JP5877403B2

Oligomer-opioid agonist conjugates

Abstract

This record has no abstract on file.

JP5877403B2, drawing sheet 1 — Sheet 1 of 62

Term

Projected expiry 9 May 2033.

14 claims: 1 independent, 13 dependent

1
以下の構造を有する化合物およびその薬剤として許容される塩であって、nが1~30である、化合物およびその薬剤として許容される塩。
2
nが1~10である、請求項1に記載の化合物。
3
請求項1に記載の化合物および必要に応じて薬剤として許容される賦形剤を含む組成物。
4
請求項1に記載の化合物を含む組成物であって、該化合物が投薬形態で存在する、組成物。
5
nが1である、請求項2に記載の化合物。
6
nが2である、請求項2に記載の化合物。
7
nが3である、請求項2に記載の化合物。
8
nが4である、請求項2に記載の化合物。
9
nが5である、請求項2に記載の化合物。
10
nが6である、請求項2に記載の化合物。
11
nが7である、請求項2に記載の化合物。
12
nが8である、請求項2に記載の化合物。
13
nが9である、請求項2に記載の化合物。
14
nが10である、請求項2に記載の化合物。

Independent claims14

151 paragraphs, as filed

Description of related application This application claims the interests of US Provisional Application No. 60 / 906,387 filed on March 12, 2007 under United States Code Vol. 35, No. 119 (e), and by reference. Incorporated into the specification.

Technical field The present invention provides chemically modified opioid agonists that have certain advantages over opioid agonists that lack (especially) chemical modifications. The chemically modified opioid agonists described herein are relevant and / or have applications in the fields of drug discovery, drug therapy, physiology, organic chemistry, and polymer chemistry. ..

Opioid agonists such as morphine have been used for many years to treat patients suffering from pain. Opioid agonists exert analgesic and other pharmacological effects through interaction with opioid receptors, including three major types of opioid receptors: mu (μ) receptor and kappa (κ) receptor. There are bodies and delta (δ) receptors. Opioid agonists typically have agonistic activity at other opioid receptors (particularly at increased concentrations), but most clinically used opioid agonists are relatively selective for mu receptors. ..

Opioids exert their effects by selectively suppressing the release of neurotransmitters such as acetylcholine, norepinephrine, dopamine, serotonin, and substance P.

Pharmacologically, opioid agonists form important agents used in pain management. Unfortunately, the use of opioid agonists entails potential abuse. In addition, oral administration of opioid agonists often results in significant first-pass metabolism. In addition, administration of opioid agonists results in significant central nervous system mediating effects such as respiratory depression, which can be fatal. Therefore, reduction of any one of these, or another property, will enhance their desirability as a therapeutic agent. The present invention attempts to address these and other needs in the prior art by providing (particularly) a complex of a water-soluble non-peptide oligomer and an opioid agonist.

In one or more embodiments of the invention, a compound is provided that comprises a residue of an opioid agonist that is covalently attached to a water-soluble non-peptide oligomer (preferably via a stable bond). In one or more embodiments of the invention, a compound is provided that comprises a residue of a kappa opioid agonist that is co-linked (preferably via a stable bond) to a water-soluble non-peptide oligomer [ Here, kappa opioid agonists can (i) be preferentially selected for kappa opioid receptors over both muopioid and delta opioid receptors within the same mammalian species, and (ii) kappa receptors. It should be understood that it has agonistic activity.] In one or more embodiments of the invention, a compound is provided that comprises a residue of a mu opioid agonist that is co-linked (preferably via a stable bond) to a water-soluble non-peptide oligomer [ Kappa opioid agonists can be (i) preferentially selected for mu opioid receptors over both kappa opioid and delta opioid receptors within the same mammalian species, and (ii) agonist activity at mu receptors. Please understand that you have.] In one or more embodiments of the invention, a compound is provided that comprises a residue of an opioid agonist covalently attached to a water-soluble non-peptide oligomer via a stable bond, the opioid agonist. It has a structure included in the following chemical formula and has a structure.<chemistry num="1"><img id="000002" he="54" wi="90" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>During the ceremony R1Is H or [methyl, ethyl, and -C (O) CH3Etc.] Organic base, R2Is H or OH, R3 is H or an organic base, R4Is an H or organic base, The dotted line ("---") indicates any double bond, Y1Is O (oxygen) or S, R5(Regardless of stereochemistry)<chemistry num="2"><img id="000003" he="10" wi="41" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Selected from the group consisting of R6Is the organic base [C (O) CH3Including]. In one or more embodiments of the invention, a compound is provided that comprises a compound comprising a residue of an opioid agonist covalently attached to a water-soluble non-peptide oligomer via a stable or degradable bond. Opioid agonists are asimadrin, blemazocine, enadrin, ethylketocyclazocine, GR89,696, ICI204448, ICI197067, PD117,302, nalbuphine, pentazocine, quadazocine (WIN). It is selected from the group consisting of 44,441-3), salvinorin A, spiradorin, TRK-820, U50488, and U69593. In one or more embodiments of the invention, the composition is provided and the composition is: (i) A compound containing an opioid agonist residue covalently attached to a water-soluble non-peptide oligomer via a stable bond. (ii) Include, optionally, pharmaceutically acceptable excipients. In one or more embodiments of the invention, dosage forms are provided that include a compound comprising a residue of an opioid agonist that is covalently attached to a water-soluble non-peptide oligomer via a stable bond. In one or more embodiments of the invention, methods are provided that include the step of covalently attaching a water-soluble non-peptide oligomer to an opioid agonist. In one or more embodiments of the invention, a method is provided that comprises administering a compound comprising a residue of an opioid agonist covalently attached to a water-soluble non-peptide oligomer via a stable bond. Including. In one or more embodiments of the invention, methods are provided that include the step of binding (eg, selectively binding) a muopioid receptor, the binding step being a water-soluble non-peptide. This is achieved by administering a compound that contains residues of the opioid agonist that are covalently attached to the oligomer. In one or more embodiments of the invention, methods are provided that include the step of binding (eg, selectively binding) a muopioid receptor, the binding step of which is an effective amount of water. Achieved by administering to mammalian patients a compound containing a residue of an opioid agonist covalently attached to a sex non-peptide oligomer. In one or more embodiments of the invention, methods are provided that include the step of binding (eg, selectively binding) a kappa opioid receptor, the binding step being a water-soluble non-peptide. This is achieved by administering a compound that contains residues of the opioid agonist that are covalently attached to the oligomer. In one or more embodiments of the invention, methods are provided that include the step of binding (eg, selectively binding) a kappa opioid receptor, the binding step being a water-soluble non-peptide. This is achieved by administering to mammalian patients a compound that contains an effective amount of opioid agonist residues covalently attached to the oligomer. For example, the present invention provides the following items.(Item 1)A compound containing an opioid agonist residue covalently attached to a water-soluble non-peptide oligomer.(Item 2)The compound according to item 1, wherein the opioid agonist is a kappa opioid agonist.(Item 3)The compound according to item 1, wherein the opioid agonist is a mu opioid agonist.(Item 4)It has the following structure<chemistry num="51"><img id="000004" he="45" wi="96" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>During the ceremonyR2Is H or OH,R3Is an H or organic base,R4Is an H or organic base,The dotted line ("---") indicates any double bond,Y1Is O or S,R5Is<chemistry num="52"><img id="000005" he="12" wi="41" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Selected from the group consisting of, in the formula, R6Is an organic base,X is the spacer part,The compound according to item 1, wherein POLY is a water-soluble non-peptide oligomer.(Item 5)It has the following structure<chemistry num="53"><img id="000006" he="44" wi="98" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>During the ceremonyR1Is an H or organic base,R2Is H or OH,R3Is an H or organic base,R4Is an H or organic base,The dotted line ("---") indicates any double bond,Y1Is O or S,X is the spacer part,The compound according to item 1, wherein POLY is a water-soluble non-peptide oligomer.(Item 6)It has the following structure<chemistry num="54"><img id="000007" he="47" wi="97" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>During the ceremonyR1Is an H or organic base,R2Is H or OH,R3Is an H or organic base,R4Is an H or organic base,Y1Is O or S,R5Is<chemistry num="55"><img id="000008" he="11" wi="40" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Selected from the group consisting of, in the formula, R6Is an organic base,X is the spacer part,The compound according to item 1, wherein POLY is a water-soluble non-peptide oligomer.(Item 7)It has the following structure<chemistry num="56"><img id="000009" he="49" wi="98" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>During the ceremonyR1Is an H or organic base,R2Is H or OH,R3Is an H or organic base,R4Is an H or organic base,The dotted line ("---") indicates any double bond,Y1Is O or S,R5Is<chemistry num="57"><img id="000010" he="12" wi="41" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Selected from the group consisting of, in the formula, R6Is an organic base,X is the spacer part,The compound according to item 1, wherein POLY is a water-soluble non-peptide oligomer.(Item 8)It has the following structure<chemistry num="58"><img id="000011" he="49" wi="97" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>During the ceremonyR1Is an H or organic base,R3Is an H or organic base,R4Is an H or organic base,The dotted line ("---") indicates any double bond,Y1Is O or S,R5Is<chemistry num="59"><img id="000012" he="12" wi="41" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Selected from the group consisting of, in the formula, R6Is an organic base,X is the spacer part,The compound according to item 1, wherein POLY is a water-soluble non-peptide oligomer.(Item 9)The opioid agonists are asimadrin, blemazocine, enadrin, ethylketocyclazocine, GR89,696, ICI204448, ICI197067, PD117,302, nalbuphine, pentazocine, quadazocine (WIN 44,441-3), salvinorin A, spiradolin, TRK-820, U50488. , And the compound according to item 1, selected from the group consisting of U69593.(Item 10)R1Is H, the compound according to any one of items 5, 6, 7, and 9.(Item 11)The compound according to any one of items 4, 5, 6, 7, 8 and 9, wherein Y is O.(Item 12)R2Is OH, the compound according to any one of items 4, 5, 6 and 7.(Item 13)R2Is H, the compound according to any one of items 4, 5, 6, and 7.(Item 14)R3Is the compound according to any one of items 4, 5, 6, 7, and 8 selected from the group consisting of H, unsubstituted alkyl, cycloalkyl substituted alkyl, and allyl.(Item 15)R4Is H, the compound according to any one of items 4, 5, 6, 7, and 8.(Item 16)R5Is<chemistry num="60"><img id="000013" he="11" wi="25" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>The compound according to any one of items 4, 6, 7, and 8 selected from the group consisting of.(Item 17)The compound according to any one of items 4, 5, and 8, wherein the optional double bond is present.(Item 18)The compound according to any one of items 4, 5, and 8, wherein the optional double bond is absent.(Item 19)The compound according to any one of items 1, 2, 3, 4, 5, 6, 7, and 8, wherein the water-soluble non-peptide oligomer is a poly (alkylene oxide).(Item 20)The compound according to item 19, wherein the poly (alkylene oxide) is poly (ethylene oxide).(Item 21)The compound according to any one of items 1, 2, 3, 4, 5, 6, 7, and 8, wherein the water-soluble non-peptide oligomer is made of 1 to 30 monomers.(Item 22)The compound according to item 21, wherein the water-soluble non-peptide oligomer is made up of 1 to 10 monomers.(Item 23)The compound according to item 19, wherein the poly (alkylene oxide) comprises an alkoxy or hydroxy end-sealing moiety.(Item 24)The compound according to any one of items 1, 2, 3, 4, 5, 6, 7, and 8, wherein a single water-soluble non-peptide oligomer is attached to the residue of the opioid agonist. ..(Item 25)The compound according to any one of items 1, 2, 3, 4, 5, 6, 7, and 8, wherein the residue of the opioid agonist is covalently bound via a stable bond.(Item 26)The compound according to any one of items 1, 2, 3, 4, 5, 6, 7, and 8, wherein the residue of the opioid agonist is covalently bound via a degradative bond.(Item 27)The compound according to item 1, wherein the bond is an ether bond.(Item 28)A composition comprising a compound comprising a residue of an opioid agonist covalently attached to a water-soluble non-peptide oligomer via a stable or degradable bond, and optionally an pharmaceutically acceptable excipient.(Item 29)A composition comprising a compound comprising a residue of an opioid agonist covalently attached to a water-soluble non-peptide oligomer via a stable or degradable bond, wherein the compound is present in a dosage form.(Item 30)A method comprising covalently attaching a water-soluble non-peptide oligomer to an opioid agonist.(Item 31)A method comprising administering a compound comprising a residue of an opioid agonist covalently attached to a water-soluble non-peptide oligomer via a stable or degradable bond.(Item 32)A method comprising the step of binding a muopioid receptor, wherein the binding step is accomplished by administering a compound comprising a residue of an opioid agonist covalently bound to a water-soluble non-peptide oligomer.(Item 33)A method comprising the step of binding a kappa opioid receptor, wherein the binding step is accomplished by administering a compound comprising a residue of an opioid agonist covalently bound to a water-soluble non-peptide oligomer. These and other purposes, aspects, embodiments, and features of the present invention will be further clarified by reading with the following embodiments for carrying out the invention.

As used herein, the singular forms "a," "an," and "the" include a plurality of indications unless the context explicitly states otherwise.

In the description and claims of the present invention, the following terms will be used in accordance with the definitions given below.

A "water-soluble non-peptide oligomer" refers to an oligomer having a solubility of at least 35% by weight, preferably greater than 70% by weight, more preferably greater than 95% by weight, in water at room temperature. In general, an unfiltered aqueous solution preparation of "water-soluble" oligomers transmits at least 75%, more preferably at least 95%, of the amount of light transmitted by the same solution after filtration. However, it is most preferred that the water-soluble oligomer is at least 95% by weight soluble in water, or completely soluble in water. As for "non-peptide", it becomes non-peptide when the oligomer has less than 35% by weight of amino acid residues.

