Novel therapeutic uses of H3-ligands

文档序号：1431350 发布日期：2020-03-17 浏览：33次中文

阅读说明：本技术 H3-配体的新治疗用途 (Novel therapeutic uses of H3-ligands ) 是由 J-M.勒康特 J-C.施瓦特兹 M·卡派特 O·拉伯尤于 2018-03-21 设计创作，主要内容包括：本发明涉及高效H3-配体(3S)-4-{4-[3-(3-甲基哌啶-1-基)丙氧基]苯基}吡啶1-氧化物的新治疗用途,包括低剂量施用。(The present invention relates to novel therapeutic uses of the highly potent H3-ligand (3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide, including low dose administration.)

1. (3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide of formula (a) or a pharmaceutically acceptable salt thereof and/or a solvate of said compound (a) or a salt thereof:

for use in the treatment and/or prevention of a disorder selected from alzheimer's disease; attention is paid; arousal and cognitive impairment; cognitive deficits in psychiatric pathological states; cognitive, mood and insomnia disorders, especially in the elderly; depression or debilitating conditions; parkinson's disease; obstructive sleep apnea; dementia with lewy bodies; vascular dementia; vertigo; motion sickness; obesity; diabetes and metabolic syndrome; sleep disorders; stress; a psychiatric disorder; epilepsy; depression; narcolepsy with or without cataplexy; disorders of hypothalamic pituitary secretion, cerebral circulation and/or the immune system; excessive daytime sleepiness, such as excessive daytime sleepiness and fatigue associated with parkinson's disease, obstructive sleep apnea, or dementia; substance, in particular alcohol abuse disorders; prevention of substance abuse withdrawal syndrome; attention deficit disorder; post-stroke fatigue, mood, cognitive and insomnia disorders; cognitive disorders in autism; chronic pain and chronic fatigue; ADHD (attention deficit hyperactivity disorder) or attention and insomnia disorders after cerebrovascular accident in a child or an adult, wherein said use comprises administering compound (a) or a pharmaceutically acceptable salt thereof and/or said salt or a solvate of said compound (a) in a human at a dose of base comprised between 10-90 μ g per day, relative to compound (a) in base form.

2. Compound (a) for use according to claim 1, wherein sleep disorders comprise insomnia, disorders of sleep initiation and maintenance, sleep fragmentation, parasomnia, REM sleep disorders, sleep disordered breathing, circadian rhythm disorders, narcolepsy with or without cataplexy, daytime hypersomnia (including "sleep onset"), such as that associated with parkinson's disease, obstructive sleep apnea or dementia.

3. Compound (A) for use according to claim 1 or 2, wherein compound (A) is in the form of its pharmaceutically acceptable salt, such as hydrochloride, oxalate, dihydrochloride, hydrobromide, dihydrobromide, naphthalene-1, 5-disulfonate, sulfate, ethane-1, 2-disulfonate, cyclohexylsulfamate, tosylate, p-toluenesulfonate, thiocyanate, nitrate, methanesulfonate, dodecylsulfate, naphthalene-2-sulfonate, benzenesulfonate, dichloroacetate, glycerophosphate, 2-hydroxyethanesulfonate, aspartate, maleate, phosphate, ethanesulfonate, camphor-10-sulfonate, glutamate, alginate, pamoate, 2-oxo-glutarate, 1-hydroxy-2-naphthoate, benzoate, pamoate, salt, napsylate, naproxylate, or a salt thereof, Malonate, gentisate, salicylate, tartrate, fumarate, galactarate, citrate, glucuronate, lactobionate, 4-aminosalicylate, glycolate, sesquiglycolate, glucoheptonate, pyroglutamate, mandelate, malate, hippurate, formate, gluconate, lactate, oleate, ascorbate, benzoate, succinate, 4-acetamidobenzoate, glutarate, cinnamate, adipate, sebacate, camphorate, acetate, hexanoate, nicotinate, isobutyrate, propionate, caraate, laurate, palmitate, stearate, undecene-10-carboxylate, octanoate, orotate, carbonate, 5-sulfosalicylate, 1-hydroxy-2-naphthoate, caprylate, orotate, fumarate, caprylate, capryl, caprylate, 3-hydroxy-2-naphthoate; and/or solvates such as hydrates, ethanolates, hemi-ethanolates.

4. Compound (a) or a pharmaceutical salt thereof for use according to claim 1,2 or 3, wherein compound (a) is in the form of the hydrochloride salt.

5. Compound (a) or a pharmaceutical salt thereof for use according to any one of the preceding claims, wherein compound (a) is in the form of the dihydrochloride salt.

6. Compound (a) or a pharmaceutical salt thereof for use according to any one of the preceding claims, wherein compound (a) is in the form of the tetrahydrate of the dihydrochloride salt.

7. Compound (a) or a pharmaceutical salt thereof for use according to any one of the preceding claims, wherein the daily dose for administration to a human patient is comprised between 20-50 μ g per day (relative to compound (a) in base form).

8. Compound (a) or a pharmaceutical salt thereof for use according to any one of the preceding claims, wherein the daily dose for administration to a human is comprised between 30-45 μ g per day (relative to compound (a) in base form).

9. Compound (a) or a pharmaceutical salt thereof for use according to any one of the preceding claims, wherein compound (a) is administered 1 time per day or 1 time per 2 days.

10. Compound (a) or a pharmaceutical salt thereof for use according to any one of the preceding claims, wherein compound (a) is administered 1 time per day.

11. Compound (a) or a pharmaceutical salt thereof for use according to any one of the preceding claims, wherein compound (a) is administered via the oral route.

12. Compound (a) for use according to any one of the preceding claims, selected from:

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide dihydrochloride tetrahydrate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide oxalate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide L-tartrate and its trihydrate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide pamoate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide fumarate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide p-toluenesulfonate and its disesquihydrate (2.5)

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide 1, 5-naphthalenedisulfonate and its hemiethanolate monohydrate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide phosphate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide hydrobromide;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide 1, 2-ethane disulfonate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide sulfate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide dihydrobromide salt;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide orotate and its dihydrate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide 5-sulfosalicylate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide 1-hydroxy-2-naphthoate and its monohydrate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide 3-hydroxy-2-naphthoate;

(3S) -4- {4- [3- (3-methylpiperidin-1-yl) propoxy ] phenyl } pyridine 1-oxide (sesqui) glycolate and its monohydrate.

13. A compound selected from: