# US 8,772,310 B2 · Peripheral opioid receptor antagonists and uses thereof

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- Number: US 8,772,310 B2
- Document ID: US8772310B2
- Status: Granted
- Kind: B2
- Application number: 13/672,885
- Filed: 2012-11-09
- Published: 2013-10-24
- Granted: 2014-07-08
- Earliest claimed: 2007-03-29
- Assignees: Wyeth
- Applicants: Wyeth LLC
- Inventors: Charles K. Melucci; John Lokhnauth
- Web page: https://patentgrep.com/patent/US8772310B2

## CPC

- C07D 221/28: Morphinans
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/36: Opioid-abuse
- A61P 39/00: General protective or antinoxious agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a compound of formula I: wherein X−, R1, and R2 are as defined herein, and compositions thereof; useful as a peripheral mu opioid receptor antagonist.

## Claims

### Claim 1

A composition of a compound of formula I:
in an amount of at least about 97% by weight of the composition; and wherein R1 and R2 are each independently C1-6 aliphatic; and X− is a suitable anion.

### Claim 2 (depends on 1)

The composition of claim 1, wherein X− is selected from the group consisting of the anion of a suitable BrØnsted acid, a hydrogen halide, a carboxylic acid, a sulfonic acid, a sulfuric acid, a phosphoric acid, chloride, bromide, iodide, fluoride, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, carboxylate, sulfate, methylsulfate and succinate.

### Claim 3 (depends on 1)

The composition of claim 1, wherein R1 is C1-4 aliphatic and R2 is lower alkyl.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the compound is a compound of formula II, formula II-1 or formula-II-2:

### Claim 5

A composition of a compound of formula I:
containing no more than 2% by HPLC area of total organic impurities relative to the total area of the HPLC chromatogram; and wherein R1 and R2 are each independently C1-6 aliphatic; and X− is a suitable anion.

### Claim 6 (depends on 5)

The composition of claim 5, wherein X− is selected from the group consisting of the anion of a suitable BrØnsted acid, a hydrogen halide, a carboxylic acid, a sulfonic acid, a sulfuric acid, a phosphoric acid, chloride, bromide, iodide, fluoride, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, carboxylate, sulfate, methylsulfate and succinate.

### Claim 7 (depends on 5)

The composition of claim 5, wherein R1 is C1-4 aliphatic and R2 is lower alkyl.

### Claim 8 (depends on 5)

The composition of claim 5, wherein the compound is a compound of formula II, formula II-1 or formula-II-2:

### Claim 9

A compound of formula I:
wherein at least about 99.6% of the compound is in the (R) configuration with respect to the nitrogen; and wherein R1 and R2 are each independently C1-6 aliphatic; and X− is a suitable anion.

### Claim 10 (depends on 9)

The compound of claim 9, wherein X− is selected from the group consisting of the anion of a suitable BrØnsted acid, a hydrogen halide, a carboxylic acid, a sulfonic acid, a sulfuric acid, a phosphoric acid, chloride, bromide, iodide, fluoride, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, carboxylate, sulfate, methylsulfate and succinate.

### Claim 11 (depends on 9)

The compound of claim 9, wherein R1 is C1-4 aliphatic and R2 is lower alky.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

### Claim 13 (depends on 12)

The pharmaceutical composition of claim 12, in a unit dosage form for administration to a patient, wherein the unit dosage form is selected from the group consisting of tablets, capsules, powders, solutions, suspensions, emulsions, granules and suppositories.

### Claim 14 (depends on 12)

A method of reducing at least one side effect of opioid therapy in a subject receiving opioid treatment comprising administering to the subject the pharmaceutical composition of claim 12 in an amount effective to reduce the side effect, wherein the side effect is selected from the group consisting of depression of respiration, papillary constriction, cardiovascular effects, chest wall rigidity and cough suppression, depression of stress response, immune suppression, aberrant migration or proliferation of endothelial cells, increased angiogenesis, and increase in lethal factor production from opportunistic infection.

### Claim 15 (depends on 14)

The method of claim 14, wherein the subject is a patient receiving short term opioid administration or a patient receiving chronic opioid administration.

