Xanomeline, Hexyloxy-TZTP, NNC-11-0232, LY-246708, Lumeron, Memcor

3-Hexyloxy-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

131986-45-3, 152854-19-8 (monotartrate), 141064-23-5 (oxalate salt)

C14-H23-N3-O-S

281.4217

Lilly (Originator), Novo Nordisk (Originator)

Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS

Phase II

　

J Med Chem

Novel functional M1selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines

The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol.

Sauerberg, P.; Olesen, P.H.; Nielsen, S.; et al.

Sauerberg, P.; Olesen, P.H.; Nielsen, S.; et al.; Novel functional M1selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines. J Med Chem 1992, 35, 12, 2274-83

J Med Chem1992,35,(12):2274-83

Drugs Fut

Xanomeline

The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol.

Graul, A.; Casta馿r, J.

Graul, A.; Casta馿r, J.; Xanomeline. Drugs Fut 1996, 21, 9, 911

Drugs Fut1996,21,(9):911

Synthesis The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II) (1), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V) (1-3). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol (1-4). Description Oxalate salt, crystals, m.p. 148-50癈 (1); oxalate salt, crystals, m.p. 148癈 (2-3); L-hydrogen tartrate, crystals, m.p. 95.5癈 (4). References 1. Sauerberg, P., Olesen, P.H., Nielsen, S. et al. Novel functional M1 selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines. J Med Chem 1992, 35: 2274-83. 2. Sauerberg, P., Olesen, P.H., Mich, C.H. (Novo Nordisk A/S). Heterocyclic cpds. and their preparation and use. EP 687265, WO 9420495. 3. Sauerberg, P., Olesen, P.H. (Novo Nordisk A/S). Piperidine cpds. and their preparation and use. EP 384288, US 5260311, US 5264444, US 5284859, US 5328925. 4. Osborne, L.M., Shipley, L.A., Treppendahl, S., Petersen, T.G. (Novo Nordisk A/S). Heterocyclic chemistry. WO 9429303.

EP 0384288; US 5260311; US 5264444; US 5328925

Piperidine cpds. and their preparation and use

The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol.

Sauerberg, P.; Olesen, P.H. (Ferrosan A/S)

Sauerberg, P.; Olesen, P.H. (Ferrosan A/S); Piperidine cpds. and their preparation and use. EP 0384288; US 5260311; US 5264444; US 5328925

EP 0384288; US 5260311; US 5264444; US 5328925,,():

EP 0687265; JP 1996507298; WO 9420495

Heterocyclic cpds. and their preparation and use

The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol.

Sauerberg, P.; Olesen, P.H.; Mitch, c.H. (Novo Nordisk A/S)

Sauerberg, P.; Olesen, P.H.; Mitch, c.H. (Novo Nordisk A/S); Heterocyclic cpds. and their preparation and use. EP 0687265; JP 1996507298; WO 9420495

EP 0687265; JP 1996507298; WO 9420495,,():

US 5834495; WO 9429303

Heterocyclic chemistry

The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol.

Osborne, L.M.; Shipley, L.A.; Treppendahl, S.; Petersen, T.G. (Novo Nordisk A/S)

Osborne, L.M.; Shipley, L.A.; Treppendahl, S.; Petersen, T.G. (Novo Nordisk A/S); Heterocyclic chemistry. US 5834495; WO 9429303

US 5834495; WO 9429303,,():