US2023183238A1PendingUtilityA1
Ring deuterated gaboxadol and its use for the treatment of psychiatric disorders
Est. expiryMay 20, 2040(~13.8 yrs left)· nominal 20-yr term from priority
A61P 25/24C07D 498/04A61K 31/437C07D 471/04A61K 45/06A61P 25/18C07B 59/002C07B 2200/05
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Claims
Abstract
Ring deuterated gaboxadol is provided. The ring deuterated gaboxadol is useful in the treatment of psychiatric disorders and is more effective than non-deuterated gaboxadol in such treatments. Deuterated gaboxadol is useful in combinations with other compounds to provide additive and synergistic effects for patient therapies. In a specific embodiment, the deuterated gaboxadol is d6-gaboxadol.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A ring carbon deuterated gaboxadol compound of Formula I
or a pharmaceutically acceptable salt thereof,
wherein R4, R4′, R5, R5′, R7 and R7′ are independently H or D, and
wherein at least one of R4, R4′, R5, R5′, R7 and R7′ is D.
2 . The compound of claim 1 wherein the percentage incorporation of deuterium is at least 1%.
3 . The compound of claim 1 wherein if none of R4, R4′, R5, and R5′ are H, then R7 and R7′ are not both D.
4 . The compound of claim 1 wherein if all of R4, R4′, R5, and R5′are D, then at least one of R7 and R7′ is D.
5 . The compound of claim 1 wherein all of R4, R4′, R5, R5′, R7 and R7′ are D.
6 . The compound of claim 2 wherein all of R4, R4′, R5, R5′, R7 and R7′ are D.
7 . A pharmaceutical composition comprising (a) the compound of claim 1 ; (b) at least one other compound selected from the group consisting of lithium, ketamine, AXS-05 (fixed combination of dextromethorphan and bupropion), SAGE-217, allopregnanolone, ganaxolone, alfadolone, alfaxolone, hydroxydione, minaxolone, pregnanolone, renanolone, AV-101 (L-4-Chlorokynurenine), rapastinel (GLYX-13), MGS0039, LY-341,495, MK-801 (dizocilpine), Ro 25-6981, rislenemdaz (CERC-301, MK-0657), apimostinel (NRX-1074), lanicemine (AZD6765), traxoprodil (CP-101606), (2R,6R)-hydroxynorketamine, decoglurant (INN) (RG1578, RO4995819), memantine, tiagabine, clozapine, and [2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504); and (c) a pharmaceutically acceptable carrier.
8 . A composition comprising one or more ring carbon deuterated gaboxadol compounds of Formula I
or a pharmaceutically acceptable salt thereof,
wherein R4, R4′, R5, R5′, R7 and R7′ are independently H or D,
and wherein at least 1% of the compounds have D at one or more of R4, R4′, R5, R5′, R7
and R7′, optionally wherein at least 1% of the compounds have D at all of R4, R4′, R5,
R5′, R7 and R7′.
9 . The composition of claim 8 wherein at least 10% of the compounds have D at one or more of R4, R4′, R5, R5′, R7 and R7′.
10 . The composition of claim 8 wherein at least 10% of the compounds have D at three or more of R4, R4′, R5, R5′, R7 and R7′.
11 . The composition of claim 8 wherein at least 10% of the compounds have D at five or more of R4, R4′, R5, R5′, R7 and R7′.
12 . The composition of claim 8 wherein in at least 70% of the compounds have D at five or more of R4, R4′, R5, R5′, R7 and R7′.
13 . The composition of claim 8 wherein at least 90% of the compounds have D at five or more of R4, R4′, R5, R5′, R7 and R7′.
14 . The composition of claim 8 wherein at least 75% of the compounds have D at all of R4, R4′, R5, R5′, R7 and R7′.
15 . The composition of claim 8 comprising at least two different compounds of Formula I.
16 . A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier.
17 . The pharmaceutical composition of claim 16 which is an oral dosage form.
18 . The pharmaceutical composition of claim 17 which is a tablet.
19 . The pharmaceutical composition of claim 17 wherein the oral dosage form is an orally disintegrating form.
20 . The pharmaceutical composition of claim 16 comprising about 1 mg to about 300 mg of the compound.
21 . The pharmaceutical composition of claim 16 comprising about 50 mg to about 100 mg of the compound.
22 . The pharmaceutical composition of claim 16 comprising about 50 mg, about 75 mg, or about 100 mg of the compound.
23 . The pharmaceutical composition of claim 16 comprising about 25 mg to about 50 mg of the compound.
24 . The pharmaceutical composition of claim 16 comprising about 10 mg to about 30 mg of the compound.
25 . A pharmaceutical composition comprising (a) the compound of claim 6 ; (b) at least one other compound selected from the group consisting of lithium, ketamine, AXS-05 (fixed combination of dextromethorphan and bupropion), SAGE-217, allopregnanolone, ganaxolone, alfadolone, alfaxolone, hydroxydione, minaxolone, pregnanolone, renanolone, AV-101 (L-4-Chlorokynurenine), rapastinel (GLYX-13), MGS0039, LY-341,495, MK-801 (dizocilpine), Ro 25-6981, rislenemdaz (CERC-301, MK-0657), apimostinel (NRX-1074), lanicemine (AZD6765), traxoprodil (CP-101606), (2R,6R)-hydroxynorketamine, decoglurant (INN) (RG1578, RO4995819), memantine, tiagabine, clozapine, and [2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504); and (c) a pharmaceutically acceptable carrier.
26 . The pharmaceutical composition of claim 21 wherein the at least one other compound is lithium.
27 . A pharmaceutical composition comprising one or more compounds of Formula I
or a pharmaceutically acceptable salt thereof,
wherein R4, R4′, R5, R5′, R7 and R7′are independently H or D,
and wherein all of R4, R4′, R5, R5′, R7 and R7′ are D in at least 75% of the compounds.
28 . The pharmaceutical composition of claim 27 wherein at least 95% of the total of all the positions R4, R4′, R5, R5′, R7 and R7′ are D.
29 . The pharmaceutical composition of claim 27 wherein not more than about 20% of the compounds are d5-gaboxadol.
30 . A pharmaceutical composition comprising one or more compounds of Formula I
or a pharmaceutically acceptable salt thereof,
wherein R4, R4′, R5, R5′, R7 and R7′are independently H or D, and wherein 3 or more of the positions R4, R4′, R5, R5′, R7 and R7′ are D in no less than about 10% of the compounds.
31 . The pharmaceutical composition of claim 30 wherein 3 or more of the positions R4, R4′, R5, R5′, R7 and R7′ are D in no less than about 50% of the compounds.
32 . The pharmaceutical composition of claim 30 wherein 3 or more of the positions R4, R4′, R5, R5′, R7 and R7′ are D in no less than about 70% of the compounds.
33 . The pharmaceutical composition of claim 30 wherein 3 or more of the positions R4, R4′, R5, R5′, R7 and R7′ are D in no less than about 95% of the compounds.
34 . A method of making d6-gaboxadol, said method comprising:
(a) treating 3-hydroxypyridine-4-carboxylic acid with deuterium oxide under catalytic hydrogenation conditions to provide 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid; (b) treating 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid from step (a) above with a methylating agent, to provide methyl 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylate; (c) treating methyl 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylate from step (b) above with hydroxylamine hydrochloride, to provide 2,3,6-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid; (d) treating 2,3,6-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid from step (c) above with an activating agent, to provide 4,5,7-trideuterioisoxazolo[5,4-c]pyridin-3-one; (e) treating 4,5,7-trideuterioisoxazolo[5,4-c]pyridin-3-one from step (d) above with a brominating agent to provide 6-benzyl-4,5,7-trideuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide; (f) treating 6-benzyl-4,5,7-trideuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide from step (e) above with a reducing agent, to provide 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridin-3-ol; and (g) deprotecting 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridin-3-ol from step (f) above to remove the benzyl group to provide d6-gaboxadol.
35 . The product of the method of claim 34 .