The terms "monomer," "monomer subunit," and "monomer unit" are used interchangeably herein to refer to one of the basic structural units of a polymer or oligomer. In the case of homo-oligomers, a single repeating structural unit forms the oligomer. In the case of co-oligomers, two or more structural units are repeated (in a pattern or randomly) to form oligomers. Suitable oligomers used in connection with the present invention are homooligomers. Water-soluble non-peptide oligomers generally include one or more monomers that are continuously linked to form a monomer chain. Oligomers can be formed from a single monomer type (ie, homooligomer) or two or three monomer types (ie, co-oligomers).

An "oligomer" is a molecule having about 2 to about 50 monomers, preferably about 2 to about 30 monomers. The composition of the oligomers can change. Specific oligomers used in the present invention include those having various shapes such as straight, branched, or forked, which are described in detail below.

"PEG" or "polyethylene glycol" is intended to include any water soluble poly (ethylene oxide) as used herein. Unless otherwise stated, a "PEG oligomer" (also referred to as oligoethylene glycol) is one in which substantially all (and more preferably all) monomer subunits are ethylene oxide subunits. However, oligomers can include well-defined end-sealings or functional groups, for example for complexing. In general, the PEG oligomers used in the present invention are "-(CH) based on whether terminal oxygen has been replaced, for example, during a synthetic transformation.2CH2O)n-"Or"-(CH2CH2O)n-1CH2CH2Includes one of the two structures "-". For PEG oligomers, "n" varies from about 2 to 50, preferably from about 2 to 30, and the composition of end groups and PEG as a whole can change. When PEG further comprises, for example, a functional group A for linking to a small molecule drug, the functional group, when attached to the PEG oligomer, (i) oxygen-oxygen bond (-OO-, peroxide bond), Or (ii) do not result in the formation of nitrogen-oxygen bonds (NO, ON).

A "terminal encapsulating group" is generally a non-reactive carbon-containing group that is attached to the terminal oxygen of a PEG oligomer. Exemplary end-capping groups include C such as methyl, ethyl, and benzyl.1-5Alkyl groups and aryl, heteroaryl, cyclo, heterocyclo and the like can be mentioned. For the present invention, suitable sealing groups have a relatively low molecular weight, such as methyl or ethyl. The end-capping group can also include a detectable label. Such labels include, but are not limited to, luminescent materials, chemical luminescent materials, moieties used for enzyme labeling, colorimetric labels (eg, dyes), metal ions, and radioactive moieties.

"Branch" refers to an oligomer having two or more polymers that represent a clearly distinguishable "arm" extending from the bifurcation point with respect to the shape or overall structure of the oligomer.

"Forked" refers to an oligomer having two or more polymers extending from a junction (generally through one or more atoms) with respect to the shape or overall structure of the oligomer.

"Branch point" refers to a branch point containing one or more atoms in which an oligomer branches from a linear structure into one or more additional arms or becomes forked.

The term "reactive" or "active" refers to a functional group that reacts easily or at a practical rate under the customary conditions of organic synthesis. This is in contrast to groups that do not react or require strong catalysts or impractical conditions to react (ie, "non-reactive" or "inactive" groups).

"Not easily reacting" means that with respect to the functional groups present on the molecule in the reaction mixture, most of them remain intact under the conditions that the groups are effective in producing the desired reaction in the reaction mixture. Indicates that.

A "protecting group" is a moiety that interferes with or prevents the reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions. Protecting groups depend on the type of chemical reactive group being protected, the reaction conditions used, and the presence of additional reactive or protecting groups in the molecule. Examples of functional groups that can be protected include carboxylic acid groups, amino groups, hydroxyl groups, thiol groups, carbonyl groups and the like. Typical protective groups for carboxylic acids include esters (p-methoxybenzyl ester, etc.), amides, and hydrazides, for amino groups, carbamate (tert-butoxycarbonyl, etc.) and amides, and for hydroxyl groups. , Ethers and esters, thioethers and thioesters for thiol groups, acetals and ketals for carbonyl groups, and the like. Such protecting groups are known to those of skill in the art, for example, TWGreen and GM. It is described in Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999 and is incorporated herein by reference.

The functional group in the "protected form" refers to a functional group carrying a protecting group. As used herein, "functional group" or any synonym thereof embraces its protective form.

A "physiologically cleaving", "hydrolyzable", or "degradable" bond is a relatively unstable bond that reacts with water (ie, is hydrolyzed) under normal physiological conditions. is there. Under normal physiological conditions, the tendency to hydrolyze in water is not only to the general type of bond that connects two central atoms, but also to the substituents that are attached to these central atoms. Dependent. Such bonds are generally recognizable to those skilled in the art. Suitable hydrolyzable or weak bonds include carboxylic acid esters, phosphate esters, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, orthoesters, peptides, oligonucleotides, thioesters, and carbonates. However, it is not limited to these.

"Enzymatic binding" means a binding that is degraded by one or more enzymes under normal physiological conditions.

A "stable" bond or bond is a chemical moiety or chemical that is substantially stable in water, i.e., not subject to hydrolysis under normal physiological conditions to the extent that it can be detected over a long period of time. Refers to a bond, typically a covalent bond. Examples of hydrolyzably stable bonds include, but are not limited to, carbon-carbon bonds (eg, in aliphatic chains), ethers, amides, urethanes, amines and the like. In general, stable binding exhibits a hydrolysis rate of less than about 1-2% per day under normal physiological conditions. Typical chemical bond hydrolysis rates can be found in most standard chemistry books.

With respect to the description of the consistency of oligomers in a given composition, "substantially" or "basically" means almost completely or completely, eg, 95 of a given quantity. It means% or more, more preferably 97% or more, further preferably 98% or more, still more preferably 99% or more, further preferably 99.9% or more, and most preferably 99.99% or more.

"Monodispersion" refers to an oligomer composition in which substantially all oligomers in the composition have a well-defined single molecular weight and a specified number of monomers as determined by chromatography or mass spectrometry. The monodisperse oligomeric composition is, in a sense, pure. That is, it comprises molecules having a substantially single and definable number of monomers, rather than several different numbers of monomers (ie, oligomeric compositions having three or more different oligomer sizes). The monodisperse oligomer composition has a MW / Mn value of 1.0005 or less, more preferably 1.0000. Thus, in a composition consisting of monodisperse complexes, substantially all oligomers of all complexes in the composition have a single (as an integer) definable number of monomers rather than a distribution. It is meant to have a MW / Mn value of 1.0005, more preferably 1.000 MW / Mn value, when the oligomer is not attached to the residue of the opioid agonist. However, compositions consisting of monodisperse complexes can include one or more non-complex materials such as solvents, reagents, excipients and the like.

By "bimodality", in relation to an oligomer composition, substantially all oligomers in the composition have a definable (as an integer) number of monomers in one of the two rather than a distribution. However, it refers to an oligomer composition whose molecular weight distribution appears as two distinct and distinguishable peaks when plotted in fractional to molecular weight. For the bimodal oligomeric compositions described herein, the two peaks may differ, but it is generally preferred that each peak be symmetrical with respect to its average. Ideally, the polydispersity index Mw / Mn of each peak in the bimodal distribution is 1.01 or less, more preferably 1.001 or less, even more preferably 1.0005 or less, and most preferably 1.000 MW / Mn. Thus, in a composition consisting of a bimodal complex, substantially all oligomers of all the complexes in the composition are not in a large distribution, but in a different number (as an integer) that can be defined in one of the two. A MW / Mn value of 1.01 or less, more preferably 1.001 or less, even more preferably 1.0005 or less, most preferably 1.000 MW / Mn value, when the oligomer has a monomer and is not attached to an opioid agonist residue. Means to have. However, a composition consisting of a bimodal complex can include one or more non-complex materials such as solvents, reagents, excipients and the like.

An "opioid agonist", as used herein, is an organic, inorganic, organic, inorganic, typically having a molecular weight of less than about 1000 daltons (and typically less than 500 daltons) and having some activity as a mu and / or kappa agonist. Or used in a broad sense to refer to an organometallic compound. Opioid agonists include oligopeptides and other biomolecules having a molecular weight of less than about 1000.

A "biological membrane" is typically any membrane made from specialized cells or tissues that acts as a barrier to at least some foreign matter or other unwanted material. As used herein, a "biological membrane" includes a membrane associated with a physiological protective barrier, such as the blood-brain barrier (BBB), blood-brain-spinal fluid barrier, blood-placement barrier, blood-milk barrier. , The blood-brain barrier, and the mucosal barrier including vaginal mucosa, urinary tract mucosa, anal mucosa, buccal mucosa, sublingual mucosa, rectal mucosa, etc. Unless the context is clearly stated differently, the term "biological membrane" does not include membranes associated with the intermediate gastrointestinal tract (eg, stomach and small intestine).

"Transverse velocity of a biological membrane", as used herein, provides a measure of the ability of a compound to cross a biological membrane (the membrane associated with the blood-brain barrier). A variety of methods can be used to assess the transfer of molecules across any given biological membrane. Methods of assessing the transversal velocity of biological membranes associated with any given biological barrier (eg, blood-brain-spinal fluid barrier, blood-placental barrier, blood-milk barrier, intestinal barrier, etc.) are known in the art. And / or can be determined by one of ordinary skill in the art, as described in the specification and / or related literature.

"Reduced rate of metabolism" as used in the present invention is a small water-soluble oligomer compared to the rate of metabolism of a small molecule drug that is not bound to a water-soluble oligomer (ie, the small molecule drug itself), or a reference reference material. Refers to a measurable decrease in the rate of metabolism of a molecular drug complex. In the special case of "decreased first-pass rate of metabolism", "decreased metabolic rate" is also present, except that the small molecule drug (or reference standard material) and the corresponding complex are administered orally. is necessary. Orally administered drugs are absorbed from the gastrointestinal tract into the portal circulation and must pass through the liver before reaching the systemic circulation. Since the liver is the main site of drug metabolism or changes in the body, a significant amount of drug can be metabolized before it reaches the systemic circulation. The degree of first-pass metabolism, and thus any reduction thereof, can be measured by many different methods. For example, animal blood samples can be collected in plasma or serum analyzed by liquid chromatography / mass spectrometry at defined intervals relative to biotransformer levels. "Reduced metabolic rates" associated with first-pass metabolism and other metabolic processes are known in the art and are described herein and / or related literature and / or determined by one of ordinary skill in the art. can do. The complex of the invention is at least one of a value of at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, and at least about 90%. It is preferable to be able to provide a reduction in metabolic rate that satisfies. Compounds that are "orally bioavailable" (such as small molecule drugs or complexes thereof) preferably have greater than 25%, preferably greater than 70% bioavailability when administered orally. The bioavailability of a compound is a fraction of the administered drug that reaches the systemic circulation in a non-metabolized form.

"Alkyl" refers to a hydrocarbon chain typically in the range of about 1 to 20 atoms in length. Such hydrocarbon chains, although not necessarily saturated, are preferably saturated and may be branched or straight, but generally straight. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, 1-methylbutyl, 1-ethylpropyl, 3-methylpentyl and the like. As used herein, "alkyl" includes cycloalkyl when three or more carbon atoms are mentioned. An "alkenyl" group is an alkyl of 2 to 20 carbon atoms with at least one carbon-carbon double bond.

"Substitution alkyl" or "substitution C" where q and r are integers representing the range of carbon atoms contained in the alkyl groupqr"Alkyl" is one, two, or three halos (eg, F, Cl, Br, I), trifluoromethyl, hydroxy, C.1-7Alkyl (eg, methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, etc.), C1-7Alkoxy, C1-7Acyloxy, C3-7It means the above-mentioned alkyl group substituted with a heterocycle, amino, phenoxy, nitro, carboxy, carboxy, acyl, cyano. Substituted alkyl groups can be substituted once, twice, or three times with the same or different substituents.

"Lower alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, even linear or branched, as exemplified by methyl, ethyl, n-butyl, i-butyl, t-butyl. Good. "Lower alkenyl" refers to a lower alkyl group of 2 to 6 carbon atoms with at least one carbon-carbon double bond.

A "non-interfering substituent", when present in a molecule, is generally a group that is non-reactive with another functional group contained within the molecule.

"Alkoxy" refers to the -OR group, where R is an alkyl or substituted alkyl, preferably C.1-C20Alkyl (eg, methoxy, ethoxy, propyloxy, benzyl, etc.), preferably C1-C7Is.

A "drug-acceptable excipient" or "drug-acceptable carrier" refers to an ingredient that can be included in the compositions of the invention, which is compared to a composition lacking that ingredient. It is an object of the invention to provide a composition that has advantages (eg, more suitable for administration to a patient) and is recognized as not causing a significantly harmful toxicological effect on the patient.

The term "aryl" means an aromatic group with a maximum of 14 carbon atoms. Examples of the aryl group include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl and the like. The "substituted phenyl" and "substituted aryl" are halo (F, Cl, Br, I) hydroxy, hydroxy, cyano, nitro, alkyl (eg C), respectively.1-6Alkoxy), Alkoxy (eg C)1-6By one, two, three, four, or five (eg, 1-2, 1-3, or 1-4 substituents) selected from alkoxy), benzyloxy, carboxy, aryl, etc. Means substituted phenyl and aryl groups.

An "aromatic-containing moiety" is a group of atoms, including at least aryl and optionally one or more atoms. Suitable aromatic-containing moieties are described herein. For brevity, the chemical part is defined and refers primarily to the monovalent chemical part (eg, alkyl, aryl, etc.) throughout this document. However, such terms are also used to convey the corresponding multivalued portion in a suitable structural environment that will be apparent to those skilled in the art. For example, the "alkyl" moiety is generally a monovalent base (eg, CH).3-CH2Refers to-), but in certain environments, the divalent link portion can be "alkyl", in which one of ordinary skill in the art will appreciate that the alkyl is the divalent base (eg, -CH).2-CH2-), And you will understand that it is equivalent to the term "alkylene". (Similarly, in an environment where a divalent moiety is required and is referred to as "aryl", one of ordinary skill in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene). All atoms have a normal number of valences for bond formation (ie, 4 for carbon, 3 for nitrogen, 2 for oxygen, and 2 for sulfur based on the oxidation state of sulfur. , 4, or 6).

