CN1988805A - Compositions containing opioid antagonists - Google Patents

Abstract

Compositions containing opioid antagonists, particularly alvimopan and its active metabolite, with improved solubility and bioavailability for oral or parenteral administration, injectable dosage formulations, kits, and methods of making and using same are disclosed. In preferred embodiments, invention provides injectable formulations containing opioid antagonists, particularly alvimopan and its active metabolite, having low solubility that may be readily prepared, are stake during storage, and provide maximum levels of opioid antagonists when administered parenterally, particularly via injection. The results are achieved by a combination of processing techniques and component selection.

Description

Compositions comprising opioid antagonists

Cross References to Related Applications

This application claims priority to U.S. Patent Application 11/143,535, filed June 2, 2005, which claims priority to U.S. Patent Application 60/576,939, filed June 4, 2004, both of which are incorporated in their entirety Included here as a reference.

technical field

The present invention relates to compositions comprising an opioid antagonist. More specifically, the present invention relates to compositions, injectable dosage forms, kits, and methods of making and using the same, comprising opioid antagonists.

Background technique

Oral dosage forms of drugs such as tablets and capsules are widely used dosage forms. However, some patients have intolerance to oral dosage forms due to old age, infirmity or lack of consciousness which prevent them from swallowing tablets or capsules. Therefore, it is desirable to be able to administer it by parenteral routes such as intravenous, intramuscular or subcutaneous injection. However, formulating solid pharmaceuticals for parenteral administration can be problematic because it is often difficult to dissolve solid active ingredients in pharmaceutically acceptable liquid solvents.

The low solubility issue has been addressed in several ways:

1. Solubilizing surfactants can be used to increase the solubility of active ingredients in solvents. Unfortunately, solubilizing surfactants can cause allergic reactions in sensitive patients.

2. Oil-in-water emulsions can be used, but this formulation has many disadvantages, including pain at the injection site, poor physical stability, possibility of causing embolism, and strict aseptic operation requirements.

3. Conjugation of the active ingredient with an amphiphilic agent that increases its solubility (eg, β-cyclodextrin) can be used, but limitations of these conjugates include higher cost and their use in human pharmaceutical products is currently subject to regulatory agency restrictions. limit.

[[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenyl Propyl]amino]acetic acid dihydrate ((USAN name alvimopan)) and its active metabolite are peripherally acting mu opioid antagonists useful in the treatment of postoperative ileus, postpartum intestinal Obstruction, pruritus, constipation, opioid bowel dysfunction, urinary retention, biliary spasm, opioid bowel dysfunction, colic, postoperative nausea and/or postoperative vomiting, and other indications. Alvimopan is currently available in solid dosage form available. However, it is desirable to provide the active ingredient in injectable form to avoid problems with swallowing tablets or capsules, or for administration to patients undergoing surgery and unconscious. Alvimopan and its active metabolites are 3, 4 - Disubstituted-4-arylpiperidines, which are zwitterions.They have very low solubility in water and many common pharmaceutically acceptable solvents.

What is desired is an injectable dosage form of alvimopan and related 4-aryl-substituted piperidine compounds that are zwitterionic in nature. The present invention addresses these and other important objects.

Contents of the invention

In one embodiment, the invention relates to a method comprising the steps of:

a. providing a composition comprising:

(i) at least one pharmaceutically acceptable metal salt of a compound of formula I:

in:

R ¹ is hydrogen or alkyl;

^R is hydrogen, alkyl or alkenyl;

^R is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ⁴ is hydrogen, alkyl or alkenyl;

A is OR ⁵ or NR ⁶ R ⁷ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ⁶ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, aralkyl, or alkylene Substituted B, or ^R6 and ^R7 form a heterocyclic ring together with the nitrogen atom to which they are attached;

B for

C(=O)W or NR ⁸ R ⁹ ;

R ⁸ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, cycloalkyl substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl substituted alkyl, aryl, or aralkyl, or ^R and ^R are combined with The nitrogen atoms to which they are attached together form a heterocycle;

W is OR ¹⁰ , NR ¹¹ R ¹² or OE;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ¹¹ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, cycloalkenyl substituted alkyl, aralkyl, or alkylene substituted C( =O)Y, or R ¹¹ and R ¹² form a heterocyclic ring together with the nitrogen atom to which they are attached;

E is

Alkylene substituted (C=O)D, or -R ¹³ OC(=O)R ¹⁴ ;

R ¹³ is an alkylene group substituted by an alkyl group;

R ¹⁴ is an alkyl group;

D is OR ¹⁵ or NR ¹⁶ R ¹⁷ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

^R is hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl or cycloalkenyl substituted alkyl;

R ¹⁷ is hydrogen or an alkyl group, or R ¹⁶ and R ¹⁷ form a heterocyclic ring together with the nitrogen atom to which they are attached;

Y is OR ¹⁸ or NR ¹⁹ R ²⁰ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ¹⁹ is hydrogen or alkyl;

R ²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, cycloalkenyl substituted alkyl, or aralkyl, or R ¹⁹ and R ²⁰ are combined with The nitrogen atoms to which they are attached together form a heterocycle;

R ²¹ is hydrogen or alkyl;

and n is 0 to 4;

(ii) at least one crystalline extender;

(iii) at least one weak base; and

(iv) water;

wherein said composition has an initial pH of at least about 10.5; and

b. adjusting the pH of the composition to a final pH in the range of about 9 to about 11;

Wherein, when administered to a patient, the composition has improved dissolution and bioavailability for oral or parenteral administration.

In another embodiment, the method to which this invention is in part further comprises the step of drying said composition to remove at least a portion of said water to form a partially or fully dry product.

In yet another embodiment, the method of the present invention further comprises the step of reconstituting said dried product by combining said dried product with a pharmaceutically acceptable solvent to form a solution of said dried product.

In other embodiments, the invention relates to products produced by each of the above methods.

In another embodiment, the method according to the present invention additionally comprises the step of administering said solution of said dry product to a patient.

In yet another embodiment, the present invention relates to compositions comprising:

a. At least one pharmaceutically acceptable metal salt of a compound of formula I:

in:

R ¹ is hydrogen or alkyl;

^R is hydrogen, alkyl or alkenyl;

^R is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ⁴ is hydrogen, alkyl or alkenyl;

A is OR ⁵ or NR ⁶ R ⁷ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ⁶ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, aralkyl, or alkylene Substituted B, or ^R6 and ^R7 form a heterocyclic ring together with the nitrogen atom to which they are attached;

B for

C(=O)W or NR ⁸ R ⁹ ;

R ⁸ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, cycloalkyl substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl substituted alkyl, aryl, or aralkyl, or ^R and ^R are combined with The nitrogen atoms to which they are attached together form a heterocycle;

W is OR ¹⁰ , NR ¹¹ R ¹² or OE;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ¹¹ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, cycloalkenyl substituted alkyl, aralkyl, or alkylene substituted C( =O)Y, or R ¹¹ and R ¹² form a heterocyclic ring together with the nitrogen atom to which they are attached;

E is

Alkylene substituted (C=O)D, or -R ¹³ OC(=O)R ¹⁴ ;

R ¹³ is an alkylene group substituted by an alkyl group;

R ¹⁴ is an alkyl group;

D is OR ¹⁵ or NR ¹⁶ R ¹⁷ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

^R is hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl or cycloalkenyl substituted alkyl;

R ¹⁷ is hydrogen or an alkyl group, or R ¹⁶ and R ¹⁷ form a heterocyclic ring together with the nitrogen atom to which they are attached;

Y is OR ¹⁸ or NR ¹⁹ R ²⁰ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ¹⁹ is hydrogen or alkyl;

R ²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, cycloalkenyl substituted alkyl, or aralkyl, or R ¹⁹ and R ²⁰ are combined with The nitrogen atoms to which they are attached together form a heterocycle;

R ²¹ is hydrogen or alkyl;

and n is 0 to 4;

b. at least one crystalline extender;

wherein said composition has a density of less than about 1.0 g/ ^cm ;

Wherein, when administered to a patient, the composition has improved dissolution and bioavailability for oral or parenteral administration.

In other embodiments, the present invention relates to compositions comprising:

a. At least one pharmaceutically acceptable metal salt of a compound of formula I:

Wherein: R ¹ is hydrogen or alkyl;

^R is hydrogen, alkyl or alkenyl;

^R is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ⁴ is hydrogen, alkyl or alkenyl;

A is OR ⁵ or NR ⁶ R ⁷ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ⁶ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, aralkyl, or alkylene Substituted B, or ^R6 and ^R7 form a heterocyclic ring together with the nitrogen atom to which they are attached;

B for

C(=O)W or NR ⁸ R ⁹ ;

R ⁸ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, cycloalkyl substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl substituted alkyl, aryl, or aralkyl, or ^R and ^R are combined with The nitrogen atoms to which they are attached together form a heterocycle;

W is OR ¹⁰ , NR ¹¹ R ¹² or OE;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ¹¹ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, cycloalkenyl substituted alkyl, aralkyl, or alkylene substituted C( =O)Y, or R ¹¹ and R ¹² form a heterocyclic ring together with the nitrogen atom to which they are attached;

E is

Alkylene substituted (C=O)D, or -R ¹³ OC(=O)R ¹⁴ ;

R ¹³ is an alkylene group substituted by an alkyl group;

R ¹⁴ is an alkyl group;

D is OR ¹⁵ or NR ¹⁶ R ¹⁷ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

^R is hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl or cycloalkenyl substituted alkyl;

R ¹⁷ is hydrogen or an alkyl group, or R ¹⁶ and R ¹⁷ form a heterocyclic ring together with the nitrogen atom to which they are attached;

Y is OR ¹⁸ or NR ¹⁹ R ²⁰ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ¹⁹ is hydrogen or alkyl;

R ²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, cycloalkenyl substituted alkyl, or aralkyl, or R ¹⁹ and R ²⁰ are combined with The nitrogen atoms to which they are attached together form a heterocycle;

R ²¹ is hydrogen or alkyl;

and n is 0 to 4;

b. at least one crystalline extender;

c. less than about 1% by weight of a solubilizing surfactant, based on the total weight of the composition;

d. less than about 10% by weight of a non-aqueous solvent, based on the total weight of the composition; and

e. less than about 500% by weight cyclodextrin, based on the total weight of the composition;

Wherein, when administered to a patient, the composition has improved dissolution and bioavailability for oral or parenteral administration.

In yet another embodiment, the present invention is directed to an injectable dosage form comprising the composition described above.

In yet another embodiment, the present invention relates to a pharmaceutical pack comprising:

a. Containers containing injectable dosage forms; and

b. Instructions for preparing the injectable solution.

In yet another embodiment, the present invention is directed to a method of preventing or treating opioid-related side effects in a patient comprising the steps of:

An effective amount of the composition described above is administered to said patient in need thereof.

The method is useful for the prophylaxis and treatment of ileus, pruritus, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, nausea or vomiting or combinations thereof, particularly postoperative ileus, postpartum ileus, opioid bowel Dysfunction, postoperative nausea or postoperative vomiting, or a combination thereof.

In other embodiments, the present invention is directed to a method of preventing or treating pain in a patient comprising the steps of:

An effective amount of the composition described above is administered to said patient in need thereof.

In a preferred embodiment, the composition additionally comprises at least one opioid.

These and other aspects of the invention will be apparent from the following detailed description.

Detailed Description of the Invention

As used above and throughout this disclosure, unless otherwise stated, it is understood that the following terms have the following meanings.

As used herein, "composition having improved dissolution and bioavailability for oral or parenteral administration" means a composition comprising at least one opioid suitable for oral or parenteral administration Antagonists of substances which, due to the method of forming the composition, have a higher level of dissolution and Bioavailability, preferably minimizing or removing undesired components such as solubilizing surfactants, non-aqueous solvents, cyclodextrins etc. used in prior art to improve active ingredient solubility.

As used herein, "parenteral administration" refers to the administration of a drug parenterally, without passing through the digestive tract. The principal routes of parenteral administration to mammalian subjects are intravenous, intramuscular, subcutaneous, intradermal, intraocular, intrasynovial, intracardiac, intraspinal, intraarticular, intrathecal, intraarterial, transepithelial ( Includes transdermal, intraperitoneal, ophthalmic, sublingual, and oral), topical (including ophthalmic, dermal, eye, nasal inhalation by insufflation, aerosol, and rectal system) administration. Preferred routes of parenteral administration are by intravenous, intramuscular, and subcutaneous injection.

As used herein, "bioavailability" refers to the rate and extent to which a drug or other substance is available to a target tissue following administration. In the context of the present invention, bioavailability refers to the degree to which an opioid antagonist is available by the central nervous system or its periphery.

As used herein, "alkyl" means an optionally substituted saturated straight alkyl having about 1 to about 20 carbon atoms (and all combinations and subcombinations within ranges and the specified number of carbon atoms). Chain, branched or cyclic hydrocarbons, preferably alkyl groups referred to herein as "lower alkyl" containing from about 1 to about 8 carbon atoms. "Branched" means an alkyl group in which a lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain. In certain preferred embodiments, the alkyl group is a C ₁ -C ₅ alkyl group, ie, a branched or straight chain alkyl group having from 1 to about 5 carbons. In other preferred embodiments, the alkyl group is C ₁ -C ₃ alkyl, ie, a branched or straight chain alkyl group having from 1 to about 3 carbons. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl base. "Lower alkyl" means an alkyl group having 1 to about 6 carbon atoms. Preferred alkyl groups include lower alkyl groups of 1 to about 3 carbons. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl , isohexyl, cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.

As used herein, "alkylene" refers to a divalent alkyl group having the general formula -( _CH2 )n-, where n is 1 to 10, and all combinations and subcombinations of ranges within that range. Alkylene groups can be linear, branched or cyclic. Non-limiting examples include methylene, methylene ( _-CH2- ), ethylene ( _{-CH2CH2-), propylene (-(CH2)3- ) , trimethylene} , pentamethylene methyl and hexamethylene. There may optionally be inserted along the alkylene group one or more oxygen, sulfur or optionally substituted nitrogen atoms wherein the nitrogen substituent is an alkyl group as previously described. Alkylene groups can be optionally substituted. The term "lower alkylene" herein refers to those alkylene groups having from about 1 to about 6 carbon atoms. Preferred alkylene groups have about 1 to about 4 carbons.

As used herein, "alkenyl" means a monovalent alkyl group containing at least one carbon-carbon double bond and having from 2 to about 10 (and combinations and subcombinations within that range) carbon atoms in the chain . Alkenyl groups can be optionally substituted. In certain preferred embodiments, the alkenyl group is a C ₂ -C ₁₀ alkenyl group, ie, a branched or straight chain alkenyl group having from 2 to about 10 carbons. In other preferred embodiments, the alkenyl group is a _C2 - _C6 alkenyl group, ie, a branched or straight chain alkenyl group having 2 to about 6 carbons. In other preferred embodiments, the alkenyl group is a C ₃ -C ₁₀ alkenyl group, ie, a branched or straight chain alkenyl group having from 3 to about 10 carbons. In other preferred embodiments, the alkenyl group is a _C2 - _C5 alkenyl group, ie, a branched or straight chain alkenyl group having 2 to about 5 carbons. Exemplary alkenyl groups include, for example, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl.

As used herein, "aryl" means an optionally substituted monocyclic ring having from about 5 to about 50 carbon atoms (and all combinations and subcombinations within ranges and the specified number of carbon atoms), Bicyclic, tricyclic or other polycyclic aromatic ring systems, preferably aryl groups containing from about 6 to about 10 carbon atoms. Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl.

As used herein, "aralkyl" refers to a group having an aryl substituent and having from about 6 to about 50 carbon atoms (and all combinations and subcombinations of ranges within the range and the specified number of carbon atoms) Alkyl, preferably aralkyl containing from about 6 to about 10 carbon atoms. Aralkyl groups can be optionally substituted in the aryl or alkyl moiety. Non-limiting examples include, for example, phenylmethyl (benzyl), benzhydryl, trityl, phenylethyl, diphenylethyl, and 3-(4-methylphenyl)propyl.

As used herein, "heteroaryl" refers to an optionally substituted monocyclic, bicyclic, tricyclic or other polycyclic ring atom comprising at least one and preferably 1 to about 4 sulfur, oxygen or nitrogen heteroatoms. Ring aromatic ring system. Heteroaryl groups can have, for example, about 3 to about 50 carbon atoms (and all combinations and subcombinations of ranges within this range and specific number of carbon atoms), with heteroaryl groups containing about 4 to about 10 carbon atoms being preferred. Non-limiting examples of heteroaryl include, for example, pyrrolyl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidinyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl , pyrimidinyl, quinolinyl, isoquinolyl, thienyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl and isoxazole base.

As used herein, "cycloalkyl" refers to an optionally substituted, in the Alkyl groups having one or more rings in their structure preferably contain about 3 to about 10 carbon atoms, more preferably about 3 to about 8 carbon atoms, more preferably about 3 to about 6 carbon atoms. The polycyclic structure may be a bridged or condensed ring structure. Cycloalkyl groups may be optionally substituted by eg alkyl (preferably C ₁ -C ₃ alkyl), alkoxy (preferably C ₁ -C ₃ alkoxy) or halo. Non-limiting examples include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl.

As used herein, "cycloalkyl-substituted alkyl" refers to straight-chain alkyl (preferably lower alkyl) substituted at a terminal carbon by cycloalkyl (preferably _C3 - _C8 cycloalkyl). Non-limiting examples include, for example, cyclohexylmethyl, cyclohexylethyl, cyclopentylethyl, cyclopentylpropyl, cyclopropylmethyl, and the like.

As used herein, "cycloalkenyl" refers to an ethylenically unsaturated cycloalkyl group having from about 4 to about 10 carbons (and all combinations and subcombinations of ranges within this range). In preferred embodiments, the cycloalkenyl group is a _C5 - _C8 cycloalkenyl group, ie, a cycloalkenyl group having 5 to about 8 carbons.

As used herein, "alkylcycloalkyl" refers to an optionally substituted ring system comprising a cycloalkyl group having one or more alkyl substituents. Non-limiting examples include, for example, alkylcycloalkyl, including 2-methylcyclohexyl, 3,3-dimethylcyclopentyl, trans-2,3-dimethylcyclooctyl, and 4-methyldeca Hydronaphthyl.

As used herein, "heteroaralkyl" refers to an optionally substituted group having from about 2 to about 50 carbon atoms (and all combinations and subcombinations of ranges within this range and the specified number of carbon atoms). Alkyl groups substituted by heteroaryl groups preferably contain from about 6 to about 25 carbon atoms. Non-limiting examples include 2-(1H-pyrrol-3-yl)ethyl, 3-pyridylmethyl, 5-(2H-tetrazolyl)methyl, and 3-(pyrimidin-2-yl)-2- Methylcyclopentyl.

As used herein, "heterocycloalkyl" refers to an optionally substituted monocyclic, bicyclic, tricyclic or other ring atom comprising at least one and preferably 1 to about 4 sulfur, oxygen or nitrogen heteroatoms. Polycyclic aliphatic ring systems. Cycloalkyl groups can have, for example, about 3 to about 20 carbon atoms (and all combinations and subcombinations of ranges within this range and specific number of carbon atoms), preferably about 4 to about 10 carbon atoms. Heterocycloalkyl groups can be unsaturated and can also be fused to an aromatic ring. Non-limiting examples include, for example, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperazinyl , Morpholinyl, piperidinyl, decahydroquinolyl, octahydrobenzopyranyl, octahydrocyclopenta[c]pyranyl, 1,2,3,4-tetrahydroquinolyl, Octahydro[2]pyridyl, octahydrocyclooctano[c]furyl and imidazolidinyl.

