed 615,4.

Example 15

Oxymorphone-3-(N-methyl-N-(2-N'-acetilsalicilico))ethylcarbamate

Connection receive and purified according to the method applied to obtain preparation 8 and example 14, but using acetic anhydride instead of BocGlyOSu. Mass spectrum: calculated 599,3 observed 600,4.

Preparation 9

Drug (product) 9 synthesized according to the method described for preparation 7 using instead of morphine Oxymorphone, obtaining the mother liquor of the depicted product, which is used later to obtain the drug 10.

The drug 10

Drug (product) 10 synthesized according to the method described for preparation 12, obtaining images of the product in the amount of 0.85 g (92%).

Example 16

Morphine-3-(N-methyl-N-(2-Argireline))ethylcarbamate

Drug (product) 16 synthesized according to the method described in example 13, to obtain a coarse product (0,93 g). Part of the gross product (0.08 g) and purified using preparative chromatography HPLC with reversed phase (gradient acetonitrile) to obtain the depicted compounds (0,043 g, 45%). The special is Tr mass: calculated 541,6, the observed 542,6.

Preparation 11

Drug (product) 11 synthesized according to the method described for preparation 13, to obtain the depicted compound (0.18 g, 84%).

Example 17

Morphine-3-(N-methyl-N-(2-N'-glycylamino))ethylcarbamate

The drug (product) 11 remove the protection by the method described in example 13, to obtain a coarse product, which is purified using preparative chromatography HPLC with reversed phase with obtaining the depicted product (0.036 g, 40%). Mass spectrum: calculated 598,7 observed 599,6.

Example 18

Morphine-3-(N-methyl-N-(2-N'-acetilsalicilico))ethylcarbamate

Connection receive and purified according to the method described for preparation 8 and example 14, but using acetic anhydride instead of BocGlyOSu. Mass spectrum: calculated 583,7 observed 584,5.

Preparation 12

Naltrexone in the form of a free base get in the way similar to that described in the patent US 4176186.

(R)-N-naltrexone synthesized by the method similar to that described in the patent WO 2006127899.

Naltrexone (0.34 g, 1.0 mmol) dissolved in dichloromethane (10 ml). Then added dropwise p-nitrophenylarsonic (0,212 g, 1.1 mmol) in dichloromethane (5 ml) for 5 minutes the Reaction mixture was then voiced within 2 h the with to obtain a stock solution of the depicted product, which is used in the next step.

Preparation 13

Drug (product) 12 (mother solution, 15 ml, 1.0 mmol) are added to a solution of 0,265 g (1.05 mmol) of benzyl-2-(methylamino)ethylcarbamate hydrochloride in 10 ml of dimethylformamide. Then bring the pH by the addition of triethylamine (of 0.28 ml, 2.0 mmol). The reaction mixture is then stirred for 2 hours. The solvent is then evaporated under vacuum and the residue is dissolved in ethyl acetate (20 ml) and washed four times with 10 ml of 1 M aqueous solution of sodium carbonate. The organic layer is then washed three times with water (10 ml) and once with saturated sodium chloride solution (10 ml), then dried over magnesium sulfate. The solvent is then removed by evaporation to obtain the depicted product (0,425 g, 74%). Mass spectrum: calculated 575,26 observed 576,4.

Preparation 14

Drug (product) 13 (0,425 g of 0.74 mmol) dissolved in 5 ml of dry acetone. Then add methyliodide (1.42 g, 10 mmol) and the mixture is heated in a test tube with a cap at 85°C for 3 days. The solvent is removed by evaporation. The residue is then dissolved in 10 ml of methanol and applied on a column with 4 g of anion exchange resin in the form of chloride (DOWEX 1×2-200). Chloride salt elute from the column using 50 ml of methanol. The solution is then evaporated to a volume of 10 ml and mixed with 2 g silicagel is. The remaining solvent is then evaporated and the residue in the form of a dry powder is applied on a column of silica gel. The remaining source material again elute with a mixture of dichloromethane with 1 M solution of ammonia in methanol (95:5). Then elute the product with a mixture of dichloromethane with 1 M solution of ammonia in methanol (70:30) to obtain the depicted compound (0.125 g, 27%).

