D-AMPHETAMINE COMPOUNDS, COMPOSITIONS, AND PROCESSES FOR MAKING AND USING THE SAME

• US 20200131130A1
• Filed: 10/29/2019
• Published: 04/30/2020
• Est. Priority Date: 10/29/2018
• Status: Active Grant

• Current Assignee: Zevra Therapeutics, Inc.
• Original Assignee: KemPharm, Inc.
• Inventors: Guenther, Sven, Chi, Guochen, Mickle, Travis
• Granted Patent: US 11,136,295 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• CPC Class Codes: C07D 213/79 Acids; Esters
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Disclosed are d-amphetamine compounds and compositions comprising at least one organic acid covalently bound to d-amphetamine, a salt thereof, a derivative thereof, or a combination thereof. Methods of making and using the same are also disclosed.

Claims

1. A compound having the structure of Formula I:

2. The compound of claim 1 having the structure of Formula IA or the pharmaceutically acceptable salt of said compound:

3. The compound of claim 1 having the structure of Formula IC or the pharmaceutically acceptable salt of said compound:

4. The compound of claim 2 or the pharmaceutically acceptable salt of said compound, wherein A is absent, Y is hydrogen, and the compound has the structure of formula IIA:

5. The compound of claim 3 or the pharmaceutically acceptable salt of said compound, wherein A is absent, Y is hydrogen, and the compound has the structure of Formula IIC:

7. The compound of claim 1, 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, 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, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, 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, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, troethamine, and a mixture thereof.

9. A composition comprising the compound of claim 1 or pharmaceutically acceptable salt of the compound.

10. The composition of claim 9, wherein the composition is formulated for oral administration or suppository administration.

11. The composition of claim 10, wherein the composition formulated for oral administration is in a dosage form selected from the group consisting of solid form, a tablet, a capsule, a caplet, a soft gel, a suppository, a troche, a lozenge, an oral powder, a solution, a syrup, an oral film, a thin strip, a slurry, an emulsion, an elixir, and a suspension.

12. The composition of claim 10, wherein the composition further comprises one or more excipients, wherein the excipients are selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, colors, glidants, lubricants, preservatives, sorbents, sweeteners, and combinations thereof.

13. The composition of claim 12 wherein the binder is selected from the group consisting of hydroxypropylmethyl cellulose, ethyl cellulose, povidone, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, gums, milk derivatives, and combinations thereof.

14. The composition of claim 9, wherein the compound present in an amount per unit dose of between about 0.1 mg and about 2000 mg per unit dose.

15. The composition of claim 13, wherein the compound is present in an amount per unit dose of between about 0.5 mg and about 500 mg per unit dose.

16. The composition of claim 15, wherein the compound is present in an amount per unit dose of between about 1 mg and about 250 mg per unit dose.

17. The composition of claim 16, wherein the compound is present in an amount per unit dose of between about 1.5 mg and about 100 mg per unit dose.

18. The composition of claim 9, wherein the composition further comprises one or more additional pharmacological substance selected from the group consisting of stimulants, anti-depressants, combinations thereof, and prodrugs thereof.

19. The composition of claim 9, wherein the composition further comprises one or more of methylphenidate, aripiprazole, atomoxetine, baclofen, clonidine, desipramine, dihydrotetrabenazine, guanfacine, haloperidol, levetiracetam, mecamylamine, etoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, tetrabenazine, topiramate, ziprasidone, or one or more of additional amphetamine, or any combination thereof.

20. The composition of claim 19, wherein the one or more additional amphetamine is unconjugated amphetamine, a conjugate of amphetamine, a prodrug of amphetamine, any isomer thereof, or any combination thereof.

21. The composition of claim 20, wherein the isomer of unconjugated amphetamine is unconjugated d-amphetamine.

22. The composition of claim 19, wherein the methylphenidate is unconjugated methylphenidate, a conjugate of methylphenidate, a prodrug of methylphenidate, any isomer thereof, or any combination thereof.

23. The composition of claim 22, wherein the isomer of unconjugated methylphenidate is unconjugated d-methylphenidate.

24. The composition of claim 22, wherein the conjugate of methylphenidate is serdexmethylphenidate.

25. The composition of claim 9, wherein the compound is provided in an amount sufficient to provide a similar or decreased AUC when compared to unconjugated d-amphetamine when orally administered at equimolar doses.

26. The composition of claim 9, wherein the compound is provided in an amount sufficient to provide a similar or decreased C_max as compared to unconjugated d-amphetamine when administered orally at equimolar doses.

27. The composition of claim 9, wherein the compound is provided in an amount sufficient to provide a decreased C_max and a similar or decreased AUC as compared to unconjugated d-amphetamine when administered orally at equimolar doses.

28. The composition of claim 9, wherein intranasal or intravenous administration of the compound provides a decreased AUC and/or C_max when compared to an equivalent molar amount of unconjugated d-amphetamine.

29. The composition of claim 9, wherein the compound provides reduced abuse potential as compared to unconjugated d-amphetamine.

30. A method of treating a patient having a disorder or condition requiring stimulation of the central nervous system, of treating a patient having a disease, disorder or condition mediated by controlling, preventing, limiting, or inhibiting neurotransmitter uptake, or treating a patient having a disease, disorder or condition mediated by increasing neurotransmitter concentrations in the synapse, the method comprising the step of administering to the patient in need thereof a pharmaceutically effective amount of the composition of claim 9.

31. The method of claim 30, wherein the composition has reduced abuse potential when administered compared to unconjugated d-amphetamine.

32. The method of claim 30, wherein the disease or condition is attention-deficit hyperactivity disorder, attention deficit disorder, autistic spectrum disorder, autism, Asperger'"'"'s disorder, pervasive developmental disorder, sleep disorder, obesity, depression, bipolar disorder, eating disorder, chronic fatigue syndrome, insomnia, schizophrenia, major depressive disorder, narcolepsy, postural orthostatic tachycardia syndrome, Tourette syndrome, nervous tics, substance use disorder, lethargy, depression, neural insult or obesity.

33. A kit comprising individual doses of a therapeutically effective amount of a composition comprising the compound of claim 1, a pharmaceutical salt thereof, or a combination thereof.

6. A compound having a structure selected from the group consisting of:

8. A compound having a structure selected from the group consisting of:

34. A compound having the structure of Formula I:

35. The compound of claim 34, 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, 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, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, 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, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, troethamine, and a mixture thereof.

36. The compound of claim 34, wherein X is located at the C-2 or C-4 position of the pyridine ring.

37. The compound of claim 34, where X is located at two or more of the C-2, C-3, C-4, C-5, or C-6 positions of the pyridine ring.

38. The compound of 34, wherein the compound has the structure of

39. The compound of claim 38, wherein the compound has the structure of

40. The compound of claim 39, wherein the compound has a structure of