As used herein, the term "spiroalkyl" refers to an optionally substituted alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group. As defined herein, a spiroalkyl group and its parent group have from 3 to 20 ring atoms. Preferably, it has 3 to 10 ring atoms. Non-limiting examples of spiroalkyl together with its parent group include 1-(1-methyl-cyclopropyl)-propan-2-one, 2-(1-phenoxy-cyclopropyl)-ethane amine, and 1-methyl-spiro[4.7]dodecane.

As used herein, the term "alkoxy" refers to an optionally substituted alkyl-O- group, wherein alkyl is as previously defined. Non-limiting examples include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and heptoxy.

As used herein, the term "aryloxy" refers to an optionally substituted aryl-O- group wherein aryl is as previously defined. Non-limiting examples include, for example, phenoxy and naphthyloxy.

As used herein, the term "aralkoxy" refers to an optionally substituted aralkyl-O- group wherein aralkyl is as previously defined. Non-limiting examples include, for example, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, and 3-naphthylheptyloxy.

As used herein, the term "aryloxyaryl" refers to an aryl group having an aryloxy substituent, wherein aryloxy and aryl are as previously defined. Aryloxyaryl groups can be optionally substituted. Non-limiting examples include, for example, phenoxyphenyl and naphthoxyphenyl.

As used herein, the term "heteroarylaryl" refers to an aryl group having a heteroaryl substituent, wherein heteroaryl and aryl are as previously defined. Heteroarylaryl groups can be optionally substituted. Non-limiting examples include, for example, 3-pyridylphenyl, 2-quinolylnaphthyl, and 2-pyrrolylphenyl.

As used herein, the term "alkoxyaryl" refers to an aryl group bearing an alkoxy substituent, wherein alkoxy and aryl are as previously defined. Alkoxyaryl groups can be optionally substituted. Non-limiting examples include, for example, p-methoxyphenyl, m-tert-butoxyphenyl, and methylenedioxyphenyl.

As used herein, "carboxy" refers to a -C(=O)OH group.

As used herein, "alkanoyl" refers to a -C(=O)-alkyl group, wherein alkyl is as previously defined. Exemplary alkanoyl groups include acetyl, n-propionyl, n-butyryl, 2-methylpropionyl, n-pentanoyl, 2-methylbutyryl, 3-methylbutyryl, 2,2-dimethylpropanoyl Acyl, Heptanoyl, Decanoyl and Palmitoyl.

As used herein, "heterocyclic" refers to a carbocyclic ring radical of a monocyclic or polycyclic ring system comprising about 4 to about 10 atoms and all combinations and subcombinations within ranges in which one or more The atoms are atoms other than carbon, such as nitrogen, oxygen or sulfur. A heterocyclic group can be aromatic or non-aromatic. Non-limiting examples include, for example, pyrrole and piperidine groups.

As used herein, "halo" refers to fluoro, chloro or bromo.

Typically, a substituted chemical moiety includes one or more substituents in place of a hydrogen. Exemplary substituents include, for example, halo (e.g., F, Cl, Br, I), alkyl, cycloalkyl, alkylcycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl , heteroaralkyl, spiroalkyl, heterocycloalkyl, hydroxyl (-OH), nitro (-NO ₂ ), cyano (-CN), amino (-NH ₂ ), -N-substituted amino ( -NHR"), -N,N-disubstituted amino (-N(R")R"), carboxyl (-COOH), -C(=O)R", -OR", -C(=O) OR", -NHC(=O)R", aminocarbonyl (-C(=O)NH ₂ ), -N-substituted aminocarbonyl (-C(=O)NHR"), -N,N-disubstituted Aminocarbonyl (-C(=O)N(R″)R″), mercaptan, thiol (SR″), sulfonic acid (SO ₃ H), phosphonic acid (PO ₃ H), S(=O ) ₂ R", S(=O) ₂ NH ₂ , S(=O) ₂ NHR", S(=O) ₂ NR"R", NHS(=O) ₂ R", NR"S(=O) ₂ R", CF ₃ , CF ₂ CF ₃ , NHC(=O)NHR", NHC(=O)NR"R", NR"C(=O)NHR", NR"C(=O)NR"R ", NR", C(=O)R", etc. For the aforementioned substituents, each moiety R" can independently be any of, for example, H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl .

As used herein, "side effect" refers to a result that is different from the result of use of said drug or measure as a side effect produced by the drug, especially an adverse effect on a tissue or organ system other than that for which the administration is being administered. In the case of eg opioids, the term "side effect" may refer to conditions such as eg ileus, itching, constipation, urinary retention, biliary spasms, opioid bowel dysfunction, colic, nausea or vomiting or combinations thereof.

As used herein, "bowel obstruction" refers to an obstruction of the bowel, particularly the colon, from the bowel or pylorus to the rectum. See, eg, Dorland's Illustrated Medical Dictionary, p.816, 27th ed. (W.B. Saunders Company, Philadelphia 1988). Bowel obstruction should be distinguished from constipation, which is infrequent or difficult bowel movements. See, eg, Dorland's Illustrated Medical Dictionary, p. 375, 27th ed. (W.B. Saunders Company, Philadelphia 1988). Ileus can be diagnosed by disruption of the normal coordinated movement of the digestive tract, resulting in a failure to propel intestinal contents. See, eg, Resnick, J. Am. J. of Gastroenterology, 1992, 751 and Resnick, J. Am. J. of Gastroenterology, 1997, 92, 934. In some cases, especially after surgery (including abdominal surgery), bowel dysfunction can be quite severe, lasting more than a week and affecting more than one part of the gastrointestinal tract. This condition is often referred to as postoperative ileus and occurs most frequently after laparotomy (see Livingston, E.H. and Passaro, E.D.Jr., Digestive Diseases and Seicnces, 1990, 35, 121). Likewise, postpartum ileus is a common problem in women in the period following childbirth and is thought to be caused by similar fluctuations in natural opioid levels caused by the stress of childbirth.

As used herein, "effective amount" refers to an amount of a compound described herein that is therapeutically effective to inhibit, prevent or treat the symptoms of a particular disease, disorder or side effect. The diseases, conditions and side effects include, but are not limited to, those pathological conditions associated with the administration of opioids (for example, in connection with the treatment and/or prevention of pain), wherein treatment or prevention includes, for example, by administering the compounds of the present invention Contact with cells, tissues or receptors to inhibit their activity. Thus, for example, the term "effective amount" when used in relation to, eg, an opioid for the treatment of pain, refers to the treatment and/or prevention of the painful condition. The term "effective amount" when used in relation to peripheral mu opioid antagonists refers to the treatment and/or prevention of side effects typically associated with opioids, including such as, for example, intestinal obstruction, pruritus, constipation, urinary retention, biliary spasm , opioid bowel dysfunction, colic, nausea or vomiting, or a combination thereof.

As used herein, "in combination with", "combination therapy" and "combination product" refer in certain embodiments to the simultaneous administration to a patient of an antiemetic and a peripheral mu opioid antagonist (including, for example, formula I compounds), or concurrently administer antiemetics, peripheral mu opioid antagonists, and opioids to patients. When administered in combination, the individual components may be administered simultaneously or sequentially in any order at different points in time. Thus, the individual components may be administered separately but in close enough time to provide the desired therapeutic effect.

As used herein, "dosage unit" refers to a physically discrete unit suited as a unitary dosage for the particular patient being treated. Each unit may contain a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the unit dosage forms of the invention may be dictated by (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of such active compounds.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are suitable for contacting human and animal tissues without excessive toxicity, irritation , allergic reactions, or other problematic complications that warrant a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable metal salts" refers to derivatives of the compounds disclosed herein wherein the parent compound has been modified by making base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, bases and the like. Pharmaceutically acceptable salts include conventional non-toxic salts of the parent compound with, for example, non-toxic inorganic or organic bases. These physiologically acceptable salts are prepared by methods known in the art, for example, by dissolving the free amine base in aqueous alcohol with excess acid, or neutralizing the free amine base with an alkali metal base such as hydroxide or with an amine. carboxylic acid.

Compounds described throughout this document can be used or prepared in alternative ways. Isomorphs, all chiral and racemic forms, N-oxides, hydrates, and solvates are also contemplated to be within the scope of this invention.

Certain acidic or basic compounds of the invention may exist as zwitterions. All forms of the compounds, including free acids, free bases and zwitterions, are contemplated within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxyl groups often exist in their zwitterionic form. Thus, for example, any compounds described throughout this document that contain both amino and carboxyl groups also include their corresponding zwitterions.

As used herein, "patient" refers to animals, including mammals, preferably humans.

As used herein, "prodrug" refers to a compound specifically designed to maximize the amount of active substance that reaches a desired reaction site, which itself is generally inactive or minimally active for the desired activity, but Biologically active metabolites through biotransformation.

As used herein, "stereoisomers" refers to compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space.

As used herein, "N-oxide" refers to a heteroaryl ring or tertiary amine in which the basic nitrogen atom is oxidized to form a quaternary nitrogen with a formal positive charge and an attached oxygen with a formal negative charge. atom.

When any variable occurs more than once in any constituent or in any formula, its definition in each instance is independent of the others. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Formula I illustrates that the piperidine derivatives useful in the methods, compositions and kits of the invention can exist as trans and cis stereochemical isomers at the 3- and 4-positions of the piperidine ring. In the most preferred compounds of formula I, the ^R2 substituent and the ^R4 substituent are in "trans" orientation on the piperidine.

In addition to the "cis" and "trans" orientations of the ^R2 and ^R4 substituents of Formula I, the absolute stereochemistry of the carbon atoms bearing the ^R2 and ^R4 substituents in Formula I was also used The definitions of "R" and "S" are generally adopted (Orchin et al., The Vocabulary of Organic Chemistry, John Wiley and Sons, Inc., page 126, which is incorporated herein by reference). Preferred compounds of the invention are those wherein the configuration of both the ^R2 substituent and the ^R4 substituent on the piperidine ring of formula I is "R".

In addition, depending on the structure of ^R4 , an asymmetric carbon atom can be introduced into the molecule. Accordingly, these classes of compounds may exist as individual "R" or "S" stereoisomers at these chiral centers, or as racemic mixtures of isomers, all of which are contemplated within the scope of this invention Inside. Preferably, substantially pure stereoisomers of the compounds of the invention are used, i.e., isomers in which the configuration of the chiral center is "R" or "S", i.e., in which at the three chiral centers I The configuration of is preferably those compounds of 3R, 4R, S or 3R, 4R, R.

As used herein, "peripherally" or "peripherally acting" means that the drug acts outside of the central nervous system.

As used herein, "centrally acting" means that the drug acts within the central nervous system.

The methods, compositions and kits of the invention relate to peripheral opioid antagonist compounds. The term "peripheral" means that the compound primarily acts on physiological systems and elements other than the central nervous system. In preferred forms, peripheral opioid antagonist compounds for use in the methods of the invention exhibit high levels of activity relative to peripheral tissues, such as those of the gastrointestinal tract, and exhibit reduced and preferably substantially no CNS activity. As used herein, the phrase "substantially free of CNS activity" refers to exhibiting in the CNS less than about 20%, preferably less than about 15%, more preferably less than about 10% of the pharmacological activity of the compounds used in the methods of the invention. %, more preferably less than about 5%, and most preferably exhibit less than about 1% of the pharmacological activity of the compounds used in the methods of the invention in the CNS.

Furthermore, in certain embodiments of the invention in which the compound is administered to antagonize the peripheral side effects of the opioid, it is preferred that the compound does not substantially cross the blood-brain barrier so as not to diminish the beneficial activity of the opioid. As used herein, the phrase "substantially does not pass" means that less than about 20% by weight of the compounds used in the methods of the present invention pass through the blood-brain barrier, preferably less than about 15% by weight, more preferably less than about 10% by weight, and more preferably less than about 10% by weight. Preferably less than about 5% by weight, and most preferably 0% by weight of the compound passes the blood-brain barrier. CNS permeability of selected compounds was assessed by measuring levels in plasma and brain following intravenous administration.

US-B-6,451,806 and US-B-6,469,030 disclose methods and compositions comprising opioids and opioid antagonists, including peripheral mu opioid antagonists, the disclosures of which are incorporated herein by reference in their entirety . The methods and compositions are particularly useful for the prevention and treatment of pain and for the treatment and/or prevention of side effects associated with opioids, including ileus, pruritus, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic , nausea or a combination thereof, especially postoperative ileus, postpartum ileus, opioid bowel dysfunction, postoperative nausea or postoperative vomiting. The methods, compositions and kits of the present invention relate to peripheral mu opioid antagonists and to combinations of peripheral mu opioid antagonists with centrally acting antiemetics and centrally acting antiemetics and opioids , for the treatment and prevention of, for example, pain and/or side effects associated with opioids, including ileus, itching, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, vomiting or nausea or combinations thereof, especially Is postoperative or postpartum ileus, opioid bowel dysfunction, postoperative nausea, or postoperative vomiting.

Accordingly, in one embodiment, the invention provides a method comprising the steps of:

a. providing a composition comprising:

(i) at least one pharmaceutically acceptable metal salt of a compound of formula I:

in:

R ¹ is hydrogen or alkyl;

^R is hydrogen, alkyl or alkenyl;

^R is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ⁴ is hydrogen, alkyl or alkenyl;

A is OR ⁵ or NR ⁶ R ⁷ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ⁶ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, aralkyl, or alkylene Substituted B, or ^R6 and ^R7 form a heterocyclic ring together with the nitrogen atom to which they are attached;

B for

C(=O)W or NR ⁸ R ⁹ ;

R is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, cycloalkyl substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl substituted alkyl, aryl, or aralkyl, or ^R and ^R are combined with The nitrogen atoms to which they are attached together form a heterocycle;

W is OR ¹⁰ , NR ¹¹ R ¹² or OE;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ¹¹ is hydrogen or alkyl;

^R is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, cycloalkenyl substituted alkyl, aralkyl, or alkylene substituted C( =O)Y, or R ¹¹ and R ¹² form a heterocyclic ring together with the nitrogen atom to which they are attached;

E is

Alkylene substituted (C=O)D, or -R ¹³ OC(=O)R ¹⁴ ;

R ¹³ is an alkylene group substituted by an alkyl group;

R ¹⁴ is an alkyl group;

D is OR ¹⁵ or NR ¹⁶ R ¹⁷ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

^R is hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl or cycloalkenyl substituted alkyl;

R ¹⁷ is hydrogen or an alkyl group, or R ¹⁶ and R ¹⁷ form a heterocyclic ring together with the nitrogen atom to which they are attached;

Y is OR ¹⁸ or NR ¹⁹ R ²⁰ ;

^R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;

R ¹⁹ is hydrogen or alkyl;

R ²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, cycloalkenyl substituted alkyl, or aralkyl, or R ¹⁹ and 20 are combined with their The nitrogen atoms attached together form a heterocycle;

R ²¹ is hydrogen or alkyl;

and n is 0 to 4;

(ii) at least one crystalline extender;

(iii) at least one weak base; and

(iv) water;

wherein said composition has an initial pH of at least about 10.5; and

b. adjusting the pH of the composition to a final pH in the range of about 9 to about 11;

Wherein, when administered to a patient, the composition has improved dissolution and bioavailability for oral or parenteral administration.

The methods of the invention are particularly useful for forming compositions relative to the prior art (including compositions containing the same or different Freeze-dried and/or anneal) or compositions that do not have the same physical properties (such as density or porosity) have improved dissolution and bioavailability, especially through injectable formulations, such as in intravenous those administered internally.

In preferred embodiments of the method, upon reconstitution, the solution is formed in less than about five minutes at ambient conditions, more preferably, in less than about one minute at ambient conditions, and more preferably, Forms in less than about 30 seconds at ambient conditions, preferably reconstituted by simple shaking, stirring or mixing. As used herein, "under ambient conditions" means at standard atmospheric pressure and room temperature in the range of about 10°C to about 50°C, without direct heating or cooling. Formation of a solution can be determined, for example, by the presence of a clear solution upon mixing by visual observation (preferably using microscope light projected into the solution through an aperture), by a Coulter tester, or by light scattering instrumentation.

In a preferred embodiment of the method, the initial pH is adjusted to at least about 11. Preferably, the initial pH does not exceed about pH 12, since such a high pH can cause the composition to be unstable. The initial pH can be adjusted with any suitable pharmaceutically acceptable pH adjusting agent, including strong or weak acids or bases, preferably pharmaceutically acceptable metal carbonates, pharmaceutically acceptable metal bicarbonates, pharmaceutically acceptable metal hydroxides Or, hydrochloric acid, more preferably wherein the pharmaceutically acceptable metal is sodium, and more preferably sodium carbonate or sodium bicarbonate, and more preferably sodium carbonate. Sodium carbonate and sodium bicarbonate are preferred because they generate carbon dioxide, thereby contributing to the desired lower composition density.

In a preferred embodiment of the method, the final pH is adjusted from about 9.5 to about 10.5. The final pH can be adjusted with any suitable pharmaceutically acceptable pH adjusting agent, including strong or weak acids or bases, preferably sodium hydroxide or hydrochloric acid.

In certain preferred embodiments of the method, at least one pharmaceutically acceptable metal salt of the compound of formula I is prepared in situ.

In certain preferred embodiments of this method, the pharmaceutically acceptable metal salt of the compound of formula I is formed from at least one weak base, wherein said weak base is added to said compound of formula I in at least about equimolar amounts. Preferably, large excesses of weak bases are not used, as such excesses can lead to undesirably high pH (greater than about 12), which can contribute to composition instability.

In certain preferred embodiments of this method, the composition is prepared by first mixing said bulking agent and said pharmaceutically acceptable metal salt of a weak base in water and then adding said compound of formula I to said mixture .

In certain other preferred embodiments, the composition is prepared by admixing said compound of formula I, said bulking agent and said pharmaceutically acceptable metal salt of a weak base in water substantially simultaneously. As used in the context of mixing, "substantially simultaneously" means that the individual components are mixed together within about five minutes, preferably within about one minute, and more preferably within about 30 seconds of each other.

In a preferred embodiment of the invention, the pharmaceutically acceptable metal is an alkali metal, such as sodium, potassium or lithium; or an alkaline earth metal, such as calcium or magnesium, or a combination thereof. Sodium, calcium and magnesium are preferred. Sodium is more preferred. For parenteral administration, potassium is preferably avoided.

The method may additionally comprise the step of drying said composition to remove at least a portion of said water to form a partially or completely dry product. In a preferred embodiment, the composition is kneaded during the drying step. As used herein, "kneading" refers to the process of heating a material and then slowly cooling it, including repeated heating and cooling cycles. Suitable drying methods include freeze drying (lyophilization), spray drying, vacuum drying and combinations thereof. A preferred method of drying is freeze drying.

The method may additionally comprise the step of reconstituting said dried product by combining said dried product with a pharmaceutically acceptable solvent to form a solution of said dried product.

In a preferred embodiment of the method, the weak base is bicarbonate or carbonate, more preferably carbonate. These weak bases are preferred because they generate carbon dioxide, thereby contributing to the desired lower composition density.

