COMPOSITIONS OF (-)-E-10-OH-NT AND METHODS FOR THEIR SYNTHESIS AND USE
This present disclosure provides compositions comprising E-10-OH-NT metabolites of AT and NT, methods for their synthesis and methods for their use.
1 . A pharmaceutical composition comprising E-10-OH-NT and a pharmaceutically acceptable excipient, carrier and/or diluent, wherein said E-10-OH-NT is enriched in the (−)-enantiomer.
2 . The pharmaceutical composition of claim 1 , wherein said E-10-OH-NT contains at least about 60% (−)-E-10-OH-NT.
3 . The pharmaceutical composition of claim 1 , wherein said E-10-OH-NT contains at least about 70% (−)-E-10-OH-NT.
4 . The pharmaceutical composition of claim 1 , wherein said E-10-OH-NT contains at least about 80% (−)-E-10-OH-NT.
5 . The pharmaceutical composition of claim 1 , wherein said E-10-OH-NT contains at least about 90% (−)-E-10-OH-NT.
6 . The pharmaceutical composition of claim 1 , wherein said E-10-OH-NT is substantially enantiomerically pure (−)-E-10-OH-NT.
7 . The pharmaceutical composition of claim 1 , wherein said E-10-OH-NT is enantiomerically pure (−)-E-10-OH-NT.
8 . The pharmaceutical composition of claim 1 , wherein said E-10-OH-NT is present in the composition as a salt.
9 . The pharmaceutical composition of claim 8 in which the salt is a D- or L-malate salt.
10 . The pharmaceutical composition of claim 8 in which the salt is a succinate salt.
11 . A method of treating pain in a mammal comprising administering to the mammal an effective amount of a pharmaceutical composition according to any one of claims 1 - 10 .
12 . The method of claim 11 in which said pain is of nociceptive origin.
13 . The method of claim 11 in which said pain is of non-nociceptive origin.
14 . The method of claim 11 in which the pain is neuropathic pain, inflammatory pain, post herpetic neuralgia, diabetic neuropathy or chemo-therapy induced neuropathic pain.
15 . The method of claim 11 in which said composition is formulated for oral administration.
16 . A method of treating depression in a mammal, comprising administering to the mammal an effective amount of a pharmaceutical according to any one of claims 1 - 10 .
17 . A method of treating a disorder in a patient that is responsive to treatment with amitriptyline or nortriptyline, comprising administering to the patient an effective amount of a pharmaceutical composition according to any one of claims 1 - 10 .
18 . The method of claim 17 in which said disorder responsive to amitriptyline or nortriptyline therapy is selected from urinary disorders, mood disorders, cognitive disorders, psychotic disorders, anxiety disorders, personality disorders, eating disorders chemical dependencies resulting from addictions to drugs or substances of abuse, withdrawal syndromes, endocrine disorders, impulse disorders, tic disorders, gastrointestinal tract disorders, vascular disorders, somatoform disorders, Parkinson's disease, shock, hypertension, sexual dysfunction, pre-menstrual syndrome and fibromyalgia syndrome.
19 . The method of claim 17 in which the patient is taking medication contraindicated for use with amitriptyline or nortriptyline.
20 . Substantially enantiomerically pure (−)-E-5-(γ-bromopropylidene)-10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]-cycloheptene.
21 . Enantiomerically pure (−)-E-5-(γ-bromopropylidene)-10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]-cycloheptene.
22 . Synthetically derived enantiomerically pure (−)-E-10-OH-NT.
23 . The synthetically derived enantiomerically pure (−)-E-10-OH-NT of claim 22 in which the E-10-OH-NT is in the form of the free base.
24 . The synthetically derived enantiomerically pure (−)-E-10-OH-NT of claim 22 in which the E-10-OH-NT is in the form of a salt.
25 . The synthetically derived enantiomerically pure (−)-E-10-OH-NT of claim 22 in which the salt is a malate salt.
26 . The synthetically derived enantiomerically pure (−)-E-10-OH-NT of claim 22 in which the salt is a succinate salt.
27 . A method of making (−)-E-5-(γ-bromopropylidene)-10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]-cycloheptene, comprising reducing E-5-(γ-bromopropylidene)-10,11-dihydro-10-oxo-5H-dibenzo[a,d]-cycloheptene in the presence of a chiral-specific oxazaborolidine catalyst.
28 . The method of claim 27 in which the oxazaborolidine catalyst is
29 . A method of making (−)-E-10-OH-NT, comprising reacting (−)-E-5-(γ-bromopropylidene)-10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]-cycloheptene with methylamine.
30 . A method of making a substantially enantiomerically pure (−)-E-10-OH-NT, comprising the steps of reacting substantially enantiomerically pure (−)-5-(γ-bromopropylidene)-10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]-cycloheptene with methylamine.
31 . A method of making (−)-E-10-OH-NT, comprising the steps of:
(i) reducing E-5-(γ-bromopropylidene)-10,11-dihydro-10-oxo-5H-dibenzo[a,d]-cycloheptene in the presence of
to yield (−)-E-5-(γ-bromopropylidene)-10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]-cycloheptene; and
(ii) reacting the (−)-E-5-(γ-bromopropylidene)-10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]-cycloheptene with methylamine.
32 . A method for inhibiting uptake of norepinephrine comprising contacting a norepinephrine transporter with a composition comprising E-10-OH-NT that is enriched in the (−) enantiomer.
33 . The method of claim 32 which is practiced in vitro.
34 . The method of claim 32 which is practiced in vivo by administering to a subject an amount of a composition comprising an amount of E-10-OH-NT effect to inhibit reuptake of nonepinephrine, wherein said E-10-OH-NT is enriched in the (−) enantiomer.