METHODS OF TREATMENT WITH DEUTERATED ANALOGS OF D-SERINE
This disclosure relates to deuterated D-serine, pharmaceutically acceptable salts thereof, analogs and prodrugs thereof, pharmaceutical compositions thereof, and methods of use.
1 . A method of treating pain, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I:
wherein
R 1 is —OH, —OD, —O—C 1-4 alkyl, or an amino acid residue;
R 2 is H, D, —C 1-4 alkyl, —C(O)—C 1-6 alkyl, or —C(O)—C 1-6 hydroxyalkyl;
R 3 is H, D, or an amino acid residue;
R 4 is H or D; and
each of Y 1 , Y 2a and Y 2b is independently H or D, provided that at least one of Y 1 , Y 2a and Y 2b is D; wherein each position designated specifically as deuterium has at least 80% incorporation of deuterium;
or a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 , wherein the pain is musculoskeletal pain, neuropathic pain, migraine pain, chronic pain, acute pain, cancer-related pain, chemo-induced pain, nociceptive pain, intractable pain, inflammatory pain, arthritis pain, complex regional pain syndrome, sympathetically mediated pain, or pain associated with gastrointestinal dysfunction.
3 . The method of claim 2 , wherein the pain is musculoskeletal pain selected from low back pain (i.e. lumbosacral pain); primary dysmenorrhea pain; arthritic pain, such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, and axial spondyloarthritis including ankylosing spondylitis; pain associated with vertebral crush fractures; fibrous dysplasia; osteogenesis imperfecta; Paget's disease; SAPHO syndrome; and transient osteoporosis.
4 . The method of claim 2 , wherein the pain is neuropathic pain selected from diabetic neuropathic pain, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, pain caused by lumbar nerve root compression, pain caused by spinal cord injury, central pain, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radio- or chemo-therapy associated neuropathy.
5 . The method of claim 2 , wherein the pain is sympathetically mediated pain selected from allodynia, hyperpathia, hyperalgesia, dysesthesia, paresthesia, deafferentation pain, and anesthesia dolorosa pain.
6 . The method of claim 2 , wherein the pain associated with gastrointestinal dysfunction is irritable bowel syndrome or mouth pain.
7 . The method of claim 2 , wherein the pain is pain associated with migraine.
8 . The method of any one of claims 1 - 7 , wherein the method further comprises administering a second agent useful for the treatment of pain.
9 . The method of claim 8 , wherein the second agent is morphine, codeine, oxycodone, hydrocodone, meperidine, fentanyl, methadone, hydromorphone, oxymorphone, tramadol, naproxen, ibuprofen, acetaminophen, aspirin or celecoxib.
10 . A method of increasing a subject's sensitivity to opioid treatment in a subject in need of pain relief, the method comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutical composition comprising a compound of Formula I:
wherein
R 1 is —OH, —OD, —O—C 1-4 alkyl, or an amino acid residue;
R 2 is H, D, —C 1-4 alkyl, —C(O)—C 1-6 alkyl, or —C(O)—C 1-6 hydroxyalkyl;
R 3 is H, D, or an amino acid residue;
R 4 is H or D; and
each of Y 1 , Y 2a and Y 2b is independently H or D, provided that at least one of Y 1 , Y 2a and Y 2b is D; wherein each position designated specifically as deuterium has at least 80% incorporation of deuterium;
or a pharmaceutically acceptable salt thereof; and
an effective amount of an opioid pain medication.
11 . The method of claim 10 , wherein the method results in one or more of the following effects: avoids or reduces the tolerance to opioid treatment alone; increases the effectiveness of opioid treatment alone; reduces breathing depression due to opioid treatment alone; and reduces opioid-induced hyperalgesia resulting from opioid treatment alone.
12 . The method of claim 10 or 11 , wherein the opioid pain medication is morphine, codeine, oxycodone, hydrocodone, meperidine, fentanyl, methadone, hydromorphone, oxymorphone or tramadol.
13 . The method of any one of claims 1 to 12 , wherein in the compound of Formula I, R 1 or R 3 is a D-D-serine residue.
14 . The method of any one of claims 1 to 12 , wherein the compound is a compound of Formula II:
wherein each of Y 1 , Y 2a and Y 2b is independently H or D, provided that at least one of Y 1 , Y 2 a and Y 2b is D;
or a pharmaceutically acceptable salt thereof.
15 . The method of any one of claims 1 to 14 , wherein in the compound of Formula I or Formula II, Y 1 is D.
16 . The method of any one of claims 1 - 15 , wherein Y 2a and Y 2b are each H.
17 . The method of any one of claims 1 - 15 , wherein Y 2a and Y 2b are each D.
18 . The method of any one of claim 15 , wherein the compound is selected from Compound 100 and Compound 103:
or a pharmaceutically acceptable salt thereof.
19 . The method of claim 18 , wherein the compound is Compound 100:
or a pharmaceutically acceptable salt thereof.
20 . The method of any one of claims 1 - 19 , wherein in the compound of Formula I or Formula II, each position designated specifically as deuterium has at least 90% incorporation of deuterium.
21 . The method of claim 20 , wherein in the compound of Formula I or Formula II, each position designated specifically as deuterium has at least 95% incorporation of deuterium.
22 . The method of claim 21 , wherein in the compound of Formula I or Formula II, each position designated specifically as deuterium has at least 97% incorporation of deuterium.
23 . The method of any one of claims 1 - 22 , wherein in the compound of Formula I or Formula II, any atom not designated as deuterium is present at its natural isotopic abundance.
24 . The method of any one of claims 1 - 23 , wherein the compound of Formula I or Formula II is at least about 90% stereomerically pure.
25 . The method of any one of claims 1 - 24 , wherein the pharmaceutical composition is suitable for oral administration.
26 . The method of any one of claims 1 - 25 , wherein the method comprises administering 0.25 g to 12 g per day of the compound of Formula I or Formula II.
27 . The method of claim 26 , wherein the method comprises administering 1 g to 6 g per day of the compound of Formula I or Formula II.
28 . The method of claim 26 or 27 , wherein the method further comprises administering intravenously 1 mg to 45 mg of morphine no more frequently than every 4 to 6 hours.
29 . The method of claim 27 or 28 , wherein the method further comprises administering orally 2.5 mg to 100 mg of morphine no more frequently than every 4 to 6 hours.