### Claim 16 (depends on 12)

A method of inhibiting, reducing, delaying, diminishing or treating a disorder comprising administering the pharmaceutical composition of claim 12 in an amount sufficient to treat the disorder, wherein the disorder is selected from the group consisting of irritable bowel syndrome, colitis, post-operative or postpartum ileus, nausea and/or vomiting, decreased gastric motility and emptying, inhibition of the stomach and small and/or large intestine propulsion, increased amplitude of non-propulsive segmental contractions, constriction of sphincter of Oddi, increased anal sphincter tone, impaired reflex relaxation with rectal distension, diminished gastric, biliary, pancreatic or intestinal secretions, increased adsorption of water from bowel contents, gastroesophageal reflux, gastroparesis, cramping, bloating abdominal or epigastric pain and discomfort, constipation, idiopathic constipation, post-operative gastrointestinal dysfunction, delayed adsorption of orally administered medications or nutritive substances, vascular proliferation, pain, inflammatory bowel syndrome, infectious disease, diseases of the musculoskeletal system, osteoporosis, arthritis, osteitis, periostitis, myopathies, sickle cell anemia, vascular wounds, retinopathy, inflammation associated disorder, immune suppression and chronic inflammation.

### Claim 17 (depends on 16)

The method of inhibiting, reducing, delaying, diminishing or treating a disorder of claim 16, wherein the composition is administered concurrently with, prior to, or subsequent to one or more other desired therapeutics or medical procedures.

### Claim 18 (depends on 16)

The method of inhibiting, reducing, delaying, diminishing or treating a disorder of claim 16, wherein the composition is administered by a method selected from the group consisting of orally, parenterally, neat and in combination with a carrier.

### Claim 19 (depends on 1)

A kit comprising a package containing a sealed container comprising the composition of claim 1, and instructions for use.

### Claim 20 (depends on 1)

The composition of claim 1, wherein the compound of formula I is in an amount of at least about 98% by weight of the composition.

### Claim 21 (depends on 1)

The composition of claim 1, wherein the compound of formula I is in an amount of at least about 99% by weight of the composition.

### Claim 22 (depends on 1)

The composition of claim 1, wherein the compound of formula I is in an amount of at least about 99.5% by weight of the composition.

### Claim 23 (depends on 1)

The composition of claim 1, wherein the compound of formula I is in an amount of at least about 99.8% by weight of the composition.

### Claim 24 (depends on 1)

The composition of claim 1, wherein R1 is a (cycloalkyl)alkyl group or alkenyl group.

### Claim 25 (depends on 1)

The composition of claim 1, wherein R1 is cyclopropyl methyl or allyl and R2 is methyl.

### Claim 26 (depends on 5)

The composition of claim 5, wherein R1 is a (cycloalkyl)alkyl group or alkenyl group.

### Claim 27 (depends on 5)

The composition of claim 5, wherein R1 is cyclopropyl methyl or allyl and R2 is methyl.

### Claim 28 (depends on 9)

The compound of claim 9, wherein at least about 99.8% of the compound of formula I is in the (R) configuration with respect to the nitrogen.

### Claim 29 (depends on 10)

The compound of claim 10, wherein at least about 99.9% of the compound of formula I is in the (R) configuration with respect to the nitrogen.

### Claim 30 (depends on 11)

The compound of claim 11, wherein at least about 99.95% of the compound of formula I is in the (R) configuration with respect to the nitrogen.

### Claim 31 (depends on 12)

The compound of claim 12, wherein X− is bromide.

### Claim 32 (depends on 13)

The compound of claim 13, wherein R1 is a (cycloalkyl)alkyl group or alkenyl group.

### Claim 33 (depends on 14)

The compound of claim 14, wherein R1 is cyclopropyl methyl or allyl and R2 is methyl.

### Claim 34 (depends on 1)

The composition of claim 1, wherein X− is bromide.

### Claim 35 (depends on 5)

The composition of claim 5, containing no more than about 1.5% by HPLC area of total organic impurities relative to the total area of the HPLC chromatogram.

### Claim 36 (depends on 5)

The composition of claim 5, wherein X− is bromide.

### Claim 37 (depends on 13)

The pharmaceutical composition of claim 13, further comprising an additional therapeutic agent.