Example 19

Drug (product) 14 (0.125 g, 0.2 mmol) dissolved in triperoxonane acid (3 ml). Add a 1 M solution of tribromide boron in dichloromethane (0.4 ml, 0.4 mmol) at 0-5°C. the Mixture is stirred for 2 hours. The solvent is removed under vacuum. To the residue is mixed with 10 ml of 3 n aqueous solution of hydrochloric acid and the mixture is stirred for 16 hours. After evaporation of the water under vacuum crude product was then purified using preparative chromatography HPLC with reversed phase (gradient acetonitrile) to obtain the depicted compounds (0,032 g, 30%). Mass spectrum: calculated 456,25 observed 456,4.

Preparation 15

Drug (product) get 15 according to the method described for preparation 1, but using BocLys(Boc) - OH to obtain the depicted product with a yield of 74%.

Preparation 16

Drug (product) 16 receive according to the method described for preparation 2, but using the drug 15 is for receiving the depicted product with a yield of 95%.

The drug is 17

Drug (product) 17 receive according to the method described for preparation 12, but using the drug 16 to obtain the depicted product with a yield of 66%.

Preparation 18

Connection receive according to the method described for preparation 14. Exit 16%.

Example 20

Connection get in the way described in example 1. Crude product was then purified using preparative chromatography HPLC with reversed phase (gradient acetonitrile) to obtain the depicted compounds (33%). Mass spectrum: calculated 584,3 observed 584,5.

Protocols for evaluation of test compounds

1A. "Kitchen" test

The stability of the test compounds in the presence of readily available household chemicals, acetic acid (vinegar) and sodium bicarbonate (baking soda) can be demonstrated using the following "kitchen" test.

Dissolve 0.5 mg of test compound in 1 ml each of the following solutions, corresponding to the possible chemicals households: 30% aqueous solution of acetic acid, 50% aqueous ethanol and a saturated aqueous solution of sodium bicarbonate (baking soda). Each solution is kept at room temperature for 20-24 h and then heated at 85°C is for 20-24 hours. Release hydromorphone and overall stability is followed by analytical HPLC. The connection is considered passed this test, if after 20 h, the concentration of hydromorphone does not exceed 10% of the source material or other product degradation.

The connection shown here as examples, have passed this test.

1B. Demonstration of a controlled release of the original medications from the "activated" prodrugs

Demonstration of in vitro

Controlled release of the original drug (e.g., hydromorphone) of prodrugs demonstrated by the synthesis and in vitro testing of several compounds shown in table 1. Compounds a and C are examples of "activated" prodrugs, where enzymatic-tsepliaeva activating group is not to assess the kinetics determined by the sequence of reactions intramolecular cyclization and release. As described above, the sequence of intramolecular reactions of cyclization and release leads to the simultaneous formation of cyclic urea and release the source drugs.

The kinetics of release of these compounds evaluated in aqueous solutions at high pH. Release hydromorphone in the course of these reactions confirmed using LC-MS (liquid chromatography in the op is Tania's story with mass spectrometry) analysis. Compound D is an interesting example of a molecule bearing a nucleophilic nitrogen atom, whilst still remaining unable to intramolecular cyclization reaction-release due to conformational restrictions imposed piperazinonyl cycle (i.e. he can't take the conformation required for nucleophilic transfer single pair of electrons on the nitrogen on the carbonyl carbon urethane link). An additional example of the structural properties required for the reaction of intramolecular cyclization-release provided by the connection that represents the molecule in the "inactive" form (i.e. a single pair of electron on atsilirovannym the nitrogen atom is not available for nucleophilic attack carbamate). It is interesting to note that such reactions by vnutrimolekulyarnoi cyclization-release can be inhibited at low pH as a result of decontamination of nucleophilic nitrogen atom by protonation.

These data confirm the functional role separation groups and "activated" nucleophilic nitrogen in the reaction vnutrimolekulyarnoi cyclization and release of a molecule of the original drug.

Table 1
The release of hydromorphone from the prodrug in water Rast is the ora
Structure% of products hydromorphone for 20 h
pH 7.51011,5
10100100And
005In
90100100
000D

Demonstration of in vivo

In order to investigate the formation of the original drug from the prodrug in vivo, the compounds shown in table 2, are synthesized and injected intravenously to rats. Following the introduction of the dose measured levels of hydromorphone in plasma, as described in the experimental section. The compounds a and b are examples of "activated" prodrugs that have fermentate is but otsepleniya activating groups are missing in order to conduct a specific assessment of the kinetics due to the sequence of reactions intramolecular cyclization-release. As described above, the sequence of reactions intramolecular cyclization-release leads to the simultaneous formation of cyclic urea and release the source drugs.