A "pharmacologically effective amount", a "physiologically effective amount", and a "therapeutically effective amount" are required to provide threshold levels of the active agent and / or complex in the bloodstream or in the target tissue. , As substituted herein to mean the amount of water-soluble oligomer small molecule drug complex present in the composition. The exact amount depends on a number of factors, such as the particular activator, composition and physical characteristics of the composition, the patient population of interest, patient problems, etc., and is associated with the information provided herein. It can be easily determined by one of ordinary skill in the art based on the information available in the document.

A "bifunctional" oligomer is an oligomer that typically contains two functional groups at its ends. When the functional groups are the same, the oligomer is said to be homobifunctional. When the functional groups are different, the oligomer is said to be heterobifunctional.

The basic or acidic reactants described herein include neutrally charged and any corresponding salt forms thereof.

The term "patient" generally, but not necessarily, a condition that can be prevented or treated by administration of the complex described herein in the form of a water-soluble oligomer small molecule drug complex. Refers to living tissue that is or tends to be in, including both humans and animals.

By "arbitrarily selected" or "arbitrarily selected" is meant that the situation described thereafter does not necessarily occur, and the description includes cases where the situation occurs and cases where it does not occur.

As mentioned above, the present invention is directed to compounds containing opioid agonist residues that are covalently attached to a water-soluble non-peptide oligomer via (especially) stable or degradable binding.

In one or more embodiments of the invention, a compound is provided that comprises a residue of an opioid agonist that is covalently attached to a water-soluble non-peptide oligomer via a stable or degradable bond, said opioid. The agonist has the following chemical formula:

<chemistry num="3"><img id="000014" he="53" wi="91" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Has a structure contained in During the ceremony R1Is H or [methyl, ethyl, and -C (O) CH3Etc.] Organic base, R2Is H or OH, R3 is H or an organic base, R4Is an H or organic base, The dotted line ("---") indicates any double bond, Y1Is O or S, R5(Regardless of stereochemistry)

<chemistry num="4"><img id="000015" he="12" wi="41" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Selected from the group consisting of R6Is the organic base [C (O) CH3Including]. Examples of specific opioid agonists include acetolphin, acetyldihydrocodein, acetyldihydrocodeinone, acetylmorphinone, alfentanil, allylprozine, alphaprozine, anirelidine, benzylmorphine, vegithramide, buprenorphine, butorphanol, chronitazen, codeine, Desomorphine, dexstromoramide, dezosin, diampromide, diamorphine, dihydrocodein, dihydromorphin, dimenoxador, dimefeptanol, dimethylthianbutene, dioxafetylbutyrate, dipipanone, eptazocin, etoheptidine, ethylmethylthianbutene, ethylmorphin, Etnitazen, ethrphin, dihydroetrufin, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomesadon, ketobemidone, levorphanol, levofenacil morphine, lofentanil, meperidine, meptazinol, metazosin, mesadon, metopon, morphine, Milophine, Narcene, Nicomorphin, Norrevorphanol, Normesadon, Narolfin, Narbufin, Normorphin, Norpipanone, Achen, Oxycodone, Oxymorphone, Papabelletum, Pentazocin, Phenadoxone, Phenomolfane, Phenazosin, Phenoperidine, Piminodin, Pyridolamide, Proheptazine Examples include properidine, propoxyphene, sufentanil, tyridine, and tramadol. In certain embodiments, the opioid agonists are hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl, dipipanone, heroin, tramadol, nalbuphine, etorphin, dihydroetruphin, butorphanol, Selected from the group consisting of levorphanol.

The advantages of the compounds of the invention are those that retain some opioid agonist activity while reducing metabolism and / or, in non-complex form, reducing the central nervous system mediating effects associated with the corresponding opioid agonist. Considered to be an ability. Although not bound by theory, the oligomer-containing complexes described herein reduce the overall affinity of the compound for substrates on which the oligomer can metabolize opioid agonists. As it serves a role, it is not considered to be easily metabolized (as opposed to uncompounded "original" opioid agonists). In addition (and again, not to be bound by theory), the excess size introduced by the oligomers crosses the blood-brain barrier (as opposed to the uncombined "original" opioid agonist). Reduces the ability of compounds to do.

The use of oligomers to form the complexes of the present invention (eg, from monodisperse or bimodal compositions of oligomers, as opposed to relatively impure compositions) is associated with the corresponding small molecule drugs. Certain properties can be changed in an advantageous manner. For example, the complex of the invention penetrates the blood-brain barrier when administered by any of many suitable routes of administration, such as parenteral, oral, transdermal, oral, transpulmonary, or nasal. Shows a decrease in sex. The complex exhibits a slowed, minimal blood-brain barrier crossing, or virtually no crossing it, but nevertheless, if oral delivery is intended, the systemic circulation through the gastrointestinal (GI) wall. It is preferable to enter. Moreover, the complexes of the present invention maintain some degree of bioactivity and bioavailability in their complex form as compared to the bioactivity and bioavailability of all oligomer-free compounds.

For the blood-brain barrier (BBB), this barrier limits the transfer of drugs from the blood to the brain. This barrier consists of a unique continuous layer of endothelial cells connected by tight junctions. Cerebral capillaries, which occupy more than 95% of the total surface area of the BBB, are the major route of entry for most solutes and drugs into the central nervous system.

For compounds for which the degree of blood-brain barrier crossing ability is not readily apparent, such ability is to use a suitable animal model, such as the in-situ rat cerebral perfusion (RBP) model described herein. Can be determined. Briefly, the RBP method involves cannulation of the carotid artery, subsequent perfusion with a compound solution under controlled conditions, and then a flushing step to remove the compound remaining in the vasculature. (Such analysis is, for example, Absorption It can be done by contract research institutes such as Systems, Exton, PA). More specifically, in the RBP model, a cannula is placed in the left carotid artery and the side branches are tied. Physiological buffer containing the analyte (typically, but not necessarily, at a concentration level of 5 micromoles) is perfused in a single-pass perfusion experiment at a flow rate of approximately 10 mL / min. After 30 seconds, perfusion is stopped and the cerebrovascular contents are rinsed with compound-free buffer for an additional 30 seconds. The brain tissue is then removed and the compound concentration analyzed by liquid chromatography using tandem mass spectrometric detection (LC / MS / MS). Alternatively, blood-brain barrier permeability is defined as the sum of the surface contributions of polar atoms (usually oxygen, nitrogen, and bound hydrogen) in a molecule, in the calculation of the molecular polar surface area (PSA) of a compound. Based on, it can be estimated. PSA has been shown to correlate with compound transport properties such as blood-brain barrier transport. Methods for determining the PSA of a compound are, for example, Ertl, P., et al., J.Med.Chem.2000,43,3714-3717, and Kelder, J., et. It can be found in al., Pharm. Res. 1999, 16, 1514-1519.

For the blood-brain barrier, the water-soluble non-peptide oligomer-small molecule drug complex exhibits a reduced blood-brain barrier crossing rate compared to the crossing rate of small molecule drugs that are not bound to the water-soluble non-peptide oligomer. The reduction in the preferred exemplary blood-brain barrier crossing rate of the compounds described herein is at least about 30%, at least when compared to the blood-brain barrier crossing rate of small molecule drugs that are not bound to water-soluble oligomers. There is a reduction of about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. The preferred reduction in blood-brain barrier crossing rate for the complex is at least about 20%.

As mentioned above, the compounds of the invention contain residues of opioid agonists. A assay for determining whether a given compound can function as an agonist at the mu or kappa receptor (whether or not the compound is in a complex form) is described below.

In some cases, opioid agonists can be obtained from commercial sources. In addition, opioid agonists can be obtained through chemical synthesis. Synthetic techniques for preparing opioid agonists are described in the literature and, for example, US Pat. Nos. 2,628,962, 2,654,756, 2,649,454, and 2,806,033.

Each of these (and other) opioid agonists can be covalently attached (directly or through one or more atoms) to a water-soluble non-peptide oligomer.

Small molecule drugs useful in the present invention generally have a molecular weight of less than 1000 Da. Exemplary molecular weights of small molecule drugs include less than about 950, less than 900, less than about 850, less than about 800, less than about 750, less than about 700, less than about 650, less than about 600, less than about 550, less than about 500. , Less than about 450, less than about 400, less than about 350, and less than about 300 molecular weights.

In the case of chiral, the small molecule drug used in the present invention can be a racemic mixture, or an optically active form such as a single optically active enantiomer, or any combination or ratio of enantiomers (ie, a scalemic mixture). In addition, small molecule drugs can have one or more geometric isomers. With respect to geometric isomers, the composition can include a single geometric isomer or a mixture of two or more geometric isomers. The small molecule drug used in the present invention can be in its customary active form or may have some modifications. For example, a small molecule drug can have a target drug, tag, or transporter attached to it before or after covalent attachment of the oligomer. Alternatively, the small molecule drug was bound to it, such as a phospholipid (eg, distearoylphosphatidylethanolamine, ie "DSPE", or dipalmitoylphosphatidylethanolamine, ie "DPPE", etc.), or a small fatty acid. It may have a lipophilic portion. However, in some cases, the small molecule drug moiety preferably does not contain binding to the lipophilic moiety.

Opioid agonists for binding to water-soluble non-peptide oligomers have free hydroxyl, carboxyl, thio, amino groups and the like (ie, "handles") suitable for covalent binding to oligomers. In addition, opioid agonists are converted by the introduction of reactive groups, preferably from one of its existing functional groups to a functional group suitable for forming a stable covalent bond between the oligomer and the drug. Can be modified by.

Thus, each oligomer is an alkylene oxide such as ethylene oxide or propylene oxide, a vinyl alcohol, an olefin alcohol such as 1-propenol or 2-propenol, a vinylpyrrolidone, preferably a hydroxyalkylmethacrylate or hydroxyalkyl methacrylate in which the alkyl is methyl. Consists of up to three different monomer types selected from the group consisting of α-hydroxy acids such as lactic acids or glycolic acids, carbohydrates such as phosphazenes, oxazolines, amino acids, monosaccharides, sugars, or mannitols, and N-acryloylmorpholins. Will be done. Suitable monomer types include alkylene oxides, olefin alcohols, hydroxyalkylmethacrylamides or methacrylates, N-acryloyl morpholine, and α-hydroxy acids. Each oligomer is preferably a co-oligomer of two monomer types independently selected from this group, or more preferably a homo-oligomer of one monomer type selected from this group.

The two monomer types in the co-oligomer can be the same monomer type, for example, two alkylene oxides such as ethylene oxide and propylene oxide. The oligomer is preferably a homooligomer of ethylene oxide. Usually, but not always, the ends (or ends) of the oligomer that are not covalently attached to the small molecule are sealed to inactivate it. Alternatively, the ends may contain reactive groups. When the terminal is a reactive group, the reactive group is protected so that it is inactive under the final oligomer-forming conditions or during covalent attachment of the oligomer to a small molecule drug, or as needed. Is selected for. One commonly used terminal functional group is hydroxyl or -OH, especially for oligoethylene oxides.

The water-soluble non-peptide oligomer (eg, "POLY" in the various structures provided herein) can have any of many different shapes. For example, it can be straight, bifurcated, or forked. Most typically, the water-soluble non-peptide oligomer is a straight line or, for example, a branch with one branch point. While much of the discussions herein focus on poly (ethylene oxide) as an exemplary oligomer, the discussions and structures presented herein include any of the water-soluble non-peptide oligomers described above. It can be easily extended to do so.

The molecular weight of the water-soluble non-peptide oligomer excluding the linker moiety is generally relatively low. Illustrative values for the molecular weight of water-soluble polymers include less than about 1500 daltons, less than about 1450 daltons, less than about 1400 daltons, less than about 1350 daltons, less than about 1300 daltons, less than about 1250 daltons, less than about 1200 daltons, about Less than 1150 daltons, less than about 1100 daltons, less than about 1050 daltons, less than about 1000 daltons, less than about 950 daltons, less than about 900 daltons, less than about 850 daltons, less than about 800 daltons, less than about 750 daltons, less than about 700 daltons, about Less than 650 daltons, less than about 600 daltons, less than about 550 daltons, less than about 500 daltons, less than about 450 daltons, less than about 400 daltons, less than about 350 daltons, less than about 300 daltons, less than about 250 daltons, less than about 200 daltons, and Less than about 100 daltons.

An exemplary range of molecular weights of water-soluble non-peptide oligomers (other than linkers) is about 100 to about 1400 daltons, about 100 to about 1200 daltons, about 100 to about 800 daltons, about 100 to about 500 daltons, about 100 to about 100. These include about 400 daltons, about 200 to about 500 daltons, about 200 to about 400 daltons, about 75 to 1000 daltons, and about 75 to about 750 daltons.

The number of monomers in the water-soluble non-peptide oligomer is between about 1 and about 30 (including 1 and 30), between about 1 and about 25, between about 1 and about 20, and between about 1 and about 15. , Is preferably in the range of one or more of between about 1 and about 12, and between about 1 and about 10. In some cases, the number of contiguous monomers in the oligomer (and the corresponding complex) is one of one, two, three, four, five, six, seven, or eight. It is one. In additional embodiments, the oligomers (and corresponding complexes) are 9, 10, 11, 12, 13, 14, 15, 16, 16, 17, 18, 19, 19, and so on. Or contains 20 monomers. In a further embodiment, the oligomer (and the corresponding complex) comprises 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 consecutive monomers. Have. So, for example, a water-soluble non-peptide oligomer can be CH3-(OCH2CH2)n-When including, "n", 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20, It can be 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and also between about 1 and about 25, between about 1 and about 20, and about 1 to about 15. An integer that can be in the range of one or more of between, about 1 to about 12, and between about 1 and about 10.