In a preferred embodiment of the method, the pharmaceutically acceptable solvent is aqueous, preferably water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, or lactated Ringer's solution (lactated Ringer's solution).

In a preferred embodiment, the method of the invention additionally comprises the step of administering said solution of said dry product to a patient. Compositions can be administered before surgery, during surgery, and/or without surgery.

In a preferred embodiment, the composition is administered by injection, in particular subcutaneous, intramuscular or intravenous injection.

Any pharmaceutically acceptable bulking agent that is crystalline may be used in the compositions of the present invention. As used herein, "bulking agent" refers to an inert diluent or additive that functions as a carrier for a drug (in the case of the present invention, a compound of formula I). Suitable bulking agents can be found in Handbook of Pharmaceutical Excipients, 3rd Ed. Washington, D.C: American Pharmaceutical Association, 1998, the disclosure of which is incorporated herein by reference. In certain other preferred embodiments, the bulking agent is a polyol, such as a carbohydrate or a sugar alcohol. Suitable carbohydrates include sucrose, trehalose, lactose, maltose and mixtures thereof. Suitable sugar alcohols include mannitol, xylitol, erythritol, lactitol, isomalt, polyalditol, maltitol and mixtures thereof. Mannitol is particularly preferred.

While not wishing to be bound by theory, it is believed that the crystalline extenders produce the desired cake-like structure with good mechanical properties. These properties are important to ensure a rapid rate of reorganization. In addition, the crystalline bulking agent nucleates rapidly during freeze-drying to produce cakes with greater surface area, resulting in higher diffusion fluxes and faster sublimation rates. Drying of amorphous extenders requires high energy and does not produce the desired cake-like structure. Because the initial crystal size depends on the nucleation rate and growth rate, small crystals formed in systems containing amorphous solids produce pores with lower surface area per volume. This lower surface area produces lower diffusion fluxes and lower sublimation rates.

In certain embodiments, the present invention relates to compositions comprising:

a. at least one pharmaceutically acceptable metal salt of a compound of formula I;

b. at least one crystalline extender;

wherein said composition has a density of less than about 1.0 g/ ^cm ;

Wherein, when administered to a patient, the composition has improved dissolution and bioavailability for oral or parenteral administration.

Preferably, the composition has a density below 0.5 g/cm ³ , more preferably below about 0.2 g/cm ³ , more preferably below about 0.15 g/cm ³ , more preferably from about 0.05 g/cm ³ to A density in the range of about 0.12 g/cm ³ , more preferably a density in the range of about 0.06 g/cm ³ to about 0.08 g/cm ³ .

In certain embodiments, the present invention relates to compositions comprising:

a. at least one pharmaceutically acceptable metal salt of a compound of formula I;

b. at least one crystalline extender;

c. less than about 1% by weight of a solubilizing surfactant, based on the total weight of the composition;

d. less than about 10% by weight of a non-aqueous solvent, based on the total weight of the composition; and

e. less than about 0.5% by weight cyclodextrin, based on the total weight of the composition;

Wherein, when administered to a patient, the composition has improved dissolution and bioavailability for oral or parenteral administration.

These compositions provide improved dissolution and bioavailability for oral or parenteral administration because they allow the compound of formula I to be reconstituted from a dry product compared to other cases of compounds of formula I (which due to amphoteric ionic nature and has very low water solubility) dissolves more easily.

Preferably, the pharmaceutically acceptable metal salt of a compound of formula I is present at a level of at least about 0.1 mg/mL, more preferably at a level of at least about 1 mg/mL, more preferably at a level of at least about 2 mg/mL.

Preferably, the compositions of the invention additionally comprise at least one pharmaceutically acceptable solvent. In a preferred embodiment of the composition, the pharmaceutically acceptable solvent is aqueous, preferably water, isotonic sodium chloride solution, Ringer's solution, dextrose solution or lactated Ringer's solution.

Preferably, the compositions have a shelf life of at least about 18 months. As used herein, "shelf life" refers to the time from the manufacture and packaging of a formulation until its chemical or biological activity is not less than a predetermined level (usually about 90%) of labeling potency and its physical properties are not appreciable or deleterious. time of change.

In certain preferred embodiments, the compositions of the present invention may include opioids, prodrugs of opioids and/or pharmacologically active metabolites, provided that their inclusions do not interfere with the dissolution rate or biological Utilization. Suitable opioids include alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol , meperidine (meperidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propyram, dextropropoxyphene, sufentanil, tramadol and their mixtures . Preferred opioids include morphine, codeine, oxycodone, hydrocodone, dihydrocodeine, dextropropoxyphene, fentanyl and tramadol.

The compositions of the present invention may additionally comprise one or more other active ingredients commonly used in combination products for analgesia and/or cough-cold-suppressants, provided that their inclusions do not interfere with the dissolution rate or bioavailability of the compound of formula I Spend. Such conventional ingredients include, for example, aspirin, COX-2 inhibitors, acetaminophen, phenylpropanolamine, phenylephrine, chlorpheniramine, caffeine and/or guaifenesin. Typical or conventional ingredients that may be included are described, for example, in Physicians' Desk Reference, 2004, the disclosure of which is incorporated herein by reference in its entirety.

In addition, the compositions of the present invention may additionally include one or more compounds designed to enhance the analgesic efficacy of the opioid and/or to reduce the development of analgesic tolerance, provided that their inclusion does not interfere with the formula Dissolution or bioavailability of I compounds. Such compounds include, for example, dextromethorphan or other NMDA antagonists (Mao, M.J. et al., Pain 1996, 67, 361), L-364,718 and other CCK antagonists (Dourish, CT. et al., Eur. J. Pharmacol ., 1988,147,469), NOS inhibitors (Bhargava, H.N. et al., Neuropeptides, 1996,30, 219), PKC inhibitors (Bilsky, EJ. et al., J.Pharmacol.Exp.Ther.1996,277 , 484), and dynorphin antagonists or antisera (Nichols, M.L. et al., Pain, 1997, 69, 317). The disclosure of each of the foregoing documents is incorporated herein by reference in its entirety.

In addition to those exemplified above, other opioids, optionally Conventional opioid components, and optional compounds, will be apparent to those skilled in the art armed with the teachings of the present disclosure.

Preferred 4-aryl-piperidine derivatives are included, for example, in US-A-5,250,542, US-A-5,159,081, US-A-5,270,328, and US-A-5,434,171, US-B-6,451,806 and US-B-6,469,030 Compounds disclosed in , the disclosure of which is incorporated herein by reference in its entirety.

In a preferred embodiment, the compound of formula I is the trans 3,4-isomer.

In certain embodiments employing compounds of formula I, preferably

R ¹ is hydrogen;

R ² is an alkyl group;

n is 1 or 2;

^R is benzyl, phenyl, cyclohexyl or cyclohexylmethyl; and

R ⁴ is an alkyl group.

In certain embodiments employing compounds of formula I, preferably

A is OR ⁵ ; and

R ⁵ is hydrogen or alkyl.

In certain embodiments employing compounds of formula I, preferably

A is NR ⁶ R ⁷ ;

^R6 is hydrogen;

R ⁷ is B substituted with alkylene; and

B is C(O)W.

In certain embodiments employing compounds of formula I, preferably

R ⁷ is (CH ₂ )qB;

q is from about 1 to about 3;

W is OR ¹⁰ ; and

R ¹⁰ is hydrogen, alkyl, phenyl-substituted alkyl, cycloalkyl, or cycloalkyl-substituted alkyl.

In certain embodiments comprising compounds of formula I, preferably

W is NR ¹¹ R ¹² ;

R ¹¹ is hydrogen or alkyl; and

R ¹² is hydrogen, alkyl or alkylene substituted C(=O)Y.

In certain embodiments employing compounds of formula I, preferably

R ¹² is (CH ₂ )mC(O)Y;

m is 1 to 3;

Y is OR ¹⁸ or NR ¹⁹ R ²⁰ ; and

R ¹⁸ , R ¹⁹ and R ²⁰ are independently hydrogen or alkyl.

In certain embodiments employing compounds of formula I, preferably

W is OE;

E is _CH2C (=O)D;

D is OR ¹⁵ or NR ¹⁶ R ¹⁷ ;

R ¹⁵ is hydrogen or alkyl;

R ¹⁶ is methyl or benzyl; and

^R17 is hydrogen.

In certain embodiments employing compounds of formula I, preferably

W is OE;

E is R ¹³ OC(=O)R ¹⁴ ;

R ¹³ is -CH(CH ₃ )- or -CH(CH ₂ CH ₃ )-; and

R ¹⁴ is an alkyl group.

In certain embodiments employing compounds of formula I, preferably

A is OR ⁵ ; and

R ⁵ is hydrogen.

In certain embodiments employing compounds of formula I, it is preferred that the configurations at the 3- and 4-positions of the piperidine ring are each R.

Preferred compounds of formula I include:

Q-CH ₂ CH(CH ₂ (C ₆ H ₅ ))C(O)OH,

Q-CH ₂ CH ₂ CH(C ₆ H ₅ )C(O)NHCH ₂ C(O)OCH ₂ CH ₂ ,

Q-CH ₂ CH ₂ CH(C ₆ H ₅ )C(O)NHCH ₂ C(O)OH,

Q-CH ₂ CH ₂ CH(C ₆ H ₅ )C(O)NHCH ₂ C(O)NHCH ₃ ,

Q-CH ₂ CH ₂ CH(C ₆ H ₅ )C(O)NHCH ₂ C(O)NHCH ₂ CH ₃ ,

G-NH(CH ₂ ) ₂ C(O)NH ₂ ,

G-NH(CH ₂ ) ₂ C(O)NHCH ₃ ,

G-NHCH ₂ C(O)NH ₂ ,

G-NHCH ₂ C(O)NHCH ₃ ,

G-NHCH ₂ C(O)NHCH ₂ CH ₃ ,

G-NH(CH ₂ ) ₃ C(O)OCH ₂ CH ₃ ,

G-NH(CH ₂ ) ₃ C(O)NHCH ₃ ,

G-NH(CH ₂ ) ₂ C(O)OH,

G-NH(CH ₂ ) ₃ C(O)OH,

Q-CH ₂ CH(CH ₂ (C ₆ H ₁₁ ))C(O)NHCH ₂ C(O)OH,

Q-CH ₂ CH(CH ₂ (C ₆ H ₁₁ ))C(O)NH(CH ₂ ) ₂ C(O)OH,

Q-CH ₂ CH(CH ₂ (C ₆ H ₁₁ ))C(O)NH(CH ₂ ) ₂ C(O)NH ₂ ,

Z-NHCH ₂ C(O)OCH ₂ CH ₃ ,

Z-NHCH ₂ C(O)OH,

Z-NHCH ₂ C(O)NH ₂ ,

Z-NHCH ₂ C(O)N(CH ₃ ) ₂ ,

Z-NHCH ₂ C(O)NHCH(CH ₃ ) ₂ ,

Z-NHCH ₂ C(O)OCH ₂ CH(CH ₃ ) ₂ ,

Z-NH(CH ₂ ) ₂ C(O)OCH ₂ (C ₆ H ₅ ),

Z-NH(CH ₂ ) ₂ C(O)OH,

Z-NH(CH ₂ ) ₂ C(O)NHCH ₂ CH ₃ ,

Z-NH(CH ₂ ) ₃ C(O)NHCH ₃ ,

Z-NHCH ₂ C(O)NHCH ₂ C(O)OH,

Z-NHCH ₂ C(O)OCH ₂ C(O)OCH ₃ ,

Z-NHCH ₂ C(O)O(CH ₂ ) ₄ CH ₃ ,

Z-NHCH ₂ C(O)OCH ₂ C(O)NHCH ₃ ,

Z-NHCH ₂ C(O)O-(4-methoxycyclohexyl),

Z-NHCH ₂ C(O)OCH ₂ C(O)NHCH ₂ (C ₆ H ₅ ), and

Z-NHCH ₂ C(O)OCH(CH ₃ )OC(O)CH ₃ ;

Among them: Q means

G means

and

Z means

More preferred compounds of formula I include:

(3R, 4R, S)-Z-NHCH ₂ C(O)OCH ₂ CH(CH ₃ ) ₂ ,

(+)-Z-NHCH ₂ C(O)OH,

(-)-Z-NHCH ₂ C(O)OH,

(3R, 4R, R)-Z-NHCH ₂ C(O)-OCH ₂ CH(CH ₃ ) ₂ ,

(3S, 4S, S)-Z-NHCH ₂ C(O)OCH ₂ CH(CH ₃ ) ₂ ,

(3S, 4S, R)-Z-NHCH ₂ C(O)OCH ₂ CH(CH ₃ ) ₂ ,

(3R,4R)-Z-NHCH ₂ C(O)NHCH ₂ (C ₆ H ₅ ), and

(3R,4R)-G-NH( _CH2 ) _3C (O)OH.

wherein Q, Z and G are as defined above.

Preferred compounds of formula I include (+)-Z- _NHCH2C (O)OH and (-)-Z- _NHCH2C (O)OH, wherein Z is as previously defined. It is particularly preferred when the compound is (+)-Z- _NHCH2C (O)OH. A particularly preferred compound is [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo - 3-Phenylpropyl]amino]acetic acid dihydrate (USAN name, Alvimopan).

More preferred compounds _of formula I include Q- _CH2CH ( _CH2 ( _C6H5 ))C(O)OH, wherein Q is as previously defined. It is particularly preferred when the compound is (3R,4R,S)-Q-CH ₂ CH(CH ₂ (C ₆ H ₅ ))C(O)OH. This compound is the active metabolite of alvimopan, but it has a much greater undesired propensity to reverse analgesia than alvimopan when administered orally. In parenteral administration, especially intravenous administration, much lower dosages may be administered to reduce this tendency.

Particular preference is given to compounds of the formula I which act locally in the intestinal tract, have high potency and are orally active. A particularly preferred embodiment of the invention is (+)-Z- _NHCH2C (O)OH, ie, a compound of the following formula (II):

Compounds of formula (II) have low water solubility except at low or high pH conditions. Zwitterionic properties may be intrinsic to the compound and may result in desirable properties such as poor systemic absorption after oral administration and sustained local action in the alimentary canal.

In a particularly preferred embodiment, the compound of formula I is a substantially pure stereoisomer.

In yet another embodiment, the present invention is directed to an injectable dosage form comprising the composition described above. In a preferred embodiment, the injectable dosage form facilitates minimal or no additional pain relative to pain caused by venipuncture, although the composition comprising the active ingredient is prepared at a pH higher than physiological pH.

In yet another embodiment, the present invention is directed to a method of preventing or treating opioid-related side effects in a patient comprising the steps of:

An effective amount of the composition described above is administered to said patient in need thereof.

The method is useful for the prophylaxis and treatment of ileus, pruritus, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, nausea or vomiting or combinations thereof, particularly postoperative ileus, postpartum ileus, opioid bowel Dysfunction, postoperative nausea or postoperative vomiting.

In other embodiments, the present invention is directed to a method of preventing or treating pain in a patient comprising the steps of:

An effective amount of the composition described above is administered to said patient in need thereof.

In a preferred embodiment, the composition additionally comprises at least one opioid.

In yet another embodiment, the present invention relates to a pharmaceutical pack comprising:

a. Containers containing injectable dosage forms; and

b. Instructions for preparing the injectable solution.

Preferably, the pack additionally comprises a syringe. Preferably, the injectable dosage form additionally comprises at least one opioid. The compositions may optionally include conventional pharmaceutical pack components.

The present invention relates to methods, compositions and kits comprising opioid compounds. As mentioned above, such opioid compounds are useful, for example, in the treatment and/or prevention of pain. However, as also mentioned above, undesired side effects include, for example, ileus, pruritus, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, vomiting or nausea or combinations thereof, especially postoperative and postpartum ileus , opioid bowel dysfunction, nausea and/or vomiting, and possibly other side effects that occur frequently in patients receiving opioid compounds. By means of the methods, compositions and kits of the invention, effective and desirable inhibition of undesired side effects that may be associated with opioid compounds is advantageously achieved. Thus, methods, compositions and kits in which an opioid is combined or co-administered in combination with an appropriate peripheral mu opioid antagonist compound may provide a more favorable efficacy than either compound or medicament alone.

In this regard, as noted above, opioids are often administered to patients for the treatment of eg painful conditions. However, as mentioned above, undesired side effects such as, for example, intestinal obstruction, itching, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, nausea or vomiting, or combinations thereof may result from the administration of opioids . These undesired side effects can act as a limiting factor with regard to the amount of opioid that can be administered to a patient. That is, the amount of opioid that can be administered to a patient may be limited due to the undesirable occurrence of the aforementioned side effects. The restricted amount of opioid that can be administered to a patient in turn detrimentally reduces the degree of pain relief. The combined methods and compositions of the present invention may advantageously increase the amount of opioid administered to a patient, thereby increasing the degree of pain relief, thereby reducing, minimizing and/or reducing undesired side effects that may be associated with opioids or avoid. Peripheral mu opioid antagonists preferred for use in the methods and compositions of the invention are substantially devoid of central nervous system activity and, therefore, do not desirably affect the analgesic potency of the opioid.

While not wishing to be bound by any theory or theory of operation, it is expected that opioid side effects such as ileus, pruritus, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, vomiting or nausea, or combinations thereof may be caused by opioids and Caused by undesired interactions of peripheral mu receptors. Administration of a peripherally acting mu opioid antagonist according to the method of the invention can block the interaction of the opioid compound with the mu receptor, thereby preventing and/or inhibiting side effects, in particular postoperative or postpartum ileus, Opioid bowel dysfunction, nausea and/or vomiting.

Other mu opioid antagonist compounds, in addition to those exemplified above, which are useful in the methods and compositions of the invention will be apparent to those skilled in the art given the teachings of the invention.

The compounds used in the methods of the invention may exist as prodrugs. As used herein, "prodrug" is intended to include any covalently bound carrier which, when such prodrug is administered to a mammalian subject, releases in vivo, for example, the active parent compound of formula I used in the methods of the invention drug. Because prodrugs are known to enhance many desirable properties of drugs (eg, dissolution rate, bioavailability, production, etc.), the compounds used in the methods of the invention can be delivered in prodrug form, if desired. Accordingly, the present invention contemplates methods of delivering prodrugs. Prodrugs of compounds of the present invention (eg, Formula I) can be obtained by modifying functional groups present in the compound such that the modification is cleaved to the parent compound during routine handling or in vivo.

Thus, prodrugs include, for example, compounds described herein wherein a hydroxy, amino, or carboxyl group is attached to any group that, upon administration of the prodrug to a mammalian subject, cleaves the linking group to form a free hydroxy, free, or carboxyl group, respectively. amino or carboxylic acid. Examples include, but are not limited to, acetates, formates, and benzoates of alcohol and amine functional groups; and esters of alkyl, carbocyclic, aryl, and alkylaryl groups such as methyl, ethyl, propyl, radical, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and phenethyl esters, etc.

The compounds used in the methods of the present invention can be prepared by a variety of methods well known to those skilled in the art. Compounds can be synthesized, for example, by the methods described below or by method variants as understood by those skilled in the art. All methods disclosed herein are contemplated to be practiced on any scale, including milligrams, grams, grams, kilograms, kilograms, or industrial scale.

