Muscarinic antagonists

Details Muscarinic antagonists Muscarinic antagonists

2002-10-08

2004-12-14

Chang, Celia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S314000, C514S318000, C546S168000, C546S186000, C546S189000, C546S191000

Reexamination Certificate

active

06831089

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds useful in the treatment of cognitive disorders, pharmaceutical compositions containing the compounds, methods of treatment using said compounds of the present invention, and to the use of said compounds in combination with acetylcholinesterase inhibitors.
BACKGROUND OF INVENTION
Alzheimer's disease and other cognitive disorders have received much attention lately, yet treatments for these diseases have not been very successful. According to Melchiorre et al. (J. Med. Chem. (1993), 36, 3734-3737), compounds that selectively antagonize M2 muscarinic receptors, especially in relation to M1 muscarinic receptors, should possess activity against cognitive disorders. Baumgold et al. (Eur. J. of Pharmacol., 251, (1994) 315-317) disclose 3-&agr;-chloroimperialine as a highly selective M2 muscarinic antagonist.
The present invention is predicated on the discovery of a class of 1,4-di-substituted piperidines, some of which have M2 selectivity even higher than that of 3-&agr;-chloroimperialine. Logemann et al (Brit. J. Pharmacol. (1961), 17, 286-296) describe certain di-N-substituted piperazines, but these are different from the compounds of the present invention. Furthermore, the compounds of Logemann et al. are not disclosed to have activity against cognitive disorders.
SUMMARY OF THE INVENTION
In one aspect, the present application provides a compound having the general structure shown in Formula I:
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
Z is N, C(H), or C-(alkyl);
X is —O—, —S—, —SO—, —S(O)
2
—, —C(O)—, —CH
2
—, or —C(S);
R
3
is 1 to 5 substituents which can be the same or different, each said substituent being either alkoxy or halo;
R
4
is hydrogen or 1 to 3 substituents which can be the same or different, each said substituent being either alkyl or haloalkyl;
R
27
is hydrogen or 1 or 2 subsitutents which can be the same or different, each said substituent being independently selected from the group consisting of alkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, alkylthio, alkylthioalkylene, carboxyalkyl, imidazolyalkyl and indolyalkyl;
R
28
is hydrogen or 1 or 2 subsitutents which can be the same or different, each said substituent being independently selected from the group consisting of alkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, alkylthio, alkylthioalkylene, carboxyalkyl, imidazolyalkyl and indolyalkyl; or R
27
and R
28
can be joined together to form an alkylene group;
R
29
is hydrogen, alkyl, —C(O)-alkyl, —C(O)-cycloalkyl, alkoxycarbonyl, aminocarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, arysulfonyl or —SO
2
—NH—R
35
;
R
31
is hydrogen or 1 or 2 subsitutents which can be the same or different, each said substituent being independently selected from the group consisting of alkyl, aryl, cycloalkyl, hydroxyalkyl, aminoalkyl, hydroxy, —N(R
35
)
2
, —O-acyl, —N(R
35
)acyl, —OC(O)OR
35
and —OC(O)N(R
35
)
2
;
R
32
is hydrogen or 1 or 2 subsitutents which can be the same or different, each said substituent being independently selected from the group consisting of alkyl, aryl, cycloalkyl, hydroxyalkyl, aminoalkyl, hydroxy, —N(R
35
)
2
, —O-acyl, —N(R
35
)acyl, —OC(O)OR
35
and —OC(O)N(R
35
)
2
, or R
31
and R
32
can be joined together to form the group —(CH
2
)
r
—, wherein r is 1, 2, 3, 4, 5 or 6;
R
33
is aryl or heteroaryl with the proviso that when R
33
is heteroaryl, the C(O)—R
33
bond is to a carbon atom in the R
33
group;
and
R
35
is hydrogen, aryl or alkyl.
The compound of formula I can be useful as M2 muscarinic receptor antagonists and can be useful in the treatment of Alzheimer's disease and other neurodegenerative or cognitive diseases. Another embodiment of this invention is directed to pharmaceutical compositions for the treatment of neurodegenerative or cognitive diseases. The compositions comprise a disease- or disorder-treating amount of a compound of formula I, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier therefor.


REFERENCES:
patent: 6294554 (2001-09-01), McComble et al .
patent: 6602885 (2003-08-01), Baroudy et al.
patent: WO 98/05292 (1998-02-01), None
Baroudy et al. “Preparation of piperidine derivatives as CCR5 antagonists” CA 136:369611 (2002).*
Miyasawa et al. “Optically active compounds . . . ” Ca 128:134484 (1998).*
Copy of International Search Report for PCT/US/ 02/32199 dated Oct. 8, 2002—5 Pages.
Logemann et al., “Influence of Dichloroacetylation on the Antimicrobial Activity of Chloramphenicol Derivatives and of Various Amines,” Brit. J. Pharmacology. 17:286-296 (1961).
Melchiorre et al., “Synthesis and Biological Activity of Some Methoctramine-Related Tetraamines Bearing a 11-Acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one Moiety as Antimuscarinics: A Second Generation of Highly Selective M2Muscarinic Receptor Antagonists” J. Med. Chem. 36:3734-3737 (1993).
Baumgold et al., “3-&agr;-Chlorimperialine: an M2-selective muscarinic receptor antagonist that penetrates into brain” Eur. J. Pharmacol. 251:315-317 (1994).

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