Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity

• US 10,421,710 B2
• Filed: 12/03/2014
• Issued: 09/24/2019
• Est. Priority Date: 03/15/2007
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Gant, Thomas G., Sarshar, Sepehr, Woo, Soon Hyung
• Primary Examiner(s): Brooks, Clinton A
• Application Number:
  US14/559,520
• Publication Number:
  US 20150152042A1
• Time in Patent Office: 1,756 Days
• Field of Search: None
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07B 59/00 Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
• CPC Class Codes: C07C 211/64 having quaternised nitrogen atoms bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 215/64 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 217/74 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07D 265/16 with only hydrogen or carbon atoms directly attached in positions 2 and 4

Abstract

Chemical syntheses and medical uses of novel inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, for the treatment and/or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, attention deficit hyperactivity disorder, fibromyalgia, irritable bowel syndrome, and/or premature ejaculation are described.

Claims

1. Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) having the formula:

2. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) as recited in claim 1, wherein said X-ray powder diffraction spectrum further comprises one or more peaks at diffraction angles (2θ

±

5%) of 16.64, 17.206, 23.923, 25.322, 26.502, 27.122, 27.567, 28.64, 29.241, 29.650, 31.079, 31.379, 31.978, 32.260, 32.701, 32.961, 34.12, 36.024, 36.842, 37.5, or 38.341.

3. A pharmaceutical composition comprising the compound as recited in claim 1 and one or more pharmaceutically acceptable carriers.

4. The pharmaceutical composition as recited in claim 3, further comprising one or more release-controlling carriers.

5. The pharmaceutical composition as recited in claim 3, further comprising one or more non-release controlling carriers.

6. The pharmaceutical composition as recited in claim 3, wherein the composition is suitable for oral, parenteral, or intravenous infusion administration.

7. The pharmaceutical composition as recited in claim 6, wherein the oral dosage form is a tablet or capsule.

8. The pharmaceutical composition as recited in claim 3, wherein the compound is administered in a dose of about 0.5 milligrams to about 1,000 milligrams.

9. The pharmaceutical composition as recited in claim 3, wherein the compound is administered in a dose of about 0.5 milligrams to about 400 milligrams.

11. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) as recited in claim 1, wherein each position designed as D has a deuterium enrichment of no less than 5% above the naturally occurring distribution of deuterium.

12. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) as recited in claim 1, wherein each position designed as D has a deuterium enrichment of no less than 10% above the naturally occurring distribution of deuterium.

13. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) as recited in claim 1, wherein each position designed as D has a deuterium enrichment of no less than 20% above the naturally occurring distribution of deuterium.

14. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) as recited in claim 1, wherein each position designed as D has a deuterium enrichment of no less than 50% above the naturally occurring distribution of deuterium.

15. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) as recited in claim 1, wherein each position designed as D has a deuterium enrichment of no less than 70% above the naturally occurring distribution of deuterium.

16. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) as recited in claim 1, wherein each position designed as D has a deuterium enrichment of no less than 80% above the naturally occurring distribution of deuterium.

17. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) as recited in claim 1, wherein each position designed as D has a deuterium enrichment of no less than 90% above the naturally occurring distribution of deuterium.

18. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) as recited in claim 1, wherein each position designed as D has a deuterium enrichment of no less than 98% above the naturally occurring distribution of deuterium.

19. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) of claim 1, which further produces a solid state infrared spectrum comprising peaks at about 3319 and 2917 cm⁻

1.

20. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) of claim 1, wherein:

each position designed as D has a deuterium enrichment of no less than 90% above the naturally occurring distribution of deuterium; and

said polymorph produces;

(i) an X-ray powder diffraction spectrum comprising at least four peaks at diffraction angles (2θ

) of 6.683, 10.201, 13.441, 15.014, 15.517, 16.84, 17.206, 18.198, 19.179, 20.258, 21.68, 22.668, 23.923, 25.322, 25.543, 26.502, 27.122, 27.567, 28.022, 28.64, 29.241, 29.650, 31.079, 31.379, 31.978, 32.260, 32.701, 32.961, 34.12, 35.02, 36.024, 36.842, 37.5, or 38.341 2θ

; and

(ii) a solid state infrared spectrum comprising peaks at about 3319 and 2917 cm<sup>−

1</sup>.

10. The Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) wherein said polymorph produces an X-ray powder diffraction spectrum substantially the same as shown in FIG. 2.