COMPOUNDS AND COMPOSITIONS FOR COGNITION-ENHANCEMENT, METHODS OF MAKING, AND METHODS OF TREATING

• US 20120046273A1
• Filed: 03/05/2010
• Published: 02/23/2012
• Est. Priority Date: 03/05/2009
• Status: Abandoned Application

• Current Assignee: NeuroSolis, Inc.
• Original Assignee: Mithridion, Inc.
• Inventors: Twose, Trevor M., Abraham, Brent D., Copp, Richard R., Farnham, James G., Hanson, Seth A., Hendrickson, Michael L., Ockuly, Jeffrey C., Verdone, Melinda L.
• Application Number:
  US13/255,096
• Publication Number:
  US 20120046273A1
• Time in Patent Office: Days
• US Class Current: 514/217.1
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond

Abstract

Muscarinic agonists, which are useful for stimulating muscarinic receptors and treating cognitive disorders, are provided. Methods of synthesizing such agonists also are provided. Also provided are compositions for enhancing cognitive function in subjects such as humans, the compositions comprising a muscarinic agonist or a pharmaceutically suitable form thereof. Also provided are methods of treating animals such as humans by administering such compositions.

Claims

1. A compound of Formula 1:

2. A compound of claim 1 wherein R¹ is

3. A compound of claim 1 wherein R¹ is

4. A compound of claim 3 wherein R² and R³ are both D or both F.

5. A compound of claim 3 wherein R⁵, R⁶, and R⁷ are each D or F.

6. A compound of claim 3 wherein R², R³, R⁵, R⁶, R⁷ each may be D or H

7. A compound of claim 3 selected from the group consisting of:

A. R², R³, R⁵, R⁶, R⁷ each are D, and the compound is of the formula 3-(ethyl-d5)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole;

B. R² is H and R³, R⁵, R⁶, R⁷ are each D and the compound is of the formula 3-(ethyl-d4)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole;

C. R², R³, R⁵and R⁶ are each D and R⁷ is H and the compound is of the formula 3-(ethyl-d4)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole;

D. R² and R³ are each H and R⁵, R⁶, R⁷ are each D and the compound is of the formula 3-(ethyl-d3)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole;

E. R² and R⁶ are each H and R³, R⁵ and R⁷ are D and the compound is of the formula 3-(ethyl-d3)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole;

F. R³ and R⁶ are each H and R², R³ and R⁷ are D and the compound is of the formula 3-(ethyl-d3)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole;

G. R⁵, R⁶ and R⁷ are each H and R² and R³ are each D and the compound is of the formula 3-(ethyl-d2)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole;

H. R², R³ and R⁵ are each H and R⁶ and R⁷ are each D and the compound is of the formula 3-(ethyl-d2)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole;

I. R², R⁵ and R⁶ are each 1-1 and R³ and R⁷ are each D and the compound is of the formula 3-(ethyl-d2)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole;

J. R², R³, R⁵ and R⁶ are each H and R⁷ is D and the compound is of the formula 3-(ethyl-d1)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole; and

K. R², R⁵, R⁶ and R⁷ are each H and R³ is D and the compound is of the formula 3-(ethyl-d1)-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole.

8. A compound of claim 3, wherein R², R³, R³, R⁶ and R⁷ are each

9. A compound of claim 1 wherein R¹ is

10-14. -14. (canceled)

15. A compound of Formula 25-27 or stereoisomers of 25-27 or pharmaceutically acceptable salts thereof, wherein the compounds have the structures:

16. A compound of claim 15 wherein X is O.

17. A compound of claim 15 wherein X is S.

26. A compound of claim 15 selected from the group consisting of 3-(methyl)-5-(piperidin-3-yl)-1,2,4-oxadiazole, (R)-3-(methyl)-5-(piperidin-3-yl)-1,2,4-oxadiazole, (S)-3-(methyl)-5-(piperidin-3-yl)-1,2,4-oxadiazole, 3-methyl-5-(4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3-methyl-5-((3S,4S)-4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3-methyl-5-((3R,4R)-4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 5-(3-fluoropiperidin-3-yl)-3-methyl-1,2,4-oxadiazole, (R)-5-(3-fluoropiperidin-3-yl)-3-methyl-1,2,4-oxadiazole, (S)-5-(3-fluoropiperidin-3-yl)-3-methyl-1,2,4-oxadiazole, 3-methyl-5-(piperidin-3-yl)-1,2,4-thiadiazole, (S)-3-methyl-5-(piperidin-3-yl)-1,2,4-thiadiazole, (R)-3-methyl-5-(piperidin-3-yl)-1,2,4-thiadiazole, 3-methyl-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole, (S)-3-methyl-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole, and (R)-3-methyl-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole

27. A compound of claim 15 selected from the group consisting of 3-(methyl-d3)-5-(piperidin-3-yl)-1,2,4-oxadiazole, (R)-3-(methyl-d3)-5-(piperidin-3-yl)-1,2,4-oxadiazole, (S)-3-(methyl-d3)-5-(piperidin-3-yl)-1,2,4-oxadiazole, 3-(methyl-d3)-5-(4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3-(methyl-d3)-5-((3S,4S)-4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3 -(methyl-d3)-5-((3R,4R)-4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 5-(3-fluoropiperidin-3-yl)-3-(methyl-d3)-1,2,4-oxadiazole, (R)-5-(3-fluoropiperidin-3-yl)-3-(methyl-d3)-1,2,4-oxadiazole, (S)-5-(3-fluoropiperidin-3-yl)-3-(methyl-d3)-1,2,4-oxadiazole, 3-(methyl-d3)-5-(piperidin-3-yl)-1,2,4-thiadiazole, (S)-3-(methyl-d3)-5-(piperidin-3-yl)-1,2,4-thiadiazole, (R)-(methyl-d3)-5-(piperidin-3-yl)-1,2,4-thiadiazole, (methyl-d3)-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole, (S)-3-(methyl-d3)-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole, and (R)-3-(methyl-d3)-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole;

28. A compound of claim 15 selected from the group consisting of 3-(methyl-d2)-5-(piperidin-3-yl)-1,2,4-oxadiazole, (R)-3-(methyl-d2)-5-(piperidin-3-yl)-1,2,4-oxadiazole, (S)-3-(methyl-d2)-5-(piperidin-3-yl)-1,2,4-oxadiazole, 3-(methyl-d2)-5-(4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3-(methyl-d2)-5-((3S,4S)-4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3-(methyl-d2)-5-((3R,4R)-4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 5-(3-fluoropiperidin-3-yl)-3-(methyl-d2)-1,2,4-oxadiazole, (R)-5-(3-fluoropiperidin-3-yl)-3-(methyl-d2)-1,2,4-oxadiazole, (S)-5-(3-fluoropiperidin-3-yl)-3-(methyl-d2)-1,2,4-oxadiazole, 3-(methyl-d2)-5-(piperidin-3-yl)-1,2,4-thiadiazole, (S)-3-(methyl-d2)-5-(piperidin-3-yl)-1,2,4-thiadiazole, (R)-(methyl-d2)-5-(piperidin-3-yl)-1,2,4-thiadiazole, (methyl-d2)-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole, (S)-3-(methyl-d2)-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole, and (R)-3-(methyl-d2)-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole

29. A compound of claim 15 selected from the group consisting of 3-(methyl-d1)-5-(piperidin-3-yl)-1,2,4-oxadiazole, (R)-3-(methyl-d1)-5-(piperidin-3-yl)-1,2,4-oxadiazole, (S)-3-(methyl-d1)-5-(piperidin-3-yl)-1,2,4-oxadiazole, 3-(methyl-d1)-5-(4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3-(methyl-d1)-5-((3S,4S)-4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3-(methyl-d1)-5-((3R,4R)-4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 5-(3-fluoropiperidin-3-yl)-3-(methyl-d1)-1,2,4-oxadiazole, (R)-5-(3-fluoropiperidin-3-yl)-3-(methyl-d1)-1,2,4-oxadiazole, (S)-5-(3-fluoropiperidin-3-yl)-3-(methyl-d1)-1,2,4-oxadiazole, 3-(methyl-d1)-5-(piperidin-3-yl)-1,2,4-thiadiazole, (S)-3-(methyl-d1)-5-(piperidin-3-yl)-1,2,4-thiadiazole, (R)-(methyl-d1)-5-(piperidin-3-yl)-1,2,4-thiadiazole, (methyl-d1)-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole, (S)-3-(methyl-d1)-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole, and (R)-3-(methyl-d1)-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole.

