Muscarinic antagonists

Details Muscarinic antagonists Muscarinic antagonists

2000-02-28

2002-09-17

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S316000, C514S318000, C514S326000, C544S238000, C546S187000, C546S193000, C546S194000, C546S212000, C546S213000

Reexamination Certificate

active

06451797

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to heteroaromatic derivatives of di-N-substituted piperazines and 1,4-di-substituted piperidines useful in the treatment of cognitive disorders, pharmaceutical compositions containing. the compounds, methods of treatment using the compounds, and to the use of said compounds in combination with acetylcholinesterase inhibitors.
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.
Logemann et al (Brit. J. Pharmacol. (1961), 17, 286-296) describe certain di-N-substituted piperazines, but these are different from the inventive compounds of the present invention. Furthermore, the compounds of Logemann et al. are not disclosed to have activity against cognitive disorders.
WO 96/26196 discloses benzylpiperidines and piperazines useful as muscarinic antagonists.
SUMMARY OF THE INVENTION
The present invention relates to compounds according to the structural formula I,
including all stereoisomers and pharmaceutically acceptable salts and solvates thereof,
wherein one of Y and Z is —N— and the other is —N— or —CH—;
X is —O—, —S—, —SO—, —SO
2
— or —CH
2
—;
Q is
R is (C
1
-C
20
)alkyl, (C
3
-C
12
)cycloalkyl, aryl, R
8
-aryl or heteroaryl;
R
1
, R
2
and R
3
are independently selected from the group consisting of H and (C
1
-C
20
)alkyl;
R
4
is (C
1
-C
20
)alkyl, (C
3
-C
12
)cyclolalkyl or
R
5
is H, (C
1
-C
20
)alkyl, —C(O)(C
1
-C
20
)alkyl, R
9
-arylcarbonyl, —SO
2
(C
1
-C
20
)alkyl, R
9
-arylsulfonyl —C(O)O(C
1
-C
20
)alkyl, R
9
-aryloxy-carbonyl, —C(O)NH-(C
1
-C
20
)alkyl or R
9
-arylaminocarbonyl;
R
6
is H or (C
1
-C
20
)alkyl;
R
7
is H, (C
1
-C
20
)alkyl, hydroxy(C
1
-C
20
)alkyl or (C
1
-C
20
)-alkoxy(C
1
-C
20
)alkyl;
R
8
is 1-3 substituents independently selected from the group consisting of H, (C
1
-C
20
)alkyl, halogen, hydroxy, (C
1
-C
20
)alkoxy or hydroxy(C
1
-C
20
)alkyl, or two adjacent R
8
groups may be joined to form a (C
1
-C
2
)alkylenedioxy group; and
R
9
is 1-3 substituents independently selected from the group consisting of H, (C
1
-C
20
)alkyl, halogen, amino or (C
1
-C
20
)alkylamino.
In a preferred group of compounds Z is N.
In another preferred group of compounds R is R
8
-substituted phenyl, especially 3,4-methylenedioxyphenyl, 3-methylphenyl, 3-chlorophenyl or 4-methoxyphenyl.
X is preferably —CH
2
— or —SO
2
—.
Q is preferably
R
1
and R
2
are each preferably H; R
3
is preferably H or CH
3
.
In another group of preferred compounds, R
4
has the formula
wherein R
7
is H or CH
3
; R
6
is H: and R
5
is R
9
-arylcarbonyl, preferably R
9
-(1-naphthyl)C(O)—, especially wherein R
9
is fluoro, or R
9
-phenyl-C(O)—, especially wherein R
9
is 2-methyl, 2-amino, 2-bromo or 2-chloro.
Another aspect of the invention is a pharmaceutical composition which comprises an effective amount of a compound having structural formula I as defined above in combination with a pharmaceutically acceptable carrier.
Another aspect of the invention is the use of a compound formula I for the preparation of a pharmaceutical composition useful in the treatment of cognitive disorders and neurodegenerative diseases such as Alzheimer's disease.
Another aspect of this invention is a method for treating a cognitive or neurodegenerative disease comprising administering to a patient suffering from said disease an effective amount of a compound of formula I.
DETAILED DESCRIPTION
Except where stated otherwise the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “alkoxy”, etc.
Alkyl represents a straight or branched saturated hydrocarbon chain having 1 to 20 carbon atoms, more preferably 1 to 8 carbon atoms.
Cycloalkyl represents a saturated carbocyclic ring having 3 to 12 carbon atoms.
Halogen represents fluoro, chloro, bromo or iodo.
Aryl represents phenyl or naphthyl.
Heteroaryl refers to 5- to 10-membered single or benzofused aromatic rings comprising 1 to 4 heteroatoms independently selected from the group consisting of —O—, —S— and —N═, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Examples of benzofused heteroaryl groups are indolyl, quinolyl, benzo-thienyl (i.e., thianaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. N-oxides of nitrogen-containing heteroaryl groups are also included. 2-, 3-, 5- and 6-positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl and 6-pyridyl.
When a variable appears more than once in the structural formula, for example R
8
, the identity of each variable appearing more than once may be independently selected from the definition for that variable.
Compounds of this invention may exist in at least two stereo configurations based on the asymmetric carbon to which R
1
is attached, provided that R
1
and R
2
are not identical. Also within formula I there are numerous other possibilities for stereoisomerism. All possible stereoisomers of formula I are within the scope of the invention.
Compound of formula I can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention.
A compound of formula I may form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methane-sulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
Compounds of formula I may be produced by processes known to those skilled in the art as shown by the following reaction schemes:
Compounds of formula IA, wherein Y is N, Z is N, Q is thienylidene, X is SO
2
, R
4
is substituted piperidinyl and R
1
and R
2
are each H, can be prepared by reacting thiophenecarboxaldehyde with a 4-N-BOC-piperazine in the presence of sodium triacetoxy borohydride and acetic acid, followed by reaction with n-butyllithium and R-sulfonyl-fluoride. The BOC group is removed with acid and the resultant piperazine is reacted with a piperidone and sodium triacetoxy borohydride and acetic acid to obtain a compound of formula IA.
Compounds of formula IB, wherein Y is N, Q is pyridazinylidene, X is SO
2
, R
4
is substituted piperidinyl and R
1
and R
2
are each H, can be prepared by reacting an alkyl 6-chloropyridazine-3-carboxylate with a compound of the formula RSO
2
Na, reducing the resultant carboxylate to the aldehyde, and coupling an N-BOC-piperidyl su

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