WO2015070253A1 - Novel methods - Google Patents
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- WO2015070253A1 WO2015070253A1 PCT/US2014/065095 US2014065095W WO2015070253A1 WO 2015070253 A1 WO2015070253 A1 WO 2015070253A1 US 2014065095 W US2014065095 W US 2014065095W WO 2015070253 A1 WO2015070253 A1 WO 2015070253A1
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- Prior art keywords
- pharmaceutically acceptable
- azabicyclo
- dichlorophenyl
- hexane
- free
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Definitions
- FSD female sexual dysfunction
- a method of treating female sexual dysfunction comprising administering a therapeutically effective amount of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, to a female in need thereof.
- a method of treating female sexual dysfunction comprising administering a therapeutically effective amount of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, to a female in need thereof.
- Figure 1 shows SFI Score for Item 1 : Amitifadine 100 mg vs. Paroxetine.
- Figure 2 shows SFI Score for Item 2: Amitifadine 100 mg vs. Paroxetine.
- Figure 3 shows SFI Score for Item 3: Amitifadine 100 mg vs. Paroxetine.
- Figure 4 shows SFI Score for Item 4: Amitifadine 100 mg vs. Paroxetine.
- Figure 5 shows SFI Score for Item 5: Amitifadine 100 mg vs. Paroxetine.
- Figure 6 shows SFI Total Score: Amitifadine 100 mg vs. Paroxetine.
- Figure 7 shows SFI Score for Item 1 by Gender: Amitifadine 100 mg vs. Placebo.
- Figure 8 shows SFI Score for Item 2 by Gender: Amitifadine 100 mg vs. Placebo.
- Figure 9 shows SFI Score for Item 3 by Gender: Amitifadine 100 mg vs. Placebo.
- Figure 10 shows SFI Score for Item 4 by Gender: Amitifadine 100 mg vs. Placebo.
- Figure 11 shows SFI Score for Item 5 by Gender: Amitifadine 100 mg vs. Placebo.
- Figure 12 shows SFI Total Score by Gender: Amitifadine 100 mg vs. Placebo
- Excitatory factors include testosterone, melanocortin, oxytocin, dopamine, and norepinephrine.
- Inhibitory factors include serotonin (5-hydroxytryptamine (5-HT)), prolactin, and endogenous opioids.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane also known as (1R,5S)-1-
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is an unbalanced triple reuptake inhibitor with the greatest potency towards serotonin reuptake (5-HT), half as much towards norepinephrine reuptake (NE), and one eighth towards dopamine reuptake (DA).
- (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride is reported to inhibit the reuptake of [ 3 H] serotonin, [ 3 H]norepinephrine, and [ 3 H]dopamine in human embryonic kidney (HEK) 293 cells expressing the corresponding human recombinant transporters at IC 50 values of 12, 23, and 96 nm, respectively.
- amitifadine in the treatment of major depressive disorder, individuals receiving amitifadine 100 mg had significantly less overall worsening of sexual function than those receiving paroxetine as assessed with the Sexual Functioning Inventory (SFl). In addition, women experienced significant improvement in SFl on 100 mg amitifadine from baseline compared with placebo, which is unexpected considering that amitifadine more strongly inhibits serotonin reuptake than dopamine reuptake.
- SFl Sexual Functioning Inventory
- amitifadine by inhibiting dopamine reuptake, may enhance the synaptic availability of dopamine enough to inhibit prolactin (PRL) release.
- prolactin is an inhibitory factor on sexual desire, inhibiting its release may enhance sexual desire.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer means containing no more than 5% w/w (weight/weight) of the corresponding (-) enantiomer, in free or pharmaceutically acceptable salt form, e.g., no more than 2% w/w of the corresponding (-) enantiomer, in free or pharmaceutically acceptable salt form, e.g., no more than 1% w/w of the corresponding (-) enantiomer, in free or pharmaceutically acceptable salt form.
- salts are known in the art and include salts that are physiologically acceptable at the dosage amount and form to be administered, for example, hydrochloride salts.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is also to be understood as embracing the compound in crystalline and amorphous form including, for example, polymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
- Crystall form and “polymorph” may be used interchangeably herein, and are meant to include all crystalline forms of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, including, for example, polymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), and conformational polymorphs, as well as mixtures thereof, unless a particular crystalline form is referred to.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane exists in at least three polymorphic forms, labeled polymorphs A, B, and C, as disclosed in U.S. Patent Publication Nos. 2007/0043100 and 2009/0326245, incorporated herein by reference in their entirety.