When the water-soluble non-peptide oligomer has one, two, three, four, five, six, seven, eight, nine, or ten monomers, these values are about, respectively. Corresponds to methoxy-terminated oligos (ethylene oxides) with molecular weights of 75, 119, 163, 207, 251, 295, 339, 383, 427, and 471 daltons. When the oligomer has 11, 12, 13, 14, or 15 monomers, these values have molecular weights corresponding to about 515, 559, 603, 647, and 691 daltons, respectively, methoxy. Corresponds to oligos (ethylene oxides) terminally sealed with.

When a water-soluble non-peptide oligomer is attached to an opioid agonist (as opposed to stepwise addition of one or more monomers to effectively "grow" the oligomer onto the opioid agonist), it is water-soluble. It is preferable that the composition containing the active form of the sex non-peptide oligomer is monodisperse. However, in those cases, when a bimodal composition is used, the composition will have a bimodal distribution centered on any two of the above-mentioned number of monomers. .. Ideally, the polydisperse index, Mw / Mn, of each peak in the bimodal distribution is 1.01 or less, more preferably 1.001 or less, and even more preferably 1.0005 or less. Most preferably, each peak has a MW / Mn value of 1.000. For example, bimodal oligomers are 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, etc., 2-3, 2 -4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, etc., 3-4, 3-5, 3-6, 3-7, 3-8, 3- 9, 3-10 etc., 4-5, 4-6, 4-7, 4-8, 4-9, 4-10 etc., 5-6, 5-7, 5-8, 5-9, 5- Illustrative monomeric subunits such as 10 mag, 6-7, 6-8, 6-9, 6-10 mag, 7-8, 7-9, 7-10 etc, and 8-9, 8-10 etc. Any of these combinations is possible.

In some cases, the composition comprising the active form of the water-soluble non-peptide oligomer is also trimodal or quaternary and has a range of monomeric units as described above. Oligomer compositions with a well-defined mixture of oligomers (ie, bimodal, trimodal, quaternary, etc.) are oligomers of the desired profile (mixtures of two oligomers that differ only in the number of monomers are bimodal). A mixture of three oligomers that differ only in the number of monomers is trimodal, and a mixture of four oligomers that differ only in the number of monomers is quaternary). Column chromatography of polydisperse oligomers, which can be obtained by mixing the oligomers, or alternative, by restoring a "center cut" to obtain a mixture of oligomers in the desired defined molecular weight range. Can be obtained from.

The water-soluble non-peptide oligomer is preferably obtained from a composition that is monomolecular or monodisperse. That is, the oligomers in the composition have the same individual molecular weight values rather than the molecular weight distribution. Some monodisperse oligomers can be purchased from commercial sources, such as those available from Sigma-Aldrich, or, alternative, can be prepared directly from commercially available starting materials such as Sigma-Aldrich. Can be done. Water-soluble non-peptide oligomers are described in Chen Y., Baker, GLJOrg.Chem., 6870-6873 (1999), International Patent WO 02/098949, and US Patent Application Publication No. 2005/0136031. Can be prepared in.

If present, the spacer moiety (where a water-soluble non-peptide polymer is passed through and attached to an opioid agonist) is a single bond, a single atom, two atoms, or many atoms, such as an oxygen atom or a sulfur atom. obtain. The spacer portion is typically, but not necessarily, a straight line. The spacer portion "X" is preferably hydrolyzably stable, and is preferably enzymatically stable. Preferably, the spacer moiety "X" has an atomic chain length of less than about 12, preferably less than about 10 atomic chain lengths, more preferably less than about 8 atomic chain lengths, and even more preferably less than about 5 atomic chain lengths. It has an atomic chain length, where length means the number of atoms in a single chain, not counting substituents. For example, this Roligomer-NH- (C = O) -NH-R'drugUrea bonds such as 3 atoms (-NH-C(O)-NIt is considered to have a chain length of H-). In the selected embodiment, the spacer partial bond does not contain additional spacer groups.

In some cases, the spacer moiety "X" comprises an ether, amide, urethane, amine, thioether, urea, or carbon-carbon bond. The functional groups discussed below and shown in the examples are typically used to form bonds. The spacer moiety may also contain (or be adjacent or laterally located) a spacer group, although less preferably, as described further below.

More specifically, in selected embodiments, the spacer moiety, X, is a "-" (ie, a small molecule opioid agonist that can be stable or degradable, and residues of water-soluble non-peptide oligomers. Covalent bond between), -O-, -NH-, -S-, -C (O)-, C (O) -NH, NH-C (O) -NH, OC (O) -NH, -C (S)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-, -CH2-O-, -O-CH2-CH2-, -CH2-O-CH2-, -CH2-CH2-O-, -O-CH2-CH2-CH2-, -CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-CH2-O-, -O-CH2-CH2-CH2-CH2-, -CH2-O-CH2-CH2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-CH2-CH2-O-CH2-, -CH2-CH2-CH2-CH2-O-, -C (O) -NH-CH2-, C (O) -NH-CH2-CH2-, -CH2-C (O) -NH-CH2-, -CH2-CH2-C (O) -NH-, -C (O) -NH-CH2-CH2-CH2-, -CH2-C (O) -NH-CH2-CH2-, -CH2-CH2-C (O) -NH-CH2-, -CH2-CH2-CH2-C (O) -NH-, -C (O) -NH-CH2-CH2-CH2-CH2-, -CH2-C (O) -NH-CH2-CH2-CH2-, -CH2-CH2-C (O) -NH-CH2-CH2-, -CH2-CH2-CH2-C (O) -NH-CH2-, -CH2-CH2-CH2-C (O) -NH-CH2-CH2-, -CH2-CH2-CH2-CH2-C (O) -NH-, -NH-C (O) -CH2-, -CH2-NH-C (O) -CH2-, -CH2-CH2-NH-C (O) -CH2-, -NH-C (O) -CH2-CH2-, -CH2-NH-C (O) -CH2-CH2, -CH2-CH2-NH-C (O) -CH2-CH2, -C (O) -NH-CH2-, -C (O) -NH-CH2-CH2-, -OC (O) -NH-CH2-, -OC (O) -NH-CH2-CH2-, -NH-CH2-, -NH-CH2-CH2-, -CH2-NH-CH2-, -CH2-CH2-NH-CH2-, -C (O) -CH2-, -C (O) -CH2-CH2-, -CH2-C (O) -CH2-, -CH2-CH2-C (O) -CH2-, -CH2-CH2-C (O) -CH2-CH2-, -CH2-CH2-C (O)-, -CH2-CH2-CH2-C (O) -NH-CH2-CH2-NH-, -CH2-CH2-CH2-C (O) -NH-CH2-CH2-NHC (O)-, -CH2-CH2-CH2-C (O) -NH-CH2-CH2-NHC (O) -CH2-, Divalent cycloalkyl group, R6Is an organic base selected from the group consisting of H, or alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl, N (R).6), Can be any one of.

However, for the purposes of the present invention, a group of atoms is not considered a spacer when directly adjacent to an oligomeric segment, and the group of atoms is such that the group merely represents an extension of the oligomeric chain. , Same as oligomeric monomer.

The bond "X" between the water-soluble non-peptide oligomer and the small molecule is typically one when it is desired to "grow" the oligomer onto a functional group (or opioid agonist) on the end of the oligomer. It is formed by the reaction of the above monomer) with the corresponding functional group of the opioid agonist. Hereinafter, exemplary reactions will be briefly described. For example, the amino group on the oligomer may be reacted with a carboxylic acid or active carboxylic acid derivative on a small molecule to form an amide bond, or vice versa. Alternatively, the reaction of the amine on the oligomer with the activated carbonate on the drug (eg, succinimidyl or benzotriazyl carbonate), or vice versa, forms a carbamate bond. The reaction of the amine on the oligomer with the isocyanate (RN = C = O) on the drug, or vice versa, forms a urea bond (R-NH (C = O) -NH-R'). Furthermore, the reaction of the alcohol (alkoxide) group on the oligomer with the alkyl halide, or halogenated group in the drug, or vice versa, forms an ether bond. In yet another binding technique, small molecules with aldehyde function bind to oligomeric amino groups by reductive amination, resulting in the formation of secondary amine bonds between the oligomers and small molecules.

A particularly suitable water-soluble non-peptide oligomer is an oligomer that carries an aldehyde functional group. In this regard, the oligomer has the following structure. CH3O- (CH2-CH2-O)n-(CH2)p-C (O) H, in the equation, (n) is one of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, and (p) is 1, It is one of 2, 3, 4, 5, 6, and 7. Suitable values for (n) include 3, 5, and 7, and suitable values for (p) are 2, 3, and 4. In addition, the carbon atom α for the -C (O) H moiety can optionally be replaced by alkyl.

Typically, the ends of the water-soluble non-peptide oligomer that do not carry a functional group are sealed to inactivate it. When the oligomer contains an additional functional group at the end, except for the purpose of forming a complex, the group is either inactive under the conditions of formation of the bond "X" or the formation of the bond "X". Selected to be protected inside.

As mentioned above, the water-soluble non-peptide oligomer contains at least one functional group prior to conjugation. Functional groups generally include electron or nucleophilic groups for covalent bonding to small molecules, based on reactive groups contained within or introduced into the small molecule. Examples of nucleophilic groups that may be present in oligomers or small molecules are hydroxylamine, amine, hydrazine (-NHNH).2), Hydrazide (-C (O) NHNH2), And thiols. Suitable nucleophiles include amines, hydrazines, hydrazides, and thiols, especially amines. Most small molecule drugs for covalent attachment to oligomers have free hydroxyl, amino, thio, aldehyde, ketone, or carboxyl groups.

Examples of electrophilic functional groups that may be present in oligomers or small molecules include carboxylic acids, carboxylic acid esters, especially imide esters, orthoesters, carbonates, isocyanates, isothiocyanates, aldehydes, ketones, thions, alkenyl, acrylates, Examples include methacrylates, acrylamides, sulfones, maleimides, disulfides, iodos, epoxys, sulfonates, thiosulfonates, silanes, alkoxysilanes, and halosilanes. More specific examples of these groups include succinimidyl ester or carbonate, imidazole ester or carbonate, benzotriazole ester or carbonate, vinyl sulfonate, chloroethyl sulfone, vinyl pyridine, pyridyl disulfide, iodoacetamide, Glyoxal, dione, mesylate, tosylate, and tresylate (2,2,2-trifluoroethanesulfonate) can be mentioned.

Also, thiones, thione hydrates, acetals, 2-thiazolidinethiones, etc., as well as hydrates or protective derivatives of any of the above moieties (eg, aldehyde hydrates, hemiacetals, acetals, ketone hydrates). , Hemiacetal, ketal, thioketal, thioacetal).

An "active derivative" of a carboxylic acid generally refers to a carboxylic acid derivative that reacts much more easily with a nucleophilic atom than a non-derivatized carboxylic acid. Active carboxylic acids include, for example, acidic halides (such as acid chlorides), anhydrides, carbonates, and esters. The general form of such esters is-(CO) ON [(CO)-]2The imide ester is, for example, N-hydroxysuccinimidyl (NHS) ester or N-hydroxyphthalimidyl ester. Imidazolyl esters and benzotriazole esters are also preferred. Active propionic acid or butane esters, as described in co-owned US Pat. No. 5,672,662, are particularly preferred. These are-(CH2)2-3Contains groups in the form of C (= O) OQ, where Q is N-succinimide, N-sulfosuccinimide, N-phthalimide, N-glutarimide, N-tetrahydrophthalimide, N-norbornene-2,3-dicarboxyimide. , Benzotriazole, 7-azabenzotriazole, and imidazole are preferred.

Other suitable electrophobic groups include succinimidyl carbonate, maleimide, benzotriazole carbonate, glycidyl ether, imidazolyl carbonate, p-nitrophenyl carbonate, acrylate, tresilate, aldehyde, and orthopyridyl disulfide.

These electrophilic groups undergo reactions with nucleophilic atoms such as hydroxy, thio, and amino groups to form various bond types. In the present invention, a reaction that easily forms a hydrolyzically stable bond is preferable. For example, carboxylic acids and active derivatives thereof, including orthoesters, succinimidyl esters, imidazolyl esters, and benzotriazole esters, react with nucleophilic atoms of the types described above to form esters, thioesters, and amides, respectively. Of these, amides are the most hydrolyzically stable. Carbonates, including succinimidyl, imidazolyl, and benzotriazole carbonates, react with transamination to form carbamate. Isocyanates (RN = C = O) react with hydroxyl or amino groups to form carbamate (RNH-C (O) -OR') or urea (RNH-C (O) -NHR') bonds, respectively. .. Aldehydes, ketones, glyoxal, diones, and their hydrates or alcohol adducts (ie, aldehyde hydrates, hemiacetals, acetals, ketone hydrates, hemicetals, and ketals) preferably react with amines. After that, the resulting imine is reduced to provide amine bonds (reducing amination), if necessary.

Some of the electrophilic functional groups include electrophilic double bonds to which nucleophilic groups such as thiols can be added, eg to form thioether bonds. These groups include maleimide, vinyl sulfone, vinyl pyridine, acrylate, methacrylate, and acrylamide. Other groups include leaving groups that can be replaced by nucleophilic atoms, including chloroethyl sulfone, pyridyl disulfide (including cleavable SS bonds), iodoacetamide, mesylate, tosylate, thiosulfonate, and tresilate. Can be mentioned. The epoxide reacts by ring opening with a nucleophilic atom to form, for example, an ether or amine bond. Reactions with complementary reactive groups as described above on oligomers and small molecules are used to prepare the complex of the invention.

