Levorphanol prodrugs and processes for making and using them

Patent metadata

Field	Value
Publication number	US-11234975-B2
Application number	US-201816604710-A
Country	US
Kind code	B2
Filing date	Apr 12, 2018
Priority date	Apr 14, 2017
Publication date	Feb 1, 2022
Grant date	Feb 1, 2022

Abstract

The presently described technology provides compositions of one or more of oxoacids, amino acids, polyethylene glycols, and/or vitamin compounds chemically conjugated to levorphanol ((−)-17-methylmorphinan-3-ol) to form novel prodrugs and compositions of levorphanol.

First claim

What is claimed is:

1. A compound having the general formula:

wherein R 3 and R 4 are each independently selected from H, alkyl, aryl, alkyl aryl, alkoxy, haloalkyl, or haloaryl;
q is 1-4;
G 2 is at least one oxoacid;
and m is 1-3
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 3 is H; R 4 is H, methyl or phenyl.

3. A compound having the general formula:

wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from H, alkyl, aryl, alkyl aryl, alkoxy, haloalkyl, or haloaryl;
q and k are independently selected from 1-4;
G 2 is at least one oxoacid and m is 1-3, or a pharmaceutically acceptable salt therefor.

4. The compound of claim 3 , wherein R 1 , R 2 and R 3 are H; R 4 is H, methyl or phenyl; q is 1; and k is 1 to 4.

5. The compound of claim 1 , wherein the oxoacid is at least one amino acid, is at least one carboxylic acid, or is a combination of at least one carboxylic acid and at least one amino acid.

6. The compound of claim 1 , wherein the compound is a neutral conjugate, a free acid, a free base or a mixture of racemates, wherein the racemate comprises racemorphan.

7. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. The composition of claim 7 , wherein the pharmaceutically acceptable salt is selected from the group consisting of 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, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 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 (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, 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 and combinations thereof.

9. A compound having the general formula:

wherein R 3 and R 4 are each independently selected from H, alkyl, aryl, alkyl aryl, alkoxy, haloalkyl, or haloaryl;
q is 1-4; G 1 is at least one oxoacid G 2 is at least one oxoacid; and m is 1-4
or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 , wherein the oxoacid is at least one amino acid, is at least one carboxylic acid, or is a combination of at least one carboxylic acid and at least one amino acid.

11. The compound of claim 10 , wherein the at least one carboxylic acid is selected from the group consisting of aliphatic carboxylic acid, aryl carboxylic acid, dicarboxylic acid, polycarboxylic acid, benzoate, phenylacetate, a branched phenylpropionate, an unbranched phenylpropionate (benzylacetate), a phenylpropenoate (cinnamate), and heteroaryl carboxylic acid, salts thereof or a combination thereof.

12. The compound of claim 11 , wherein the benzoate is selected from the group consisting of benzoic acid, hydroxybenzoate, and combinations thereof.

13. The compound of claim 12 , wherein the hydroxybenzoate is selected from the group consisting of salicylic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids, 4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflunisal, o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylic acid, protocatechuic acid, gentisic acid, piperonylic acid, 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylic acid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid, 4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid, vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid (3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid, 2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA), 4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringic acid, and 3,4,5-trimethoxybenzoic acid.

14. The compound of claim 11 , wherein the heteroaryl carboxylic acid is selected from the group consisting of nicotinic acid, isonicotinic acid, picolinic acid, 3-hydroxypicolinic acid, 6-hydroxynicotinic acid, citrazinic acid, 2,6-dihydroxynicotinic acid, kynurenic acid, xanthurenic acid, 6-hydroxykynurenic acid, 8-methoxykynurenic acid, 7,8-dihydroxykynurenic acid, and 7,8-dihydro-7,8-dihydroxykynurenic acid.

15. The compound of claim 11 , wherein the phenylpropenoate (cinnamate) is selected from the group consisting of cinnamic acid, o,m,p-coumaric acid, 2,3-dihydroxycinnamic acid, 2,6-dihydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid, 5-hydroxyferulic acid, sinapic acid, and 2-hydroxy-3-phenylpropenoic acid.

16. The compound of claim 10 wherein the at least one amino acid is a standard amino acid.

17. The compound of claim 9 , wherein the compound is a neutral conjugate, a free acid, a free base or a mixture of racemates, wherein the racemate comprises racemorphan.

18. A composition comprising the compound of claim 9 or a pharmaceutically acceptable salt of the compound.

19. The composition of claim 18 , wherein the pharmaceutically acceptable salt is selected from the group consisting of 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, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 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 (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salic

Assignees

• Kempharm Inc

Inventors

• Mickle Travis
• Guenther Sven
• Bera Sanjib

Classifications

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K47/542

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title

• C07D221/28

  Morphinans · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title