36 . The method of claim 34 comprising:
(a) treating 3-hydroxypyridine-4-carboxylic acid with deuterium oxide in the presence of Pt/C and/or Pd/C and hydrogen gas at a temperature greater than 100° C., to provide 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid;
(b) treating 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid from step (a) above with methanol and sulfuric acid at reflux temperature, to provide methyl 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylate;
(c) treating methyl 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylate from step (b) above with hydroxylamine chloride and aqueous sodium hydroxide solution, to provide 2,3,6-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid;
(d) treating 2,3,6-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid from step (c) above with thionyl chloride, to provide 4,5,7-trideuterioisoxazolo[5,4-c]pyridin-3-one;
(e) treating 4,5,7-trideuterioisoxazolo[5,4-c]pyridin-3-one from step (d) above with benzyl bromide, to provide 6-benzyl-4,5,7-trideuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide;
(f) treating 6-benzyl-4,5,7-trideuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide from step (e) above with deuterated sodiumborohydride (NaBD4) in a mixture of deuterated ethanol and/or deuterium oxide, to provide 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridin-3-ol; and
(g) treating 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridin-3-ol from step (f) above with (i) methyl chloroformate in the presence of an inorganic base, followed by treatment with hydrobromic acid, or (ii) deuterated hydrobromic acid, to provide d6-gaboxadol.
37 . The product of the method of claim 36 .
38 . The compound 4,5,7-trideuterioisoxazolo[5,4-c]pyridin-3-one.
39 . A method of treating a psychiatric disorder comprising administering to a human patient in need thereof a therapeutically effective amount of (a) a compound of Formula I
or a pharmaceutically acceptable salt thereof,
wherein R4, R4′, R5, R5′, R7 and R7′ are independently H or D, and
wherein at least one of R4, R4′, R5, R5′, R7 and R7′ is D;
(b) a composition comprising a compound of Formula I wherein R4, R4′, R5, R5′, R7 and R7′ are independently H or D,
and wherein at least 1% of the compounds have D at one or more of R4, R4′, R5, R5′, R7
and R7′, optionally wherein at least 1% of the compounds have D at all of R4, R4′, R5, R5′, R7 and R7′; or
a pharmaceutical composition comprising (a) or (b) and a pharmaceutically acceptable carrier.
40 . The method of claim 39 wherein the psychiatric disorder is depression.
41 . The method of claim 39 wherein the psychiatric disorder is major depression.
42 . The method of claim 39 wherein the psychiatric disorder is suicidality.
43 . The method of claim 39 wherein the psychiatric disorder is treatment resistant depression.
44 . The method of claim 39 wherein the psychiatric disorder is bipolar disorder.
45 . The method of claim 39 wherein the administering is once daily.
46 . The method of claim 45 wherein the administering is of a daily dose of about 50-100 mg of the compound.
47 . The method of claim 46 wherein the daily dose is 50, 75 or 100 mg of the compound.
48 . The method of claim 45 wherein the psychiatric disorder is depression.
49 . The method of claim 41 which further comprises administering lithium to the patient to treat the psychiatric disorder.
50 . The method of claim 49 wherein the compound and the lithium are in a single oral dosage form.
51 . The method of claim 49 wherein the compound and the lithium are in separate oral dosage forms.
52 . The method of claim 39 wherein the administering is daily for a first time period, followed by a washout period of at least one day during which the compound is not administered, followed by daily administering for a second time period.
53 . The method of claim 39 wherein the administering is two or three times per week.
54 . The method of 49 wherein the daily administering is of a daily dose of about 50-100 mg of the compound.
55 . The method of claim 50 wherein the daily dose is 50, 75 or 100 mg of the compound.
56 . The method of claim 52 wherein the compound, composition or pharmaceutical compositon, the compound of Formula I is the sole active agent administered to treat said psychiatric disorder.
57 . The method of claim 52 wherein the psychiatric disorder is bipolar mania.
58 . The method of claim 39 wherein the compound of (a) or (b) is d6-gaboxadol.
59 . A method for treating a subject diagnosed with a psychiatric disorder comprising administering to the subject an effective amount of ring carbon deuterated gaboxadol or a pharmaceutically acceptable salt thereof.
60 . The method of claim 59 , wherein the psychiatric disorder is bipolar disorder.
61 . The method of claim 59 , wherein the psychiatric disorder is depression.
62 . The method of claim 59 , wherein the psychiatric disorder is major depression.
63 . The method of claim 59 , wherein the psychiatric disorder is treatment-resistant depression and suicidality.
64 . A method for treating a subject diagnosed with a psychiatric disorder comprising administering to the subject an effective amount of a ring carbon deuterated gaboxadol compound of Formula I
or a pharmaceutically acceptable salt thereof,
wherein R4, R4′, R5, R5′, R7 and R7′ are independently H or D, and
wherein at least one of R4, R4′, R5, R5′, R7 and R7′ is D.
