Substituted acetylenic compounds useful for the treatment of diseases

Abstract

The invention relates to novel compounds according to formula Ia and Ib; (Formula Ia and Ib) wherein A represents substituted or unsubstituted C1-10heteroaryl, C6-14aryl or C6- 10heterocycloalkylaryl; R1 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6amino, C3-6 cycloalkyl, or C1-6heterocycloalkyl, each of which are optionally substituted; X represents -CR3R4-(CR5R6)n-(CR7=CR8)m-(C6-14aryl)r-(C1-10heteroaryl)s-(CR9R10)p- (CR11 = CR12)q, R2 represents C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6amino, C1-12alkylsilyl, C6-30alkylarylsilyl, C1-10heteroaryl, C6-14aryl, C1-10heterocycloalkyl, C1-10heterocycloalkenyl, C1-8cycloalkyl, C1-18cycloalkenyl, each of which is optionally substituted, or R2 represents hydrogen, carboxy, or hydroxy; or a pharmaceutically acceptable salt, solvate, or ester thereof; to processes for the preparation thereof, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, wherein said compounds being useful, e.g. in the treatment of diseases associated with disturbances of CaSR activity, such as hyperparathyroidism.

Description

technical field

[0001] The present invention relates to novel substituted acetylenic compounds and derivatives thereof, processes for their preparation, said compounds for use in therapy, pharmaceutical compositions containing said compounds, methods of using said compounds in the treatment of diseases and the preparation of said compounds Uses in medicine. Background technique

[0002] Calcium-sensing receptors (CaSR) are G-protein-coupled receptors (GPCRs) that signal by activating phospholipase C, increasing levels of inositol 1,4,5-triphosphate and cytosolic calcium. CaSR belongs to subfamily C of the GPCR superfamily, which also includes glutamate, gamma aminobutyric acid (GABA), pheromone and odorant receptors, all of which have extremely large extracellular domains. This domain is highly negatively charged and is involved in the binding of calcium and other positively charged molecules. CaSR has been found not only in the parathyroid glands, but also in the brain, i...

Examples

Embodiment 1

[0497]

[0498] (R)-But-2-ynyl-(1-naphthalen-1-yl-ethyl)-amine hydrochloride (compound 101)

[0499]1-Bromo-but-2-yne (0.66 g, 5.0 mmol) and (R)-1-naphthalen-1-yl-ethylamine (2.0 g, 11.7 mmol) were treated as described in General Method 1. The crude product was purified by chromatography (PE / EtOAc 5:1) to obtain the free amine. The free amine was redissolved in MeOH. To this solution was added aqueous hydrochloric acid (1N) until the pH was 2 and the product crystallized out. Filtration and washing of the crystals with a small amount of diethyl ether afforded the title compound as a white solid.

[0500] 13 C NMR (DMSO-d 6 ): δ=129.3, 127.2, 126.5, 125.9, 124.9, 122.9, 85.2, 70.8, 51.2, 34.8, 20.2, 3.6.

Embodiment 2

[0502]

[0503] (R)-(1-naphthalen-1-yl-ethyl)-pent-4-ynyl-amine (compound 102)

[0504] (R)-1-Naphthalen-1-yl-ethylamine (4.1 g, 24.0 mmol) and 5-chloro-pent-1-yne (2.1 g, 20.0 mmol) were dissolved in DMF (25 mL). K was added to the solution at room temperature 2 CO 3 (3.9 g, 28 mmol) and NaI (1.0 g). The reaction mixture was stirred at 50 °C for 48 h, then poured into H 2 O middle. The obtained mixture was extracted with EtOAc. The combined organic phases were subjected to MgSO 4 Dry and concentrate in vacuo. The residue was purified by chromatography (PE / EtOAc 1:1 to PE / EtOAc 0:1) to obtain the title compound as an oil.

[0505] 13 C NMR (DMSO-d 6 ): δ=130.6, 129.4, 129.3, 127.2, 126.5, 125.9, 124.9, 122.9, 85.2, 70.8, 51.2, 34.8, 20.2, 3.6.

Embodiment 3

[0507]

[0508] (E) / (R)-(6,6-Dimethyl-hept-2-en-4-ynyl-(1-naphthalen-1-yl-ethyl)-amine (compound 103) and (Z) / (R)-(6,6-dimethyl-hept-2-en-4-ynyl)-(1-naphthalen-1-yl-ethyl)-amine (compound 104)

[0509] Mix (E) / (Z)-1-bromo-6,6-dimethyl-hept-2-en-4-yne (374 mg, 2.0 mmol) and (R)-1-naphthalen-1-yl-eth The amine (342 mg, 2.0 mmol) was worked up as described in General Method 1. The crude product was purified by chromatography (PE / EtOAc 6:1) to obtain compound 103 and compound 104 as colorless oils.

