MUSCARINIC COMBINATIONS AND THEIR USE FOR COMBATING HYPOCHOLINERGIC DISORDERS OF THE CENTRAL NERVOUS SYSTEM

• US 20190314354A1
• Filed: 04/23/2019
• Published: 10/17/2019
• Est. Priority Date: 03/06/2015
• Status: Abandoned Application

• Current Assignee: Chase Pharmaceuticals Corp. (Abbvie Incorporated)
• Original Assignee: Chase Pharmaceuticals Corp. (Abbvie Incorporated)
• Inventors: CHASE, Thomas N., CLARENCE-SMITH, Kathleen E.
• Application Number:
  US16/391,694
• Publication Number:
  US 20190314354A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/7023 Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006

Abstract

A combination of a muscarinic cholinergic receptor agonist, a non-anticholinergic antiemetic agent and a non-selective, peripheral anticholinergic agent for the treatment of hypocholinergic disorders of the central nervous system.

Claims

1. A pharmaceutical combination comprising as Components:

(a) a muscarinic cholinergic receptor agonist (MCRA)

(b) a non-anticholinergic antiemetic agent (naAEA); and

(c) a muscarinic receptor antagonist selected from the group consisting of the non-selective, peripheral anticholinergic agents (nsPAChAs).

2. The combination of claim 1, wherein said MCRA Component (a) is in a pharmaceutical composition in admixture with a pharmaceutical carrier;

said naAEA Component (b) is in a pharmaceutical composition in admixture with a pharmaceutical carrier, and said nsPAChA Component (c) is in a pharmaceutical composition in admixture with a pharmaceutical carrier.

3. The combination of claim 1, wherein said MCRA Component (a) is in a pharmaceutical composition in admixture with a pharmaceutical carrier;

said naAEA Component (b) is in a pharmaceutical composition in admixture with a pharmaceutical carrier, and said nsPAChA Component (c) is oxybutynin or a pharmaceutically acceptable salt thereof in a transdermal therapeutic system (TTS).

4. The combination of claim 3, wherein said MCRA Component (a) is selected from the group consisting of cevimeline and pharmaceutically acceptable salts thereof, milameline and pharmaceutically acceptable salts thereof;

xanomeline and pharmaceutically acceptable salts thereof, and MK-7622 and pharmaceutically acceptable salts thereof;

said naAEA Component (b) is selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, domperidone and pharmaceutically acceptable salts and solvates thereof and metoclopramide and pharmaceutically acceptable salt and solvates thereof; and

said nsPAChA Component (c) is oxybutynin in a transdermal patch.

5. The combination of claim 4, wherein said MCRA Component (a) is selected from the group consisting of cevimeline and pharmaceutically acceptable salts thereof, in an amount (in cevimeline) of from 34.5 mg to 180 mg;

milameline and pharmaceutically acceptable salts thereof, in an amount (in milameline) of from 2.4 mg to 12 mg;

xanomeline and pharmaceutically acceptable salts thereof, in an amount (in xanomeline) of from 90 mg to 450 mg; and

MK-7622 and pharmaceutically acceptable salts thereof, in an amount (in MK-7622) of from 5 mg to 270 mg;

in a pharmaceutical composition in admixture with a pharmaceutical carrier;

said naAEA Component (b) is selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in ondansetron) of from 4 mg to 64 mg, domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount, in domperidone of from 5 mg to 30 mg; and

metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount (in metoclopramide) of from 5 mg to 30 mg;

in a pharmaceutical composition in admixture with a pharmaceutical carrier; and

said nsPAChA Component (c) is oxybutynin in admixture with a pharmaceutical carrier or vehicle in a transdermal patch releasing from 3.9 mg/24 h to 7.8 mg/24 h oxybutynin.

6. The combination of claim 5, wherein said MCRA Component (a) is cevimeline or a pharmaceutically acceptable salt thereof;

said naAEA Component (b) is ondansetron or a pharmaceutically acceptable salt thereof; and

(c) said nsPAChA is oxybutynin in a transdermal patch releasing 3.9 mg/24 h oxybutynin.

7. A method for treating hypocholinergic disorders of the central nervous system, which comprises administering, to a patient in need of such a treatment, the combination according to claim 1.

8. The method of claim 7, wherein Component (a), Component (b) and Component (c) of the combination are administered concurrently or sequentially to a patient suffering from a hypocholinergic disorder of the central nervous system, each Component being administered to said patient by the same or by a different administration route.

9. The method of claim 8, wherein said hypocholinergic disorder of the central nervous system is selected from the group consisting of Alzheimer'"'"'s disease (AD), Alzheimer-type dementia, mild cognitive impairment, Lewy body disease, Parkinson'"'"'s disease dementia, Frontotemporal lobe dementia (FTD), Frontotemporal lobar degeneration, post-stroke dementia, vascular dementia, traumatic brain injury, Senile dementia, Autism, Down syndrome, anorexia nervosa, Tourette syndrome, tardive dyskinesia, Pick'"'"'s disease, Huntington'"'"'s disease, Friedrich'"'"'s ataxia, chronic neuropathic pain, falls, post-operative delirium, schizophrenia, Cognitive Impairment associated with Multiple Sclerosis, and other disorders of the nervous system involving a deficit in acetyl-choline neurotransmission.