65 . A method for treating a subject diagnosed with a psychiatric disorder comprising administering to the subject an effective amount of a composition comprising one or more ring carbon deuterated gaboxadol compounds of Formula I
or a pharmaceutically acceptable salt thereof,
wherein R4, R4′, R5, R5′, R7 and R7′ are independently H or D,
and wherein at least 1% of the compounds have D at one or more of R4, R4′, R5, R5′, R7 and R7′.
66 . The method of claim 65 wherein at least 10% of the compounds have D at one or more of R4, R4′, R5, R5′, R7 and R7′.
67 . The method of claim 65 wherein at least 10% of the compounds have D at three or more of R4, R4′, R5, R5′, R7 and R7′.
68 . The method of claim 65 wherein at least 10% of the compounds have D at five or more of R4, R4′, R5, R5′, R7 and R7′.
69 . The method of claim 65 wherein in at least 70% of the compounds have D at five or more of R4, R4′, R5, R5′, R7 and R7′.
70 . The method of claim 65 wherein at least 90% of the compounds have D at five or more of R4, R4′, R5, R5′, R7 and R7′.
71 . The method of claim 65 wherein at least 75% of the compounds have D at all of R4, R4′, R5, R5′, R7 and R7′.
72 . The method of claim 65 wherein the composition comprises at least two different compounds of Formula I.
73 . The method of claim 65 wherein the ring carbon deuterated gaboxadol is provided in a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
74 . The method of claim 73 , wherein the psychiatric disorder is bipolar disorder.
75 . The method of claim 73 , wherein the psychiatric disorder is depression.
76 . The method of claim 73 , wherein the psychiatric disorder is treatment-resistant depression.
77 . The method of claim 73 , wherein the psychiatric disorder is suicidality.
78 . The method of claim 73 wherein the pharmaceutical composition is an oral dosage form.
79 . The method of claim 78 wherein the pharmaceutical composition comprises from about 1 mg to about 300 mg of a compound of Formula I.
80 . The method of claim 7 wherein the pharmaceutical composition comprises from about 50 mg to about 100 mg of a compound of Formula I.
81 . The method of claim 78 wherein the pharmaceutical composition comprises from about 25 mg to about 50 mg of a compound of Formula I.
82 . The method of claim 78 wherein the pharmaceutical composition comprises from about 10 mg to about 30 mg of a compound of Formula I.
83 . The method of claim 73 wherein the effective amount comprises an amount sufficient to rapidly alleviate risk of suicide, bipolar disorder and/or depressive symptoms.
84 . The method of claim 83 further comprising administering a second pharmaceutical composition comprising ring carbon deuterated gaboxadol within less than 6 hours immediately following the prior administering step.
85 . The method of claim 84 , wherein the second pharmaceutical composition comprising ring carbon deuterated gaboxadol is administered after a step of determining that a neurological test of the patient demonstrates an insufficient response within about 180 minutes immediately after the prior administering step.
86 . The method of claim 85 , wherein the insufficient response is an electroencephalogram (EEG) power density increase of less than 30% over baseline within about 180 minutes after the prior administering step.
87 . The method of claim 86 , wherein the electroencephalogram (EEG) power density is calculated in a 0.25-8.0 Hz range.
88 . The method of claim 86 , wherein the electroencephalogram (EEG) power density is calculated in a 4.75-8.0 Hz range.
89 . The method of claim 85 , wherein the insufficient response is a whole head magnetoencephalography (MEG) planar gradiometer increase of less +3 in a combined delta, theta and alpha activity within about 180 minutes after the prior administering step.
90 . The method of claim 65 wherein the effective amount is administered daily.
91 . The method of claim 65 wherein the effective amount is administered intermittently, separated by washout periods of at least one day during which no deuterated gaboxadal is administered.