As discussed in detail above, the compounds used in the methods of the invention may contain one or more asymmetrically substituted carbon atoms and may be isolated in optically active or racemic forms. Accordingly, all chiral, diastereomeric, racemic forms and all geometric isomeric forms are intended to be included unless a specific stereochemistry or isomeric form is specifically indicated. How to prepare and isolate such optically active forms is well known in the art. For example, mixtures of stereoisomers can be separated by standard techniques including, but not limited to, resolution of racemic forms, normal and reverse phase and chiral chromatography, preferential salt formation, recrystallization, etc. , either by chiral synthesis starting from active starting materials or by carefully planned chiral synthesis of targeted chiral centers.

It is readily understood that functional groups present may contain protecting groups during synthesis. Protecting groups are chemical functional groups known per se, which can be selectively attached to and removed from functionalities such as hydroxyl and carboxyl. These groups are present in the compound such that this functionality is inert to the chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups can be used in the present invention. Preferred protecting groups include benzyloxycarbonyl and t-butoxycarbonyl. Other preferred protecting groups useful in the present invention are described in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991 .

The 4-aryl-piperidine derivatives of formula I of the present invention can be used, for example, in US-A-5,250,542, US-A-5,434,171, US-A-5,159,081, US-A-5,270,328, US-B-6,451,806, US-A-5,451,806, - Synthesis by the methods taught in B-6,469,030, and Werne R, J.A. et al., Journal of Organic Chemistry, 61, 587-597 (1996), the disclosures of which are hereby incorporated by reference in their entirety. For example, 3-substituted-4-methyl-4-(3-hydroxy- or alkanoyloxyphenyl)piperidine derivatives used as starting materials in the synthesis of compounds of the present invention can be found in US-A - Preparation by the general methods taught in 4,115,400 and US-A-4,891,379, the disclosures of which are hereby incorporated by reference in their entirety. The starting material (3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine used in the synthesis of the compounds described herein can be found in US-A-4,581,456 and US-A- - Prepared by the method described in 5,136,040, the disclosure of which is incorporated herein by reference in its entirety, but adjusted to a preferred β-stereochemistry as stated.

The first step of the process may involve the formation of a 3-alkoxyphenyllithium reagent by reacting a 3-alkoxybromobenzene with an alkyllithium reagent. This reaction can be carried out under inert conditions and in the presence of a suitable non-reactive solvent such as anhydrous diethyl ether or preferably anhydrous tetrahydrofuran. A preferred alkyllithium reagent for this method is n-butyllithium, especially sec-butyllithium. Typically, an approximately equimolar amount to a slight excess of the alkyllithium reagent is added to the reaction mixture. The reaction can be carried out at a temperature of about -20°C to about -100°C, preferably at a temperature of about -50°C to about -55°C.

After formation of the 3-alkoxyphenyllithium reagent, an approximately equimolar amount of 1-alkyl-4-piperidone was added to the mixture while maintaining the temperature between -20°C and -100°C. The reaction is typically complete after about 1 to 24 hours. At this point, the reaction mixture can be gradually warmed to room temperature. The product was isolated by adding saturated sodium chloride solution to the reaction mixture to quench any remaining lithium reagent. The organic layer is separated and further purified if desired to give the appropriate 1-alkyl-4-(3-alkoxyphenyl)piperidinol derivative.

The dehydration of the above-prepared 4-phenylpiperidinol can be accomplished with a strong acid according to known methods. Although dehydration with any of several strong acids such as hydrochloric acid, hydrobromic acid, etc. occurs in varying amounts, dehydration is preferably performed with phosphoric acid, especially p-toluenesulfonic acid in toluene or benzene. This reaction typically can be performed under reflux conditions, more usually between about 50°C and 150°C. The product thus formed can be isolated by basifying an aqueous acidic solution of the product's salt form and extracting with a suitable water immiscible solvent. The residue obtained after evaporation is then further purified if necessary.

1-Alkyl-4-methyl-4-(3-alkoxyphenyl)tetrahydropiperidine derivatives can be prepared by alkylation of metal enamines. Preferably this reaction is performed using n-butyllithium in tetrahydrofuran (THF) under an inert atmosphere such as nitrogen or argon. Typically, a slight excess of n-butyllithium is added to a stirred 1-alkyl-4- (3-Alkoxyphenyl)-tetrahydropiperidine. This mixture was stirred for about 10 to 30 minutes, then about 1.0 to 1.5 equivalents of methyl halide was added to the solution while maintaining the temperature of the reaction mixture below 0°C. After about 5 to 60 minutes, water can be added to the reaction mixture and the organic phase collected. The product was purified according to standard methods, but preferably the crude product was purified by distillation under vacuum or by slurrying it in hexane:ethyl acetate (65:35, v:v) and silica gel for about two hours. According to the latter method, the product can then be isolated by filtration and subsequent evaporation of the filtrate under reduced pressure.

The next step in the method involves the Mannich reaction for the aminomethylation of non-conjugated bridged enamines. Preferably this reaction is carried out by mixing about 1.2 to 2.0 equivalents of aqueous formaldehyde and about 1.3 to 2.0 equivalents of the appropriate secondary amine in a suitable solvent. While water may be the preferred solvent, other non-nucleophilic solvents such as acetone and acetonitrile can also be used in this reaction. The pH of this solution can be adjusted to about 3.0 to 4.0 with an acid providing a non-nucleophilic anion. Examples of such acids include sulfuric acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, phosphoric acid and tetrafluoroboric acid, preferably sulfuric acid. To this solution was added 1 equivalent of 1-alkyl-4-methyl-4-(3-alkoxyphenyl)tetrahydropyridine (typically dissolved in aqueous sulfuric acid), and either a non-nucleophilic acid or Appropriate secondary amines again adjust the pH of the solution. Preferably, the pH is maintained at about 1.0 to 5.0 during the reaction, more preferably at about 3.0 to 3.5. When carried out at a temperature of from about 50°C to about 80°C, more preferably about 70°C, the reaction is substantially complete after about 1 to 4 hours, more typically in about 2 hours. The reaction can then be cooled to about 30°C and added to the sodium hydroxide solution. This solution can then be extracted with a water-immiscible organic solvent such as hexane or ethyl acetate, and the organic phase can be evaporated to dryness under reduced pressure after washing well with water to remove any residual formaldehyde.

The next step in the process may involve the catalytic hydrogenation of the prepared 1-alkyl-4-methyl-4-(3-alkoxyphenyl)-3-tetrahydropyridinemethanamine to the corresponding trans-1-alkane -3,4-dimethyl-4-(3-alkoxyphenyl)piperidine. This reaction actually proceeds in two steps. The first step is a hydrogenolysis reaction in which the exo C-N bond is reductively cleaved to yield 3-methyltetrahydropyridine. In the second step, the 2,3-double bond of the tetrahydropyridine ring is reduced to give the desired piperidine ring.

Reduction of the enamine double bond introduces a critical relative stereochemistry at the 3 and 4 carbon atoms of the piperidine ring. Reduction usually does not occur with complete stereoselectivity. The catalyst used in the method can be selected from various palladium, preferably platinum catalysts.

Preferably the catalytic hydrogenation step of the process is carried out in an acidic reaction medium. Suitable solvents for this method include alcohols, such as methanol or ethanol; and ethyl acetate, tetrahydrofuran, toluene, hexane, and the like.

Proper stereochemical yields may depend on the amount of catalyst employed. The amount of catalyst required to produce the desired stereochemical result may vary depending on the purity of the starting material, the presence or absence of different catalyst poisons.

The hydrogen pressure in the reaction vessel is not critical, but can be from about 5 to about 200 psi. Preferably, the concentration of starting material by volume is about 20 mL of liquid per gram of starting material, although higher or lower concentrations of starting material may also be used. Under the conditions specified herein, the duration of the catalytic hydrogenation is not critical since the molecules are unlikely to be over-reduced. While the reaction may continue up to about 24 hours or more, it may not be necessary to continue reducing conditions beyond the theoretical two moles of hydrogen absorbed. The product can then be isolated by filtering the reaction mixture through celite and evaporating the filtrate to dryness under reduced pressure. Further purification of the product thus isolated may not be necessary, preferably the mixture of diastereomers can be used directly in subsequent reactions.

The alkyl substituent can be removed from the 1-position of the piperidine ring by standard dealkylation procedures. Preferably, chloroformate derivatives, especially vinyl or phenyl derivatives, can be used and removed with acid. The prepared alkoxylates can then be dealkylated to give the corresponding phenols. This reaction can usually be carried out by reacting the compound in 48% aqueous hydrobromic acid. This reaction may be substantially complete after about 30 minutes to about 24 hours when carried out at a temperature of from about 50°C to about 150°C, more preferably at the reflux temperature of the reaction mixture. The mixture can then be worked up by cooling the solution followed by neutralization with base to a pH value of about 8. This aqueous solution can be extracted with a water-immiscible organic solvent. The residue of the evaporated organic phase was used directly in the next step.

Compounds used as starting materials for compounds of the present invention can also be brominated at the 3-position by 1-alkyl-4-methyl-4-(3-alkoxyphenyl)-3-tetrahydropicolylamine , lithiation of the bromo compound thus prepared, and reaction of the lithiated intermediate with a methyl halide such as methyl bromide to give the corresponding 1-alkyl-3,4-dimethyl-4-(3-alkane Oxyphenyl) tetrahydropicolylamine. This compound can then be reduced and converted to the starting material as described above.

As stated above, the compounds of the present invention may exist as individual stereoisomers. Preferably, the reaction conditions as described in US-A-4,581,456 or as described in Example 1 of US-A-5,250,542 are adjusted to be substantially stereoselective and to provide a racemic mixture of substantially two enantiomers. These enantiomers are then resolved. Methods that can be used to prepare resolved starting materials used in the synthesis of these compounds include treatment of alkyl-3,4-dimethyl-4-(3- Alkoxyphenyl)piperidine racemic mixture. This compound can then be dealkylated at the 1-position with vinyl chloroformate and finally converted to the desired 4-(3-hydroxyphenyl)piperidine isomer.

Alternatively, the stereoselective synthesis of 3,4-alkyl-substituted-4-(3-hydroxyphenyl)piperidines can be achieved by WerneR, J.A. Journal of Organic Chemistry, 61, 587-597 (1996) and The method described in US-A-5136,040 uses alkoxyphenyllithium (-20°C to -100°C) or the corresponding Grignard reagent (40°C to 60°C) and 1,3-dialkyl-4 -Piperidone carried out.

The resulting alcohol is acylated with ethyl chloroformate to give the racemic carbonate, which is efficiently resolved with (+)-di-p-toluoyl-D-tartaric acid (DTTA). Thermal elimination (170-200° C.) of the free base of the chiral pure carbonate affords the desired alkene.

For example, methylation of alkenes with dimethyl sulfate in the presence of n-butyllithium affords trans-3,4-dimethylenamines. Reduction of the enamine with sodium borohydride followed by purification by (+)-DTTA afforded the compound with >99.5% purity of the enamine. Demethylation of the free base with phenyl chloroformate, followed by removal of the protecting group, affords (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol, which is useful for the preparation of compounds of formula I key intermediates. Alvimopan is produced by the methods described in Journal of Organic Chemistry, 61, 587-597 (1996) and US-A-5,136,040.

The individual enantiomers of the invention may also be isolated from the corresponding racemic mixtures of the compounds of the invention using (+) or (-) dibenzoyl tartaric acid as desired, as will be understood by those skilled in the art. Preferably, the (+)-trans enantiomer is obtained.

While the (+) trans-3,4 stereoisomer is preferred, all possible stereoisomers of the compounds described herein are contemplated by the present invention. Racemic mixtures of stereoisomers as well as substantially pure stereoisomers are within the scope of the present invention. As used herein, the term "substantially pure" means that at least about 90 mole percent, more preferably at least about 95 mole percent, and most preferably at least about 98 mole percent of the desired stereoisomer is present relative to other possible stereoisomers. Stereoisomers.

The intermediate can be prepared by reacting a 3,4-alkyl-substituted-4-(3-hydroxyphenyl)piperidine with a compound of formula LCH ₂ (CH ₂ ) _n-1 CHR ₃ C(O)E, where L is a leaving group such as chlorine, bromine or iodine, E is a carboxylic acid, ester or amide, R ^and n are as defined above. Preferably, L may be chlorine and the reaction is carried out in the presence of a base, thereby alkylating the nitrogen of the piperidine. For example, ethyl 4-chloro-2-cyclohexylbutanoate can be contacted with (3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine to provide 4-[( 3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimethyl-1-piperidine]butanoic acid ethyl ester. While esters of carboxylic acids may be preferred, the free acids themselves or amides of the carboxylic acids may be used.

In an alternative synthetic method, the nitrogen of the piperidine can be alkylated by contacting the substituted piperidine with a methylene alkyl ester. For example, 2-methylene-3-phenylpropanoic acid can be used to contact the desired piperidine to provide ethyl 2-benzyl-3-piperidinepropionate.

Another synthetic route may involve the reaction of substituted piperidines with haloalkylnitriles. The nitrile group of the resulting piperidinylnitrile can be hydrolyzed to the corresponding carboxylic acid.

For each synthetic route, the resulting ester or carboxylic acid can be reacted with an amine or alcohol to provide the resulting modified chemical structure. In the preparation of amides, piperidine-carboxylic acid or piperidine-carboxylate can be reacted with amine in the presence of a coupling agent such as dicyclohexylcarbodiimide, boronic acid, borane-trimethylamine, and the like. Esters can be prepared by contacting piperidine-carboxylic acids with appropriate alcohols in the presence of coupling agents such as p-toluenesulfonic acid, boron trifluoride etherate, or N,N'-carbonyldiimidazole. Alternatively, piperidine-acyl chlorides can be prepared using reagents such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and the like. This alkanoyl chloride can be reacted with the appropriate amine or alcohol to pass through the corresponding amide or ester.

Combining a compound of formula I with a pharmaceutically acceptable bulking agent selected according to the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA, 1980), The disclosure thereof is incorporated herein by reference in its entirety.

Compounds of formula I can be administered to a mammalian subject in a variety of forms suitable for the chosen route of administration (eg, oral or parenteral). In this regard, parenteral administration includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial (including transdermal, ophthalmic, sublingual and buccal); Topical (including ophthalmic, dermal, eye, rectal and nasal inhalation by insufflation, aerosol, and rectal) administration.

The amount of active compound in such therapeutically useful compositions is preferably such that a suitable dosage will be obtained. Preferred compositions or formulations of the invention may be prepared so that unit dosage forms contain from about 0.1 to about 1000 mg of active compound, more preferably from about 1 to 100 mg of active compound.

Depending on the intended use, these preparations may contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include, for example, sterile aqueous solutions and sterile powders for the extemporaneous preparation of sterile injectable solutions and dispersions. In all cases, the preferred dosage form is sterile and must be liquid for ease of syringability. Preferably it is stable under the conditions of manufacture and storage and is preferably preserved against the contaminating action of microorganisms such as bacteria and fungi. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and others.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the sterilized active ingredient into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders or cakes for the preparation of sterile injectable solutions, preferred methods of preparation may include spray-drying, vacuum-drying and lyophilization (freeze-drying) techniques which yield the active ingredient plus Filter the powder of any additional desired ingredients of the solution.

The compositions of the present invention can be administered orally. For example, dry compositions of the invention may be packaged in hard or soft shell gelatin capsules, which may be compressed into tablets (e.g. fast-dissolving oral tablets, orally disintegrating tablets, including those for buccal administration) ), or it can be combined directly with food.

Tablets, lozenges, pills, capsules, etc. intended for oral administration may also contain one or more of the following, provided they do not interfere with improved dissolution and bioavailability of the composition: Binders such as tragacanth , gum arabic, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; sweeteners, such as sucrose, lactose or saccharin; or flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring. When the unit dosage form is a capsule, it may contain a liquid carrier in addition to materials of the above type. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with a coating of shellac, a coating of sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, it is preferred that any material used in the preparation of any unit dosage form be pharmaceutically pure and substantially nontoxic in the amounts employed. Additionally, the active compounds can be incorporated into sustained release formulations and compositions.

As noted above, the relative proportions of active ingredient to carrier can be determined by, for example, the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practice.

The most suitable prophylactic or therapeutic dose of a compound of the invention will vary with the form of administration, the particular compound chosen and the physiological characteristics of the particular patient undergoing treatment. Usually, small doses will be used initially and, if necessary, increased by small increments until the desired effect under the circumstances is achieved.

Combinations (e.g., pharmaceutical compositions) of the invention comprising an opioid conjugated to a peripheral mu opioid antagonist compound (e.g., a compound of Formula I) may be in any parenteral dosage form, such as described herein Those parenteral dosage forms of , and can also be administered in a variety of ways, as described herein. In a preferred embodiment, the combination products of the invention are formulated together in a single dosage form (ie combined together in one liquid, etc.). When the combination product is not formulated together in a single dosage form, the opioid compound and the peripheral mu opioid antagonist compound may be administered simultaneously or concurrently (ie, together) or in any order. When not administered simultaneously or simultaneously, i.e., when administered sequentially, it is preferred that the administration of the peripheral mu opioid antagonist and the opioid occur within an interval of less than about one hour, more preferably less than about 30 minutes. intervals, more preferably intervals of less than about 15 minutes, more preferably intervals of less than about 5 minutes.

While it is preferred that the peripheral mu opioid antagonist and the opioid are administered in the same manner (i.e., e.g., both parenterally), if desired, they may each be administered in a different manner (i.e., e.g., a combination product The opioid component of the drug can be administered orally, and the peripheral μ opioid antagonist component can be administered intravenously). Dosages of the combination products of the present invention may vary depending on various factors, such as the pharmacodynamic profile of the particular drug and its mode and route of administration; age, health status and weight of the recipient; nature and extent of symptoms; concomitant treatments type; frequency of treatment, and desired effect.

While appropriate dosages for the combination products of the present invention can be determined by those skilled in the art having knowledge of the present disclosure, as a general guide, when an opioid compound is combined with a peripheral mu opioid antagonist, for example, typically The daily dose may be from about 0.01 to about 100 mg of the opioid (and all combinations and subcombinations within this range) and from about 0.001 to about 100 mg of the peripheral mu opioid antagonist (and in the all combinations and subcombinations of ranges within that range). Preferably, the daily dosage may be from about 0.1 to about 10 mg of the opioid and from about 0.01 to about 10 mg of the peripheral mu opioid antagonist per kilogram of patient body weight. More preferably, the daily dosage may be about 1.0 milligram of the opioid and about 0.1 milligram of the peripheral mu opioid antagonist per kilogram of patient body weight. Typical dosage forms for such combination products are generally present in amounts of about 5 to about 200 mg for the opioid compound (eg, morphine) and about 0.1 to about 12 mg for the peripheral mu opioid antagonist.