When such drugs are administered to rats, hydromorphone released. The connection is an interesting example of a molecule bearing a nucleophilic nitrogen atom, whilst still remaining incapable of reactions intramolecular cyclization-release due to conformational restrictions imposed piperazinone cycle (i.e. he can't take the conformation required for nucleophilic transfer single pair of electrons from the nitrogen to the carbonyl carbon urethane link). When this compound is administered to rats, hydromorphone is not detected. Compound D is an example of a prodrug, where enzymatic-tsepliaeva protective group attached to the nitrogen of the piperazine. Investigate whether this molecule direct indirect enzyme hydrolysis of the urethane link. Data show that this process does not occur in vivo. Interestingly, when rats administered the compound D is formed a connection With and hydromorphone is not released, which provides additional evidence of the activation of the considered prodrugs in vivo.

Table 3
Release hydromorphone (NM) of prodrugs after intravenous administration to rats
StructureWithmaxNM (ng/ml) after intravenous doses
And1050
In204
0
D0

2. Analysis of binding of human receptor µ-opiate-in vitro

In this test measure the affinity of test compounds to the receptor µ-opiate compared to hydromorphone.

Basic procedure:

The basic procedure is carried out according to the method described by Wang, J.-B., Johnson, P.S., Perscio, A.M., Hawkins, A.L., Griffin, CA. and UhI, G.R. (1994). FEBS Lett., 338: 217-222.

Analysis: the receptor µ-opiate.

Origin: human recombinant (cells SOME 293).

Control connection: [d-Ala2N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO).

Radioactive ligand: [ 3H]DAMGO (0.5 nm).

Non-specific ligand: naloxone (10 μm).

Incubation of 120 min at 22°C.

Method of detecting scintillation counter.

The analysis and presentation of results. Specific binding to the receptor is defined as the difference between total binding and nonspecific binding determined in the presence of excess unlabeled ligand. The result is presented as a percent of control specific binding and how the observed inhibition of control specific binding obtained in the presence of test compounds. The values of the IC50(concentration in moles, leading to half-maximal inhibition of control specific binding) and hill coefficients (nH) is determined using an approximation curves competitive inhibition by the hill equation using nonlinear regression.

The results:

Table 4
ExampleIC50for the human µ-opioid receptors
Hydromorphone hydrochloride (nm)1×10-9
7of 7.9×10-7
12,1×10 -6
3of 1.3×10-6
6of 7.9×10-7

The above results are consistent with the data on the relationship between structure and activity of opiates, known from the literature, obtained by screening these representative molecules show the inactivation of opiates when joining progroup to the phenolic residue hydromorphone.

3. Pharmacokinetic data

The concentration of hydromorphone in plasma depending on time after intravenous administration in rats

Intravenous administration of test compound dissolved in physiological solution (2 mg/ml) and administered by injection into the tail vein or the jugular vein through the cannula to male rats Sprague-Dawley. Hydromorphone (NM) in an amount of 1 mg/kg, oxyhydrogen (Ω) in the amount of 0.5 mg/kg morphine (MR) in an amount of 1 mg/kg and N-methylnaltrexone (N-MTX) in an amount of 2 mg/kg used as positive controls and test compounds dosed at the equivalent dose of the original opiate (e.g., equivalent to 1 mg/kg, 0.5 mg/kg or 2 mg/kg). At specific points in time the blood is taken, repay with methanol, centrifuged at 14000 rpm at 4°C and stored at -80°C until analysis. Samples quantitatively evaluated using LS/MS/MS using ABI3000 triple quadrup the high mass spectrometer.

Oral introduction. The test compound dissolved in saline (20 mg/ml) and administered orally to male rats Sprague-Dawley with a cannula in the jugular vein. NM, OM, MR at 10 mg/kg and N-MTX (20 mg/kg used as positive controls and test compound dose approximately equivalent to the dose of the original opiate (e.g., equivalent to 10 or 20 mg/kg). At specific points in time the blood is taken, repay with methanol, centrifuged at 14000 rpm at 4°C and stored at -80°C until analysis. Samples quantitatively evaluated using LS/MS/MS using ABI3000 triple quadrupole mass spectrometer.