- Crystalline and amorphous forms of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane may be used in any combination or in forms that are substantially free of one or more of the other crystalline forms or free of the amorphous form.
- substantially free of other polymorphic forms means that the crystalline material contains no more than 5% w/w of any other crystalline form, e.g., no more than 2% w/w of any other crystalline form, e.g., no more than 1% w/w of any other crystalline form.
- therapeutically effective amount refers to an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as amelioration of symptoms.
- the specific dose of substance administered to obtain a therapeutic benefit will, of course, be determined by the particular circumstances surrounding the case, including, for example, the specific substance administered, the route of administration, the condition being treated, and the individual being treated.
- composition As used herein, “concurrently” means the compounds are administered simultaneously or within the same composition. In some embodiments, the compounds are administered simultaneously. In some embodiments, the compounds are administered within the same composition.
- female sexual dysfunction generally refers to impairment of sexual function.
- female sexual dysfunction includes, but is not limited to, hypoactive sexual desire, sexual aversion disorder, sexual arousal disorder, orgasmic disorder, sexual pain disorder (including, e.g., dyspareunia, vaginismus, and noncoital sexual pain disorder), and combinations thereof.
- female includes premenopausal and post-menopausal females.
- treatment and “treating” embrace enhancing or improving sexual response and/or sexual pleasure and/or sensation.
- “Enhancing” or “improving” sexual response and/or sexual pleasure and/or sensation means that administration of (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane increases the female's satisfaction with the sexual activity as compared to the activity when in the absence of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane.
- Method 1 Provided herein is a method (Method 1) of prophyalaxis or treatment of female sexual dysfunction comprising administering a therapeutically effective amount of (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, to a female in need thereof.
- Method 1 wherein the method is for the treatment of female sexual dysfunction.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in pharmaceutically acceptable salt form is (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane hydrochloride.
- Method 1 or 1.1-1.11 comprising administering 10 mg to 1800 mg, e.g., 25 mg to 1800 mg, e.g., 10 mg to 1600 mg, e.g., 10 mg to 1200 mg, e.g., 50 mg to 1200 mg, e.g., 75 mg to 1000 mg, e.g., 75 mg to 800 mg, e.g., 75 mg to 500 mg, e.g., 100 mg to 500 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to 300 mg, e.g., 100 mg to 200 mg, e.g., 10 mg to 100 mg, 200 mg, or 300 mg, e.g., 25 mg to 100 mg, 200 mg, or 300 mg, e.g., 50 mg to 100 mg, 200 mg, or 300 mg, of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.
- Method 1 or 1.1-1.12 comprising administering 75 mg to 1000 mg, e.g., 100 mg to 600 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to 200 mg, of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.
- Method 1 or 1.1-1.13 comprising administering 25 mg to 600 mg, 50 mg to 600 mg, e.g., 25 mg to 200 mg, e.g., 50 mg to 200 mg, e.g., 50 mg to 100 mg, e.g., 100 mg to 600 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to 200 mg, of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.
- Method 1 or 1.1-1.16 comprising administering (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, once, twice, three, or four times daily.
- Method 1 or 1.1-1.19 comprising administering (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, at least three times daily.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is administered concurrently or sequentially, in either order, with a hormone or a derivative thereof (e.g., estrogen, testosterone (e.g., micronized oral testosterone), methyltestosterone, testosterone propionate, dehydroepiandrosterone, dehydroepiandrosterone sulfate), a prostaglandin (e.g., alprostadil), a melanocortin agonist (e.g., bremelanotide), a phosphodiesterase inhibitor (e.g., a PDE5 inhibitor, e.g., Viagra, or, e.g., a PDE1 inhibitor), a dopamine- norepinephrine reuptake inhibitor (e.g., bupropion), a 5-hydroxytryptaminei a receptor
- Method 1 or 1.1-1.25 wherein the female is taking an anti-hypertensive (e.g., a diuretic, a beta blocker, a calcium-channel blocker, an anti-adrenergic), an anticholinergic (e.g., propantheline, methantheline), a barbiturate, a benzodiazepine (e.g, diazepam, alprazolam), an anti-depressant (e.g., a selective serotonin re-uptake inhibitor, a serotonin-norepinephrine re -uptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, or a monoamine oxidase inhibitor, e.g., a selective serotonin re-uptake inhibitor, e.g., paroxetine), a chemotherapeutic (e.g., cyclophosphamide, an anti- estrogen), or an
- Method 1 or 1.1-1.26 wherein the sexual dysfunction is a side effect of a drug e.g., an anti-hypertensive (e.g., a diuretic, a beta blocker, a calcium-channel blocker, an anti- adrenergic), an anticholinergic (e.g., propantheline, methantheline), a barbiturate, a benzodiazepine (e.g, diazepam, alprazolam), an anti-depressant (e.g., a selective serotonin re-uptake inhibitor, a serotonin-norepinephrine re-uptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, or a monoamine oxidase inhibitor, e.g., selective serotonin re-uptake inhibitor, e.g., paroxetine), a chemotherapeutic (e.g., cyclopho
- subthreshold amount is the subthreshold amount of (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, for treatment of depression.