In some cases, opioid agonists may not have functional groups suitable for conjugation. In this case, it is possible to modify the "original" opioid agonist to have the desired functional group. For example, if the opioid agonist has an amide group but an amine group is desired, then the Hofmann rearrangement, Curtius rearrangement (amide is converted to azide once), or Lossen rearrangement (amide is converted to hydroxyamide once). It is then possible to modify the amide group to an amine group via (followed by treatment with toluene-2-sulfonyl chloride / base).

A small molecule in which a small molecule opioid agonist carrying a carboxyl group carries a carboxyl group attached to an amino-terminated oligomaethylene glycol so as to provide a complex having an amide group that covalently binds the small molecule opioid agonist to an oligomer. It is possible to prepare a complex of opioid agonists. This is done, for example, by binding a small molecule opioid agonist carrying a carboxyl group to an amino-terminal oligomaethylene glycol in the presence of a binding reagent (dicyclohexylcarbodiimide, or "DCC") in an anhydrous organic solvent. be able to.

In addition, the small molecule opioid agonist carrying a hydroxyl group carries a hydroxyl group attached to oligomaethylene glycol so as to result in a small molecule complex of ether (-O-) binding, a complex of small molecule opioid agonists. It is possible to prepare. This can be done, for example, by deprotonating the hydroxyl group with sodium hydride and then reacting with the halogenated terminal oligomaethylene glycol.

In other examples, it is possible to prepare a complex of small molecule opioid agonists carrying a ketone group by first reducing the ketone group to form the corresponding hydroxyl group. The small molecule opioid agonist that now carries the hydroxyl group at that stage can then be attached as described herein.

In yet other cases, it is possible to prepare a complex of small molecule opioid agonists carrying an amine group. In one approach, a small molecule opioid agonist carrying an amine group and an oligomer carrying an aldehyde are dissolved in a suitable buffer followed by a suitable reducing agent (eg, NaCNBH).3) Is added. Following the reduction, as a result, an amine bond is formed between the amine group of the amine group-containing small molecule opioid agonist and the carbonyl carbon of the aldehyde-carrying oligomer.

In other techniques for preparing complexes of small molecule opioid agonists carrying amine groups, oligomers carrying carboxylic acids and small molecule opioid agonists carrying amine groups are typically combined with binding reagents ( For example, combine in the presence of DCC). As a result, an amide bond is formed between the amine group of the amine group-containing small molecule opioid agonist and the carbonyl of the oligomer carrying the carboxylic acid.

Exemplary complexes of opioid agonists of Chemical Formula I include those having the following structures:

<chemistry num="5"><img id="000016" he="43" wi="93" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>In the formula, R2, R3, R4, Dotted line ("---"), Y1, And R5Each of is as defined for Chemical Formula I, where X is the spacer moiety and POLY is the water-soluble non-peptide oligomer.

Additional exemplary complexes of opioid agonists of Formula I include those having the following structures:

<chemistry num="6"><img id="000017" he="45" wi="98" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>In the formula, R1, R2, R3, R4, Dotted line ("---"), and Y1Each of is as defined for Chemical Formula I, where X is the spacer moiety and POLY is the water-soluble non-peptide oligomer.

Additional additional exemplary complexes of opioid agonists of Formula I include those having the following structures:

<chemistry num="7"><img id="000018" he="45" wi="95" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>In the formula, R1, R2, R3, R4, Y1, And R5Each of is as defined for Chemical Formula I, where X is the spacer moiety and POLY is the water-soluble non-peptide oligomer.

Further exemplary complexes of opioid agonists of Chemical Formula I include those having the following structures:

<chemistry num="8"><img id="000019" he="44" wi="97" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>In the formula, R1, R2, R3, R4, Y1, And R5Each of is as defined for Chemical Formula I, where X is the spacer moiety and POLY is the water-soluble non-peptide oligomer.

Additional exemplary complexes of opioid agonists of Formula I include those having the following structures:

<chemistry num="9"><img id="000020" he="47" wi="97" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>In the formula, R1, R3, R4, Dotted line ("---"), Y1, And R5Each of is as defined for Chemical Formula I, where X is the spacer moiety and POLY is the water-soluble non-peptide oligomer.

Further exemplary complexes include those having the following chemical formulas:

<chemistry num="11"><img id="000022" he="193" wi="91" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>If present in the formula, R1, R2, R3, R4, Dotted line ("---"), Y1, And R5Each of is as defined for formula I, where the variable "n" is an integer from 1 to 30.

Further complexes include those provided below.

<chemistry num="16"><img id="000027" he="59" wi="49" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>In the formula, for each of the above complexes, X is a linker (eg, a covalent "-" or one or more atoms) and POLY is a water-soluble non-peptide oligomer.

Further complexes include those provided below.

<chemistry num="17"><img id="000028" he="41" wi="46" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>During the ceremony R1Is an acyl, R2Is selected from the group consisting of hydrogen, halogens, unsubstituted alkyls and halogen-substituted alkyls. R3Is selected from the group consisting of halogens and alkoxys, R5Is selected from the group consisting of hydroxyl, ester, alkoxy, and alkoxyalkyl, A1Is alkylene, X is a linker, POLY is a water-soluble non-peptide oligomer.

The complexes of the present invention may exhibit reduced blood-brain barrier crossing rates. In addition, the complex maintains at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% or more of the biological activity of the unmodified parent small molecule drug.

Although it is believed that the entire range of complexes disclosed herein has been described, the optimal size oligomer can be determined as follows.

First, oligomers obtained from monodisperse or bimodal water-soluble oligomers are complexed with small molecule drugs. The drug is preferably orally bioavailable and, by itself, exhibits a non-negligible blood-brain barrier crossing rate. The ability of the complex to cross the blood-brain barrier is then determined using an appropriate model and compared to that of the unmodified parent drug. If the results are favorable, that is, for example, if the crossing rate is significantly reduced, the biological activity of the complex is further evaluated. The compounds according to the invention preferably have a significant degree of biological activity relative to the parent drug, i.e. greater than about 30% of the biological activity of the parent drug, more preferably more than about 50% of the biological activity of the parent drug. maintain.

The above steps are repeated one or more times using oligomers of the same monomer type but with different numbers of subunits and the results are compared.

Assess its oral bioavailability for individual complexes whose ability to cross the blood-brain barrier is reduced compared to uncomplexed small molecule drugs. Based on these results, i.e., comparison of complexes of different sized oligomers with a given small molecule at a given position or location within a small molecule, biological transmembrane reduction, oral organisms. The size of the most effective oligomers can be determined in providing a complex that has the optimal balance between physiologic availability and biological activity. The small size of the oligomer allows for such screening and allows effective preparation of the properties of the resulting complex. Innovatively varying size of oligomers, design of experiments is used to create a complex with a favorable balance between reduced biological transmembrane speed, biological activity, and oral bioavailability. , Can be effectively identified. In some cases, the binding of oligomers described herein is effective in actually enhancing the bioavailability of the drug.

For example, those skilled in the art who use experiments on a daily basis first prepare a series of oligomers with different weights and functional groups, then administer the complex to the patient and regularly sample blood and / or urine. The required clearance profile can be obtained by harvesting to determine the optimal molecular size and binding for improved oral bioavailability. For each complex tested, a set of clearance profiles can be obtained to identify suitable complexes.

Animal models (rods and dogs) can also be used to study oral drug transport. In addition, non-internal methods include rodent reversal bowel resection tissue and Caco-2 cell monolayer tissue culture models. These models are useful in predicting the bioavailability of oral drugs.

It is possible to test such compounds to determine if an opioid antagonist, or a complex of an opioid antagonist and a water-soluble non-peptide polymer, has activity as a muopioid receptor antagonist. For example, KD(Binding affinity) and Bmax(Number of receptors) is described by Malatynska et al. (1995) Neuro Report 6It can be determined using a modified technique from that described in: 613-616. Briefly, the human mu receptor can be expressed in Chinese hamster ovary cells by recombinant technology. Radioligand with a final ligand concentration of [0.3 nM] [3H] -Diprenorfin (30-50 Ci / mmol) can be used. Naloxone is used as a non-specific determination [3.0 nM], a reference compound, and a positive control. 5 mM MgCl for 150 minutes at 25 ° C2The reaction is carried out in 50 mM TRIS-HCl (pH 7.4) containing. Rapid vacuum filtration over the fiberglass filter terminates the reaction. Radioactivity trapped on the filter is measured and compared to control values to confirm the interaction of the test compound with the mu binding site of the clone.

Similar tests can be performed on kappa opiroid receptor agonists. For example, Lahti et al. (1985) Eur. Jrnl. Pharmac.109: 281-284, Rothman et al. (1992) Peptides13: 977-987, Kinouchi et al. (1991) Eur. Jrnl. Pharmac.207See: 135-141. In short, human kappa receptors can be obtained from the guinea pig cerebellar membrane. Radioligand with a final ligand concentration of [0.75 nM] [3H] -U-69593 (40-60 Ci / mmol) can be used. U-69593 is used as a non-specific confirmation [1.0 nM], reference compound and positive control. The reaction is carried out at 30 ° C. for 120 minutes at 50 mM HEPES (pH 7.4). The reaction is terminated by rapid vacuum filtration over a glass fiber filter. Radioactivity trapped on the filter is measured and compared to control values to confirm the interaction of the test compound with the kappa binding site of the clone.

The present invention also includes pharmaceuticals comprising the complexes provided herein in combination with pharmaceutical excipients. In general, the complex itself is in solid form (eg, precipitate) and can be combined with suitable pharmaceutical excipients that can be in either solid or liquid form.

Exemplary excipients include those selected from the group consisting of carbohydrates, inorganic salts, antibacterial agents, antioxidants, surfactants, buffers, acids, bases and combinations thereof. Not limited.

Derivatized sugars such as sugars and alditol, aldonic acids, esterified sugars, and / or carbohydrates such as sugar polymers can be present as excipients. Specific carbohydrate excipients include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannitol, sorbitol, disaccharides such as lactose, sucrose, trehalose, cellobiose, raffinose, meletitos, maltodextrin, etc. Examples thereof include polysaccharides such as dextran and starch, and algitols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol) pyranosylsorbitol, and myoinositol.

Examines also include inorganic salts or buffers such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, basic sodium phosphate, dibasic sodium phosphate, and combinations thereof.

The preparation may contain an antibacterial agent to inhibit or inhibit microbial growth. Non-limiting examples of antibacterial agents suitable for the present invention include benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercury nitrate, thimerosal, and combinations thereof. Can be mentioned.

Antioxidants can also be present at the time of preparation. Antioxidants are used to prevent oxidation, thereby preventing degradation of other components of the complex or formulation. Suitable antioxidants used in the present invention include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate. , Sodium metabisulfite, and combinations thereof.

Surfactants can be present as excipients. Exemplary surfactants include polysorbates such as "Tween 20" and "Tween 80", and pluronic, sorbitan esters, lecithins such as F68 and F88 (both available from BASF, Mount Olive, New Jersey). And other phospholipids such as phosphatidylcholine, phosphatidylethanolamine (but not preferably in liposome form), fatty acids, and lipids such as fatty acid esters, steroids such as cholesterol, and EDTA, zinc, and other such suitable Examples include chelating agents such as cations.

A pharmaceutically acceptable acid or base may be present as an excipient in the formulation. Non-limiting examples of acids that can be used include hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof. Some are selected from the group consisting of. Examples of suitable bases are sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate. , Potassium fumarate, and bases selected from groups consisting of combinations thereof, but are not limited thereto.

The amount of complex in the composition varies depending on a number of factors, but is optimally a therapeutically effective dose when the composition is stored in a unit dose container. The therapeutically effective dose can be determined experimentally by increasing the amount of the complex and repeatedly administering it to determine which amount achieves the clinically desired end point.

The amount of any individual excipient in the composition will vary depending on the activity of the excipient and the specific needs of the composition. In general, the optimum amount of any individual excipient is through routine experimentation, i.e., preparing compositions containing various amounts of excipients (from small to large amounts), stability and another. It is determined by inspecting the parameters and then determining the range in which optimum performance is obtained without any significant adverse effects.

However, in general, the excipient is shaped in an amount of about 1 to about 99% by weight, preferably about 5 to 98% by weight, more preferably about 15 to 95% by weight, most preferably less than 30% by weight. As an agent, it is present in the composition.

General teachings on these above-mentioned pharmaceutical excipients, and pharmaceutical compositions, along with other excipients, are described in Remington: The Science & Practice of Pharmacy, 19.th ed., Williams & Williams (1995), "Physician's Desk Reference", 52nd ed., Medical Economics, Montvale, NJ (1998), and Kibbe, AH, Pharmaceutical Excipients, 3rd Listed in Edition, American Pharmacists Association, Washington, DC, 2000.

The pharmaceutical composition can take multiple forms and the present invention is not limited in this regard. Exemplary formulations include tablets, caplets, capsules, gel caps, lozenges, dispersions, suspensions, solutions, elixirs, syrups, confectionery tablets (lozenge), percutaneous patches, sprays, suppositories, and powders. , Most preferably in a form suitable for oral administration.

Orally dosage forms are suitable for orally effective complexes, including tablets, caplets, capsules, gel caps, suspensions, solutions, elixirs, and syrups, and optionally encapsulated, plural. Can also include granules, beads, powders, or pellets. Such dosage forms are prepared using conventional methods known in the field of pharmaceutical formulations and described in related documents.