Pharmaceutical pack comprising a therapeutically effective amount of an opioid and a therapeutically effective amount of a peripheral mu opioid antagonist compound in one or more sterile containers, for example, for the treatment of side effects of opioid administration or pain therapy Also within the scope of the present invention. Sterilization of the containers can be performed using conventional sterilization methods known to those skilled in the art. Sterile containers of materials may comprise individual containers, or one or more multi-compartment containers, as exemplified by UNTVIAL ^™ two-compartment containers (available from Abbott Labs, Chicago, Illinois), as desired. The optional opioid compound and peripheral mu opioid antagonist compound may be separated, or combined in a single dosage form as described above. If desired, such packs may further comprise one or more of various conventional pharmaceutical pack components, such as, for example, additional vials for mixing the components, etc., as will be apparent to those skilled in the art. Instructions (either as an insert or as a label) indicating the amounts of the components to be administered, guidelines for dosing, and/or guidelines for mixing the components, may also be included in the pack.

Compounds, including compounds of Formula I, for use in the methods, compositions and kits of the invention have been characterized in opioid receptor binding assays showing preferential binding to the mu opioid receptor. Studies in isolated tissues (guinea pig ileum and mouse vas deferens) and in other in vitro systems (eg, GTPyS) have shown that these compounds act as antagonists, with no detectable agonistic activity. Studies in animals have shown that the compounds of the present invention reverse constipation in morphine-dependent mice when administered orally or parenterally at very low doses without blocking the analgesic effects of morphine, except at a hundredfold or higher doses. Collectively, these data suggest that the compounds described herein can possess an extremely high degree of peripheral selectivity.

Example

The invention will now be illustrated by reference to the following specific non-limiting examples. The examples are not intended to limit the scope of the invention.

Example 1: Synthesis of Alvimopan

Alvimopan was prepared according to the following synthetic method.

Synthesis of 1-bromo-3-(1-methylethoxy)benzene (compound 1)

Reagent MW Quantity (kg) Kilomole The molar ratio of 3-Bromophenol 173.01 80.0 0.4624 1.00 2-Bromopropane 123.0 85.6 0.6959 1.51 Potassium carbonate, ground 138.2 96.0 0.6946 1.50 Ethanol 1X ^* 46.07 144 -- -- water 18.02 739 -- -- Hydrochloric acid, 31% 36.46 6.6 -- -- Sodium Hydroxide, 50%, w/w 40.0 44.4 -- -- Heptane 100.2 185 -- --

^* Ethanol 1X denatured with 0.5% toluene.

Ground potassium carbonate (96.0 kg) and ethanol IX (134 kg) were added to the reactor. The reaction mixture was adjusted to 20 to 25°C.

3-Bromophenol (80.0 kg) was added to the reactor with stirring while maintaining the temperature at 20 to 35°C. The transfer device was rinsed quickly with ethanol 1X (5 kg). Adjust the temperature to 20 to 25°C. 2-Bromopropane (85.6 kg) was charged to the reactor. The transfer device was rinsed quickly with ethanol 1X (5 kg). Water (20 L) was added to the reactor.

The solution in the reactor was heated to 60 to 65°C and maintained in this range for at least 16 hours. The mixture was cooled to 45 to 50°C and the mixture was tested for 3-bromophenol. The mixture was allowed to warm to 60 to 65°C while awaiting the results. The mixture was cooled again to 45 to 50°C.

Water (303 L) was added to the reactor. The reaction mixture was concentrated to an amount of 400 L by atmospheric distillation. The concentrated mixture was cooled to 20 to 25°C.

Heptane (185 kg) was added to the reactor, followed by stirring at a temperature of 20 to 25°C for at least 20 minutes.

The biphasic solution was separated and the organic layer was washed with a solution of water (45 L) and hydrochloric acid (31%, 6.6 kg). The organic layer was washed with water (56 L), followed by a solution of water (49 L) and sodium hydroxide (50%, 6.6 kg). The organic layer was washed with water (56 L) one final time.

The organic solution was dried by azeotropic distillation until no more water was collected. The reaction mixture was then concentrated to an amount of 150 to 170 L by atmospheric distillation, and cooled to 20 to 25°C. Pack the solution for the next step. The packaged product (Compound 1) was sampled and tested: the HPLC purity was not less than 98% a/a and the HPLC test was not less than 55% w/w.

Synthesis of cis-(±)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol (compound 2)

Reagent MW Quantity (kg) kilomole The molar ratio of Compound 1 215.1 27.9 0.07514 ^* 1.21 Magnesium filings 24.3 2.1 0.08642 1.39 1,3-Dimethyl-4-piperidone 127.2 7.9 0.06211 1.00 Tetrahydrofuran 72.01 162 -- -- ammonium chloride 53.5 6.6 -- -- water 18.02 56 -- -- Hyflo supercel -- 4 -- -- Heptane 100.2 86.5 -- --

^* Calculated according to the inspection of reagents

Before the entire batch is used, a sample of THF used is analyzed for water content.

Tetrahydrofuran (18 kg) was added to the reactor and heated to reflux without stirring. The solvent was kept at reflux for 1 hour and cooled to 30°C or lower. A KF analysis was performed to ensure that the water content in the reactor met the specification. The THF was vented to waste and the reactor was dried.

Magnesium (2.1 kg) was charged to the reactor followed by tetrahydrofuran (80 kg). With stirring, the reaction mixture was concentrated to an amount of 40 to 44 L by atmospheric distillation. The concentrate was cooled to 40 to 45°C.

Tetrahydrofuran (18 kg) was added to a portable stirred stainless steel tank and stirred for at least 20 minutes. A KF analysis was performed to ensure that the water content in the reactor met the specification. Drain THF to waste.

1-Bromo-3-(1-methylethoxy)benzene (27.9 kg) and tetrahydrofuran (31 kg) were added to the tank. The solution was stirred at room temperature for at least 20 minutes.

A 2.5 kg portion of the mixture in the tank was transferred to a reactor at 40 to 45°C. The mixture is maintained at 40 to 60° C. for at least 30 minutes with stirring.

A second 2.5 kg portion of the tank mixture was transferred to the reactor at 40 to 45°C. With stirring, the mixture is maintained at 40 to 60°C for at least 30 minutes.

A 5 kg portion of the mixture in the tank was transferred to a reactor at 40 to 45°C. With stirring, the mixture is maintained at 40 to 60°C for at least 30 minutes.

1,3-Dimethyl-4-piperidone (7.9 kg) was added to the tank and the transfer apparatus was rinsed quickly with tetrahydrofuran (5 kg).

A 15 kg portion of the mixture in the tank was transferred to the reactor at 40 to 45° C. within at least 1 hour. The mixture is maintained at 40 to 60° C. for 15 to 30 minutes with stirring. The reaction mixture was cooled to 40 to 45°C.

The second 15 kg portion of the mixture in the tank was transferred to the reactor at 40 to 45° C. within at least 1 hour. With stirring, the mixture was maintained at 40 to 60°C for 15 to 30 minutes. The reaction mixture was cooled to 40 to 45°C.

The third 15 kg portion of the mixture in the tank was transferred to the reactor at 40 to 45° C. within at least 1 hour. With stirring, the mixture was maintained at 40 to 60°C for 15 to 30 minutes. The reaction mixture was cooled to 40 to 45°C.

The remainder of the mixture in the tank was transferred to the reactor at 40 to 45°C over at least 1 hour. The transfer device was rinsed quickly with THF (5 kg). With stirring, the mixture was maintained at 40 to 60°C for 15 to 30 minutes. The reaction mixture was cooled to 40 to 45°C.

After the reaction was complete, the mixture was cooled to 20 to 25°C.

Water (40 L) and ammonium chloride (6.6 kg) were charged to the second reactor. With moderate agitation, the mixture was maintained at 20 to 25°C for at least 20 minutes.

Once the solids had dissolved, Hyflo supercel (4 kg) was added to the second reactor. The aqueous mixture was cooled to 0 to 5°C.

The organic mixture in the first reactor was transferred to the second reactor with stirring. The transfer device was rinsed quickly with THF (5 kg). The mixture was heated to 20 to 25°C and held for at least 15 minutes.

The mixture was filtered into the first reactor, rinsed rapidly with heptane (2 x 6 kg), and held at 20 to 25°C for at least 20 minutes.

The biphasic solution was separated and the organic layer was washed with water (16 L). The organic solution was concentrated to an amount of 30 to 34 L by atmospheric distillation, and cooled to 45 to 50°C.

Heptane (54 kg) was added to the reactor and the solution was concentrated by atmospheric distillation to an amount of 69 to 73 L. The solution was cooled to 30 to 35°C. Check the reaction mixture for residual THF and water content. The reaction was seeded with product crystals and the mixture was cooled to 0 to 5°C over a minimum of 1 hour and held for at least 3 hours.

The solid product was isolated by filtration, washed with cold heptane (2 x 10 kg) and dried. Samples of the product were collected, dried and packaged. The packaged product (compound 2) was sampled, tested: HPLC purity not less than 97% a/a, and the package was opened before being used in the next step.

Purification of cis-(±)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol (compound 2)

Reagent MW Quantity (kg) kilomole The molar ratio of Compound 2 263.4 96.1 0.3648 1.00 Heptane 100.2 590 -- --

Compound 2 (96.1 kg) and heptane (328 L) were charged to the reactor. The mixture was heated to 55 to 60°C for at least 1 hour. Check the mixture to ensure all solids are dissolved.

Cool the solution to 30 to 35°C over at least 1 hour and hold for at least 1 hour. Check the mixture to ensure that precipitation has occurred. The mixture was cooled to 0 to 5°C over at least two hours and held for at least 4 hours.

Solid pure compound 2 was isolated by filtration, washed with cold heptane (2 x 131 kg) and dried. Product samples were collected for drying and packaged. The packaged product was sampled, tested for HPLC purity, not less than 97% a/a, and opened before being used in the next step.

Ethyl carbonate (3S, 4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinyl ester compound and (+)-D-2 , Synthesis of 3-bis[(4-methylbenzoyl)oxy]succinic acid (1:1) (compound 3)

Reagent MW Quantity (kg) kilomole The molar ratio of Compound 2 263.4 10.8 0.04100 1.00 ethyl chloroacetate 108.52 5.6 0.05160 1.26 Triethylamine, anhydrous 101.19 0.4 0.003953 0.10 (+)DTTA 386.36 15.8 0.04089 1.00 Sodium Hydroxide, 50% w/w 40.0 47.6 -- -- Ethyl acetate 88.11 52 -- -- Ethanol 1X 46.07 285 -- --

Compound 2 (10.8 kg) and ethyl acetate (48 L) were added to the reactor. The mixture was maintained at 20 to 25°C for at least 30 minutes until all solids had dissolved. The solution was cooled to 0 to 5°C.

Triethylamine (0.4 kg) was added to the reactor and the transfer apparatus was rinsed quickly with ethyl acetate (1 kg).

Ethyl chloroformate (5.6 kg) was added to the reactor while maintaining a temperature of 0 to 15°C. The transfer device was rinsed quickly with ethyl acetate (3 kg). The mixture was maintained at 20 to 25°C for at least 3 hours.

50% sodium hydroxide (7.6 kg) was added to the reactor while maintaining a temperature of 0 to 38°C. The transfer device was rinsed quickly with water (17 L). Keep the solution at 20 to 25°C for at least 20 minutes and check the pH of the solution to ensure that the pH is greater than 10.

The biphasic solution was separated and the organic layer was washed twice with water (22 L). The organic solution was dried by azeotropic distillation, and then concentrated to an amount of 20 to 24 L by atmospheric distillation. The solution was cooled to 40 to 50°C.

Ethanol 1X (60 kg) was added to the reactor. The organic solution was concentrated to an amount of 30 to 34 L by atmospheric distillation, and cooled to 55°C to 60°C.

Into a glass-lined reactor was charged (+)-di-p-toluoyl-D-tartaric acid (15.8 kg) and ethanol 1X (51 kg). With moderate agitation, adjust the temperature to 60 to 65°C.

The reaction mixture was transferred to an acidic solution while maintaining a temperature of 60 to 70°C. The transfer device was rinsed quickly with ethanol 1X (17 kg). The solution was maintained at 60 to 65°C for 1 to 1.5 hours. The suspension was cooled to 50 to 55°C and maintained for 2 to 2.5 hours. The suspension is cooled to 20 to 25°C over at least 3 hours and maintained for at least 10 hours.

The solid was isolated by filtration, washed with ethanol IX (17 kg), dried and packaged. The packaged crude product was sampled and tested for chiral purity of Compound 3.

The reactor was charged with crude product and ethanol 1X (according to calculation). The mixture was adjusted to 60 to 65°C and held for 2 to 2.5 hours. The suspension was cooled to 20 to 25°C over at least 2 hours. The suspension was cooled to 0 to 5°C for at least 3 hours.

Solid compound 3 was isolated by filtration, washed with cold ethanol 1X (17 kg), dried and packaged. The packaged product was sampled, tested, HPLC purity not less than 99.0% a/a; chiral HPLC, not less than 99.5%, and the package was opened before being used in the next step.

Synthesis of (3R,4R)-3-(3,4-Dimethyl-4-piperidinyl)phenol (Compound 4)

Reagent MW Quantity (kg) kilomole The molar ratio of Compound 3 647.8 18.3 0.02825 1.00 toluene 92.14 50 -- -- water 18.02 434 -- -- Sodium Hydroxide, 50% w/w 40.0 110.7 -- -- Phenyl chloroformate 156.57 5.3 0.03385 1.20 Hydrochloric acid, 31% 36.46 2.8 -- -- Glacial acetic acid 60.05 17.6 0.2931 10.38 hydrobromic acid 80.92 19 0.1127 4.00 tert-butyl methyl ether 88.15 56 -- -- Methanol 32.04 8.7 -- --

Compound 3 (18.3 kg), toluene (48 kg) and water (32 L) were added to the reactor. The mixture was adjusted to 20 to 25°C.

Sodium hydroxide (50%, 9.2 kg) was added to the reactor while maintaining a temperature of 20 to 30°C. The transfer device was rinsed quickly with water (4 L). The mixture was cooled to 20 to 25°C with stirring and held for 1 hour. Check the pH of the aqueous layer to ensure the pH is greater than 12.

The biphasic solution was separated and the organic layer was washed with a solution of water (14 L) and sodium hydroxide (50%, 0.7 kg). The organic layer was washed twice with water (15 L) and dried by azeotropic distillation. The solution was cooled to 80 to 85°C.

Phenyl chloroformate (5.3 kg) was added to the reactor over at least 1.5 hours while maintaining a temperature of 80 to 85°C. The transfer apparatus was rinsed quickly with toluene (2 kg). The solution was heated to reflux for at least 3 hours, then cooled to 50 to 55°C. While awaiting the results, the mixture was kept at reflux.

The mixture was cooled to 20 to 25 °C and water (14 L) was added to the reactor. Sodium hydroxide (50%, 2.3 kg) was added to the reactor over at least 1 hour while maintaining a temperature of 20 to 30°C. The transfer device was rinsed quickly with water (4 L). The solution was maintained at 20 to 25°C for at least 1 hour.

The biphasic solution was separated and the organic layer was washed with a solution of water (15 L) and hydrochloric acid (31%, 1.9 kg). The organic solution was concentrated to an amount of 23 to 26 L by atmospheric distillation, and cooled to 65 to 70°C.

Water (7 L) and acetic acid (13.6 kg) were charged to the reactor. The transfer device was rinsed quickly with water (2 L). The organic solution was concentrated to an amount of 26 to 29 L by atmospheric distillation, and cooled to 50°C to 60°C.

Hydrobromic acid (19 kg) was added to the reactor followed by acetic acid (4 kg). The solution was heated to reflux for at least 18 hours. The solution was cooled to 55 to 60°C. The solution was cooled to 10 to 15°C.

Sodium hydroxide (50%, 6 kg) was added to the reactor over at least 1 hour while maintaining a temperature of 10 to 30°C. The transfer device was rinsed quickly with water (5 L). Adjust the temperature to 20 to 25°C and check the pH to ensure it is less than 1.7.

Tert-butyl methyl ether (16 kg) was charged to the reactor while maintaining a temperature of 20 to 25°C. Water (27 L) was added to the reactor and the solution was maintained at 20 to 25°C for at least 30 minutes.

The biphasic solution was separated and the aqueous solution was transferred to the reactor. The organic solution was transferred to a 200L glass receiver. The aqueous solution was washed twice with tert-butyl methyl ether (16 kg).

The organic layer was transferred from the glass receiver to the reactor. Water (5 L) was added to the reactor followed by hydrochloric acid (31%, 0.9 kg) while maintaining a temperature of 20 to 25°C. The transfer device was rinsed quickly with water (2 L). The biphasic solution was maintained at 20 to 25°C for at least 20 minutes.

The biphasic solution was separated and the aqueous solution was washed twice with tert-butyl methyl ether (4 kg).

Transfer the acidic solution from a new PE drum to the 200L reactor. The transfer device was rinsed quickly with water (2 L).

Methanol (8.7 kg) was added to the reactor over at least 30 minutes while maintaining a temperature of 20 to 25°C.

Water (41 L) and sodium hydroxide (50%, 12.5 kg) were added to a portable stirred stainless steel tank. The transfer device was rinsed quickly with water (4 L). The solution was transferred to the reactor to achieve a pH of 10.0 to 10.5 while maintaining a temperature of 20 to 35°C.

The suspension was cooled to 0 to 5°C for at least 4 hours.

Compound 4 was isolated by filtration, washed with cold water (2 x 9 L), dried and packaged. The packaged product was sampled, tested: HPLC purity not less than 98.5% a/a; chiral purity not less than 99.0%, and HPLC test not less than 95% w/w, and opened the package before being used in the next step.

(αS,3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimethyl-α-(phenylmethyl)-1-piperidine propionic acid methyl ester hydrochloride (compound 6) Synthesis

Compound 4 Compound 5 Compound 6

Reagent MW Quantity (kg) kilomole The molar ratio of Compound 4 205.3 19.2 0.09352 1.00 Methyl acrylate 86.09 8.5 0.09875 1.05 Tetrahydrofuran 72.11 692 -- -- n-BuLi 64.06 87.4 0.2056 2.20 Diisopropylamine 101.19 21.8 0.2154 2.30 Benzyl bromide 171.04 32.0 0.1871 2.00 Heptane 100.21 209 -- -- Methanol 32.04 659 -- -- Hydrochloric acid, 31% 36.46 36.2 0.3078 3.29 Sodium Hydroxide, 50%, w/w 40.0 4.9 0.06125 0.65 hydrogen chloride gas 36.46 14.4 0.3950 4.23 Hyflo supercel -- 1.9 -- -- water 18.02 566 -- --

Compound 4 (19.2 kg) and tetrahydrofuran (222 kg) were charged to the reactor. The mixture was heated to 40 to 45°C with 50% stirring.

Methyl acrylate (8.5 kg) was added to the reactor over at least 30 minutes while maintaining a temperature of 40 to 45°C. The transfer device was rinsed quickly with THF (17 kg). The reaction mixture was maintained at 40 to 45°C for 18 to 19 hours. The reaction mixture was cooled to 20 to 25°C.

Hyflo supercel (1.9 kg) and heptane (13 kg) were added to a portable stirred stainless steel tank. Stir the mixture for at least five minutes. The mixture was transferred to the reactor and rinsed quickly with heptane (5 kg). The mixture was maintained at 20 to 25°C for at least 20 minutes.

The mixture was filtered into the reactor for clarification, rinsed quickly with heptane (26 kg) and cooled to -5 to 0°C. The solution was concentrated to an amount of 29 to 48 L by vacuum distillation to obtain a solution of Compound 5.

Heptane (26 kg) was charged to the reactor at 30°C or lower. The solution was cooled to -5 to 0°C and concentrated by vacuum distillation to an amount of 29 to 48 L.

Tetrahydrofuran (333 kg) was charged to the reactor followed by diisopropylamine (21.8 kg). The transfer apparatus was rinsed quickly with tetrahydrofuran (12 kg). The solution was cooled to -15 to -10°C.

The reactor was fed with n-butyllithium in hexane (87.4 kg) over at least 1 hour while maintaining a temperature of -15 to -5°C. The transfer device was rinsed quickly with THF (2 x 5 kg). The solution was maintained at -10 to -5°C for 1 to 3 hours and then cooled to -25 to -20°C.

The acrylate solution in the reactor was transferred to this reactor while maintaining a temperature of -25 to -15°C. The transfer device was rinsed quickly with THF (8 kg). The suspension was kept at -25 to -20°C for 30 to 60 minutes.

Benzyl bromide (32.0 kg) was added to the reactor over at least 2 hours while maintaining a temperature of -25 to -20°C. The transfer device was rinsed quickly with THF (8 kg). The mixture was maintained at -25 to -20°C for at least 16 hours.

Water (61 L) and hydrochloric acid (31%, 18.1 kg) were added to the portable storage tank and stirred for at least two minutes to form a solution. Water (61 L) and hydrochloric acid (31%, 18.1 kg) were added to a second portable storage tank and stirred for at least two minutes to form a solution. The two acidic solutions were transferred to the reactor over a period of at least two hours while maintaining a temperature of -25 to -15°C. The solution was warmed to 20 to 25°C over at least three hours.

Water (29 L) and sodium hydroxide (50%, 4.9 kg) were added to a portable storage tank. The transfer device was rinsed quickly with water (15 L) and the mixture was stirred for at least two minutes to form a solution.

The alkaline solution (29 kg) was transferred into the reactor while maintaining a temperature of 20 to 25°C until a pH of 9.0 to 9.5 was obtained. The biphasic solution was separated and the aqueous solution was transferred to a 600L reactor.

The aqueous solution was washed with heptane (26 kg). The resulting organic solution was transferred to a 1500 L reactor and the transfer apparatus was rinsed quickly with heptane (17 kg). The solution was cooled to -30 to -20°C.

Methanol (113 kg) was charged to the reactor and cooled to -30 to -20°C. Hydrogen chloride gas (14.4 kg) was fed to the reactor while maintaining a temperature of -30 to -10°C.

The acidic solution was added to the above reactor while maintaining a temperature of -30 to -5°C. The transfer apparatus was rinsed quickly with methanol (19 kg). The temperature of the solution was adjusted to -10 to -5°C. The solution was concentrated by vacuum distillation to an amount of 168 to 216 L.

The solution was transferred to a 600L reactor and rinsed quickly with methanol (48kg). The solution was cooled to -10 to -5°C and concentrated by vacuum distillation to an amount of 48 to 68 L.

Methanol (77 kg) was added to the 1500 L reactor and rinsed into the reactor. The solution was then cooled to -10 to -5°C and concentrated by vacuum distillation to an amount of 48 to 68 L.

Methanol (106 kg) was charged to the reactor at 30°C or lower, followed by heating to 40 to 45°C. The solution was maintained at 40 to 45°C for 1 to 2 hours. The solution was cooled to 20 to 25°C over at least 3 hours and held in this range for at least 1 hour. The solution was cooled to 2 to 7°C over at least 1 hour and held in this range for at least 1 hour.

Crude compound 6 was isolated by filtration, washed with cold methanol (2 x 15 kg), and checked for purity. The filtrate was retained for further processing.

The wet cake and methanol (60 kg) were charged to the reactor. The mixture was heated to reflux and maintained at reflux for 1 to 2 hours. The solution was cooled to 2 to 7°C over at least 4 hours and held in this range for at least 1 hour.

The crude product was isolated by filtration, washed with cold methanol (2 x 15 kg), and checked for purity. The filtrate was retained for further processing.

The wet cake and methanol (60 kg) were charged to the reactor. The mixture was heated to reflux and maintained at reflux for 1 hour. The solution was cooled to 2 to 7°C over at least 4 hours and held in this range for at least 1 hour.

The crude product was isolated by filtration, washed with cold methanol (2 x 15 kg), and checked for purity and chiral HPLC.

The wet cake and methanol (60 kg) were charged to the reactor. The mixture was heated to reflux and maintained at reflux for 1 hour. The solution was cooled to 2 to 7°C over at least 4 hours and held in this range for at least 1 hour.

The product compound 6 was isolated by filtration, washed with cold methanol (2 x 15 kg), sampled for analysis of HPLC purity, chiral HPLC and isomers and packaged. The packaged product was sampled, assayed: HPLC >99.0% a/a; chiral HPLC, 3.0%: and packaged before being used in the next step.

Synthesis of (αS,3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-α-(phenylmethyl)-1-piperidinepropionic acid monohydrate (compound 7)

Compound 6 Compound 7

Reagent MW Quantity (kg) kilomole The molar ratio of Compound 6 417.97 9.9 0.02369 1.00 Methanol 32.04 107 -- - Hydrochloric acid, 31% 36.46 9.4 0.07992 3.37 Sodium Hydroxide, 50%, w/w 40.0 7.9 0.09875 4.16 water 18.02 ~244 -- --

Compound 6 (9.9 kg) and water (74 L) were charged to the reactor. The mixture was adjusted to 20 to 25°C.

Sodium hydroxide (50%, 7.9 kg) was added to the reactor over at least 10 minutes. The transfer device was rinsed quickly with water (10 L). Check the pH of the mixture to ensure the pH is greater than 12.

The solution was kept at a temperature of 20 to 25°C and stirred for at least 4 hours. The reaction mixture was then filtered into the reactor for clarification. The product was rinsed quickly with water (8 L).

Methanol (84 kg) was added to the reactor and adjusted to 20 to 25°C.

Hydrochloric acid (31%, 6.9 kg) was added portionwise to the reactor until a pH of 9.0 to 10.0 was reached.

Water (7.6 L) and hydrochloric acid (31%, 2.5 kg) were added to a new PE bucket. The transfer device was rinsed quickly with water (4.0 L) and the solution was stirred for at least two minutes to mix.

Methanol (0.4 kg), water (0.5 L) and compound 7 (100 g) were added to the beaker. The reaction mixture was seeded by adding the mixture to the reactor and rinsing rapidly with a solution of water (0.3 L) and methanol (0.2 kg).

The pH of the reaction mixture was adjusted with the prepared acidic solution (10.4 kg) until a pH of 5.8 to 6.2 was obtained. The mixture was maintained at 20 to 25°C for at least 1 hour and checked to ensure that crystallization had occurred. The suspension was cooled to 0 to 5°C and concentrated by vacuum distillation to an amount of 107 to 124 L. The suspension was adjusted to 20 to 25°C and the pH checked to ensure that it was between 5.8 and 6.2.

The suspension was cooled to 2 to 7°C and stirred for at least 4 hours.

The product was isolated by filtration, washed with cold water (2 x 30 L), dried, sampled for water content and packaged. The packaged product was sampled, assayed: HPLC purity 98.%% a/a; chiral HPLC: 98%, and HPLC assay 98.0% w/w, and packaged before being used in the next step.

[[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3- Synthesis of Phenylpropyl]amino]acetic Acid Dihydrate (Alvimopan)

Compound 7 Compound 8 Alvimopan

Reagent MW Quantity (kg) kilomole The molar ratio of Compound 7 385.5 7.9 2.02049 1.00 Glycine ethyl ester hydrochloride 139.58 3.1 0.02254 1.10 1-Hydroxybenzotriazole hydrate 135.13 3.5 0.02562 1.25 Triethylamine 101.2 2.3 0.02254 1.10 1,3-Dicyclohexylcarbodiimide 206.33 4.7 0.02254 1.10 Tetrahydrofuran 72.11 156 -- -- Ethyl acetate 88.11 858 -- -- Soda Ash (Sodium Carbonate) 105.99 4.8 -- -- sodium bicarbonate 84.00 3.1 -- -- salt water -- 112 -- -- Ethanol 1X 46.07 743 -- -- purified water 18.02 1196 -- -- Sodium Hydroxide, 50%, w/w 40.0 16.8 -- -- Hydrochloric acid, 31% 36.46 30.0 -- --

Tetrahydrofuran (15 kg) and 1,3-dicyclohexylcarbodiimide (4.7 kg) were added to a portable stirred stainless steel tank (PAST). The transfer device was rinsed quickly with THF (16 kg).

Compound 7 (7.9 kg), glycine ethyl ester hydrochloride (3.1 kg), 1-hydroxybenzotriazole hydrate (3.5 kg), tetrahydrofuran (99 kg), and purified water (3.3 kg) were added to the reactor. With 60% agitation, the mixture was adjusted to 20 to 25°C.

Triethylamine (2.3 kg) was added to the reactor. The transfer device was rinsed quickly with tetrahydrofuran (3 kg). The solution was maintained at 20 to 25°C for 20 to 60 minutes.

The 1,3-dicyclohexylcarbodiimide solution was transferred to the reactor while maintaining a temperature of 20 to 25°C. The transfer apparatus was rinsed quickly with tetrahydrofuran (23 kg).

The reaction mixture was maintained at 20 to 25°C for 36 to 38 hours with 100% stirring.

The reaction mixture was cooled to 0 to 5 °C. The mixture was kept in this range for 1 to 2 hours, then filtered into another reactor. The reaction mixture was rinsed quickly with ethyl acetate (20 kg). The mixture was cooled to 0 to 5 °C and concentrated by vacuum distillation to an amount of 140 to 149 L.

Ethyl acetate (731 kg) was charged to the reactor and cooled to 0 to 5°C. The solution was concentrated by vacuum distillation to an amount of 140 to 149 L. The reaction mixture was checked for residual tetrahydrofuran.

Purified water (94 kg), alkali powder (4.8 kg) and sodium bicarbonate (3.1 kg) were added to a portable stirring stainless steel tank. Stir the mixture for at least two minutes until the solids dissolve.

The basic solution was added to the reactor and the temperature was adjusted to 20 to 25°C. Stirring was maintained at 60% for 20 to 60 minutes. Check the solution at 60% to make sure it is 9.5 to 10 at 60%, and adjust as necessary. The biphasic solution was separated and the organic solution was washed with brine (112 kg).

Ethyl acetate (87 kg) was added to the reactor and cooled to 0 to 5°C. The solution was concentrated by vacuum distillation to an amount of 140 to 149 L, and cooled to -25 to -20°C. Hold at this temperature for 10 to 11 hours.

The suspension was filtered into the reactor, rinsed rapidly with ethyl acetate (20 kg) and warmed to 0 to 5°C. The filtrate was concentrated by vacuum distillation to an amount of 39 to 51 L.

Add ethanol 1X (199 kg) to the reactor and cool to 0 to 5°C. The solution was concentrated by vacuum distillation to an amount of 136 to 161 L. Ethanol 1X (93 kg) was added to the reactor and the mixture was checked for residual ethyl acetate.

Purified water (83 L) and sodium hydroxide (50%, 5.6 kg) were charged to a portable storage tank. The transfer equipment was rinsed quickly with purified water (19 kg). Stir the mixture for at least two minutes to form a solution. The alkaline solution was transferred to the reactor and maintained at 20 to 25°C for 1.5 to 3.5 hours. The suspension was filtered into the reactor and adjusted to 20 to 25°C. The 600L reactor was quickly rinsed with purified water (13 kg).

Purified water (15 L) and hydrochloric acid (31%, 11.2 kg) were charged to a portable storage tank. The transfer equipment was rinsed quickly with purified water (5 kg). Stir the mixture for at least two minutes to form a solution. The acidic solution was added to the reactor in portions until a pH of 5.8 to 6.2 was achieved.

The crude product was isolated by filtration, washed with purified water (2 x 26 kg), washed with ethanol 1X (2 x 26 kg), dried and packaged.

The crude product and purified water (according to calculation) were charged to the reactor.

Purified water (1.9 L) and sodium hydroxide (50%, 5.3 kg) were added to a new PE bucket. The transfer equipment was rinsed quickly with purified water (1.0 kg). Stir the mixture for at least two minutes to form a solution.

The reaction mixture was adjusted to a minimum pH of 13 using alkaline solution (7.5 kg). The mixture is maintained at 20 to 25°C for 20 to 60 minutes.

The reaction mixture was filtered into the reactor for clarification. The reactor was rinsed quickly with purified water (10 kg) and ethanol was added 1X (according to calculation).

Purified water (14 L) and hydrochloric acid (31%, 9.6 kg) were charged to a portable storage tank. The transfer equipment was rinsed quickly with purified water (4 kg). Stir the mixture for at least two minutes to form a solution. The acidic solution was added to the reactor in portions until a pH of 4.0 to 4.5 was obtained.

Purified water (1.9 L) and sodium hydroxide (50%, 0.3 kg) were added to a new PE bucket. The transfer equipment was rinsed quickly with purified water (1.0 kg). Stir the mixture for at least two minutes to form a solution. The basic solution was added to the reactor in portions until a pH of 5.8 to 6.2 was obtained.

The mixture was checked for solids and the suspension was maintained at 20 to 25°C for at least 12 hours.

The product was isolated by filtration, washed first with purified water (according to calculation), then with ethanol 1X (according to calculation), and again in purified water (according to calculation). The filter cake is dried and packaged.

The crude product and purified water (according to calculation) were charged to the reactor.

Purified water (1.9 L) and sodium hydroxide (50%, 5.3 kg) were added to a new PE bucket. The transfer equipment was rinsed quickly with purified water (1.0 kg). Stir the mixture for at least two minutes to form a solution. The basic solution was added to the reactor in portions until a minimum pH of 13 was obtained.

The mixture was stirred at 20 to 25°C for 20 to 60 minutes. The reaction mixture was filtered into another reactor for clarification. The reactor was rinsed quickly with purified water (10 kg). Add ethanol 1X (according to calculation) to the reactor.

Purified water (13.5 L) and hydrochloric acid (31%, 9.2 kg) were added to a portable storage tank. The transfer equipment was rinsed quickly with purified water (3.9 kg). Stir the mixture for at least two minutes to form a solution. The acidic solution was added to the reactor in portions until a pH of 4.0 to 4.5 was obtained.

Purified water (1.9 L) and sodium hydroxide (50%, 0.3 kg) were added to a new PE bucket. The transfer equipment was rinsed quickly with purified water (1.0 kg). Stir the mixture for at least two minutes to form a solution. The basic solution was added to the reactor in portions until a pH of 5.8 to 6.2 was obtained.

The mixture was checked for solids and the suspension was maintained at 20 to 25°C for at least 12 hours.

The product was isolated by filtration, washed first with purified water (according to calculation), then with ethanol 1X (according to calculation), and again in purified water (according to calculation). The filter cake was sampled for chloride analysis, dried and packaged.

The overdried product and purified water (2.0 kg) were added to the desiccator, purged with nitrogen and allowed to stand at room temperature until the specified level of hydration was achieved.

The hydrated product was then packaged and added to a 50 LL product mixer. The product was mixed for twenty to thirty minutes and sampled dry. The product was mixed for an additional twenty to thirty minutes and resampled.

Alvimopan was then packaged, sampled, and tested: HPLC purity not less than 99.2% w/w; chiral HPLC, not less than 99.0%; HPLC assay, 98.0 to 102.0% w/w; and residual solvent not more than 1.2 % w/w total amount, and unpack it.

Example 2: Evaluation of Injectable Formulations (Formulaability and Stability Tests)

Preparation of Injectable Formulations Containing Alvimopan

Alvimopan is [[(25)-2-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-1 -Oxo-3-phenylpropyl]amino]acetic acid dihydrate. Use it in its naturally hydrated form. All weight measurements and concentrations of Alvimopan are expressed on an anhydrous basis.

Product formulation with four 100ml batches:

preparation describe 1 (for comparison) Alvimopan (1 mg/ml) in 2% glycine (bulking agent), pH 10.5, adjusted with 10N and 1N sodium hydroxide 2 (for comparison) Alvimopan (1 mg/ml) in 5% sodium carbonate (buffer), pH 10.5, adjusted with 1N hydrochloric acid 3 Alvimopan (1 mg/ml) in 3% mannitol (bulk) with 50 mM sodium carbonate (buffer), pH 10.5, adjusted with 1 N hydrochloric acid 4 (for comparison) Alvimopan (1 mg/ml) in 3% mannitol (extender) with 50 mM boric acid (buffer), pH 10.5, adjusted with 1 N sodium hydroxide

Buffers and bulking agents were added to 80% of the final solution volume and the pH was adjusted to 10.5 prior to the addition of the active ingredient (Alvimopan). The solution was then readjusted to pH 10.5 and mixed to a clear solution. The solution was then brought to final volume and the pH was adjusted to pH 10.5 with 1 N sodium hydroxide. The final solution was sterile filtered. Aliquots of 12.5 mL were dispensed into vials, which were then capped and placed on lyophilizer shelves for drying. Formulations 1 to 4 were then freeze-dried while the formulations were kneaded as follows:

steps temperature pressure time 1 Set to 5℃±3℃ 2 Dipping at 5℃±3℃ at least 60 minutes 3 Inclined shelf temperature reaches -40℃±3℃ in about 90 minutes 4 Keep at -40℃±3℃ about 120 minutes 5 Inclined shelf temperature reaches -20°C±3°C in about 60 minutes 6 Keep at -20℃±3℃ within about 120 minutes 7 Inclined shelf temperature reaches -40℃±3℃ in about 60 minutes 8 Keep at -40℃±3℃ within about 120 minutes 9 Freeze the condenser to -50°C or lower and evacuate the chamber 10 Use nitrogen purge to control the vacuum at 100±10 microns 11 Inclined shelf temperature reaches -15°C±3°C in about 50 minutes 12 Keep at -15℃±3℃ Within about 3000 minutes 13 Inclined shelf temperature reaches -30℃±3℃ in about 90 minutes 14 At the end of the cycle, slowly return the chamber to 11 ± 0.5 psi with nitrogen N.F., filter through a retentive filter that kills microorganisms 15 Fold the divider to keep the plug in place 16 Return chamber to ambient pressure

The results of the freeze-drying and kneading treatments are shown below:

preparation result 1 (for comparison) product of severe melting 2 (for comparison) Uniform cake, but slightly cloudy when reconstituted in water 3 Uniform cake with approximately fill volume and uniform white color; reconstitution with 12.2 ml of water for injection or sodium chloride for injection yielded a clear colorless solution with no particles found on visual inspection (pH 10.6 after reconstitution -10.7) 4 (for comparison) collapsed and shrunken pie

Formulation 3 resulted in a lyophilized product that appeared to be physically stable and readily reconstituted at 1 mg/mL in water for injection or sodium chloride.

Embodiment 3: bioavailability test

The following formulations containing Alvimopan were prepared to compare the bioavailability of different dosage forms (oral capsule, oral solution and intravenous solution).

oral capsule

Oral capsules (6 mg) contain a homogeneously dispersed suspension of alvimopan in polyethylene glycol (PEG; molecular weight 3350). As evidenced by the analysis, the actual content of the capsule was determined to be 5.868 mg (97.8% of 6 mg).

oral solution

The oral solution contains Alvimopan, propylene glycol (USP), orange drink mix, and purified water (USP). The unit dose of oral solution contains 12 mg of alvimopan per 50 mL (0.24 mg/mL). According to the analysis certificate, the actual content of the oral solution was determined to be 11.868 mg (98.9% of 12 mg).