- subthreshold amount is the subthreshold amount of (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, for treatment of female sexual dysfunction.
- (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane in free or pharmaceutically acceptable salt form, for treatment or prophylaxis of female sexual dysfunction, e.g., for use in any of Method 1 or 1.1-1.31.
- (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for treatment or prophylaxis of female sexual dysfunction, e.g., for use in any of Method 1 or 1.1-1.31.
- composition comprising (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable diluent or carrier for use in treatment or prophylaxis of female sexual dysfunction, e.g., for use in any of Method 1 or 1.1-1.31.
- (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane in free or pharmaceutically acceptable salt form, for treating female sexual dysfunction, e.g., for use in any of Method 1 or 1.1-1.31.
- (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for treating female sexual dysfunction, e.g., for use in any of Method 1 or 1.1- 1.31.
- composition comprising (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable diluent or carrier for use in treating female sexual dysfunction, e.g., for use in any of Method 1 or 1.1-1.31.
- Method 2 of prophyalaxis or treatment of female sexual dysfunction comprising administering a therapeutically effective amount of (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, to a female in need thereof.
- Method 2 wherein the method is for the treatment of female sexual dysfunction.
- Method 2 or 2.1 wherein the therapeutically effective amount of (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, comprises less than or equal to 2% w/w of the corresponding (-) enantiomer.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in pharmaceutically acceptable salt form is an acid addition salt substantially free of the corresponding (-) enantiomer.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in pharmaceutically acceptable salt form is (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane hydrochloride substantially free of the corresponding (-) enantiomer.
- Method 2 or 2.1-2.11 comprising administering 75 mg to 1000 mg, e.g., 100 mg to 600 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to 200 mg, of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer.
- Method 2 or 2.1-2.12 comprising administering 25 mg to 600 mg, 50 mg to 600 mg, e.g., 25 mg to 200 mg, e.g., 50 mg to 200 mg, e.g., 50 mg to 100 mg, e.g., 100 mg to 600 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to 200 mg, of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer.
- Method 2 or 2.1-2.13 comprising administering 100 mg to 600 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to 300 mg, e.g., 100 mg to 200 mg, e.g., 100, 200, 300, or 400 mg, of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer.
- Method 2 or 2.1-2.14 comprising administering 100 mg to 200 mg, e.g., 100 mg, of (+)- l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer.
- Method 2 or 2.1-2.15 comprising administering (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, once, twice, three, or four times daily.
- Method 2 or 2.1-2.16 comprising administering (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, at least once daily.
- Method 2 or 2.1-2.17 comprising administering (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, at least twice daily.
- Method 2 or 2.1-2.18 comprising administering (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, at least three times daily.
- Method 2 or 2.1-2.20 comprising administering (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, 24 hours or less, e.g., 12 hours, e.g., 10 hours, e.g., 8 hours, e.g., 6 hours, e.g., 4 hours, e.g., 3 hours, e.g., 2 hours, e.g., 1 hour or less, before sexual activity.
- Method 2 or 2.1-2.24 wherein the female is taking an anti-hypertensive (e.g., a diuretic, a beta blocker, a calcium-channel blocker, an anti-adrenergic), an anticholinergic (e.g., propantheline, methantheline), a barbiturate, a benzodiazepine (e.g, diazepam, alprazolam), an anti-depressant (e.g., a selective serotonin re-uptake inhibitor, a serotonin -norepinephrine re-uptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, or a monoamine oxidase inhibitor, e.g., a selective serotonin re-uptake inhibitor, e.g., paroxetine), a chemotherapeutic (e.g., cyclophosphamide, an anti- estrogen), or an
- Method 2 or 2.1-2.25 wherein the sexual dysfunction is a side effect of a drug e.g., an anti-hypertensive (e.g., a diuretic, a beta blocker, a calcium-channel blocker, an anti- adrenergic), an anticholinergic (e.g., propantheline, methantheline), a barbiturate, a benzodiazepine (e.g, diazepam, alprazolam), an anti-depressant (e.g., a selective serotonin re-uptake inhibitor, a serotonin-norepinephrine re-uptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, or a monoamine oxidase inhibitor, e.g., selective serotonin re-uptake inhibitor, e.g., paroxetine), a chemotherapeutic (e.g., cyclophos
- Method 2.25 or 2.26 comprising administering a subthreshold amount of (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer.
