Muvadenant

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Muvadenant

CAS 2459881-03-7

MF C21H26N4O4S , 430.5 g/mol

(5S)-N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy[1,3]thiazolo[4,5-c]pyridin-2-yl]-7-oxa-2-azaspiro[4.5] decane-2-carboxamide

(5S)-N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1,3]thiazolo[4,5-c]pyridin-2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide
adenosine receptor antagonist, antineoplastic, 6LSF69F6A8, M1069 , M 1069

Muvadenant is a small molecule drug. The usage of the INN stem ‘-adenant’ in the name indicates that Muvadenant is a adenosin receptor antagonist. Muvadenant has a monoisotopic molecular weight of 430.17 Da.

Adenosine is an ubiguitous modulator of numerous physiological activities, particularly within the cardiovascular, nervous and immune systems. Adenosine is related both structurally and metabolically to the bioactive nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP), to the biochemical methylating agent S-adenosyl-L-methione (SAM) and structurally to the coenzymes NAD, FAD and coenzym A and to RNA.

Via cell surface receptors, adenosine modulates diverse physiological functions including induction of sedation, vasodilatation, suppression of cardiac rate and contractility, inhibition of platelet aggregability, stimulation of gluconeogenesis and inhibition of lipolysis. Studies show that adenosine is able to activate adenylate cyclases, open potassium channels, reduce flux through calcium channels, and inhibit or stimulate phosphoinositide turnover through receptor-mediated

mechanisms (Muller C. E. and Stein B., Current Pharmaceutical Design, 2: 501 , 1996; Muller C. E., Exp. Opin. Ther. Patents, 7(5): 419, 1997).

Adenosine receptors belong to the superfamily of G-protein-coupled receptors (GPCRs). Four major subtypes of adenosine receptors have been

pharmacologically, structurally and functionally characterized (Fredholm et al., Pharm. Rev., 46: 143-156, 1994) and referred to as A₁, A2A, A2B and A3. Though the same adenosine receptor can couple to different G-proteins, adenosine A₁ and A3 receptors usually couple to inhibitory G-proteins referred to as G, and Go which inhibit adenylate cyclase and down-regulate cellular cAMP levels. In contrast, the adenosine A_2A and A_2B receptors couple to stimulatory G-proteins referred to as Gs that activate adenylate cyclase and increase intracellular levels of cAMP (Linden J., Annu. Rev. Pharmacol. Toxicol., 41 : 775-87 2001).

PAT

Thiazolopyridine derivatives as adenosine receptor antagonistsPublication Number: US-2022119412-A1Priority Date: 2019-01-22
Thiazolopyridine derivatives as adenosine receptor antagonistsPublication Number: EP-3914600-B1Priority Date: 2019-01-22Grant Date: 2024-08-07
Thiazolopyridine derivatives as adenosine receptor antagonistsPublication Number: CN-113939520-BPriority Date: 2019-01-22Grant Date: 2024-11-22
Thiazolopyridine derivatives as adenosine receptor antagonistsPublication Number: ES-2992081-T3Priority Date: 2019-01-22Grant Date: 2024-12-09
Thiazolopyridine derivatives as adenosine receptor antagonists.Publication Number: JP-7600119-B2Priority Date: 2019-01-22Grant Date: 2024-12-16
Thiazolopyridine derivatives as adenosine receptor antagonistsPublication Number: AU-2020211697-A1Priority Date: 2019-01-22
Thiazolopyridine derivatives as adenosine receptor antagonistsPublication Number: KR-20210116572-APriority Date: 2019-01-22
Thiazolopyridine derivatives as adenosine receptor antagonistsPublication Number: CN-113939520-APriority Date: 2019-01-22
Thiazolopyridine derivatives as adenosine receptor antagonistsPublication Number: EP-3914600-A1Priority Date: 2019-01-22
Thiazolopyridine derivative as an adenosine receptor antagonistPublication Number: JP-2022524914-APriority Date: 2019-01-22
Combination therapy for cancerPublication Number: CN-117858723-APriority Date: 2021-06-07
Combination treatment of cancerPublication Number: EP-4351640-A1Priority Date: 2021-06-07
Combination Treatment of CancerPublication Number: JP-2024520764-APriority Date: 2021-06-07
Combination Treatment of CancerPublication Number: US-2024279338-A1Priority Date: 2021-06-07
Thiazolopyridine derivatives as adenosine receptor antagonistsPublication Number: WO-2020152132-A1Priority Date: 2019-01-22
Novel crystalline forms of (s)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2h-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide and co-crystal forms thereofPublication Number: TW-202415667-APriority Date: 2022-08-02
Novel crystalline forms of (s)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2h-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide and co-crystal forms thereofPublication Number: WO-2024028273-A1Priority Date: 2022-08-02
Combination treatment of cancerPublication Number: WO-2022258622-A1Priority Date: 2021-06-07
Combination treatment of cancerPublication Number: AU-2022288571-A1Priority Date: 2021-06-07
Combination treatment of cancerPublication Number: CA-3220380-A1Priority Date: 2021-06-07