Results

Table 5
The maximum concentration (Cmax) of hydromorphone (NM)found in the blood of rats after intravenous doses
ExampleCmax NM (ng/ml) after intravenous doses
Hydromorphone352
7208
817
155
3 17
9231
63
278
1133
1248

Table 6
The maximum concentration of hydromorphone (NM)found in the blood of rats after oral (PO) administration
ExampleCmax NM (ng/ml) after oral administration
Hydromorphone45
744
311
235
618
1134
1221

Compared with hydromorphone, the compounds according to the invention show smaller values of Cmax hydromorphone when administered intravenously, however, are similar to gidromehanizaciya Cmax for oral administration.

Table 7
The maximum concentration (Cmax) of Oxymorphone (Ω)found in the blood of rats after intravenous doses
ExampleCmax Ω (ng/ml) after intravenous doses
Oxymorphone432
13303
14205
154

Table 8
The maximum concentration of Oxymorphone (Ω)found in the blood of rats after oral administration of doses
ExampleCmax Ω (ng/ml) after oral administration of doses
Oxymorphone7,8
137,8
1415,5
1513,3

Compared with Oxymorphone, the compounds according to the invention shows Aut smaller values of Cmax of Oxymorphone intravenous, however, are similar to Oxymorphone values of Cmax when administered orally.

Table 9
The maximum concentration (Cmax) of morphine (MR)found in the blood of rats after intravenous doses
ExampleCmax MR (ng/ml) after intravenous doses
Morphine111,5
1757,7
180

Table 10
The maximum concentration of morphine (MR)found in the blood of rats after oral administration of doses
ExampleCmax MR (ng/ml) after oral administration of doses
Morphine41,7
1723,7
1855,2

Compared with morphine, the compounds according to the invention show smaller values of Cmax of morphine when administered intravenously, but the show is similar to morphine Cmax values for oral administration.

Table 11
The maximum concentration of (R)-N-methylnaltrexone (N-MTX)found in the blood of rats after oral administration of doses. It should be noted that unlike the previous examples of prodrugs, which are batched in equimolar concentrations, these compounds are dosed in equal masses (20 mg/kg)
ExampleCmax of N-MTX (ng/ml) after oral administration of doses
N-methylnaltrexone6
1971

The compound of example 19, which is the secondary urethane prodrug of (R)-N-methylnaltrexone, describes one aspect of the invention, representing a way to provide patient-activated after the introduction of antagonist phenolic opiate controlled release, in this case, the opiate antagonist with peripheral action. Compared with (R)-N-methylnaltrexone connection shows the best values of Cmax (R)-N-methylnaltrexone in oral introduction.

Figure 1. The concentration of N-MTX in plasma depending on time after oral administration in rats. The solid line represents the concentration of N-MTX in plasma after oral call is placed N-MTX (20 mg/kg The dotted line represents the concentration of N-MTX in plasma after oral administration of the compound of example 19 in the amount of 20 mg/kg

Figure 2. The concentration of hydromorphone and N-MTX in plasma depending on time after oral administration of prodrugs in rats. The solid line represents the concentration of hydromorphone in plasma after oral administration of the compound of example 3 in an amount of 10 mg/kg Dotted line represents the concentration of N-MTX in plasma after oral administration of the compound of example 19 in the amount of 20 mg/kg

When considering the curves of changes in plasma concentrations depending on time figure 1 it is clear that the use of (R)-N-methylnaltrexone may be limited due to its poor pharmacokinetic profile (e.g., bioavailability in oral introduction). This limitation can be overcome by using prodrugs represented by the compound of example 19, showing the improved pharmacokinetic profile (e.g., increased bioavailability in oral introduction). Additionally, figure 2 shows that the use of prodrugs represented by the compounds according to examples 3 and 19, leads to higher and possibly complementary (complimentary) levels of agonist and atagonist opiates in the plasma, which can be obtained in oral introduction of the respective prodrugs.

Conc is of hydromorphone in plasma depending on time after intravenous administration in dogs.