- Method 2.25-2.29 comprising administering 10 mg to 400 mg, e.g., 25 mg to 400 mg, e.g., 25 mg to 300 mg, e.g., 50 mg to 400 mg, e.g., 50 mg to 300 mg, e.g., 50 mg to 200 mg, e.g., 50 to 100 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to 300 mg, e.g., 100 mg to 200 mg, e.g., 100 mg, 200 mg, 300 mg, or 400 mg, of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer.
- 10 mg to 400 mg e.g., 25 mg to 400 mg, e.g., 25 mg to 300 mg, e.g., 50 mg to 400 mg, e.g., 50 mg to 300 mg
- (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, for treatment or prophylaxis of female sexual dysfunction, e.g., for use in any of Method 2 or 2.1-2.30.
- (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, in the manufacture of a medicament for treatment or prophylaxis of female sexual dysfunction, e.g., for use in any of Method 2 or 2.1-2.30.
- composition comprising (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, in combination with a pharmaceutically acceptable diluent or carrier for use in treatment or prophylaxis of female sexual dysfunction, e.g., for use in any of Method 2 or 2.1-2.30.
- (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, for treating female sexual dysfunction, e.g., for use in any of Method 2 or 2.1-2.30.
- (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, in the manufacture of a medicament for treating female sexual dysfunction, e.g., for use in any of Method 2 or 2.1-2.30.
- a dose or method of administration of the dose of the present disclosure is not particularly limited. Dosages employed in practicing the present disclosure will of course vary depending, e.g. on the mode of administration and the therapy desired. In general, satisfactory results, e.g. for the treatment of female sexual dysfunction are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg. In larger females, for example human females, an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 mg to 150 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for oral administration thus for example may comprise from about 0.2 mg to 75 mg or 150 mg, e.g.
- (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer, together with a pharmaceutically acceptable diluent or carrier therefor.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in free or pharmaceutically acceptable salt form, may be administered by any suitable route, including orally, parenterally, transdermally, inhalation, slow release, controlled release, although various other known delivery routes, devices and methods can likewise be employed.
- (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, substantially free of the corresponding (-) enantiomer may be administered by any suitable route, including orally, parenterally, transdermally, inhalation, slow release, controlled release, although various other known delivery routes, devices and methods can likewise be employed.
- a sustained release pharmaceutical composition e.g., an oral sustained release pharmaceutical composition, comprising (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, which provides therapeutically effective levels of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane over a sustained delivery period of approximately 6 hours or longer, e.g., 8 hours or longer, e.g., 12 hours or longer, e.g., 18 hours or longer, e.g., 24 hours or longer.
- the therapeutically effective amount of each agent may be below the amount needed for activity as monotherapy. Accordingly, a subthreshold amount (i.e., an amount below the level necessary for efficacy as monotherapy) may be considered therapeutically effective. Indeed, an advantage of administering different agents with different mechanisms of action and different side effect profiles may be to reduce the dosage and side effects of either or both agents, as well as to enhance or potentiate their activity as monotherapy.
- MDD major depressive disorder
- SPCD sequential parallel comparison design
- the trial requires: 1) diagnosis of MDD, based on the Structured Clinical Interview for DSM Disorders Clinical Trials version (SCID- CT), validated by remote independent raters using the SAFER criteria interview, 2) one and only one antidepressant therapy (ADT) failure in the current episode of MDD, treated with an adequate dose of one of an allowed standard antidepressant (paroxetine or an monoamine oxidase inhibitor (MAO I) not allowed) during the current episode for > 6 weeks, with the same, adequate dose for > 4 weeks, 3) HAM-D 17 > 18 at the end of screening phase, 4) ⁇ 25% reduction in Quick Inventory of Depressive Symptoms Self-Rated (QIDS-SR) score between the screen and baseline visits.
- QIDS-SR Quick Inventory of Depressive Symptoms Self-Rated
- Inadequate response defined as ⁇ 50% reduction in depressive symptom severity, assessed by the MGH Antidepressant Treatment Response Questionnaire (ATRQ) administered by remote, independent raters (Targum, S. et al, CNS Neuroscience & Therapeutics, 2010, 16 (5), 322-325).
- An adequate trial is defined as an ADT > 6 weeks at least at the minimum dose specified in the MGH ATRQ. Patients do not have to be on the failed ADT medication at the time of screening visit.
