# US 10,441,661 B2 · Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydromorphone, prodrugs, methods of making and use thereof

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- Number: US 10,441,661 B2
- Document ID: US10441661B2
- Status: Granted
- Kind: B2
- Application number: 16/290,496
- Filed: 2019-03-01
- Published: 2019-06-27
- Granted: 2019-10-15
- Earliest claimed: 2011-10-26
- Assignees: KemPharm, Inc.
- Applicants: KemPharm, Inc.
- Inventors: Travis Mickle; Sven Guenther; Guochen Chi; Jaroslaw Kanski; Andrea K Martin; Bindu Bera
- Web page: https://patentgrep.com/patent/US10441661B2

## CPC

- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0043: {Nose}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/185: Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids (hydroxamic acids A61K31/16; peroxy acids A61K31/327)
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 31/616: by carboxylic acids, e.g. acetylsalicylic acid
- A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047)
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61P 11/14: Antitussive agents
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/36: Opioid-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The presently described technology provides compositions comprising aryl carboxylic acids chemically conjugated to hydromorphone (4,5-α-epoxy-3-hydroxy-17-methyl morphinan-6-one) to form novel prodrugs/compositions of hydromorphone. The hydromorphone prodrugs of the present technology have decreased side effects and decreased potential for abuse compared to unconjugated hydromorphone. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesizing conjugates of the present technology.

## Claims

### Claim 1

A compound selected from the group consisting of
and salts of the compound.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the salt of the compound is a pharmaceutically acceptable salt.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the pharmaceutically acceptable salt is selected from the group consisting of an acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, mesotartrate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesufonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, tromethamine, and a mixture thereof.

### Claim 4 (depends on 1)

A method of treating a patient in need of an analgesic effect said method comprising selecting a patient in need thereof and administering an effective amount of at least one compound of claim 1, a salt of the compound, or a combination thereof.

### Claim 5 (depends on 4)

The method of claim 4, wherein the salt of the compound is a pharmaceutically acceptable salt.

### Claim 6 (depends on 5)

The method of claim 5, wherein the pharmaceutically acceptable salt is selected from the group consisting of an acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, mesotartrate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesufonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, tromethamine, and a mixture thereof.

### Claim 7 (depends on 4)

The method of claim 4, wherein the patient is a human or animal patient.

### Claim 8 (depends on 7)

The method of claim 7, wherein human patient is selected from the group consisting of pediatric patients, geriatric patients, and normative patients.

### Claim 9

A kit comprising individual doses, wherein each individual dose comprises a pharmaceutically effective amount of at least one compound having the formula
a pharmaceutically acceptable salt of said compound, or a combination thereof.

### Claim 10 (depends on 9)

The kit of claim 9, wherein the pharmaceutically acceptable salt is selected from the group consisting of an acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, mesotartrate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesufonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, tromethamine, and a mixture thereof.

### Claim 11 (depends on 9)

The kit of claim 9, wherein the kit further comprises instructions regarding use of said kit for reduction or prevention of narcotic or opioid abuse of a patient, for treating pain of a patient.

### Claim 12 (depends on 11)

The kit of claim 11, wherein the pain is selected from the group consisting of acute, chronic, mild, moderate, and severe pain.

### Claim 13 (depends on 9)

The kit of claim 9, wherein the kit contains from about 1 to about 100 individual dosages.

### Claim 14 (depends on 9)

The kit of claim 9, wherein the individual dosages comprise at least about 0.1 mg of the at least one compound or pharmaceutically acceptable salt of said compound.