Intravenous preparations

The formulation for injection is formulated as a freeze-dried powder comprising 12.5 mg of Alvimopan (solvent-free, anhydrous base) with mannitol (USP), and anhydrous sodium carbonate (NG). Sodium hydroxide (NP) and hydrochloric acid (NF) were used to adjust the pH prior to lyophilization to form a lyophilized powder. After adding 12.2 ml of Sodium Chloride for Injection to the lyophilized powder, the reconstituted solution contained 11 mg/mL. The product is stored in 12 mg vials. The actual content of the intravenous formulation was determined to be 11.928 mg (99.4% of 12 mg) as evidenced by analysis.

Evaluation of Bioavailability, Crossover Study of Relative Bioavailability of Alvimopan Oral Capsule Formulation to Oral Solution Alvimopan, and Absolute Bioavailability of Oral Capsule Formulation vs. cross study.

Thirty-six subjects were divided into equal numbers of male and female subjects in the respective procedures and approximately equal numbers of each sex in the study. Subjects received a single dose of Alvimopan on three separate occasions (Day 1 of each of the three cycles) with a minimum washout of 14 days from the day of dosing for each cycle. Each subject received a single 12 mg oral capsule dose (2 x 6 mg capsules), a single 12 mg oral solution dose, and a single 12 mg intravenous dose in each of three cycles (one formulation per cycle). Each cycle consisted of individual Alvimopan doses and 5-day study evaluations. The order in which subjects received each single dose formulation was determined by order of treatment and was randomized for the subjects. One of six processing orders may be determined by a random schedule.

Subjects fasted (NPO) for at least 10 hours before each test drug administration and remained NPO for 1 hour after test drug administration. Blood samples for Alvimopan pharmacokinetic analysis were collected before each test drug dose and at given time points during the 96 hours after test drug dose, depending on whether or not an oral dosage form (i.e., capsule or oral solution) or intravenous formulation. A total of approximately 460 mL of blood was obtained from each subject during the study. For each cycle, subjects were confined to the clinical facility until completion of all 3-day sessions. Subjects were then asked to return to the clinical facility on days 4 and 5 for 72-hour and 96-hour blood sample collections, respectively.

sample collection

Blood samples (7 mL) were drawn into tubes containing sodium heparin at the following times relative to dosing the oral formulation: 0 hours (within 15 minutes prior to dosing), and 0.5, 1 , 1.5, 2, 3, 4, 6, 9, 12, 18, 24, 36, 48, 72 and 96 hours. For the intravenous solution, in addition to those samples obtained from above, four additional samples were drawn at 0.2 hours (end of infusion), 0.25, 0.33, and 0.75 hours after the start of the infusion. Immediately after each sample was collected, each tube was gently inverted and placed on ice. Within 30 minutes of sample collection, the tubes were centrifuged at about 1200 xg for 15 minutes at about 5°C to separate the cells from the plasma. No separation aids are used. Plasma was transferred with clean pipettes and placed in two polypropylene storage tubes in equal volumes. Label the storage tube with the following information: protocol number, body number, cycle number, relative time of sampling and analyte. Wrap the marker with clear tape to ensure marker adherence. Prior to shipping, place storage tubes in a freezer at 70°C or below. Samples are sent frozen to the analytical facility and kept frozen until analyzed.

bioanalytical method

Alvimopan concentrations in plasma samples were determined using a validated and sensitive LC/MS/MS (liquid chromatography/mass spectrometry/mass spectrometry) method. The assay uses a solid-phase extraction process for the extraction of alvimopan, its metabolites, and internal standards from plasma. The solvent was evaporated and the residue was dissolved in solvent, a portion of which was injected into the liquid chromatography system. Detection was performed by MS/MS (mass spectrometry/mass spectrometry) using a SCIEX API 3000(R) mass spectrometer. Include calibration curves and quality control samples in each run. The assay range for both analytes was 0.25 ng/mL to 250 ng/mL, and the limit of quantitation for both analytes was 0.25 ng/mL. Three concentrations of quality control standards (low at 0.75 ng/mL; middle at 25 ng/mL; and high at 175 ng/mL) were included in each analytical run. Another standard (800 ng/mL) was added due to the high concentration obtained from the intravenous solution. The intra-assay precision, expressed as the coefficient of deviation (%CV), was 12.9% for Alvimopan for the lower quality control standard; Vimopan at 1.2%.

Pharmacokinetic Measurements

Enter the Alvimopan concentration in plasma into the spreadsheet. After the spreadsheet data was adapted for compatibility as an input file, the information was processed with WinNonlin(R) Professional (Version 3.3) to obtain pharmacokinetic variables and generate concentration-time curves and tables. Use WinNonlin Validation Kit (Version3.3) to verify the WinNonlin program. Pharmacokinetic variables of alvimopan during oral treatment were obtained using a non-compartmental Model200 with extravascular infusion. Plasma concentrations of alvimopan following intravenous administration were analyzed using a non-compartmental Model202 with a constant infusion rate. For all subjects, the infusion time was 12 minutes.

Standard sampling times were used for the pharmacokinetic analysis of alvimopan, and any deviations in sampling times from the scheduled times were considered not significant. Concentration values reported below the limit of quantitation (BLQ) were treated as zero for calculation of mean concentrations and concentration-time curves.

For the pharmacokinetic analysis of alvimopan, include BLQ results in the input file. Reported plasma concentrations were used directly, but measurable concentrations observed after BLQ results were obtained were excluded from the analysis.

The following pharmacokinetic parameters for alvimopan were obtained from the WinNonlin output file:

Cmax The maximum observed plasma drug concentration

· Cp Plasma drug concentration at a given time point

·Tmax Time to reach maximum plasma drug concentration, obtained directly from concentration-time data

tλz Half-life of the final part of the disposal phase

AUC(0- _tlast ) is the area under the plasma drug concentration-time curve from time 0 to the time of the last measurable concentration

AUC(0-∞) The area under the plasma drug concentration-time curve from time 0 to time infinity

CL Total body plasma clearance (mL/min and mL/min/kg), for I.V. preparations only.

Vss Apparent volume of distribution at steady state (L and L/kg), only for I.V. preparations

CL/F apparent oral clearance (mL/min and mL/min/kg) for oral formulations

Vz/F Apparent oral volume of distribution (L and L/kg) for oral formulations

Vz Apparent oral volume of distribution (L and L/kg) during the terminal exponential phase, for I.V. formulations only

CL _β blood clearance (mL/min), only for IV preparations

Tlag Time from 0 hours to first measurable concentration

Clinically relevant tβ is based on the half-life of the disposition phase of the clinically relevant portion of the plasma drug concentration-time curve representing the manually selected time point of the first disposition phase (see below)

AUC(0-∞)' describes the area under the plasma drug concentration-time curve from time 0 to infinity for the clinically relevant portion of the plasma drug concentration-time curve

AUC ratio AUC(0-∞)′/AUC(0-∞)

To calculate clinically relevant tβ, a second noncompartmental simulation of the data was performed with WinNonlin using manually selected ranges for judging λz. The range was selected by identifying time points that were not part of the second and later treatment phases. To determine whether this second simulation was relevant, AUC(0-∞)'/AUC(0-∞) was calculated from Alvimopan's Day 1 data. AUC(0-∞)' was considered a clinically relevant fraction of AUC(0-∞) if the mean of the ratios was > 85%. Clinically relevant tβ was also based on this second simulation using manually selected ranges.

To determine relative and absolute bioavailability, specific AUC ratios were calculated. For relative bioavailability, the oral capsule was used as a test (Test), and the oral solution was used as a reference (Reference). For absolute bioavailability, the oral administration formulation was used as a test (Test), while the IV formulation was used as a reference (Reference). AUC ratios (and 95% confidence intervals) were calculated using AUC(0- _tlast ) and AUC(0-∞). Mainly consider AUC(0-∞). Calculation of least square means (LS means) derived from analysis of variance (ANOVA). The difference in the LS means of the two comparative treatments was then converted to raw scale to obtain the bioavailability ratio. The following ratios were calculated for the determination of relative and absolute bioavailability:

Relative bioavailability: oral capsule (test) vs oral solution (reference)

· Absolute bioavailability: oral capsule (test) versus I.V. formulation (reference)

Oral solution (test) vs. I.V. formulation (reference)

AUC(0-∞) test

AUC(0-∞) reference

AUC(0-t _last ) test

AUC(0-t _last ) reference

Total blood clearance (CL _β ) following intravenous administration was calculated using the following equation:

CLB=CL*(Cp/Cβ)

Where: CL is the geometric mean CL (ml/min) after IV administration, and Cp/Cβ is the reciprocal of the blood:plasma distribution ratio of 0.68 (ie, Cp = 1; _Cβ = 0.68).

The results are shown in the following table:

After administration of a single dose of alvimopan 12 mg in oral capsules (2 x 6 mg capsules), a single dose of oral solution (0.24 mg/mL) containing alvimopan 12 mg, and a single dose of Summary of Pharmacokinetic Parameters of Alvimopan Following Intravenous Formulation (1 mg/mL)

Avimopan 12mg parameters Oral capsule N＝30 Oral solution N=30 I.V. Preparation N=30 Cmax (ng/mL) mean ± SD (% CV) geometric mean 9.49±5.72(60.2)7.66 21.81±9.99(45.8)19.99 1017±275(27.0)981 Tmax (hr) mean ± SD (% CV) geometric mean median (minimum, maximum) 2.0±0.7(35.2)1.82.0(1.0,4.0) 1.4±0.6(45.5)1.31.0(0.5,3.0) 0.2±0.0(7.4)0.20.2(0.2,0.25) tλz (hr) mean ± SD (% CV) geometric mean 6.2±6.7(108.5)3.9 5.5±4.4(81.0)4.4 5.3±3.8(72.5)4.2 Clinically relevant t(hr) mean ± SD (%CV) geometric mean 1.6±0.6(39.6)1.5 1.7±0.7(38.4)1.6 3.0±2.3(79.0)2.4 AUC (0-t _last ) (hr ^* ng/mL) mean ± SD (% CV) geometric mean 34.3±19.7(57.5)27.3 77.7±35.3(45.4)70.5 520.0±121.9(23.5)507.1 AUC (0-∞) (hr ^* ng/mL) mean ± SD (% CV) geometric mean 37.4±21.2(56.6)30.2 80.7±36.7(45.5)73.2 522.5±122.4(23.4)509.5

Vss (L) mean ± SD (% CV) geometric mean -- -- 30±10(34.4)29 Vss (L/kg) ^a mean ± SD (% CV) geometric mean -- -- 0.43±0.19(43.5)0.40 Vz (L) mean ± SD (% CV) geometric mean -- -- 173±122(70.5)143 Vz (L/kg) ^a mean ± SD (% CV) geometric mean -- -- 2.51±2.11(84.0)1.99 Vz/F (L) mean ± SD (% CV) geometric mean 3071±2813(91.6)2226 1219±771(63.3)1031 -- CL (mL/min) mean ± SD (% CV) geometric mean -- -- 402±89(22.1)393 CL (mL/min/kg) ^a mean ± SD (% CV) geometric mean -- -- 5.62±1.30(23.2)5.47 CL/F (mL/min) mean ± SD (% CV) geometric mean 8809±7579(86.0)6614 3014±1423(47.2)2731 --

^a Values are normalized to body weight.

The absolute bioavailability of alvimopan for oral capsules and oral solution was 6.0% (95% confidence interval: 4.7-7.7%) and 14.3% (95% confidence interval: 11.1-18.3%), respectively. The bioavailability of Alvimopan's capsules relative to its oral solution was 41.9% (95% confidence interval: 32.6-53.7%). The intravenous formulation of Alvimopan produced systemic exposures 6-fold and 14-fold higher than those provided by oral capsules and oral solution, respectively.

When a range expressing a physical property such as molecular weight or a chemical property such as a chemical formula is used herein, all combinations and subcombinations of the specific embodiments within that range are intended to be included.

Each patent, patent application, and publication cited or described herein is hereby incorporated by reference in its entirety.

Those skilled in the art will appreciate that many changes and modifications can be made to the preferred embodiments of the present invention and that such changes and modifications can be made without departing from the spirit of the invention. Accordingly, the claims cover all such equivalents as fall within the true spirit and scope of the invention.

Claims (102)

1. may further comprise the steps the method for a and b:

A., composition is provided, and said composition comprises:

(i) the pharmaceutically acceptable slaine of at least a formula I compound:

Wherein:

R ¹Be hydrogen or alkyl;

R ²Be hydrogen, alkyl or alkenyl;

R ³Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ⁴Be hydrogen, alkyl or alkenyl;

A is OR ⁵Or NR ⁶R ⁷

R ⁵Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ⁶Be hydrogen or alkyl;

R ⁷The B that alkyl, aralkyl, aralkyl or the alkylidene that replaces for the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, aryl, cycloalkyl substituted, cycloalkenyl group, cycloalkenyl group replaces, or R ⁶And R ⁷Form heterocycle with the nitrogen-atoms that they connected;

B is

C (=O) W or NR ⁸R ⁹

R ⁸Be hydrogen or alkyl;

R ⁹The alkyl, aryl or the aralkyl that replace for the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl substituted, cycloalkyl, cycloalkenyl group, cycloalkenyl group, or R ⁸And R ⁹Form heterocycle with the nitrogen-atoms that they connected;

W is OR ¹⁰, NR ¹¹R ¹²Or OE;

R ¹⁰Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹¹Be hydrogen or alkyl;

R ¹²C (=O) the Y, or R that alkyl, aralkyl or the alkylidene that replaces for the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, cycloalkenyl group replaces ¹¹And R ¹²Form heterocycle with the nitrogen-atoms that they connected;

E is

(C=O) D that alkylidene replaces or-R ¹³OC (=O) R ¹⁴

R ¹³Alkylidene for the alkyl replacement;

R ¹⁴Be alkyl;

D is OR ¹⁵Or NR ¹⁶R ¹⁷

R ¹⁵Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹⁶Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, aralkyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted or the alkyl of cycloalkenyl group replacement;

R ¹⁷Be hydrogen or alkyl, or R ¹⁶And R ¹⁷Form heterocycle with the nitrogen-atoms that they connected;

Y is OR ¹⁸Or NR ¹⁹R ²⁰

R ¹⁸Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹⁹Be hydrogen or alkyl;

R ²⁰Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces, or R ¹⁹And R ²⁰Form heterocycle with the nitrogen-atoms that they connected;

R ²¹Be hydrogen or alkyl;

With n be 0 to 4;

The (ii) incremental agent of at least a crystallization;

(iii) at least a weak base; With

(iv) water;

Wherein said composition has the initial pH at least about 10.5; With

B. the pH that regulates described composition arrives the final pH that arrive in about 11 scopes about 9;

Wherein, to patient's administration the time, described composition has the dissolution rate and the bioavilability of the improvement that is used for oral or parenterai administration.

2. the method for claim 1, it comprises that in addition dry described composition is to remove the described water of at least a portion to form the partially or completely step of dry products.

3. the method for claim 2, it comprises in addition by described dry products and pharmaceutically useful solvent are combined to form the solution of described dry products and organizes the step of the described dry products of structure again.

4. the process of claim 1 wherein that the pharmaceutically acceptable slaine of described at least a formula I compound forms on the spot.

5. the process of claim 1 wherein that the pharmaceutically acceptable slaine of described formula I compound is formed by the pharmaceutically acceptable slaine of weak base.

6. the method for claim 5, wherein said weak base adds to be at least about equimolar amount with respect to described formula I compound.

7. the process of claim 1 wherein that initial pH is at least about 11.

8. the process of claim 1 wherein that final pH arrives in about 10.5 the scope about 9.5.

9. the process of claim 1 wherein that described composition makes by the compound that at first the pharmaceutically acceptable slaine of described incremental agent and described weak base is mixed, adds then described formula I in water in described mixture.

10. the process of claim 1 wherein that described composition makes by the pharmaceutically acceptable slaine of the compound of described formula I, described incremental agent and described weak base is mixed basically simultaneously in water.

11. the process of claim 1 wherein that described pharmaceutically acceptable metal is sodium, calcium, magnesium or its combination.

12. the method for claim 11, wherein said pharmaceutically acceptable metal is a sodium.

13. the process of claim 1 wherein that described weak base is bicarbonate or carbonate.

14. the process of claim 1 wherein that described weak base is carbonate.

15. the method for claim 2, wherein said composition is mediated in described drying steps process.

16. the method for claim 2, wherein said drying steps comprises the technology that is selected from freeze drying, atomized drying, vacuum drying and combination thereof.

17. the method for claim 16, wherein said technology are freeze drying.

18. being lower than under environmental condition in about five minutes, the method for claim 3, wherein said solution form.

19. being lower than under environmental condition in about one minute, the method for claim 3, wherein said solution form.

20. being lower than under environmental condition in about 30 seconds, the method for claim 3, wherein said solution form.

21. the method for claim 3, wherein said pharmaceutically useful solvent is moisture.

22. the method for claim 21, wherein said pharmaceutically useful solvent is water, isotonic sodium chlorrde solution, ringer's solution, dextrose solution or Lactated Ringer'S Solution.

23. the method for claim 3, it comprises the step of the described solution of described dry products being given usefulness to the patient in addition.

24. the method for claim 23, wherein said giving with step carried out before operation.

25. the method for claim 23 is wherein said to being carried out in surgical procedure with step.

26. the method for claim 23, wherein said giving with step carried out under the situation that does not have operation.

27. the method for claim 23 is wherein said to being undertaken by non-oral route with step.

28. the method for claim 27 is wherein said to being undertaken by injection with step.

29. the method for claim 28, wherein said injection are hypodermic injection, intramuscular injection or intravenous injection.

30. the process of claim 1 wherein that the compound of formula I is trans 3, the 4-isomer.

31. the process of claim 1 wherein:

R ¹Be hydrogen;

R ²Be alkyl;

N is 1 or 2;

R ³Be benzyl, phenyl, cyclohexyl or cyclohexyl methyl; With

R ⁴Be alkyl.

32. the process of claim 1 wherein:

A is OR ⁵With

R ⁵Be hydrogen or alkyl.

33. the process of claim 1 wherein:

A is NR ⁶R ⁷

R ⁶Be hydrogen;

R ⁷B for the alkylidene replacement; With

B is C (O) W.

34. the process of claim 1 wherein:

R ⁷Be (CH ₂) q-B;

Q is about 1 to about 3;

W is OR ¹⁰With

R ¹⁰The alkyl of alkyl, cycloalkyl or the cycloalkyl substituted that replaces for hydrogen, alkyl, phenyl.

35. the process of claim 1 wherein:

W is NR ¹¹R ¹²

R ¹¹Be hydrogen or alkyl; With

R ¹²The C that replaces for hydrogen, alkyl or alkylidene (=O) Y.

36. the process of claim 1 wherein:

R ¹²Be (CH ₂) mC (O) Y;

M is 1 to 3;

Y is OR ¹⁸Or NR ¹⁹R ²⁰With

R ¹⁸, R ¹⁹And R ²⁰Be hydrogen or alkyl independently.