92 . A method for treating a subject diagnosed with a psychiatric disorder comprising administering to the subject a combination of a first pharmaceutical composition comprising an effective amount of ring carbon deuterated gaboxadol or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising an agent selected from the group consisting of lithium, ketamine, SAGE-217, allopregnanolone ganaxolone, alfadolone, alfaxolone, hydroxydione, minaxolone, pregnanolone, renanolone and other pregnane neurosteroids, AV-101 (L-4-Chlorokynurenine), rapastinel (GLYX-13), MGS0039, LY-341,495, MK-801 (dizocilpine), Ro 25-6981, rislenemdaz (CERC-301, MK-0657), apimostinel (NRX-1074), lanicemine (AZD6765), traxoprodil (CP-101606), (2R,6R)-hydroxynorketamine, decoglurant (INN) (RG1578, RO4995819), memantine, tiagabine, gaboxadol, clozapine, [2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504), AXS-05 (fixed combination of dextromethorphan and bupropion) and pharmaceutically acceptable salts thereof.
93 . The method of claim 92 , wherein the active agent in the second pharmaceutical composition is ketamine.
94 . The method of claim 93 , wherein the effective amount of ring carbon deuterated gaboxadol, or a pharmaceutically acceptable salt thereof, is about 20 mg or less.
95 . The method of claim 93 wherein the effective amount of ketamine is about 10 mg or less.
96 . A method for treating a subject diagnosed with a psychiatric disorder comprising administering at least once per day a combination of ring carbon deuterated gaboxadol and lithium, wherein the lithium is administered
(a) in an amount of about 50 mg to about 1800 mg lithium carbonate; or (b) in an amount from about 0.8 mg/kg to about 30 mg/kg lithium carbonate; or (c) in an amount sufficient to achieve a lithium serum concentration of about 0.2 to 1.2 mmol/L.
97 . The method of claim 96 wherein ring carbon deuterated gaboxadol is administered in an amount from about 10 mg to about 100 mg, and the lithium is administered (a) in an amount from about 50 mg to about 900 mg lithium carbonate, or (b) in an amount sufficient to achieve a lithium serum concentration of 0.2 to 1.0 mmol/L.
98 . The method of claim 96 wherein ring carbon deuterated gaboxadol is administered in an amount from about 15 mg to about 50 mg, and the daily dose of lithium is administered (a) in an amount from about 50 mg to about 600 mg lithium carbonate, or (b) in an amount sufficient to achieve a lithium serum concentration of about 0.2 to 0.8 mmol/L.
99 . The method of claim 96 , wherein the psychiatric disorder is bipolar disorder.
100 . The method of claim 96 , wherein the psychiatric disorder is depression.
101 . The method of claim 96 , wherein the psychiatric disorder is treatment-resistant depression.
102 . The method of claim 96 , wherein the psychiatric disorder is suicidality.
103 . The use of a combination of ring carbon deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of either or both compounds thereof, for treating a psychiatric disorder.
104 . The use of a combination of ring carbon deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of either or both compounds thereof, in the manufacture of a medicament for treating a psychiatric disorder.
105 . A pharmaceutical composition comprising a ring carbon deuterated gaboxadol of Formula I
or a pharmaceutically acceptable salt thereof,
wherein R4, R4′, R5, R5′, R7 and R7′ are independently H or D, and
wherein at least one of R4, R4′, R5, R5′, R7 and R7′ is D;
and (b) lithium or a pharmaceutically acceptable salt of lithium.
106 . The pharmaceutical composition of claim 105 wherein ring carbon deuterated gaboxadol is present in the pharmaceutical composition in an amount that is about two-thirds or less of the dose of non-deuterated gaboxadol required to achieve an equivalent effect.
107 . The pharmaceutical composition of claim 105 , wherein the lithium is present in the pharmaceutical composition an amount that is a sub-standard daily dose of lithium.
108 . The pharmaceutical composition of claim 107 , wherein the sub-standard dose of lithium, when administered daily to a subject in need thereof, is below the medically recommended dose for treating psychiatric disorders comprising bipolar disorder, depression, treatment-resistant depression, suicidality.
109 . The pharmaceutical composition of claim 107 wherein the dose of ring carbon deuterated gaboxadol is about one third or less of the amount of non-deuterated gaboxadol required to achieve an equivalent effect.
110 . The pharmaceutical composition of claim 105 , wherein the pharmaceutical composition is in a form of a single dosage unit having separate compartments for the lithium and ring carbon deuterated gaboxadol or a pharmaceutically acceptable salt of either or both compounds thereof.
111 . The pharmaceutical composition of claim 105 wherein the ring carbon deuterated gaboxadol is d6-gaboxadol.
112 . A kit comprising the pharmaceutical composition of claim 105 .Cited by (0)
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