Fifteen male dog breed Beagle away from the colony at the test station (Test Facility) animals and divided into five groups of three animals in the group. Animals selected for study on the basis of satisfactory health, as defined by the staff veterinarian with tests on the state of health prior to the study. Animals subjected to starvation during the night before each dose and give them food after approximately 4 hours after each dose. All substances stored at 22±5°C to a dose in dry conditions.

Intravenous

Test compounds are prepared in 0.9% NaCl solution in the desired concentration of 0.4 mg/ml (0.4 mg/kg of the final dose) for intravenous injection. Hydromorphone is prepared in 0.9% NaCl solution in the desired concentration of 0.2 and 0.1 mg/ml (0.1 and 0.2 mg/kg final dose) for intravenous injection.

The sample, comprising a dose selected from each formulation for intravenous doses up to its introduction before and after filtering. All sample compositions doses maintained at -20±5°C until analysis.

The test compound is injected through temporary transcutaneous catheters placed in a peripheral vein in an amount of 0.4 mg/kg and the dose volume of 1 ml/kg Animals get slow intravenous bolus entered for 1.5 minutes hydromorphone is administered in a similar manner in the number of the e 0,2 MK/kg and the dose volume of 1 ml/kg Animals get slow intravenous bolus injected for 2 minutes Immediately after intravenous catheters washed with 3 ml of saline before removal. Blood samples (0.5 ml, whole blood, anticoagulant Li-heparin) taken before the dose and at certain time points within 24 h after intravenous injection. All samples are taken by direct puncture of peripheral veins, covered with methanol, centrifuged at 14000 rpm and stored at -80°C until analysis. Samples quantitatively evaluated using LS/MS/MS using ABI3000 triple quadrupole mass spectrometer.

Oral administration

Test compounds are prepared in 0.9% NaCl solution in the desired concentration of 4 mg/ml (4 mg/kg final dose) for oral administration. Hydromorphone is prepared in 0.9% NaCl solution in the desired concentration of 2 mg/ml (2 mg/kg of the final dose) for oral administration. Compositions for oral administration are mixed by stirring and, if necessary, speak to dissolve. A sample of the compound dose (0.15 ml) are selected from each formulation for oral administration before administration of the dose. All sample compositions doses maintained at -20±5°C until analysis.

Test compounds administered orally through a feeding tube in the amount of 4 mg/kg and the dose volume of 1 ml/kg hydromorphone administered orally che is ez feeding tube in the amount of 2 mg/kg and the dose volume of 1 ml/kg Immediately after oral administration of tube feeding washed with 10 ml of water before you delete them. Blood samples (0.5 ml, whole blood, anticoagulant Li-heparin) taken before the dose and at certain points in time within 24 hours after oral administration. All samples are taken by direct puncture of peripheral veins, quenched with methanol, centrifuged at 14000 rpm and stored at -80°C until analysis. Samples quantitatively evaluated using LS/MS/MS using ABI3000 triple quadrupole mass spectrometer.

Results

Table 12
The maximum concentration (Cmax) of hydromorphone (NM)found in the blood of dogs after intravenous doses
ExampleCmax H (ng/ml) after intravenous doses
Hydromorphone55,7
234,3
30
617,2

Table 13
Maximum conc who trace hydromorphone (NM), detected in the blood of dogs after oral administration of doses
ExampleCmax NM (ng/ml) after oral administration of doses
Hydromorphone58,2
235,8
355,9
621,8

Compared with hydromorphone, the compounds according to the invention show smaller values of Cmax hydromorphone when administered intravenously, however, are similar to hydromorphone values of Cmax when administered orally.

Taken together, these test data show that the compounds according to the invention is able to provide patients activated after the introduction of phenolic opioids controlled release. In particular, the data show that the prodrug release opioids when administered orally, but withheld from release of opiates in the conditions normally applied by those who would like to abuse the medication.

1. The compound of structural formula (I)

or its pharmaceutically acceptable salt, MES or hydrate,
where X is a phenolic opiate, in which the hydrogen atom of the hydroxyl group of the substituted phenol is Valentey connection with-C(O)-Y-(C(R 1)(R2))n-N-C(R3)(R4);
Y is-NR5-, R5is (C1-6) alkyl;
n is 2 or 3,
each of R1and R2independently is hydrogen, alkyl or substituted alkyl;
R3is hydrogen or stands;
R4is a residue of L-amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, shed, serine, threonine, tryptophan, tyrosine, lysine and valine, residue of the dipeptide or Tripeptide, consisting of two or three L-amino acid residues independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine, lysine and valine, or the remainder of their N-acyl derivatives.