Tablets and caplets can be manufactured, for example, using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferred when preparing tablets or caplets containing the complexes described herein. In addition to the complex, tablets and caplets generally contain carrier materials that are acceptable as inert agents, such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, colorants and the like. .. Binders are used to give the tablets stickiness and thus keep the tablets intact. Suitable binder materials include starch (including corn starch and pregelatinized starch), gelatin, sugar (including cellulose, glucose, glucose, and lactose), polyethylene glycol, wax, and natural and synthetic gums such as acacia. Examples include, but are not limited to, sodium alginate, polyvinylpyrrolidone, cellulose polymers (including, but not limited to, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, etc.), and Veegum. Lubricants are used to facilitate tablet production, facilitate powder flow, and prevent particle colonization when pressure is reduced. Useful lubricants are magnesium stearate, calcium stearate, and stearic acid. Disintegrants are used to facilitate the disintegration of tablets and are generally starch, clay, cellulose, algin, gum or crosslinked polymers. Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, and solubles such as mannitol, urea, sucrose, lactose, glucose, sodium chloride, and sorbitol. Materials can be mentioned. Stabilizers are, as is known in the art, used, for example, to suppress or interfere with drug degradation reactions, including oxidative reactions.

Capsules are also a preferred form of oral administration, where the complex-containing composition comprises liquids or gels (eg, in the case of gel caps), or solids (granule, beads, powder, or pellets, etc.). ) Can be encapsulated. Suitable capsules include hard and soft capsules and are generally made of gelatin, starch, or cellulosic material. The two-piece hard gelatin capsule is preferably sealed with a gelatin band or the like.

Substantially dry parenteral formulations (generally in the form of powders or cakes, as lyophilized or precipitates), and generally liquid, dry parenteral formulations. Examples include formulations prepared for injection that require a step of reconstitution. Examples of suitable diluents for reconstitution of the solid composition prior to injection include bacteriostatic water for injection, 5% glucose water, phosphate buffered saline, Ringer solution, saline, sterile water, desorption. Ionized water and combinations thereof can be mentioned.

In some cases, compositions intended for parenteral administration can take the form of non-aqueous solutions, suspensions, or emulsions, which are generally sterile, respectively. Examples of non-aqueous solvents or vehicles include vegetable oils such as propylene glycol, polyethylene glycol, olive oil or corn oil, gelatin, and injectable organic esters such as ethyl oleate.

The parenteral formulations described herein can also contain auxiliaries such as preservatives, wetting agents, emulsifiers, and dispersants. The formulation is sterilized by filtration through a filter containing sterilizers, bacteria, irradiation, or introduction of heat.

The complex can also be administered through the skin using a conventional percutaneous patch or another percutaneous delivery system, the complex within a laminated structure that acts as a drug delivery device that is secured to the skin. Is contained in. In such a structure, the complex is housed in a layer below the upper support layer, a "reservoir". The laminated structure can accommodate a single reservoir or can accommodate multiple reservoirs.

The complex can also be prescribed in suppositories for rectal administration. For suppositories, the complex comprises coca butter (cacao fat), polyethylene glycol, glycerinized gelatin, fatty acids, and combinations thereof (eg, solid at room temperature but softened, melted, or dissolved at body temperature). Shape) Suppository base material is mixed. Suppositories are used, for example, by melting the suppository base material to form a melt, introducing the complex (before or after melting the suppository base material), and injecting the solution into the mold. Prepared by performing the steps of cooling the melt (eg, placing the melt-containing mold in a room temperature environment), thereby forming a suppository, and removing the suppository from the mold. Can be (not necessarily in the order shown).

The present invention also provides a method for administering the complex provided herein to a patient who is responsive to treatment with the complex. The method generally comprises the step of orally administering a therapeutically effective amount of the complex (preferably provided as part of a pharmaceutical product). Other modes of administration such as lung, nasal, oral, rectal, sublingual, transdermal, parenteral, etc. are also intended. As used herein, the term "parenteral" includes subcutaneous, intravenous, intraarterial, intraperitoneal, intracardiac, intramedullary, and intramuscular injections, as well as infusion injections.

In cases where parenteral administration is used, it is somewhat larger than those mentioned above and has a molecular weight of about 500-30 K daltons (eg, molecular weights of about 500, 1000, 2000, 2500, 3000, 5000, 7500, 10000). , 15000, 20000, 25000, 30000, or more) may be required.

This method of administration can be used to treat any condition that can be cured or prevented by administration of a particular complex. Those skilled in the art are aware of which conditions can be effectively treated by a particular complex. Actual doses will vary based on the subject's age, weight, and general condition, as well as the severity of the disease being treated, the judgment of healthcare professionals, and the complex being administered. Therapeutically effective amounts are known to those of skill in the art and / or described in relevant references and literature. In general, therapeutically effective doses range from about 0.001 mg / day to 1000 mg, preferably 0.01 mg / day to 750 mg / day, more preferably 0.10 mg / day to 500 mg / day.

Unit doses of any given complex (also preferably provided as part of the drug) can be administered on a variety of dosing schedules, depending on the clinician's discretion, patient requirements, etc. .. Specific dosing schedules are known to those of skill in the art or can be determined experimentally using routine methods. An exemplary medication schedule includes 5 times a day, 4 times a day, 3 times a day, 2 times a day, once a day, 3 times a week, twice a week, once a week, twice a month, a month. Once, and any combination thereof, but not limited to these. When the clinical termination point is achieved, dosing of the composition is stopped.

One advantage of administering the complex of the present invention is that a reduction during first-pass metabolism can be achieved as compared to the parent drug. Such results are favorable for a large number of orally administered drugs that are significantly metabolized by passing through the intestine. In this way, the clearance of the complex can be adjusted by choosing the size, binding, and covalent position of the oligomeric molecules that provide the desired clearance properties. One of ordinary skill in the art can determine the ideal molecular size of the oligomer based on the teachings herein. A preferred reduction in first-pass metabolism of the complex compared to the corresponding non-complex small drug molecule is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least. Approximately 60%, at least about 70%, at least about 80% and at least about 90%.

Therefore, the present invention provides a method for reducing the metabolism of an activator. The method is a step of providing a monodisperse or bimodal complex, each complex comprising a small molecule drug-derived moiety covalently attached to a water-soluble oligomer by stable binding. Includes steps that exhibit a reduced rate of metabolism compared to the rate of metabolism of small molecule drugs that are not bound to water-soluble oligomers, and steps that administer the complex to the patient. In general, administration is performed via one mode of administration selected from the group consisting of oral administration, transdermal administration, oral administration, transmucosal administration, intravaginal administration, rectal administration, parenteral administration, and pulmonary administration. Will be.

Although it is useful to be able to reduce many types of metabolism (including both Phase 1 and Phase 2 metabolism), this complex allows small molecule drugs to be used with liver enzymes (eg, cytochrome P450 iso). It is especially useful when metabolized by one or more of the forms) and / or by one or more intestinal enzymes.

All articles, books, patents, patent gazettes, and other publications cited in the specification of the present application are incorporated by reference in their entirety. In the event of any discrepancy between the teachings herein and the teachings incorporated by reference, the meaning of the teachings herein takes precedence.

Experiment Although the present invention has been described with respect to certain preferred specific embodiments, the above description and subsequent examples are intended to be exemplary and do not limit the scope of the invention. Please understand. Other aspects, advantages, and modifications within the scope of the invention will be apparent to those skilled in the art relating to the invention.

Unless otherwise stated, all chemical reagents cited in the accompanying examples are commercially available. The preparation of PEG-mer is described, for example, in US Patent Application Publication No. 2005/0136031.

All of1H NMR (Nuclear Magnetic Resonance) data was generated by an NMR spectrometer manufactured by Bruker (MHz 300). A list of specific compounds, as well as compound sources, is provided below.