PAT

WO-2020152132

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020152132&_cid=P10-MHPOEV-06540-1

1. (5R)-N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin- 2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide 24

and (5S)-N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5- c]pyridin-2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide 25

a. 4-chloro-5-iodo-3-nitropyridin-2-ol

Into a 250-mL round-bottom flask was placed 4-chloro-3-nitropyridin-2-ol (10.0 g, 54.4 mmol, 95%), N-lod-succinimid (NIS, 14.2 g, 59.9 mmol, 95%) in acetonitrile (115 mL). The solution was stirred for 1 h overnight at 80°C in an oil bath. The mixture was concentrated and the precipitate formed collected by filtration. The residue was washed with twice with petrol ether (500 mL) dried under vacuum at 60°C overnight. This resulted in 4-chloro-5-iodo-3-nitropyridin-2-ol (16.5 g, 97.9%, 97% purity) as a yellow solid. MS: m/z = 300.9 [M+H]⁺.

b. 4-chloro-5-iodo-2-methoxy-3-nitropyridine

Into a 500-mL round-bottom flask was placed 4-chloro-5-iodo-3-nitropyridin-2-ol (16.5 g, 53.3 mmol, 97%), Ag₂CO₃ (15.5 g, 53.3 mmol, 95%) in toluene (310 mL). To this suspension CH₃I (15.9 g, 107 mmol, 95%) was added at 50°C and the mixture was stirred at 80°C for 4 h. The precipitate was collected by filtration and discarded. The filtrate was evaporated to dryness under vacuum and the residue purified by silica gel chromatography with ethyl acetate/petroleum ether (15:85).

This resulted in 4-chloro-5-iodo-2-methoxy-3-nitropyridine (9.90 g, 52.6%, 89% purity) as a light yellow solid. MS: m/z = 315.5 [M+H]⁺.

c. 4-chloro-5-iodo-2-methoxypyridin-3-amine

Into a 250-mL 3-necked round-bottom flask was placed 4-chloro-5-iodo-2-methoxy-3-nitropyridine (9.90 g, 28.0 mmol, 89%), iron (16.5 g, 281 mmol, 95%) and NH ₄C (9.40 g, 174 mmol, 99%) in ethanol (152 mL) and water (30 mL). The mixture was stirred for 2 h at 80°C in an oil bath. The reaction mixture was filtered over Celite, washed with ethanol and the mother liquor was concentrated to dryness. The residue was stirred for 30 min. with 100 ml water at 60°dried in vacuo. This resulted in 4-chloro-5-iodo-2-methoxypyridin-3-amine (7.20 g, 75%, 83% purity) as an off-white solid. It was used without further purification in the next step. MS: m/z = 285.9 [M+H]⁺.

d. N-[7-iodo-4-methoxy-[1,3]thiazolo[4,5-c]pyridin-2-yl]benzamide

Into a 500-mL round-bottom flask was placed 4-chloro-5-iodo-2-methoxypyridin-3-amine (7.20 g, 21.0 mmol, 83%) in acetone (150 mL) and benzoyl isothiocyanate (5.21 g, 31.5 mmol, 99%) was added dropwise at room temperature. The solution was stirred for 1 h at 50 °C in an oil bath. The solids were collected by filtration, washed with acetone and dried in vacuo to give N-[7-iodo-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-yl]benzamide (8.73 g, 91 %, 90% purity) as a white solid. MS: m/z = 412.2 [M+H]⁺.

e. N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1,3]thiazolo[4,5-c]pyridin- 2-yl]benzamide

To a solution of N-[7-iodo-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-yl]benzamide (6.00 g, 13.1 mmol, 90%) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (6.13 g, 27.7 mmol, 95%) in dioxane (200 mL) and water (40.00 mL) were added NaOH (2.90 g, 68.9 mmol, 95%) and Pd(dppf)Cl₂^* dichloromethane (1.20 g, 1.40 mmol, 95%). After stirring for 1 h at 100°C under a nitrogen atmosphere, the mixture was concentrated to dryness under vacuo. The residue was purified by silica gel chromatography with ethyl acetate/hexane (95:5). This resulted in 3.32 g (62%, 90% purity) of N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-yl]benzamide as colorless solid. MS: m/z = 368.1 [M+H]⁺.