2. The compound according to claim 1, where each X is Oxymorphone, hydromorphone or morphine.

3. The compound according to claim 1 or 2, where R5is1-4the alkyl.

4. The compound according to claim 3, where R5is stands.

5. The connection according to one of claims 1 to 4, where each R1and R2independently is hydrogen or alkyl.

6. The compound according to claim 5, where each of R1and R2the two who is hydrogen.

7. The compound according to any one of claims 1 to 6, where R3is hydrogen.

8. The connection section 12, where R4is a residue of L-amino acids.

9. The compound according to claim 1, where R4is a remnant of the N-acyl derivative of L-amino acids selected from alanine, arginine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine, lysine and valine.

10. The compound according to claim 1, where R5is (C1-4)alkyl; each of R1and R2is hydrogen.

11. The connection of claim 10, where R3is hydrogen.

12. The compound according to claim 1, where R5is stands; R1and R2each is hydrogen; n is equal to 2.

13. The connection section 12, where R3is hydrogen.

14. The compound according to claim 1, where R4is a residue of arginine, N-acetylarginine, N-tert-mutanolysin, N-benzoylecgonine, N-piperacillin, N-glycinergic, lysine, glutamic acid, aspartic acid, tyrosine, Proline and N-lisiniprol.

15. The connection 14, where R4is a residue of arginine, N-acetylarginine, N-tert-mutanolysin, N-benzoylecgonine, N-piperacillin, N-glycinergic, lysine, glutamic acid, Proline and N-lisiniprol.

16. Hydromorphone 3-(N-methyl-N2-N'-acetilsalicilico)ethylcarbamate or its pharmaceutically acceptable salt.

17. The method of obtaining the compounds of formula (I) or its pharmaceutically acceptable salt as defined in any one of claims 1 to 16, which includes the interaction of the compounds of formula (III)

or a protected derivative,
in which Y, R1, R2, n, R3and R4as defined for formula I, with a compound of formula (IV)

where X is as defined for formula I, M represents a leaving atom or group,
with the subsequent removal of any protective group and, if necessary, by acylation of this compound and/or the formation of pharmaceutically acceptable salts.

18. Pharmaceutical composition, controlling the release of phenolic opioids, including compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

19. A method of treating pain in a patient who needs it, including the introduction of an effective amount of a compound according to any one of claims 1 to 16.



 

Same patents:

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: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to specific compounds of 1-substituted 3,4-tetrahydroisoquinoline derivative. Invention also relates to pharmaceutical composition based on claimed compounds, to blocker of N-type Ca2+- channel based on claimed compounds, to application of claimed compounds, as well as to method of prevention or treatment of some pathologic conditions.

EFFECT: obtained are novel 3,4-tetrahydroisoquinoline derivatives, having substituent in 1-position and possessing blocking action on N-type Ca2+- channels.

15 cl, 129 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for preventing and/or treating neuropathic pain containing (+) or (-) 2-[(substituted-indene-7-uloxy)methyl]morpholine of formula (I) or its pharmaceutically acceptable salt as an active ingredient. What is presented is the agent for preventing or treating allodynia, hyperalgesia, hyperesthesia, spontaneous pain, cancer-associated pain, trifacial neuralgia, phantom limb pain, postherpetic pain, fibromyalgia, low back/leg pain, thalamic pain, peripheral compression neuropathy, atypical facial pain, spinal injury accompanying pain, multiple sclerosis accompanying pain, chemotherapy induced neuropathy accompanying pain, cancer-associated pain an analgesic effect on which of a narcotic analgesic such as morphine is insufficient, diabetic neuropathy accompanying pain, etc.

EFFECT: invention provides the excellent agent for preventing or treating neuropathic pain.

4 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form contains oxycodone hydrochloride as a physiologically active substance (A), optionally one or more physiologically combined excipients (B), a synthetic or natural polymer (C) and optionally natural, semisynthetic or synthetic wax (D).

EFFECT: dosage form of oxycodone hydrochloride possess degradation resistance of at least 400 N to less than 500 N, and releases max 99% of oxycodone hydrochloride in the physiological conditions after 5 h.

