Morphinan compounds

Patent metadata

Field	Value
Publication number	US-2019038618-A1
Application number	US-201816036164-A
Country	US
Kind code	A1
Filing date	Jul 16, 2018
Priority date	Sep 19, 2008
Publication date	Feb 7, 2019
Grant date	—

Abstract

This invention relates to novel morphinan compounds and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σ1 receptor agonist that also has NMDA antagonist activity.

First claim

1 - 27 . (canceled)

28 . A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

29 . The compound of claim 28 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.

30 . The compound of claim 28 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.

31 . A pharmaceutical composition comprising the compound of claim 28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

32 . The pharmaceutical composition of claim 31 , further comprising a second therapeutic agent selected from quinidine, quinidine sulfate, oxycodone, and gabapentin.

33 . A method of treating a subject suffering from a disease or condition selected from emotional lability; pseudobulbar affect; autism; neurological disorders and neurodegenerative diseases; brain injuries; disturbances of consciousness disorders; cardiovascular diseases; glaucoma; tardive dyskinesia; cancer; rheumatoid arthritis; diabetic neuropathy; retinopathic diseases; diseases or disorders caused by homocysteine-induced apoptosis; diseases or disorders caused by elevated levels of homocysteine; chronic pain; intractable pain; neuropathic pain, sympathetically mediated pain; pain associated with gastrointestinal dysfunction; mouth pain; back pain; central pain syndrome; complex regional pain syndrome; epileptic seizures; epileptic hemiplegia; acquired epileptiform aphasia (Landau-Kleffner syndrome); severe myoclonic epilepsy of infancy (SMEI); early infantile epileptic encephalopathy; post-stroke seizure; febrile seizures; post-traumatic seizures; tinnitus; sexual dysfunction; intractable coughing; dermatitis; addiction disorders; Rett syndrome (RTT); voice disorders due to uncontrolled laryngeal muscle spasms; methotrexate neurotoxicity; and fatigue caused by cancer; comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

34 . The method of claim 33 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.

35 . The method of claim 33 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.

36 . The method of claim 33 , wherein the subject is suffering from epileptic seizures.

37 . The method of claim 36 , wherein the epileptic seizures are generalized epileptic seizures or partial epileptic seizures.

38 . The method of claim 33 , wherein the subject is suffering from severe myoclonic epilepsy of infancy (SMEI), early infantile epileptic encephalopathy, post-stroke seizures, febrile seizures, or post-traumatic seizures.

39 . The method of claim 33 , wherein the subject is suffering from autism, amyotrophic lateral sclerosis (ALS), or Rett Syndrome (RTT).

40 . The method of claim 33 , wherein the subject is suffering from neuropathic pain or chronic pain.

41 . The method of claim 33 , wherein the amount of the compound administered is in the range from 0.4 mg to 400 mg.

42 . The method of claim 33 , wherein the amount of the compound administered is in the range from 4 mg to 350 mg.

43 . The method of claim 33 , wherein the amount of the compound administered is in the range from 10 mg to 90 mg.

44 . The method of claim 33 , wherein the amount of the compound administered is in the range from 30 mg to 45 mg.

45 . The method of claim 33 , further comprising the step of co-administering to the subject a second therapeutic agent selected from quinidine, quinidine sulfate, oxycodone, and gabapentin.

46 . A method of agonizing sigma-1 receptor activity in a subject comprising the step of administering to the subject in need thereof a therapeutically effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

47 . The method of claim 46 , wherein the subject is suffering from a disease or condition selected from emotional lability; pseudobulbar affect; neurological disorders and neurodegenerative diseases; brain injuries; disturbances of consciousness disorders; cardiovascular diseases; glaucoma; tardive dyskinesia; cancer; rheumatoid arthritis; diabetic neuropathy; retinopathic diseases; diseases or disorders caused by homocysteine-induced apoptosis; diseases or disorders caused by elevated levels of homocysteine; chronic pain; intractable pain; neuropathic pain, sympathetically mediated pain; pain associated with gastrointestinal dysfunction; mouth pain; back pain; central pain syndrome; complex regional pain syndrome; epileptic seizures; epileptic hemiplegia; acquired epileptiform aphasia (Landau-Kleffner syndrome); severe myoclonic epilepsy of infancy (SMEI); early infantile epileptic encephalopathy; post-stroke seizure; febrile seizures; post-traumatic seizures; tinnitus; sexual dysfunction; intractable coughing; dermatitis; addiction disorders; Rett syndrome (RTT); voice disorders due to uncontrolled laryngeal muscle spasms; methotrexate neurotoxicity; and fatigue caused by cancer.

Assignees

• Concert Pharmaceuticals Inc

Inventors

• Graham Philip B
• Silverman I Robert

Classifications

• C07B59/002

  Heterocyclic compounds · CPC title

• C07D221/28 Primary

  Morphinans · CPC title

• A61K45/06

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

• C07D471/08

  Bridged systems · CPC title

• A61P29/00

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