Use of (2R, 6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain

Patent metadata

Field	Value
Publication number	US-9650352-B2
Application number	US-201214351441-A
Country	US
Kind code	B2
Filing date	Oct 15, 2012
Priority date	Oct 14, 2011
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The disclosure provides pharmaceutical preparations containing (2R,6R)-hydroxynorketamine, or (R)- or (S)-dehydronorketamine, or other stereoisomeric dehydro or hydroxylated ketamine metabolite. (2R,6R)-hydroxynorketamine The disclosure also provides novel ketamine metabolite prodrugs. The disclosure provides methods of treating, bipolar depression, major depressive disorder, neuropathic and chronic pain, including complex regional pain disorder (CRPS) by administering a purified ketamine metabolite or a ketamine metabolite prodrug directly to patients in need of such treatment.

First claim

What is claimed is:

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
R 1 is hydroxyl or -A 1 B 1 where A 1 is —O—, —O(C═O)—, —(C═O)O—, —O(C═O)O—, —O(C═O)NR 6 —, —OS(O) 2 —, —OS(O) 3 , or —OP(O) 3 —, and B 1 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (carbocycle)C 0 -C 4 alkyl or (heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; with the proviso that -A 1 B 1 is not (4-methylphenyl)-S(O) 2 O—;
wherein the six-membered ring to which R 1 is bound is fully saturated when R 1 is hydroxyl or -A 1 B 1 ;
R 2 is hydrogen or -A 2 B 2 where A 2 is a bond, —O(C═O)—, —(C═O)O—, —S(O) 2 —, —(S═O)NR 6 —, or —(C═O)NR 6 —, B 2 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 6 alkanoyl, (carbocycle)C 0 -C 4 alkyl, (heterocycle)C 0 -C 4 alkyl, or an amino acid or dipeptide covalently bound to A 2 by its C-terminus, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; with the proviso that B 2 is not methyl when A 2 is a bond or —(C═O)O—;
R 1 is not hydroxyl when R 2 is hydrogen;
R 3 is hydrogen;
R 4 and R 5 are 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and
R 6 is hydrogen or C 1 -C 6 alkyl.

2. A compound or salt of claim 1 , of the formula

3. A compound of the formula

or a pharmaceutically acceptable salt thereof,
where A 1 is —O—, —O(C═O)—, or —O(C═O)O—and B 1 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (carbocycle)C 0 -C 4 alkyl or (heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
R 2 is hydrogen or -A 2 B 2 where A 2 is a bond, —O(C═O)—, —(C═O)O—, —S(O) 2 —, —(S═O)NR 6 —, or —(C═O)NR 6 —, B 2 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 6 alkanoyl, (carbocycle)C 0 -C 4 alkyl, (heterocycle)C 0 -C 4 alkyl, or an amino acid or dipeptide covalently bound to A 2 by its C-terminus, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; with the proviso that B 2 is not methyl when A 2 is a bond or —(C═O)O—;
R 3 is hydrogen or C 1 -C 6 alkyl;
R 4 and R 5 are 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and
R 6 is hydrogen or C 1 -C 6 alkyl.

4. A compound or salt of claim 3 , wherein
R 3 is hydrogen;
R 4 and R 5 are each 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, C 1 -C 2 alkyl, and C 1 -C 2 alkyl; and
R 6 is hydrogen or methyl.

5. A compound or salt of claim 4 , wherein
R 2 is -A 2 B 2 where A 2 is a bond, —(C═O)O—, —S(O) 2 —, —(S═O)NR 6 —, or —(C═O)NR 6 —, B 2 is C 1 -C 6 alkyl, C 2 -C 4 alkanoyl, (phenyl)C 0 -C 2 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, (5- or 6-membered heteroaryl)C 0 -C 2 alkyl, or an amino acid covalently bound to A 2 by its C-terminus, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

6. A compound or salt of claim 4 , where
A 2 is a bond or —(C═O)O— and B 2 is C 2 -C 6 alkyl, (phenyl)C 0 -C 2 alkyl, or (C 3 -C 7 alkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- and di-(C 1 -C 4 alkyl)amino.

7. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is -A 1 B 1 where A 1 is —O—, —O(C═O)—, —(C═O)O—, —O(C═O)O—, —O(C═O)NR 6 —, —OS(O) 2 —, —OS(O) 3 , or —OP(O) 3 —, and B 1 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (carbocycle)C 0 -C 4 alkyl or (heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; with the proviso that -A 1 B 1 is not (4-methylphenyl)-S(O) 2 O—;
R 2 is hydrogen;
R 3 is hydrogen;
R 4 and R 5 are each 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, C 1 -C 2 alkyl, and C 1 -C 2 alkyl; and
R 6 is hydrogen or methyl.

8. A compound or salt of claim 7 , where
R 1 is -A 1 B 1 where A 1 is —O(C═O)— or —O(C═O)O—, and B 1 is C 1 -C 6 alkyl, (phenyl)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, or (5- or 6-membered heteroaryl)C 0 -C 2 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylester, mono- and di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

9. A method of treating bipolar depression, major depressive disorder, schizophrenia, Alzheimer's dementia, amyotrophic lateral sclerosis, complex regional pain syndrome (CRPS), chronic pain, or neuropathic pain comprising administering an effective amount of a compound or salt of claim 1 , to a patient in need of such treatment.

10. The method of claim 9 , wherein an effective amount is an amount effective to decrease painful symptoms; wherein a decrease in painful symptom is the achievement of a 50% or greater reduction of painful symptoms on a pain rating scale.

11. A pharmaceutical composition comprising a compound or salt of claim 1 , together with a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11 , wherein the composition is a solution and contains from about 0.05 mg/ml to about 0.5 mg/ml.

13. A compound or sa

Assignees

• Cooper Health System
• Stanford Res Inst Int
• Us Health

Inventors

• Wainer Irving W
• Moaddel Ruin
• Bernier Michel
• Zarate Carlos A
• Torjman Marc C
• Goldberg Michael E
• Tanga Mary J

Classifications

• A61P25/24

  Antidepressants · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title