14 cl, 7 dwg, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide, and/or their mixture, as well as to applying it in a pharmaceutical composition, a method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease. Also, the invention refers to methods for preparing N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide and its intermediate compounds. .

EFFECT: developing the method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease.

12 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: medicine.

SUBSTANCE: there are described substituted imidazo[2,1-b]thiazoles of general formula the R1, R1, R3 R4, M1, M2 radical values are presented in the patent claim cl. 1, as well as methods for making them, drug preparations containing these compounds and application of these compounds for making the drug preparations.

EFFECT: higher efficacy.

23 cl, 3 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaadamantane derivatives of formula (I), to their pharmaceutically acceptable salts possessing the properties of nAChR ligands, their application, a method of treating and based pharmaceutical compositions, and also to intermediate compounds of formula (VI) and (VII) and to application of the compound of formula (V) for preparing the compound (I). In general formulas

L1 represents -O- or -NRa-; A represents -Ar1 or -Ar2-L2- Ar3; Ar1 represents 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxyalkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2, (NH2)carbonyl and oxido; Ar2 represents 5-6-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxy alkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2 and (NH2) carbonyl; Ar3 represents aryl, optionally substituted alkoxy, alkoxyhalogenalkyl, alkyl, aryl, halogenalkoxy, halogen, hydroxy and -NH2; or Ar3 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, carboxy, carboxyalkyl, halogenalkyl, heterocyclyl and tritylaryl; L2 represents a bond, -O- or -C(O)NRa-; and Ra represents hydrogen.

EFFECT: preparing the pharmaceutically acceptable salts possessing the properties of nAChR ligands.

41 cl, 11 dwg, 162 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form for pain management and controlled release of 3-(2-dimethylaminomethylcyclohexyl)phenol or one of its pharmaceutically acceptable salts contains said active substance and a polymer matrix of cellulose ether, which has a viscosity ranging within 3000 to 150000 mPa·s in the concentration of 2.0 wt % in a water solution at 20°C. Cellulose ether is selected from a group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. The dosage form ensures in vivo a maximum plasma level of the active substance in 2-10 h.

EFFECT: dosage form under the invention provides maintaining the plasma concentration of the active substance 3-(2-dimethylaminomethylcyclohexyl)phenol at a pharmacologically effective level for at least 12 h and shows minimum spectrum of side effects including nausea and/or vomiting.

35 cl, 1 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a sublingual tablet and a method for preparing it. The sublingual tablet contains an opioid 20 mg/tablet applicable for sublingual application, a directly compressible diluent in the form of an inert core presenting considerably spherical granules containing sucrose and starch. The inert core is covered with at least one active layer containing at least 5 wt % of the inert core of said opioid. A method for preparing the sublingual low-dose opioid tablet involves a stage of producing microgranules by spraying a solution, a suspension or a colloidal dispersion containing said opioid on a surface of the inert core, and compressing the prepared microgranules. The sublingual tablets under the invention have disintegration time making less than 15 min., and fragility making less than 1%.

EFFECT: fast opioid release promotes immediate absorption of the latter in a buccal cavity and fast pain management.

22 cl, 1 dwg, 5 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents an agent showing adaptogenic, tonic and general tonic action and containing ascorbic acid, nicotinamide, riboflavin, pyridoxine, differing by the fact that it additionally contains dry guarana extract, magnesium gluconate, magnesium citrate, calcium pantotenate, thiamine hydrochloride, folic acid, fructose, citric acid, aromatiser, sweetening agent, a preserving agent, water with the ingredients found in certain proportions, wt %.

EFFECT: invention provides intensified pharmacological action.

2 cl, 8 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and represents composition, which possesses adaptogenic, general tonic and working capacity-increasing action, which contains nicotineamide, alfa-tocopherol acetate, pyridoxine hydrochloride, riboflavin beta-carotene, folic acid, biotin, cyanocarbolomine, coenzyme Q10, potassium hydrogen orthophosphate, inositol, choline, soy lecithin, zinc gluconate, calcium pantothenate, thiamine hydrochloride, vitamin D, fructose, citric acid, ascorbic acid, preservative, sweetener, fragrance, water, components in composition being in specified weight ratio.

EFFECT: invention ensures increase of work capacity and endurance.

7 ex, 1 tbl

Up!