37. the process of claim 1 wherein:

W is OE;

E is CH ₂C (=O) D;

D is OR ¹⁵Or NR ¹⁶R ¹⁷

R ¹⁵Be hydrogen or alkyl;

R ¹⁶Be methyl or benzyl; With

R ¹⁷Be hydrogen.

38. the process of claim 1 wherein:

W is OE;

E is R ¹³OC (=O) R ¹⁴

R ¹³For-CH (CH ₃)-or-CH (CH ₂CH ₃-; With

R ¹⁴Be alkyl.

39. the process of claim 1 wherein 3 of piperidine ring and 4 s' the configuration R type of respectively doing for oneself.

40. the process of claim 1 wherein that described compound is selected from:

Q-CH ₂CH(CH ₂(C ₆H ₅))C(O)OH，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)OCH ₂CH ₂，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)OH，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)NHCH ₃，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)NHCH ₂CH ₃，

G-NH(CH ₂) ₂C(O)NH ₂，

G-NH(CH ₂) ₂C(O)NHCH ₃，

G-NHCH ₂C(O)NH ₂，

G-NHCH ₂C(O)NHCH ₃，

G-NHCH ₂C(O)NHCH ₂CH ₃，

G-NH(CH ₂) ₃C(O)OCH ₂CH ₃，

G-NH(CH ₂) ₃C(O)NHCH ₃，

G-NH(CH ₂) ₂C(O)OH，

G-NH(CH ₂) ₃C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NHCH ₂C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NH(CH ₂) ₂C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NH(CH ₂) ₂C(O)NH ₂，

Z-NHCH ₂C(O)OCH ₂CH ₃，

Z-NHCH ₂C(O)OH，

Z-NHCH ₂C(O)NH ₂，

Z-NHCH ₂C(O)N(CH ₃) ₂，

Z-NHCH ₂C(O)NHCH(CH ₃) ₂，

Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

Z-NH(CH ₂) ₂C(O)OCH ₂(C ₆H ₅)，

Z-NH(CH ₂) ₂C(O)OH，

Z-NH(CH ₂) ₂C(O)NHCH ₂CH ₃，

Z-NH(CH ₂) ₃C(O)NHCH ₃，

Z-NHCH ₂C(O)NHCH ₂C(O)OH，

Z-NHCH ₂C(O)OCH ₂C(O)OCH ₃，

Z-NHCH ₂C(O)O(CH ₂) ₄CH ₃，

Z-NHCH ₂C(O)OCH ₂C(O)NHCH ₃，

Z-NHCH ₂C (O) O-(4-methoxyl group cyclohexyl),

Z-NHCH ₂C (O) OCH ₂C (O) NHCH ₂(C ₆H ₅) and

Z-NHCH ₂C(O)OCH(CH ₃)OC(O)CH ₃；

Wherein: Q represents

G represents

With

Z represents

41. the method for claim 40, wherein said chemical combination is selected from:

(3R，4R，S)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(+)-Z-NHCH ₂C(O)OH，

(-)-Z-NHCH ₂C(O)OH，

(3R，4R，R)-Z-NHCH ₂C(O)-OCH ₂CH(CH ₃) ₂，

(3S，4S，S)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(3S，4S，R)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(3R, 4R)-Z-NHCH ₂C (O) NHCH ₂(C ₆H ₅) and

(3R，4R)-G-NH(CH ₂) ₃C(O)OH。

42. the method for claim 41, wherein said compound is selected from (+)-Z-NHCH ₂C (O) OH and (-)-Z-NHCH ₂C (O) OH.

43. the method for claim 42, wherein said compound are (+)-Z-NHCH ₂C (O) OH.

44. the method for claim 43, wherein said compound are Q-CH ₂CH (CH ₂(C ₆H ₅)) C (O) OH.

45. the method for claim 44, wherein said compound be (3R, 4R, S)-Q-CH ₂CH (CH ₂(C ₆H ₅)) C (O) OH.

46. the process of claim 1 wherein that described compound is pure basically stereoisomer.

47. the process of claim 1 wherein that described incremental agent is a polyalcohol.

48. the method for claim 47, wherein said polyalcohol are carbohydrate or sugar alcohol.

49. the method for claim 48, wherein said carbohydrate are sucrose, trehalose, lactose, maltose or its mixture.

50. the method for claim 48, wherein said sugar alcohol are mannitol, xylitol, erythrite, lactitol, isomalt, polyalditol, maltitol or its mixture.

51. the method for claim 50, wherein said sugar alcohol are mannitol.

52. the process of claim 1 wherein that described composition comprises at least a opioid in addition.

53. the method for claim 52, wherein said opioid is selected from alfentanil, buprenorphine, butorphanol, codeine, dezocine, Dihydrocodeine, fentanyl, hydrocodone, Hydromorphone, levorphanol, meperidine(pethidine), methadone, morphine, Nalbuphine, Oxycodone, Oxymorphone, pentazocine, propiram, dextropropoxyphene, sufentanil, tramadol and composition thereof.

54. pass through the product that the method for claim 1 is produced.

55. pass through the product that the method for claim 2 is produced.

56. having, the product of claim 55, wherein said product be lower than about 1.0g/cm ³Density.

57. pass through the product that the method for claim 3 is produced.

58. composition, it comprises:

The pharmaceutically acceptable slaine of a. at least a formula I compound:

Wherein:

R ¹Be hydrogen or alkyl;

R ²Be hydrogen, alkyl or alkenyl;

R ³Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ⁴Be hydrogen, alkyl or alkenyl;

A is OR ⁵Or NR ⁶R ⁷

R ⁵Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ⁶Be hydrogen or alkyl;

R ⁷The B that alkyl, aralkyl, aralkyl or the alkylidene that replaces for the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, aryl, cycloalkyl substituted, cycloalkenyl group, cycloalkenyl group replaces, or R ⁶And R ⁷Form heterocycle with the nitrogen-atoms that they connected;

B is

C (=O) W or NR ⁸R ⁹

R ⁸Be hydrogen or alkyl;

R ⁹The alkyl, aryl or the aralkyl that replace for the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl substituted, cycloalkyl, cycloalkenyl group, cycloalkenyl group, or R ⁸And R ⁹Form heterocycle with the nitrogen-atoms that they connected;

W is OR ¹⁰, NR ¹¹R ¹²Or OE;

R ¹⁰Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹¹Be hydrogen or alkyl;

R ¹²C (=O) the Y, or R that alkyl, aralkyl or the alkylidene that replaces for the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, cycloalkenyl group replaces ¹¹And R ¹²Form heterocycle with the nitrogen-atoms that they connected;

E is

(C=O) D that alkylidene replaces or-R ¹³OC (=O) R ¹⁴

R ¹³Alkylidene for the alkyl replacement;

R ¹⁴Be alkyl;

D is OR ¹⁵Or NR ¹⁶R ¹⁷

R ¹⁵Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹⁶Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, aralkyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted or the alkyl of cycloalkenyl group replacement;

R ¹⁷Be hydrogen or alkyl, or R ¹⁶And R ¹⁷Form heterocycle with the nitrogen-atoms that they connected;

Y is OR ¹⁸Or NR ¹⁹R ²⁰

R ¹⁸Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹⁹Be hydrogen or alkyl;

R ²⁰Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces, or R ¹⁹And R ²⁰Form heterocycle with the nitrogen-atoms that they connected;

R ²¹Be hydrogen or alkyl;

With n be 0 to 4;

B. the incremental agent of at least a crystallization;

Wherein said composition has and is lower than about 1.0g/cm ³Density;

Wherein, to patient's administration the time, described composition has the dissolution rate and the bioavilability of the improvement that is used for oral or parenterai administration.

59. having, the composition of claim 58, wherein said composition be lower than about 0.5g/cm ³Density.

60. composition, it comprises:

The pharmaceutically acceptable slaine of a. at least a formula I compound:

Wherein:

R ¹Be hydrogen or alkyl;

R ²Be hydrogen, alkyl or alkenyl;

R ³Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ⁴Be hydrogen, alkyl or alkenyl;

A is OR ⁵Or NR ⁶R ⁷

R ⁵Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ⁶Be hydrogen or alkyl;

R ⁷The B that alkyl, aralkyl, aralkyl or the alkylidene that replaces for the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, aryl, cycloalkyl substituted, cycloalkenyl group, cycloalkenyl group replaces, or R ⁶And R ⁷Form heterocycle with the nitrogen-atoms that they connected;

B is

C (=O) W or NR ⁸R ⁹

R ⁸Be hydrogen or alkyl;

R ⁹The alkyl, aryl or the aralkyl that replace for the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl substituted, cycloalkyl, cycloalkenyl group, cycloalkenyl group, or R ⁸And R ⁹Form heterocycle with the nitrogen-atoms that they connected;

W is OR ¹⁰, NR ¹¹R ¹²Or OE;

R ¹⁰Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹¹Be hydrogen or alkyl;

R ¹²C (=O) the Y, or R that alkyl, aralkyl or the alkylidene that replaces for the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, cycloalkenyl group replaces ¹¹And R ¹²Form heterocycle with the nitrogen-atoms that they connected;

E is

(C=O) D that alkylidene replaces or-R ¹³OC (=O) R ¹⁴

R ¹³Alkylidene for the alkyl replacement;

R ¹⁴Be alkyl;

D is OR ¹⁵Or NR ¹⁶R ¹⁷

R ¹⁵Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹⁶Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, aralkyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted or the alkyl of cycloalkenyl group replacement;

R ¹⁷Be hydrogen or alkyl, or R ¹⁶And R ¹⁷Form heterocycle with the nitrogen-atoms that they connected;

Y is OR ¹⁸Or NR ¹⁹R ²⁰

R ¹⁸Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹⁹Be hydrogen or alkyl;

R ²⁰Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces, or R ¹⁹And R ²⁰Form heterocycle with the nitrogen-atoms that they connected;

R ²¹Be hydrogen or alkyl; With

N is 0 to 4;

B. the incremental agent of at least a crystallization;

C. based on composition total weight, be lower than the solubilizing surfactant of about 1 weight %;

D. based on composition total weight, be lower than the nonaqueous solvents of about 10 weight %; With

E. based on composition total weight, be lower than the cyclodextrin of about 500 weight %;

Wherein, to patient's administration the time, described composition has the dissolution rate and the bioavilability of the improvement that is used for oral or parenterai administration.

61. the composition of claim 58 or 60, the content of the pharmaceutically acceptable slaine of wherein said formula I compound is at least about 0.1mg/mL.

62. the composition of claim 58 or 60, the content of the pharmaceutically acceptable slaine of wherein said formula I compound is at least about 1mg/mL.

63. the composition of claim 58 or 60, the content of the pharmaceutically acceptable slaine of wherein said formula I compound is at least about 2mg/mL.

64. the composition of claim 58 or 60, wherein said composition has the pot-life at least about 18 months.

65. the composition of claim 58 or 60, it comprises at least a opioid in addition.

66. the composition of claim 65, wherein said opioid are selected from alfentanil, buprenorphine, butorphanol, codeine, dezocine, Dihydrocodeine, fentanyl, hydrocodone, Hydromorphone, levorphanol, meperidine(pethidine), methadone, morphine, Nalbuphine, Oxycodone, Oxymorphone, pentazocine, propiram, dextropropoxyphene, sufentanil and bent horse.

67. the composition of claim 58 or 60, it comprises at least a pharmaceutically useful solvent in addition.

68. the composition of claim 67, wherein said pharmaceutically useful solvent is moisture.

69. the composition of claim 68, wherein said pharmaceutically useful solvent is water, isotonic sodium chlorrde solution, ringer's solution, dextrose solution or Lactated Ringer'S Solution.

70. the composition of claim 58 or 60, the compound of its Chinese style I are trans-3, the 4-isomer.

71. the composition of claim 58 or 60, wherein:

R ¹Be hydrogen;

R ²Be alkyl;

N is 1 or 2;

R ³Be benzyl, phenyl, cyclohexyl or cyclohexyl methyl; With

R ⁴Be alkyl.

72. the composition of claim 58 or 60, wherein:

A is OR ⁵With

R ⁵Be hydrogen or alkyl.

73. the composition of claim 58 or 60, wherein:

A is NR ⁶R ⁷

R ⁶Be hydrogen;

R ⁷B for the alkylidene replacement; With

B is C (O) W.

74. the composition of claim 58 or 60, wherein:

R ⁷Be (CH ₂) q-B;

Q is about 1 to about 3;

W is OR ¹⁰With

R ¹⁰The alkyl of alkyl, cycloalkyl or the cycloalkyl substituted that replaces for hydrogen, alkyl, phenyl.

75. the composition of claim 58 or 60, wherein:

W is NR ¹¹R ¹²

R ¹¹Be hydrogen or alkyl; With

R ¹²The C that replaces for hydrogen, alkyl or alkylidene (=O) Y.

76. the composition of claim 58 or 60, wherein:

R ¹²Be (CH ₂) mC (O) Y;

M is 1 to 3;

Y is OR ¹⁸Or NR ¹⁹R ²⁰With

R ¹⁸, R ¹⁹And R ²⁰Be hydrogen or alkyl independently.

77. the composition of claim 58 or 60, wherein:

W is OE;

E is CH ₂C (=O) D;

D is OR ¹⁵Or NR ¹⁶R ¹⁷

R ¹⁵Be hydrogen or alkyl;

R ¹⁶Be methyl or benzyl; With

R ¹⁷Be hydrogen.

78. the composition of claim 58 or 60, wherein:

W is OE;

E is R ¹³OC (=O) R ¹⁴

R ¹³For-CH (CH ₃)-or-CH (CH ₂CH ₃)-; With

R ¹⁴Be alkyl.

79. the composition of claim 58 or 60, wherein 3 of piperidine ring and 4 s' configuration all is the R type.

80. the composition of claim 58 or 60, wherein said compound is selected from:

Q-CH ₂CH(CH ₂(C ₆H ₅))C(O)OH，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)OCH ₂CH ₂，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)OH，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)NHCH ₃，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)NHCH ₂CH ₃，

G-NH(CH ₂) ₂C(O)NH ₂，

G-NH(CH ₂) ₂C(O)NHCH ₃，

G-NHCH ₂C(O)NH ₂，

G-NHCH ₂C(O)NHCH ₃，

G-NHCH ₂C(O)NHCH ₂CH ₃，

G-NH(CH ₂) ₃C(O)OCH ₂CH ₃，

G-NH(CH ₂) ₃C(O)NHCH ₃，

G-NH(CH ₂) ₂C(O)OH，

G-NH(CH ₂) ₃C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NHCH ₂C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NH(CH ₂) ₂C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NH(CH ₂) ₂C(O)NH ₂，

Z-NHCH ₂C(O)OCH ₂CH ₃，

Z-NHCH ₂C(O)OH，

Z-NHCH ₂C(O)NH ₂，

Z-NHCH ₂C(O)N(CH ₃) ₂，

Z-NHCH ₂C(O)NHCH(CH ₃) ₂，

Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

Z-NH(CH ₂) ₂C(O)OCH ₂(C ₆H ₅)，

Z-NH(CH ₂) ₂C(O)OH，

Z-NH(CH ₂) ₂C(O)NHCH ₂CH ₃，

Z-NH(CH ₂) ₃C(O)NHCH ₃，

Z-NHCH ₂C(O)NHCH ₂C(O)OH，

Z-NHCH ₂C(O)OCH ₂C(O)OCH ₃，

Z-NHCH ₂C(O)O(CH ₂) ₄CH ₃，

Z-NHCH ₂C(O)OCH ₂C(O)NHCH ₃，

Z-NHCH ₂C (O) O-(4-methoxyl group cyclohexyl),

Z-NHCH ₂C (O) OCH ₂C (O) NHCH ₂(C ₆H ₅) and

Z-NHCH ₂C(O)OCH(CH ₃)OC(O)CH ₃；

Wherein: Q represents

Trans-3, the 4-dimethyl

G represents

With

Z represents

81. the composition of claim 58 or 60, wherein said compound is selected from:

(3R，4R，S)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(+)-Z-NHCH ₂C(O)OH，

(-)-Z-NHCH ₂C(O)OH，

(3R，4R，R)-Z-NHCH ₂C(O)-OCH ₂CH(CH ₃) ₂，

(3S，4S，S)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(3S，4S，R)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(3R, 4R)-Z-NHCH ₂C (O) NHCH ₂(C ₆H ₅) and

(3R，4R)-G-N-H(CH ₂) ₃C(O)OH。

82. the composition of claim 58 or 60, wherein said compound is selected from (+)-Z-NHCH ₂C (O) OH and (-)-Z-NHCH ₂C (O) OH.

83. the composition of claim 58 or 60, wherein said compound are (+)-Z-NHCH ₂C (O) OH.

84. the composition of claim 58 or 60, wherein said compound are Q-CH ₂CH (CH ₂(C ₆H ₅)) C (O) OH.

85. the composition of claim 58 or 60, wherein said compound be (3R, 4R, S)-Q-CH ₂CH (CH ₂(C ₆H ₅)) C (O) OH.

86. the composition of claim 58 or 60, wherein said compound are pure basically stereoisomer.

87. the composition of claim 58 or 60, wherein said pharmaceutically acceptable metal are sodium, calcium, magnesium or its combination.

88. the composition of claim 58 or 60, wherein said pharmaceutically acceptable metal is a sodium.

89. the composition of claim 58 or 60, wherein said incremental agent are polyalcohol.

90. the composition of claim 89, wherein said polyalcohol are carbohydrate or sugar alcohol.

91. the composition of claim 90, wherein said carbohydrate are sucrose, trehalose, lactose, maltose or its mixture.

92. the composition of claim 90, wherein said sugar alcohol are mannitol, xylitol, erythrite, lactitol, isomalt, polyalditol or maltitol.

93. the composition of claim 92, wherein said sugar alcohol are mannitol.

94. injectable dosage formulations, it comprises the composition of claim 58 or 60.

95. cartridge bag, it comprises:

A. the container that comprises the injectable dosage formulations of claim 94; With

B. be used to prepare the specification of Injectable solution.

96. the cartridge bag of claim 95, it comprises syringe in addition.

97. the method for the side effect relevant with opioid among prevention or the treatment patient, it comprises step:

To the claim 58 of described patient's effective dosage or 60 composition.

98. the method for claim 97, wherein said side effect be intestinal obstruction, scratch where it itches, constipation, the retention of urine, courage spasm, opium bowel dysfunction, angina, n or V or its combination.

99. the method for claim 98, wherein said side effect be postoperative ileus, postpartum intestinal obstruction, scratch where it itches, constipation, the retention of urine, courage spasm, opium bowel dysfunction, angina, postoperative nausea or postoperative vomiting or its combination.

100. the method for prevention or treatment patient's pain, it comprises step:

To claim 58 that the described patient's effective dosage that needs is arranged or 60 composition.

101. the method for claim 100, wherein said Pharmaceutical composition comprises at least a opioid in addition.

102. the method for claim 101, wherein said opioid is selected from alfentanil, buprenorphine, butorphanol, codeine, dezocine, Dihydrocodeine, fentanyl, hydrocodone, Hydromorphone, levorphanol, meperidine(pethidine), methadone, morphine, Nalbuphine, Oxycodone, Oxymorphone, pentazocine, propiram, dextropropoxyphene, sufentanil, tramadol and composition thereof.