10. The combination according to claim 1, for use in the treatment of hypocholinergic disorders of the CNS.

11. The combination of claim 10, wherein said hypocholinergic disorder of the central nervous system is selected from the group consisting of Alzheimer'"'"'s disease (AD), Alzheimer-type dementia, mild cognitive impairment, Lewy body disease, Parkinson'"'"'s disease dementia, Frontotemporal lobe dementia (FTD), Frontotemporal lobar degeneration, post-stroke dementia, vascular dementia, traumatic brain injury, Senile dementia, Autism, Down syndrome, anorexia nervosa, Tourette syndrome, tardive dyskinesia, Pick'"'"'s disease, Huntington'"'"'s disease, Friedrich'"'"'s ataxia, chronic neuropathic pain, falls, post-operative delirium, schizophrenia, Cognitive Impairment associated with Multiple Sclerosis, and other disorders of the nervous system involving a deficit in acetyl-choline neurotransmission.

12. The combination of claim 1, further comprising an AChEI.

13. A pharmaceutical combination comprising as Components:

(a) a muscarinic receptor antagonist selected from the group consisting of the non-selective, peripheral anticholinergic agents (nsPAChAs); and

(b) a muscarinic receptor agonist selected from the group consisting of cholinergic receptor agonists (CRA).

14. The combination of claim 13, wherein said muscarinic receptor antagonist is an nsPAChA selected from the group consisting of quaternary ammonium nsPAChAs, sulfonium nsPAChAs, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2 (1H)-iso-quinolinecarboxylate (solifenacin) and its pharmaceutically acceptable salts, 1-methylpiperidin-4-yl) 2,2-di(phenyl)-2-propoxyacetate (propiverine) and its pharmaceutically acceptable salts, 1,4,5,6-tetrahydro-1-methylpyrimidin-2-ylmethyl α

-cyclohexyl-α

-hydroxy-α

-phenylacetate (oxyphencyclimine) and its pharmaceutically acceptable salts, (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine (tolterodine) and its pharmaceutically acceptable salts, [2-[(1R)-3-(Di(propan-2-yl)amino)-1-phenylpropyl1-4-(hydroxymethyl)phenyl] 2-methylpropanoate (fesoterodine) and its pharmaceutically acceptable salts.

15. The combination of claim 14 wherein said quaternary ammonium nsPAChAs or sulfonium nsPAChAs has the formula (I)

wherein

R is a radical selected from the group consisting of those of formulas (a)-(e)

16. The combination of claim 13, wherein said muscarinic receptor antagonist is a nsPAChA selected from the group consisting of azoniaspiro[3β

-benziloyloxy-(1α

,5α

)-nortropane-8,1′

-pyrrolidine] (trospium) chloride, 3-[2-cyclopentyl(hydroxy)phenylacetoxy]-1,1-dimethylpyrrolidinium (glycopyrronium) bromide, solifenacin and the compound thereof with succinic acid (solifenacin succinate), propiverine and the hydrochloride thereof, oxyphencyclimine and the hydrochloride thereof, tolterodine and the hydrogen tartrate thereof, fesoterodine and the fumarate thereof

17. The combination of claim 13, wherein said muscarinic receptor agonist is a CRA selected from the group consisting of 1-methylpiperidine-4-spiro-5′

(2′

-ethyl-1′

,4′

-thiazoline-3′

-one) (AF267) and pharmaceutically acceptable salts and solvates thereof;

cis-2′

-methylspiro {1-azabicyclo [2.2.2] octane-3,5′

-[1,3] oxathiolane} (cevimeline) and pharmaceutically acceptable salts and solvates thereof;

3-[3-(3-(3-fluorophenyl)-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine and pharmaceutically acceptable salts and solvates thereof;

(E)-N-methoxy-1-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)methylamine (milameline) and pharmaceutically acceptable salts and solvates thereof 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione (RS-86) and pharmaceutically acceptable salts and solvates thereof;

(3R)-N-methoxyquinuclidine-3-carboximidoyl cyanide (sabcomeline) and pharmaceutically acceptable salts and solvates thereof;

(3R)-3-(prop-2-yn-1-yloxy)-1-azabicyclo[2.2.2]octane (talsaclidine) and pharmaceutically acceptable salts and solvates thereof 5-[4-(hexylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-methyl-1,2,3,6-tetrahydropyridine and pharmaceutically acceptable salts and solvates thereof;

3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1-methyl-5,6-dihydro-2H-pyridine (xanomeline), 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h] quinazolin-4(3H)-one (MK-7622) and pharmaceutically acceptable salts and solvates thereof

18-33. -33. (canceled)