(Example 1) Preparation of Oligomer-Nalbuphine Complex- "Method A" PEG-nalbuphine was prepared using the first method. Schematically, the method applied to this example is shown below.<chemistry num="18"><img id="000029" he="35" wi="120" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> Desalination of Nalbuphine Hydrochloride Dihydrate Nalbuphine hydrochloride dihydrate (600 mg, from Sigma) was dissolved in water (100 mL). Saturated aqueous K2CO3Was added, and then the pH was adjusted to 9.3 with a 1N HCl solution saturated with sodium chloride. The solution was extracted with dichloromethane (5 x 25 mL). Wash the combined organic solution with saline solution (100 mL) and Na2SO4It was dried on top, concentrated to dryness and dried under high vacuum to produce nalbuphine (483.4 mg, 97% recovery). The product, CDCl3Inside1Confirmed by 1 H-NMR. 3-O-mPEG3-Synthesis of Nalbuphine (2) (n = 3) <chemistry num="19"><img id="000030" he="28" wi="69" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Nalbuphine (28.5 mg, 0.08 mmol) was dissolved in a mixture of acetone (2 mL) and toluene (1.5 mL). Potassium carbonate (21 mg, 0.15 mmol) is added, followed by mPEG at room temperature3-Br (44.5 mg, 0.20 mmol) was added. The resulting mixture was stirred at room temperature for 27.5 hours. Further, potassium carbonate (24 mg, 0.17 mmol) was added. The mixture was heated with CEM microwaves to reach 60 ° C in 20 minutes and then to 100 ° C in 30 minutes. DMF (0.2 mL) was added. The mixture was microwave heated at 60 ° C for 20 minutes and at 100 ° C for 30 minutes. The reaction was concentrated to remove the organic solvent and the residue was mixed with water (10 mL) and extracted with dichloromethane (4 x 15 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The crude product was confirmed by HPLC and LC-MS. The residue was remixed with water (10 mL), adjusted to pH 2.3 with 1N HCl and washed with dichloromethane (2 x 15 mL). The aqueous solution was adjusted to pH 10.4 with 0.2 N NaOH and extracted with dichloromethane (4 x 15 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was purified by Biotage flash column chromatography with 0-10% MeOH in dichloromethane to produce the desired product 3-O-mPEG in 81% yield.3-Nalbuphine (2) (n = 3) (32.7 mg) was obtained. The product,1Confirmed by 1 H-NMR and LC-MS. 3-O-mPEG4-Synthesis of nalbuphine (2) (n = 4)<chemistry num="20"><img id="000031" he="27" wi="50" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Nalbuphine (96 mg, 0.27 mmol) and mPEG in acetone (8 mL)4A mixture of -OMs (131 mg, 0.46 mmol) was heated to reflux for 16 hours in the presence of potassium carbonate (113 mg, 0.82 mmol), cooled to room temperature, filtered and the solid washed with acetone and DCM. The solution was collected and concentrated to dryness. The residue was purified by Biotage automatic flash column chromatography with 0-10% MeOH in dichloromethane to produce product 3-O-mPEG in 74% yield.4-Nalbuphine (2) (n = 4) (109 mg) was obtained. The product,1Confirmed by 1 H-NMR and LC-MS. 3-O-mPEG5-Synthesis of Nalbuphine (2) (n = 5)<chemistry num="21"><img id="000032" he="27" wi="49" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Nalbuphine (78.3 mg, 0.22 mmol) and mPEG in acetone (8 mL)5A mixture of -OMs (118 mg, 0.36 mmol) was heated to reflux for 16 hours in the presence of potassium carbonate (93 mg, 0.67 mmol), cooled to room temperature, filtered and the solid washed with acetone and DCM. The solution was collected and concentrated to dryness. The residue was purified by Biotage automatic flash column chromatography with 0-10% MeOH in dichloromethane to produce product 3-O-mPEG in 76% yield.5-Nalbuphine (2) (n = 5) (101 mg) was obtained. The product,1Confirmed by 1 H-NMR and LC-MS. 3-O-mPEG6-Synthesis of nalbuphine (2) (n = 6)<chemistry num="22"><img id="000033" he="27" wi="48" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Nalbuphine (89.6 mg, 0.25 mmol) and mPEG in acetone (8 mL)6A mixture of -OMs (164 mg, 0.44 mmol) was heated to reflux for 18 hours in the presence of potassium carbonate (98 mg, 0.71 mmol), cooled to room temperature, filtered and the solid washed with acetone and DCM. The solution was collected and concentrated to dryness. The residue was purified by Biotage automatic flash column chromatography with 0-10% MeOH in dichloromethane, yielding 91%, product 3-O-mPEG.6-Nalbuphine (2) (n = 6) (144 mg) was obtained. The product,1Confirmed by 1 H-NMR and LC-MS. 3-O-mPEG7-Synthesis of nalbuphine (2) (n = 7) Nalbuphine (67 mg, 0.19 mmol) and mPEG in acetone (10 mL)7A mixture of -Br (131 mg, 0.33 mmol) was heated to reflux for 6 hours in the presence of potassium carbonate (67 mg, 0.49 mmol), cooled to room temperature, filtered and the solid washed with acetone and dichloromethane. The solution was concentrated to dryness. The residue was purified by Biotage automatic flash column chromatography with 2-10% MeOH in dichloromethane to produce product 3-O-mPEG.7-Nalbuphine (2) (n = 7) (40.6 mg) was obtained. The product,1Confirmed by 1 H-NMR and LC-MS. 3-O-mPEG8-Synthesis of nalbuphine (2) (n = 8)<chemistry num="23"><img id="000034" he="26" wi="49" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Nalbuphine (60 mg, 0.17 mmol) and mPEG in toluene / DMF (3 mL / 0.3 mL)8A mixture of -Br (105.7 mg, 0.24 mmol) was heated with CEM microwaves in the presence of potassium carbonate (40.8 mg, 0.30 mmol) to reach 100 ° C in 30 minutes. Then acetone (1 mL) was added. After heating the mixture with CEM microwaves to reach 100 ° C in 90 minutes, further K2CO3(31 mg, 0.22 mmol) and mPEG8-Br (100 mg, 0.22 mmol) was added. The mixture was heated with CEM microwaves to reach 100 ° C in 60 minutes. mPEG8-Br (95 mg, 0.21 mmol) was added again. The mixture was reheated with CEM microwaves to reach 100 ° C in 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was mixed with water (2 mL) and saline (10 mL). The pH of the solution was adjusted to 1.56 with 1N HCl and extracted with dichloromethane (3 x 20 mL). Combined organic solutions, Na2SO4It was dried in and concentrated to give residue I (a mixture of the desired product and precursor material). The aqueous solution was extracted with dichloromethane (4 x 15 mL), changing the pH to 10.13 with 0.2 N NaOH. Wash the organic solution with saline solution and Na2SO4It was dried on top and concentrated to give Residue II (19.4 mg) containing the product and starting material nalbuphine. Residue I was purified by Biotage automatic flash column chromatography with 2-10% MeOH in dichloromethane and product 3-O-mPEG.8-Nalbuphine (2) (n = 8) (44.6 mg) was obtained. The product,1Confirmed by 1 H-NMR and LC-MS. (Example 2) Preparation of Oligomer-Nalbuphine Complex- "Method B" PEG-nalbuphine was prepared using a second technique. Schematically, the method applied to this example is shown below.<chemistry num="24"><img id="000035" he="27" wi="109" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry><chemistry num="25"><img id="000036" he="30" wi="105" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> 3-O-MEM-Synthesis of Nalbuphine (3)<chemistry num="26"><img id="000037" he="30" wi="44" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Nalbuphine (321.9 mg, 0.9 mmol) was dissolved in acetone / toluene (19 mL / 8 mL). Then, potassium carbonate (338 mg, 2.45 mmol) was added, and then MEMCl (160 μL, 1.41 mmol) was added. The resulting mixture was stirred at room temperature for 21 hours. MeOH (0.3 mL) was added and the reaction was stopped. The reaction mixture was concentrated under reduced pressure and dried. The residue was mixed with water (5 mL) and brine (15 mL) and extracted with dichloromethane (3 x 15 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was separated by Biotage automatic flash column chromatography with 2-10% MeOH in dichloromethane to give the product 3-O-MEM-nalbuphine (3) (341 mg) and the starting material nalbuphine (19.3 mg). Obtained. The product,1Confirmed by 1 H-NMR and LC-MS. 6-O-mPEG3-3-O-MEM-Synthesis of nalbuphine (4) (n = 3)<chemistry num="27"><img id="000038" he="29" wi="62" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>A 20 mL vial was filled with 3-O-MEM-nalbuphine (3) (85 mg, 0.19 mmol) and toluene (15 mL). The mixture was concentrated to remove 7 mL of toluene. Anhydrous DMF (0.2 mL) was added. The vial was washed with nitrogen. NaH (60% dispersion in mineral oil, 21 mg, 0.53 mmol) was added, followed by mPEG3-OMs (94 mg, 0.39 mmol) were added. The resulting mixture was heated at 45 ° C. for 22.5 hours before additional NaH (22 mg, 0.55 mmol) was added. The mixture was heated at 45 ° C for an additional 6 hours, NaH (24 mg) was added and the mixture was heated at 45 ° C for an additional 19 hours. When the mixture was cooled to room temperature, saturated aqueous NaCl solution (1 mL) was added to terminate the reaction. The mixture was diluted with water (10 mL) and extracted with EtOAc (4 x 15 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was separated by Biotage automatic flash column chromatography with 0-10% MeOH in dichloromethane and the product 6-O-mPEG in 71% yield.3-3-O-MEM-Nalbuphine (4) (n = 3) (79.4 mg) was obtained. The product,1Confirmed by 1 H-NMR and LC-MS. 6-O-mPEG3-Synthesis of Nalbuphine (5) (n = 3)<chemistry num="28"><img id="000039" he="28" wi="44" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>6-O-mPEG3-3-O-MEM-Nalbuphine (4) (79.4 mg) was stirred at room temperature for 6 hours in 2M HCl in methanol. The mixture was diluted with water (5 mL) and concentrated to remove methanol. The aqueous solution was washed with dichloromethane (5 mL) and the pH of the solution was adjusted to 0.2 N NaOH and solid LVDS.3Was adjusted to 9.35 and extracted with dichloromethane (4 x 30 mL). Wash the combined organic solution with saline solution and Na2SO4Dry on top, concentrate, 93% yield, product 6-O-mPEG3-Nalbuphine (5) (n = 3) (62.5 mg) was obtained. The product,1Confirmed by 1 H-NMR and LC-MS. 6-O-mPEG4-3-O-MEM-Synthesis of nalbuphine (4) (n = 4)<chemistry num="29"><img id="000040" he="29" wi="69" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-O-MEM-nalbuphine (3) (133.8 mg, 0.3 mmol), mPEG in a 50 mL round bottom flask4-OMs (145 mg, 0.51 mmol) and toluene (20 mL) were added. The mixture was concentrated to remove about 12 mL of toluene. Anhydrous DMF (0.2 mL) was added. NaH (60% dispersion in mineral oil, 61 mg, 1.52 mmol) was added. The resulting mixture was heated at 45 ° C. for 21.5 hours before additional NaH (30 mg, 0.75 mmol) was added. The mixture was heated at 45 ° C for an additional 5 hours. When the mixture was cooled to room temperature, saturated aqueous NaCl solution (1 mL) was added to terminate the reaction. The mixture was diluted with water (15 mL) and extracted with EtOAc (4 x 15 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was purified by Biotage automatic flash column chromatography on silica gel with 0-10% MeOH in dichloromethane to produce 6-O-mPEG.4-3-O-MEM-Nalbuphine (4) (n = 4) (214.4 mg) was obtained.11 H-NMR has some mRNA in the product4-Oms was shown. No attempt was made for further purification. The product,1Confirmed by 1 H-NMR and LC-MS. 6-O-mPEG4-Synthesis of Nalbuphine (5) (n = 4)<chemistry num="30"><img id="000041" he="27" wi="47" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>6-O-mPEG4-3-O-MEM-Nalbuphine (4) (214.4 mg) was stirred at room temperature for 6 hours in 2 M HCl in methanol (30 mL). The mixture was diluted with water (5 mL) and concentrated to remove methanol. The aqueous solution was adjusted to pH 9.17 with 1N NaOH and extracted with dichloromethane (4 x 25 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue is purified by flash column chromatography on silica gel using 3-8% MeOH / DCM (Biotage) and is pure product 6-O-mPEG with some impure product.4-Nalbuphine (5) (n = 4) (90.7 mg) was obtained. The product,1Confirmed by 1 H-NMR and LC-MS. The impure portion was dissolved in DCM (approximately 1.5 mL). 1N HCl in ether (20 mL) was added and centrifuged. The residue was collected and re-dissolved in DCM (25 mL). DCM solution, 5% LVDS3Wash with aqueous solution (20 mL), saline solution (2 x 30 mL), Na2SO4It was dried on top and concentrated to give another pure product (24.8 mg). 6-O-mPEG5-3-O-MEM-Synthesis of nalbuphine (4) (n = 5)<chemistry num="31"><img id="000042" he="29" wi="65" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-O-MEM-nalbuphine (3) (103.9 mg, 0.23 mmol), mPEG in a 50 mL round bottom flask5-OMs (151 mg, 0.46 mmol) and toluene (38 mL) were added. The mixture was concentrated to remove about 20 mL of toluene. Anhydrous DMF (0.5 mL) was added. NaH (60% dispersion in mineral oil, 102 mg, 2.55 mmol) was added. The resulting mixture was heated at 45 ° C. for 18 hours before additional NaH (105 mg) was added. The mixture was heated at 45 ° C for an additional 5.5 hours. NaH (87 mg) was added and the mixture was heated at 45 ° C for an additional 17.5 hours. When the mixture was cooled to room temperature, saturated aqueous NaCl solution (3 mL) was added to terminate the reaction. The mixture was diluted with water (10 mL) and extracted with EtOAc (4 x 20 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue is separated by Biotage automatic flash column chromatography on silica gel with 3-8% MeOH in dichloromethane to produce 6-O-mPEG.5-3-O-MEM-Nalbuphine (4) (n = 5) was obtained. 6-O-mPEG5-Synthesis of Nalbuphine (5) (n = 5)<chemistry num="32"><img id="000043" he="26" wi="46" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>6-O-mPEG mentioned above5-3-O-MEM-Nalbuphine (4) was stirred at room temperature for 2.5 hours in 2M HCl in methanol (30 mL). The mixture was diluted with water (5 mL) and concentrated to remove methanol. The aqueous solution was adjusted to pH 9.19 with 1N NaOH and extracted with dichloromethane (4 x 15 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. After purification by flash column chromatography on silica, mPEG5-Oms1Observed by 1 H-NMR. The residue was dissolved in DCM (about 1 mL). 1N HCl in ether (18 mL) was added and centrifuged. The residue was collected and re-dissolved in DCM (25 mL). DCM solution, 5% LVDS3Wash with aqueous solution (2 x 20 mL), saline solution (2 x 30 mL), Na2SO4It was dried on top and concentrated. The residue was purified by Biotage automatic flash column chromatography on silica gel with 4-8% MeOH in dichloromethane to produce 6-O-mPEG.5-Nalbuphine (5) (n = 5) (55 mg) was obtained. 6-O-mPEG6-3-O-MEM-Synthesis of nalbuphine (4) (n = 6)<chemistry num="33"><img id="000044" he="30" wi="67" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-O-MEM-Nalbuphine (3) (77.6 mg, 0.17 mmol) and mPEG6-OMs (199 mg, 0.53 mmol) were dissolved in toluene (20 mL). The mixture was concentrated to remove about 12 mL of toluene. Anhydrous DMF (0.2 mL) was added, followed by NaH (60% dispersion in mineral oil, 41 mg, 1.03 mmol). The resulting mixture was heated at 45 ° C. for 23 hours before the addition of NaH (46 mg). The mixture was heated at 45 ° C for an additional 24 hours. When the mixture was cooled to room temperature, saturated aqueous NaCl solution (5 mL) was added and the reaction was stopped. The mixture was diluted with water (10 mL) and extracted with EtOAc (4 x 15 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was used directly in the next step. 6-O-mPEG6-Synthesis of Nalbuphine (5) (n = 6)<chemistry num="34"><img id="000045" he="26" wi="44" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>6-O-mPEG mentioned above6-3-O-MEM-Nalbuphine (4) was stirred at room temperature for 20 hours in 2M HCl in methanol (30 mL). The mixture was diluted with water (5 mL) and concentrated to remove methanol. The aqueous solution was adjusted to pH 9.30 with 1N NaOH and extracted with dichloromethane (5 x 20 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was dissolved in DCM (about 1 mL). 1N HCl in ether (20 mL) was added and centrifuged. The residue was collected and re-dissolved in DCM (40 mL). DCM solution, 5% LVDS3Wash with aqueous solution (2 x 20 mL), water (30 mL), saline solution (2 x 30 mL), Na2SO4Dry on top, concentrate and product 6-O-mPEG6-Nalbuphine (5) (n = 6) (68 mg) was obtained. 6-O-mPEG7-3-O-MEM-Synthesis of nalbuphine (4, n = 7)<chemistry num="35"><img id="000046" he="31" wi="68" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-O-MEM-nalbuphine (3) (82.8 mg, 0.186 mmol), mPEG in a 50 mL round bottom flask7-Br (151 mg, 0.46 mmol) and toluene (15 mL) were added. The mixture was concentrated to remove about 9 mL of toluene. Anhydrous DMF (0.2 mL) was added. NaH (60% dispersion in mineral oil, 50 mg, 1.25 mmol) was added. The resulting mixture was heated at 45 ° C. for 22.5 hours before additional NaH (38 mg, 0.94 mmol) was added. The mixture was heated at 45 ° C for an additional 5 hours. When the mixture was cooled to room temperature, saturated aqueous NaCl solution (5 mL) was added and the reaction was stopped. The mixture was diluted with water (10 mL) and extracted with EtOAc (4 x 10 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was used directly in the next step. 6-O-mPEG7-Synthesis of Nalbuphine (5) (n = 7)<chemistry num="36"><img id="000047" he="30" wi="47" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>6-O-mPEG mentioned above7-3-O-MEM-Nalbuphine (4) was stirred at room temperature for 20 hours in 2M HCl in methanol (20 mL). The mixture was diluted with water and concentrated to remove methanol. An aqueous solution, LVDS3The pH was adjusted to 9.30 with 0.2 N NaOH and extracted with dichloromethane (4 x 20 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was purified by flash column chromatography on silica gel, washed with DCM under acidic conditions, adjusted to pH 9.35 and extracted by DCM. The product was still contaminated with low molecular weight PEG. The residue was dissolved in DCM (about 2 mL). 1N HCl in ether (10 mL) was added and centrifuged. The residue was collected and re-dissolved in DCM (10 mL). DCM solution, 5% LVDS3Wash with aqueous solution and saline solution, Na2SO4Dry on top, concentrate and product 6-O-mPEG7-Nalbuphine (5) (n = 7) (49 mg) was obtained. 6-O-mPEG8-3-O-MEM-Synthesis of nalbuphine (4) (n = 8)<chemistry num="37"><img id="000048" he="28" wi="64" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-O-MEM-nalbuphine (3) (80.5 mg, 0.181 mmol), mPEG in a 50 mL round bottom flask8-Br (250 mg, 0.56 mmol) and toluene (15 mL) were added. The mixture was concentrated to remove about 6 mL of toluene. Anhydrous DMF (0.2 mL) was added. NaH (60% dispersion in mineral oil, 49 mg, 1.23 mmol) was added. The resulting mixture was heated at 45 ° C. for 23 hours, the mixture was cooled to room temperature, saturated aqueous NaCl solution (5 mL) and water (10 mL) were added and the reaction was stopped. The mixture was extracted with EtOAc (4 x 20 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was used directly in the next step. 6-O-mPEG8-Synthesis of nalbuphine (5) (n = 8)<chemistry num="38"><img id="000049" he="29" wi="47" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>6-O-mPEG mentioned above8-3-O-MEM-Nalbuphine (4) was stirred at room temperature for 17 hours in 2M HCl in methanol (20 mL). The mixture was diluted with water and concentrated to remove methanol. An aqueous solution, LVDS3The pH was adjusted to 9.32 with 0.2N NaOH and extracted with dichloromethane (4 x 20 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was dissolved in DCM (about 1 mL). 1N HCl in ether (20 mL) was added and centrifuged. The residue was collected and re-dissolved in DCM (30 mL). DCM solution, 5% LVDS3Wash with aqueous solution (60 mL), water (30 mL), saline solution (30 mL), Na2SO4It was dried on top and concentrated. The residue was purified by flash column chromatography on silica gel using 0-10% MeOH in dichloromethane to produce 6-O-mPEG.8-Nalbuphine (5) (n = 8) (78.4 mg) was obtained. 6-O-mPEG9-3-O-MEM-Synthesis of nalbuphine (4) (n = 9)<chemistry num="39"><img id="000050" he="30" wi="66" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-O-MEM-nalbuphine (3) (120 mg, 0.27 mmol), mPEG in a 50 mL round bottom flask9-OMs (245 mg, 0.48 mmol) and toluene (20 mL) were added. The mixture was concentrated to remove about 10 mL of toluene. NaH (60% dispersion in mineral oil, 63 mg, 1.57 mmol) was added, followed by anhydrous DMF (0.5 mL). The resulting mixture was heated at 45 ° C for 17 hours. Further NaH (60% dispersion in mineral oil, 60 mg) was added based on the HPLC results, after which the mixture was heated at 45 ° C. for an additional 5.5 hours. The mixture was cooled to room temperature, saturated aqueous NaCl solution (2 mL) and water (15 mL) were added and the reaction was stopped. The mixture was extracted with EtOAc (4 x 20 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was purified by flash column chromatography on silica gel using 3-8% methanol in dichloromethane (biotage), product 6-O-mPEG in 90% yield.9-Nalbuphine (207 mg) was obtained. 6-O-mPEG9-Synthesis of Nalbuphine (5) (n = 9)<chemistry num="40"><img id="000051" he="28" wi="46" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>6-O-mPEG mentioned above9-3-O-MEM-Nalbuphine (4) (207 mg, 0.24 mmol) was stirred at room temperature for 17 hours in 2 M HCl in methanol (33 mL). The mixture was diluted with water and concentrated to remove methanol. The aqueous solution was adjusted to pH 9.16 with 1N NaOH and extracted with dichloromethane (4 x 25 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was purified by flash column chromatography on silica gel using 3-8% methanol in dichloromethane and in 70% yield, product 6-O-mPEG.9-Nalbuphine (4) (n = 9) (129.3 mg) was obtained. (Example 3) Preparation of Oligomer-Nalbuphine Complex- "Method C" PEG-nalbuphine was prepared using a third technique. Schematically, the method applied to this example is shown below. <chemistry num="41"><img id="000052" he="45" wi="123" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>TrO-PEG5-Synthesis of OH (7) (n = 5)<chemistry num="42"><img id="000053" he="12" wi="24" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>PEG5-Di-OH (6) (n = 5) (5.88 g, 24.19 mmol) was dissolved in toluene (30 mL) and concentrated under reduced pressure to remove toluene. The residue was dried under high vacuum. Anhydrous DMF (40 mL) was added, followed by DMAP (0.91 g, 7.29 mmol) and TrCl (trityl chloride) (1.66 g, 5.84 mmol). The resulting mixture was heated at 50 ° C. for 22 hours. The mixture was concentrated to remove the solvent (high vacuum, 50 ° C). The residue was mixed with water and extracted with EtOAc (3 x 25 mL). Wash the combined organic solution with saline solution and Na2CO3It was dried on top and concentrated. The residue was purified by flash column chromatography on silica gel to give 1.29 g of product in 46% yield. The product, CDCl3Inside1Confirmed by 1 H-NMR. TrO-PEGn-Synthesis of OH (7) (n = various values) TrO-PEG5-Following similar procedures for the preparation of OH, other TrO-PEGn-OH, corresponding PEGn-Synthesized from di-OH. TrO-PEG5-Composite of OMs (8) (n = 5)<chemistry num="43"><img id="000054" he="12" wi="24" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Methanesulfonyl chloride (0.35 mL, 4.48 mmol), TrO-PEG in dichloromethane (15 mL)5It was added dropwise to a stirred solution of -OH (8) (n = 5) (1.29 g, 2.68 mmol) and triethylamine (0.9 mL, 6.46 mmol) at 0 ° C. After the addition, the resulting solution was stirred at room temperature for 16.5 hours. Water was added and the reaction was stopped. The organic phase was separated and the aqueous solution was extracted with dichloromethane (10 mL). Wash the combined organic solution with saline solution (3 x 30 mL) and Na2SO4It was dried on top and concentrated to give the product (1.16 g) as an oil in 78% yield. Product (8) (n = 5), CDCl3Inside1Confirmed by 1 H-NMR. TrO-PEGn-Composition of OMs (8) (n = various values) TrO-PEG5-Following similar procedures for the preparation of OMs, other TrO-PEGsn-OMs, corresponding TrO-PEGnSynthesized from -OH. 3-O-MEM-6-O-TrO-PEG4-Synthesis of Nalbuphine (9) (n = 4)<chemistry num="44"><img id="000055" he="37" wi="60" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>In a round bottom flask, 3-O-MEM-nalbuphine (3) (120 mg, 0.27 mmol) [pre-prepared according to the synthesis of compound (3) provided in Example 2], TrO-PEG4-OMs (8) (n = 4) (143.4 mg, 0.28 mmol) and toluene (40 mL) were added. The mixture was concentrated to remove about 30 mL of toluene. NaH (60% dispersion in mineral oil, 150 mg, 3.75 mmol) was added, followed by anhydrous DMF (0.2 mL). The resulting mixture was heated at 45 ° C for 4.5 hours. Further NaH (60% dispersion in mineral oil, 146 mg) was added and the mixture was stirred at 45 ° C. for an additional 18 hours. The mixture was cooled to room temperature, saturated with aqueous NaCl solution (2 mL), water (15 mL) was added and the reaction was stopped. The mixture was extracted with EtOAc (4 x 20 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was purified by flash column chromatography on silica gel using 0-10% methanol in dichloromethane (Biotage) to produce product 3-O-MEM-6-O-TrO-PEG.4-Nalbuphine (9) (n = 4) (about 150 mg) was obtained. 6-O-HO-PEG4-Synthesis of Nalbuphine (10) (n = 4)<chemistry num="45"><img id="000056" he="35" wi="56" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>6-O-TrO-PEG mentioned above4-3-O-MEM-Nalbuphine (9) (n = 4) (150 mg) was stirred at room temperature for 1 day in 2M HCl in methanol (12 mL). The mixture was diluted with water and concentrated to remove methanol. The aqueous solution was adjusted to pH 9.08 with NaOH and extracted with EtOAc (3 x 20 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was purified by flash column chromatography on silica gel to produce product 6-O-OH-PEG.4-Nalbuphine (10) (n = 4) (26.9 mg) was obtained. The product,1Confirmed by 1 H-NMR, LC-Ms, HPLC. 3-O-MEM-6-O-TrO-PEG5-Synthesis of Nalbuphine (9) (n = 5)<chemistry num="46"><img id="000057" he="35" wi="60" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>In a round bottom flask, 3-O-MEM-nalbuphine (3) (318 mg, 0.71 mmol) [pre-prepared according to the synthesis of compound (3) provided in Example 2], TrO-PEG5-OMs (8) (n = 5) (518.5 mg, 0.93 mmol) and toluene (100 mL) were added. The mixture was concentrated to remove about 75 mL of toluene. NaH (60% dispersion in mineral oil, 313 mg, 7.8 mmol) was added, followed by anhydrous DMF (1.0 mL). The resulting mixture was stirred at room temperature for 30 hours and then at 60 ° C. for 19.5 hours. The mixture was cooled to room temperature, saturated with aqueous NaCl solution (5 mL), water (5 mL) was added and the reaction was stopped. The organic phase was separated and the aqueous solution was extracted with EtOAc. Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was purified by flash column chromatography on silica gel using 0-10% methanol in dichloromethane (Biotage) to produce product 3-O-MEM-6-O-TrO-PEG.5-Nalbuphine (718 mg) was obtained. Product (9) (n = 5) was impure and was used in the next step without further purification. 6-O-HO-PEG5-Synthesis of Nalbuphine (10) (n = 5)<chemistry num="47"><img id="000058" he="36" wi="57" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>6-O-TrO-PEG mentioned above5-3-O-MEM-Nalbuphine (9) (n = 5) (718 mg) was stirred at room temperature for 19 hours in 2 M HCl in methanol (30 mL). The mixture was diluted with water and concentrated to remove methanol. The aqueous solution was adjusted to pH 9.16 with NaOH and extracted with DCM (3 x 20 mL). Wash the combined organic solution with saline solution and Na2SO4It was dried on top and concentrated. The residue was purified twice by flash column chromatography on silica gel to produce a very pure product 6-O-OH-PEG.5-Nalbuphine 10 (n = 5) (139 mg) and a less pure product (48 mg) were obtained. The product,1Analyzed by 1 H-NMR, LC-Ms, HPLC. (Example 4) Binding activity data Several molecules were analyzed using conventional binding affinity methods to determine the binding activity of opioid receptors on the kappa, mu, and delta opioid subtypes. The results are shown in Table 1.<tables num="1"><img id="000059" he="173" wi="143" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></tables> (Example 5) Preparation of oligomer-U50488 complex PEG-U50488 can be prepared generally according to the procedure shown below. Traditional organic synthesis techniques are used to carry out the techniques.<chemistry num="48"><img id="000060" he="210" wi="159" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry><chemistry num="49"><img id="000061" he="171" wi="157" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (Example 6) Preparation of oligomer-U69593 complex PEG-U69593 can be prepared generally according to the procedure shown below. Traditional organic synthesis techniques are used to carry out the techniques.<chemistry num="50"><img id="000062" he="150" wi="111" file="JP5877403B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (Example 7) Preparation of complexes using other than nalbuphine, U50488, and U69593 Complexes of opioid agonists other than nalbuphine, U50488, and U69593 can be prepared, wherein the opioid agonists of formula I are general described in Example 1 except that they are replaced with nalbuphine, U50488, and U69593. Synthetic schemes and procedures can be followed.

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Document	Relation	Office
US05475019A	Cites	United States of America
WO2005058367A1	Cites	World Intellectual Property Organization (WIPO)
WO2004039317A1	Cites	World Intellectual Property Organization (WIPO)
JP2005506351A	Cites	Japan

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60906387	United States of America	–	2007-03-12
90638707	United States of America	P	2007-03-12
90638707	United States of America	P	2007-03-12
60906387	–	–	–
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AU2008226822A1	Australia	A1	2008-09-18
CA2679479A1	Canada	A1	2008-09-18
WO2008112288A2	World Intellectual Property Organization (WIPO)	A2	2008-09-18
WO2008112288A3	World Intellectual Property Organization (WIPO)	A3	2008-12-24
MX2009009851A	Mexico	A	2009-09-24
KR20090118952A	Republic of Korea	A	2009-11-18
EP2134371A2	European Patent Office (EPO)	A2	2009-12-23
CN101646464A	China	A	2010-02-10
US2010048602A1	United States of America	A1	2010-02-25
AU2009292631A1	Australia	A1	2010-03-25
CA2734333A1	Canada	A1	2010-03-25
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IL200845A0	Israel	A0	2010-05-17
JP2010521466A	Japan	A	2010-06-24
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MX2011002748A	Mexico	A	2011-04-21
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IL211762A0	Israel	A0	2011-06-30
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EP2340044A1	European Patent Office (EPO)	A1	2011-07-06
CN102159249A	China	A	2011-08-17
US2011237614A1	United States of America	A1	2011-09-29
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AU2010276244A1	Australia	A1	2012-03-15
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JP5420427B2	Japan	B2	2014-02-19
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EP2134371B1	European Patent Office (EPO)	B1	2015-01-14
US8946285B2	United States of America	B2	2015-02-03
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PT2134371E	Portugal	E	2015-04-16
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US9233167B2	United States of America	B2	2016-01-12
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JP5877403B2This record	Japan	B2	2016-03-08
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US2016243111A1	United States of America	A1	2016-08-25
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US9458166B2	United States of America	B2	2016-10-04
US9512135B2	United States of America	B2	2016-12-06
US2016375009A1	United States of America	A1	2016-12-29
EP2628489B1	European Patent Office (EPO)	B1	2017-03-01
CY1117368T1	Cyprus	T1	2017-04-26
US2017112826A1	United States of America	A1	2017-04-27
EP2620163B1	European Patent Office (EPO)	B1	2017-05-03
MX347741B	Mexico	B	2017-05-10
EP3222293A1	European Patent Office (EPO)	A1	2017-09-27
KR101788886B1	Republic of Korea	B1	2017-10-20
US9827239B2	United States of America	B2	2017-11-28
IL217634A	Israel	A	2018-01-31
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CA2768392C	Canada	C	2018-04-17
EP3342427A1	European Patent Office (EPO)	A1	2018-07-04
US2018256563A1	United States of America	A1	2018-09-13
US10143690B2	United States of America	B2	2018-12-04
IL256822A	Israel	A	2018-12-31
IL256822B	Israel	B	2018-12-31
IL263713A	Israel	A	2019-01-31
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US2019046523A1	United States of America	A1	2019-02-14
US10307416B2	United States of America	B2	2019-06-04
US2019247388A1	United States of America	A1	2019-08-15
EP3222293B1	European Patent Office (EPO)	B1	2019-11-27

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