PHARMACEUTICAL COMPOSITION FOR TREATING ALZHEIMER'S DISEASE

• US 20100160290A1
• Filed: 04/23/2008
• Published: 06/24/2010
• Est. Priority Date: 04/24/2007
• Status: Active Grant

• Current Assignee: Shionogi & Co., Ltd.
• Original Assignee: Shionogi & Co., Ltd.
• Inventors: Suzuki, Shinji, Kato, Akira, Ueda, Kazuo, Yukimasa, Akira, Kanda, Yasuhiko, Haraguchi, Hidekazu, Yasui, Ken, Itoh, Naohiro, Hori, Akihiro, Kooriyama, Yuuji, Sakaguchi, Gaku, Kobayashi, Naotake
• Granted Patent: US 8,653,067 B2
• Time in Patent Office: Days
• US Class Current: 514/211.10
• 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 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 31/54 having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/14 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
• CPC Class Codes: C07D 265/08 having one double bond between ring members or between a ring member and a non-ring member
• CPC Class Codes: C07D 277/18 Nitrogen atoms
• CPC Class Codes: C07D 279/06 not condensed with other rings
• CPC Class Codes: C07D 281/02 Seven-membered rings
• CPC Class Codes: C07D 285/36 Seven-membered rings
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/192 from aromatic carboxylic acids
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

A pharmaceutical composition for treating Alzheimer'"'"'s disease containing a compound represented by the general formula (I);

• wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
• E is lower alkylene, etc.;
• X is S, O, or NR¹;
• R¹ is a hydrogen atom or lower alkyl;
• R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are each independently a hydrogen atom, halogen, hydroxy, etc.;
• n and m are each independently an integer of 0 to 3;
• n+m is an integer of 1 to 3; and
• R⁵ is a hydrogen atom, optionally substituted lower alkyl, etc.;
• its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient.

Claims

1. A pharmaceutical composition for treating Alzheimer'"'"'s disease containing a compound represented by the general formula (I):

wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,

wherein Alk¹ is lower alkylene or lower alkenylene;

R⁰ is a hydrogen atom, lower alkyl, or acyl;

X is S, O, or NR¹;

R¹ is a hydrogen atom or lower alkyl;

R^2a and R^2b are each independently a hydrogen atom, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted amino, optionally substituted amidino, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted carbamoylcarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group;

R^3a, R^3b, R^4a, and R^4b are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group;

n and m are each independently an integer of 0 to 3;

n+m is an integer of 1 to 3;

each R^3a, each R^3b, each R^4a, and each R^4b may be independently different;

R⁵ is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group;

R⁵ and ring A can be taken together to form

wherein R^5a and R^5b are each independently a hydrogen atom or lower alkyl;

s is an integer of 1 to 4;

each R^5a and each R^5b may be different;

with the proviso that the compound wherein n+m is 2;

R⁵ is a hydrogen atom; and

ring A is non-substituted phenyl is excluded,

its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient.

2. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 1, wherein X is S.

3. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 1, wherein n is 2 and m is 0.

4. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 1, wherein E is a bond.

5. A pharmaceutical composition for treating Alzheimer'"'"'s disease containing a compound represented by the general formula (I):

wherein each symbols are the same as described in claim 1, with the proviso that the compounds;

i) wherein n+m is 2, R⁵ is a hydrogen atom, and ring A is non-substituted phenyl;

ii) wherein n is 2, m is 0, R^2a is a hydrogen atom, R^2b is a hydrogen atom, acetyl, or phenyl, R⁵ is methyl, and ring A is phenyl or 4-methoxyphenyl;

iii) wherein n is 2, m is 0, R^2a is a hydrogen atom, R^2b is a hydrogen atom, acetyl, or phenyl, R⁵ is ethyl, and ring A is 3,4-dimethoxyphenyl;

iv) wherein n is 2, m is 0, R^2a is a hydrogen atom, R^2b is a hydrogen atom or acetyl, and R⁵ and ring A is phenyl;

v) wherein n is 2, m is 0, R^2a and R^2b are a hydrogen atom, R⁵ and ring A are taken together to form

wherein Me is methyl, and each symbols are the same as described above; and

vi) wherein n+m is 2,

R⁵ is a hydrogen atom, and

ring A is phenyl substituted with one or two substituent(s) selected from the group consisting of hydroxy, halogen, lower alkyl, lower alkoxy, nitro, amino, lower alkylcarbonylamino, mercapto, lower alkylthio, and carbamoyl,

non-substituted phenyl,

or non-substituted naphthyl;

are excluded,

its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient.

6. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein X is S.

7. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein n is 2 and m is 0.

8. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein R⁵ is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group.

9. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein R^2a is a hydrogen atom;

and R^2b is a hydrogen atom, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl, or optionally substituted amidino.

10. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein NR^2aR^2b is represented by the formula:

wherein R⁶, R⁷, and R⁸ are each independently a hydrogen atom, lower alkyl, or acyl;

Y is optionally substituted lower alkylene, optionally substituted lower alkenylene, or optionally substituted lower alkynylene; and

Z is O or S.

11. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein ring A is optionally substituted phenyl.

12. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein ring A is represented by the formula:

wherein R⁹, R¹⁰, and R¹¹ are a hydrogen atom or G;

G is halogen, hydroxy, cyano, nitro, mercapto, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkoxycarbonyloxy, optionally substituted lower aryloxycarbonyloxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted carbamoyloxy, optionally substituted lower alkylthio, optionally substituted arylthio, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted lower alkyl sulfinyl, optionally substituted arylsulfinyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, optionally substituted sulfamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy, an optionally substituted heterocyclic group, or optionally substituted heterocyclicoxy;

each G may be independently different.

13. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 12, wherein G is represented by the formula:

wherein Q¹, Q², and Q³ are each independently a bond, optionally substituted lower alkylene, or optionally substituted lower alkenylene;

Q⁴ is optionally substituted lower alkylene or optionally substituted lower alkenylene;

W¹ and W² are each independently O or S;

W³ is O, S, or NR¹²;

R¹² is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic lower alkyl, or acyl;

R¹⁴ is a hydrogen atom or lower alkyl;

ring B is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;

Alk² is optionally substituted lower alkyl; and

p is 1 or 2;

if there are multiple W¹, multiple W³ and multiple R¹², each are independently different.

14. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 13, wherein ring B is aryl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, cyano, optionally substituted carbamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy, and an optionally substituted heterocyclic group or

heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, cyano, optionally substituted carbamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy, and an optionally substituted heterocyclic group.

15. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 13, wherein G is represented by the formula:

16. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein R⁵ is C1 to C3 alkyl.

17. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein R⁵ is methyl.

18. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein R^3a and R^3b are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, or optionally substituted aryl.

19. The pharmaceutical composition for treating Alzheimer'"'"'s disease according to claim 5, wherein all of R^3a and all of R^3b are hydrogen atoms.

20. Use of the compound as defined in claim 1 in the manufacture of a medicament for the treatment of Alzheimer'"'"'s disease.

21. A method for treating Alzheimer'"'"'s disease characterizing in administering the compound as defined in claim 1.

22. Use of the compound as defined in claim 5 in the manufacture of a medicament for the treatment of Alzheimer'"'"'s disease.

23. A method for treating Alzheimer'"'"'s disease characterizing in administering the compound as defined in claim 5.