f. 7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1,3]thiazolo[4,5-c]pyridin-2- amine

To a stirred mixture of N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-yl]benzamide (3.27 g, 8.00 mmol, 90%) in water/methanol (1 :1 , 300 mL) was added NaOH (3.36 g, 80.0 mmol, 95%) at room temperature under nitrogen atmosphere. The mixture was stirred for overnight at 90°C under nitrogen atmosphere and evaporated to dryness. The residue was taken up in water and extracted 3 times with dichloromethane (100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography, eluted with petrol ether/ethyl acetate (1 :1) to afford 7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-amine (1.50 g, 68%, 96% purity) as a light brownish solid. MS: m/z = 264.1 [M+H]⁺.

g. phenyl N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy- [1,3]thiazolo[4,5c]pyridin-2-yl]-N-(phenoxycarbonyl)carbamate

To a stirred solution of 7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-amine (600 mg, 2.19 mmol, 96%) and phenyl chloroformate (1.81 g,

11.0 mmol, 95%) in THF (50 mL) was added K₂CO₃ (1.59 g, 11.0 mmol, 95%) and pyridine (913 mg, 11.0 mmol, 95%) at room temperature under nitrogen

atmosphere. The mixture was stirred for 6 h at 50° and then after re-cooling to room temperature quenched by the addition of water (300 mL). The mixture was extracted 3 times with dichloromethane (200 mL), the combined organic layers were washed once with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness under reduced pressure. This resulted in phenyl N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-yl]-N-(phenoxycarbonyl)carbamate (1.00 g, 69%, 76% purity) as a light yellow solid. The crude product was used in the next step directly without further purification. MS: m/z = 504.1 [M+H]⁺.

h. N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1,3]thiazolo[4,5-c]pyridin- 2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide

To a mixture of phenyl N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-yl]-N-(phenoxycarbonyl)carbamate (1.00 g, 1.52 mmol, 76.) and bis(7-oxa-2-azaspiro[4.5]decane), oxalic acid (1.19 g, 3.03 mmol, 95%) in THF (50 mL) was added diisopropylethyl amine (1.24 g, 9.09 mmol, 95%) at room temperature under nitrogen atmosphere. The mixture was stirred for 1 h at 60°. After re-cooling to room temperature, the mixture was extracted twice with dichloromethane (100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography, eluted with petrol ether/ethyl acetate (1 :1) to afford N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide (600 mg, 92%) as a white solid. HPLC: 99.9 % purity, RT = 1.17 min. MS: m/z = 431.1 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) d 1 1.37 (s, 1 H), 7.95 (s, 1 H), 6.25 (s, 1 H), 4.30-4.29 (m, 2H), 3.99 (s, 3H), 3.89 (t, J=5.4Hz, 2H), 3.61-3.29 (m, 8H), 2.55-2.51 (m, 2H), 1.82-1.54 (m, 6H).

i. (5R)-N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin- 2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide 24

and (5S)-N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5- c]pyridin-2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide 25

N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide (450 mg, 1.044 mmol, 1 equiv, 99.9%) was purified by chiral-preparative HPLC (Preparative HPLC-032, column: ChiralPak IA, 2*25cm, 5 mm; mobile phase, dichloromethane:ethanol (20:80); detector, UV). This resulted in (5R)-N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide (178 mg, 39%) as a white solid. HPLC: 99.7 % purity, RT (chiral) = 3.86 min, 100% ee. MS: m/z = 431.2 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) d 1 1.36 (s, 1 H), 7.94 (s, 1 H), 6.24 (s, 1 H), 4.29-4.27 (m, 2H), 3.97 (s,3H), 3.88 (t, J=5.2 Hz, 2H), 3.51-3.19 (m, 8H), 2.55-2.50 (m, 2H), 1.83-1.53 (m, 6H) and (5S)-N-[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-[1 ,3]thiazolo[4,5-c]pyridin-2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide (171 mg, 38%) as a white solid. HPLC: 99.8 % purity, RT (chiral) = 5.23 min, 99.9% ee. MS: m/z = 431.2 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) d 1 1.35 (s, 1 H), 7.94 (s, 1 H), 6.24 (s, 1 H), 4.29-4.28 (m, 2H), 3.99 (s, 3H), 3.88-3.85 (m, 2H), 3.61-3.29 (m, 8H), 2.55-2.50 (m,2H), 1.83-1.53 (m,6H).

PAT

WO-2024028273-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024028273&_cid=P10-MHPOFP-06905-1