[0510] Compound 103:

[0511] 13 C NMR (CDCl 3 ): δ=140.9, 140.5, 134.0, 131.3, 129.0, 127.2, 125.7, 125.7, 125.3, 123.0, 122.7, 111.3, 98.4, 77.2, 52.9, 49.3, 31.0, 27.9, 23.6.

[0512] Compound 104:

[0513] 13 C NMR (CDCl 3 ): δ=141.1, 139.8, 134.0, 131.4, 128.9, 127.2, 125.7, 125.7, 125.3, 123.0, 122.7, 111.4, 103.8, 75.2, 52.7, 46.6, 30.9, 28.0, 23.4.

technical field

[0001] The present invention relates to novel substituted acetylenic compounds and derivatives thereof, processes for their preparation, said compounds for use in therapy, pharmaceutical compositions containing said compounds, methods of using said compounds in the treatment of diseases and the preparation of said compounds Uses in medicine. Background technique

[0002] Calcium-sensing receptors (CaSR) are G-protein-coupled receptors (GPCRs) that signal by activating phospholipase C, increasing levels of inositol 1,4,5-triphosphate and cytosolic calcium. CaSR belongs to subfamily C of the GPCR superfamily, which also includes glutamate, gamma aminobutyric acid (GABA), pheromone and odorant receptors, all of which have extremely large extracellular domains. This domain is highly negatively charged and is involved in the binding of calcium and other positively charged molecules. CaSR has been found not only in the parathyroid glands, but also in the brain, i...

Examples

Embodiment 1

[0497]

[0498] (R)-But-2-ynyl-(1-naphthalen-1-yl-ethyl)-amine hydrochloride (compound 101)

[0499]1-Bromo-but-2-yne (0.66 g, 5.0 mmol) and (R)-1-naphthalen-1-yl-ethylamine (2.0 g, 11.7 mmol) were treated as described in General Method 1. The crude product was purified by chromatography (PE / EtOAc 5:1) to obtain the free amine. The free amine was redissolved in MeOH. To this solution was added aqueous hydrochloric acid (1N) until the pH was 2 and the product crystallized out. Filtration and washing of the crystals with a small amount of diethyl ether afforded the title compound as a white solid.

[0500] 13 C NMR (DMSO-d 6 ): δ=129.3, 127.2, 126.5, 125.9, 124.9, 122.9, 85.2, 70.8, 51.2, 34.8, 20.2, 3.6.

Embodiment 2

[0502]

[0503] (R)-(1-naphthalen-1-yl-ethyl)-pent-4-ynyl-amine (compound 102)

[0504] (R)-1-Naphthalen-1-yl-ethylamine (4.1 g, 24.0 mmol) and 5-chloro-pent-1-yne (2.1 g, 20.0 mmol) were dissolved in DMF (25 mL). K was added to the solution at room temperature 2 CO 3 (3.9 g, 28 mmol) and NaI (1.0 g). The reaction mixture was stirred at 50 °C for 48 h, then poured into H 2 O middle. The obtained mixture was extracted with EtOAc. The combined organic phases were subjected to MgSO 4 Dry and concentrate in vacuo. The residue was purified by chromatography (PE / EtOAc 1:1 to PE / EtOAc 0:1) to obtain the title compound as an oil.

[0505] 13 C NMR (DMSO-d 6 ): δ=130.6, 129.4, 129.3, 127.2, 126.5, 125.9, 124.9, 122.9, 85.2, 70.8, 51.2, 34.8, 20.2, 3.6.

Embodiment 3

[0507]

[0508] (E) / (R)-(6,6-Dimethyl-hept-2-en-4-ynyl-(1-naphthalen-1-yl-ethyl)-amine (compound 103) and (Z) / (R)-(6,6-dimethyl-hept-2-en-4-ynyl)-(1-naphthalen-1-yl-ethyl)-amine (compound 104)

[0509] Mix (E) / (Z)-1-bromo-6,6-dimethyl-hept-2-en-4-yne (374 mg, 2.0 mmol) and (R)-1-naphthalen-1-yl-eth The amine (342 mg, 2.0 mmol) was worked up as described in General Method 1. The crude product was purified by chromatography (PE / EtOAc 6:1) to obtain compound 103 and compound 104 as colorless oils.

[0510] Compound 103:

[0511] 13 C NMR (CDCl 3 ): δ=140.9, 140.5, 134.0, 131.3, 129.0, 127.2, 125.7, 125.7, 125.3, 123.0, 122.7, 111.3, 98.4, 77.2, 52.9, 49.3, 31.0, 27.9, 23.6.

[0512] Compound 104:

[0513] 13 C NMR (CDCl 3 ): δ=141.1, 139.8, 134.0, 131.4, 128.9, 127.2, 125.7, 125.7, 125.3, 123.0, 122.7, 111.4, 103.8, 75.2, 52.7, 46.6, 30.9, 28.0, 23.4.

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