3- (1H-indol- 3-ydindan-1-ylamine derivatives for the treatment of depression and anxiety

Abstract

The invention provides novel indane compounds which are useful in the treatment of affective disorders, pain disorders, attention deficit hyperactivity disorder (ADHD), cognitive disorders, substance abuse, smoking cessation and stress urinary incontinence. The compounds are inhibitors of serotonin, norepinephrine and dopamine re-uptake.

Description

field of invention

[0001] The present invention provides novel indan compounds useful in the treatment of depression, anxiety and other CNS disorders. Background of the invention

[0002] All currently available antidepressants can be divided into 3 categories:

[0003] 1) Monoamine oxidase inhibitors (MAOIs),

[0004] 2) biogenic amine neurotransmitters [serotonin (5-HT), norepinephrine (NE), and dopamine (DA)] transporter weight uptake blockers, and

[0005] 3) Modulators, especially blockers of one or more 5-HT and / or NE receptors.

[0006] Since depression is associated with a relative deficiency of biogenic amines, the use of 5-HT and / or NE-receptor blockers (ie 5-HT and / or NE-antagonists) has not proven to be very successful in the treatment of depression and anxiety, The preferred and currently most effective therapy is based on blocking the reuptake of 5-HT and / or NE neurotransmission from the synaptic cleft to enhance its neurotransmission (Slattery, D.A. et al.,...

Examples

Embodiment

[0172] Synthesis of 3-bromo-indan-1-one

[0173] Add 390 g (2.2 mol) of N-bromosuccinimide (powder without lumps) and 0.5 g of benzoyl peroxide in 1500 mL of CCl 4 In the 264g indan-1-one, and reflux with mechanical stirring for 1.5 hours. The color of the reaction mixture suddenly changed to yellow, all N-bromosuccinimide (than CCl 4 Heavy) into succinimide (than CCl 4 light). The reaction mixture was cooled to 20 °C, filtered and concentrated in vacuo. Crude 3-bromo-indan-1-one was dissolved in 600 mL of ethyl acetate / heptane (1:2), cooled in an ice bath for 2 hours, and then placed in the refrigerator overnight to yield 257 g of 3 - Crystals of bromo-indan-1-one (62% yield).

[0174] Synthesis of 3-(7-fluoro-1H-indol-3-yl)-indan-1-one (Method 1)

[0175] Triethylamine (4.5 mL; 32 mmol; 1.2 equiv) was added to 3-bromo-indan-1-one (5.6 g; 27 mmol) in 100 ml THF at 0°C and stirred at room temperature for 1 hour. The reaction mixture was filtered to remove triethylammoni...

Embodiment 7

[0237] Example 7: Synthesis of [(1S,3R)-3-(1H-indol-3-yl)-indan-1-yl]-methyl-amine (Method 10)

[0238]

[0239] Using Emry Optimizer TM Apparatus, under microwave irradiation at 150 °C, in 10 mL of methanol with stirring (R)-3-(1H-indol-3-yl)-indan-1-one, methylamine (5 mL, 2 M in THF ) and 1 mL of tetraethoxysilane for 11 minutes. Join PtO 2 (10 mg), the reaction mixture was stirred at room temperature under 1 atmosphere of hydrogen overnight, filtered and concentrated in vacuo. After flash chromatography (ethyl acetate, methanol, triethylamine, silica gel), [(1S,3R)-3-(1H-indol-3-yl)-indan-1-yl]-methyl -Amine, yield 66%.

[0240] The following compounds were synthesized in a similar manner:

Embodiment 1

[0242] Racemic cis-[3-(5-fluoro-2-methyl-1H-indol-3-yl)-indan-1-yl]-methyl-amine

[0243]

field of invention

[0001] The present invention provides novel indan compounds useful in the treatment of depression, anxiety and other CNS disorders. Background of the invention

[0002] All currently available antidepressants can be divided into 3 categories:

[0003] 1) Monoamine oxidase inhibitors (MAOIs),

[0004] 2) biogenic amine neurotransmitters [serotonin (5-HT), norepinephrine (NE), and dopamine (DA)] transporter weight uptake blockers, and

[0005] 3) Modulators, especially blockers of one or more 5-HT and / or NE receptors.

[0006] Since depression is associated with a relative deficiency of biogenic amines, the use of 5-HT and / or NE-receptor blockers (ie 5-HT and / or NE-antagonists) has not proven to be very successful in the treatment of depression and anxiety, The preferred and currently most effective therapy is based on blocking the reuptake of 5-HT and / or NE neurotransmission from the synaptic cleft to enhance its neurotransmission (Slattery, D.A. et al.,...

Examples

Embodiment

[0172] Synthesis of 3-bromo-indan-1-one

[0173] Add 390 g (2.2 mol) of N-bromosuccinimide (powder without lumps) and 0.5 g of benzoyl peroxide in 1500 mL of CCl 4 In the 264g indan-1-one, and reflux with mechanical stirring for 1.5 hours. The color of the reaction mixture suddenly changed to yellow, all N-bromosuccinimide (than CCl 4 Heavy) into succinimide (than CCl 4 light). The reaction mixture was cooled to 20 °C, filtered and concentrated in vacuo. Crude 3-bromo-indan-1-one was dissolved in 600 mL of ethyl acetate / heptane (1:2), cooled in an ice bath for 2 hours, and then placed in the refrigerator overnight to yield 257 g of 3 - Crystals of bromo-indan-1-one (62% yield).

[0174] Synthesis of 3-(7-fluoro-1H-indol-3-yl)-indan-1-one (Method 1)

[0175] Triethylamine (4.5 mL; 32 mmol; 1.2 equiv) was added to 3-bromo-indan-1-one (5.6 g; 27 mmol) in 100 ml THF at 0°C and stirred at room temperature for 1 hour. The reaction mixture was filtered to remove triethylammoni...

Embodiment 7

[0237] Example 7: Synthesis of [(1S,3R)-3-(1H-indol-3-yl)-indan-1-yl]-methyl-amine (Method 10)

[0238]

[0239] Using Emry Optimizer TM Apparatus, under microwave irradiation at 150 °C, in 10 mL of methanol with stirring (R)-3-(1H-indol-3-yl)-indan-1-one, methylamine (5 mL, 2 M in THF ) and 1 mL of tetraethoxysilane for 11 minutes. Join PtO 2 (10 mg), the reaction mixture was stirred at room temperature under 1 atmosphere of hydrogen overnight, filtered and concentrated in vacuo. After flash chromatography (ethyl acetate, methanol, triethylamine, silica gel), [(1S,3R)-3-(1H-indol-3-yl)-indan-1-yl]-methyl -Amine, yield 66%.

[0240] The following compounds were synthesized in a similar manner:

Embodiment 1

[0242] Racemic cis-[3-(5-fluoro-2-methyl-1H-indol-3-yl)-indan-1-yl]-methyl-amine

[0243]

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