- Placebo non-responders are defined as those patients who fail to achieve at least a 50% decrease from Phase 1 baseline in their MADRS score at visit 8 (Week 6), and had a MADRS score of > 16 at visit 8 (Week 6) of Phase 1.
- the SCID- CT is administered by study clinicians at the screening visit to diagnose Axis I disorders.
- the remote, independent raters also administer the SAFER Criteria Inventory (SCI) during the screening phase to assess whether the MDD is a "valid" clinical entity.
- SCI SAFER Criteria Inventory
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EP14859559.8A EP3068226A4 (en) | 2013-11-11 | 2014-11-11 | Novel methods |
US15/035,894 US20160279098A1 (en) | 2013-11-11 | 2014-11-11 | Novel methods |
JP2016553276A JP2016535796A (en) | 2013-11-11 | 2014-11-11 | New method |
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US201361902762P | 2013-11-11 | 2013-11-11 | |
US61/902,762 | 2013-11-11 | ||
US201462077107P | 2014-11-07 | 2014-11-07 | |
US62/077,107 | 2014-11-07 |
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WO2015070253A1 true WO2015070253A1 (en) | 2015-05-14 |
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PCT/US2014/065095 WO2015070253A1 (en) | 2013-11-11 | 2014-11-11 | Novel methods |
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EP (1) | EP3068226A4 (en) |
JP (1) | JP2016535796A (en) |
WO (1) | WO2015070253A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022165017A1 (en) * | 2021-01-28 | 2022-08-04 | Sage Therapeutics, Inc. | Use of neuroactive steroids for treatment of sexual dysfunction |
Citations (5)
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US20080045725A1 (en) * | 2006-04-28 | 2008-02-21 | Murry Jerry A | Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
US20100016401A1 (en) * | 2006-09-29 | 2010-01-21 | Actelion Phamaceuticals Ltd. | 3-aza-bicyclo[3.1.0]hexane derivatives |
US20100029740A1 (en) * | 2006-12-18 | 2010-02-04 | Giorgio Bonanomi | Azabicyclic compounds as serotonin, dopamine and norepinephrine re-uptake inhibitors |
WO2010130672A1 (en) * | 2009-05-12 | 2010-11-18 | Glaxo Group Limited | Azabicyclo [4.1.0] heptane derivatives and their use as monoamine reuptake inhibitors |
US8283474B2 (en) * | 2004-02-23 | 2012-10-09 | Glaxo Group Limited | Azabicyclo (3.1.0) hexane derivatives useful as modulators of dopamine D3 receptors |
-
2014
- 2014-11-11 WO PCT/US2014/065095 patent/WO2015070253A1/en active Application Filing
- 2014-11-11 US US15/035,894 patent/US20160279098A1/en not_active Abandoned
- 2014-11-11 JP JP2016553276A patent/JP2016535796A/en active Pending
- 2014-11-11 EP EP14859559.8A patent/EP3068226A4/en not_active Withdrawn
Patent Citations (5)
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US8283474B2 (en) * | 2004-02-23 | 2012-10-09 | Glaxo Group Limited | Azabicyclo (3.1.0) hexane derivatives useful as modulators of dopamine D3 receptors |
US20080045725A1 (en) * | 2006-04-28 | 2008-02-21 | Murry Jerry A | Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
US20100016401A1 (en) * | 2006-09-29 | 2010-01-21 | Actelion Phamaceuticals Ltd. | 3-aza-bicyclo[3.1.0]hexane derivatives |
US20100029740A1 (en) * | 2006-12-18 | 2010-02-04 | Giorgio Bonanomi | Azabicyclic compounds as serotonin, dopamine and norepinephrine re-uptake inhibitors |
WO2010130672A1 (en) * | 2009-05-12 | 2010-11-18 | Glaxo Group Limited | Azabicyclo [4.1.0] heptane derivatives and their use as monoamine reuptake inhibitors |
Non-Patent Citations (2)
Title |
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See also references of EP3068226A4 * |
TRAN ET AL.: "Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder A randomized, double-blind, placebo-controlled trial", JOUMAL OF PSYCHIATRIC RESEARCH, vol. 46, 2012, pages 64 - 71, XP028117195 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022165017A1 (en) * | 2021-01-28 | 2022-08-04 | Sage Therapeutics, Inc. | Use of neuroactive steroids for treatment of sexual dysfunction |
Also Published As
Publication number | Publication date |
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EP3068226A4 (en) | 2017-05-17 |
JP2016535796A (en) | 2016-11-17 |
US20160279098A1 (en) | 2016-09-29 |
EP3068226A1 (en) | 2016-09-21 |
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