18-25. -25. (canceled)

30-32. -32. (canceled)

33. A method comprising treating a compound of Formula 2 or a salt thereof

34. The method of claim 33 wherein the formate ester equivalent is selected from triethylorthoformate, trimethylorthoformate, diethoxymethyl acetate or ethyl formate.

35. (canceled)

36. The method of claim 35, wherein the base-stable N-protecting groups are selected from t-butyloxycarbonyl, benzyloxycarbonyl, or chlorobenzyloxycarbonyl.

37-70. -70. (canceled)

71. A pharmaceutical composition for administration to a subject in need thereof comprising:

(i) an amount of at least one M1 or M1/M4 selective muscarinic agonist, or a pharmaceutically acceptable form thereof, sufficient to achieve a cognition-enhancing effect in said subject,

wherein the amount of said at least one M1 or M1/M4 selective muscarinic agonist is sufficient to cause at least one moderate cholinergic side effect in said subject, said cholinergic side effect being selected from the group consisting of diaphoresis, hypersalivation, flushing, gastro-intestinal tract upsets, increased stomach acid, nausea, vomiting and diarrhea, breathing difficulties, tachycardia, dizziness, syncope, headache, convulsions, somnolence and combinations thereof, and

(ii) an amount of at least one muscarinic antagonist, or pharmaceutically acceptable form thereof, sufficient to cause said at least one cholinergic side effect to be at most mild in said subject.

73. A pharmaceutical composition of claim 71, wherein said at least one M1 or M1/M4 selective muscarinic agonist is MCD-386.

74. A pharmaceutical composition of claim 73, wherein said amount of MCD-386 present in said composition is sufficient to produce a sacrum or plasma concentration in a human subject within a range selected from the group consisting of at least 25-30 ng/ml, at least 30-35 ng/ml, at least 40-45 ng/ml and at least 45-50 ng/ml.

72. (canceled)

75-85. -85. (canceled)

86. A method for treating a subject with a cognitive disorder comprising:

administering to said subject a at least one muscarinic agonists, wherein said at least one muscarinic agonists is an M1 or M1/M4 selective muscarinic agonist and wherein the amount of M1 or M1/M4 selective muscarinic agonist is sufficient to achieve in the blood stream of the subject, in the absence of a muscarinic antagonist, a concentration sufficient to cause the subject to experience at least one moderate cholinergic side effect selected from the group consisting of diaphoresis, hypersalivation, flushing, gastro-intestinal tract upsets, increased stomach acid, nausea, vomiting and diarrhea, breathing difficulties, tachycardia, dizziness, syncope, headache, convulsions, somnolence and combinations thereof, and

administering to said subject at least one muscarinic antagonist, wherein the amount of said at least one muscarinic antagonist is sufficient to achieve in the blood stream of said subject a concentration of said at least one muscarinic antagonist sufficient to cause the subject to experience at most only mild or moderate cholinergic side effects during at least a portion of the time that the antagonist is present in the blood stream.

87. The method of claim 86, wherein the subject experiences at most only mild cholinergic side effects during at least a portion of the time that the antagonist is present in the blood stream.

88-101. -101. (canceled)

102. A pharmaceutical composition for administration to a human subject in need thereof comprising:

(i) an amount of at least one selective muscarinic agonist, or a pharmaceutically acceptable form thereof, sufficient to achieve a cognition-enhancing effect in said subject, and

(ii) an amount of at least one muscarinic antagonist, or pharmaceutically acceptable form thereof,

wherein the pharmaceutical composition causes at most mild cholinergic side effects when administered to a human subject.

103. A pharmaceutical composition according to claim 102, wherein the muscarinic antagonist is fesoterodine or a salt thereof.

104. A pharmaceutical composition according to claim 103, wherein the muscarinic antagonist is fesoterodine fumarate.

105. A pharmaceutical composition according to claim 103, wherein the muscarinic antagonist is a chloride salt of fesoterodine.

106-112. -112. (canceled)