Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-17
2002-10-01
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S230000, C546S234000, C546S247000, C546S186000, C546S326000, C546S112000, C514S316000, C514S326000
Reexamination Certificate
active
06458812
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to amide derivatives of 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.
Piperidine-derivative muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer's disease are disclosed in U.S. Pat. No. 6,037,352. In particular, U.S. Pat. No. 6,037,352 discloses compounds of the generic formula:
wherein, inter alia, Y is CH; Z is N; X is —NHCO—; R is substituted benzyl; R
1
and R
21
are each H; R
3
, R
4
, R
27
and R
28
are hydrogen; and R
2
is cycloalkyl. Similar compounds wherein the benzene ring is replaced by a pyridinyl ring are disclosed in U.S. Pat. No. 6,066,636. Compounds of the present invention represent a selection invention over U.S. Pat. Nos. 6,037,352 and 6,066,636.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the structural formula I:
or a pharmaceutically acceptable salt, ester or solvate thereof, wherein
R
1
is R
5
—(C
3
-C
8
)cycloalkyl, R
5
—(C
3
-C
8
)cycloalkyl(C
1
-C
6
)alkyl, R
5
-aryl, R
5
-aryl-(C
1
-C
6
)alkyl or R
5
-heteroaryl;
R
2
is H, (C
1
-C
6
)alkyl, R
6
—(C
3
-C
8
)cycloalkyl, R
6
—(C
3
-C
8
)cycloalkyl-(C
1
-C
6
)alky, R
6
-heterocycloalkyl, R
6
—(C
6
-C
10
)bridged cycloalkyl, or R
6
-bridged heterocycloalkyl;
R
3
is C
1
-C
6
alkyl or —CH
2
OH;
R
4
is H or C
1
-C
6
alkyl;
R
5
is 1-4 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, halogen, —OH, C
1
-C
6
alkoxy, CF
3
, —CN, —CO
2
R
4
, —CONHR
4
, —SO
2
NHR
4
, —NHSO
2
R
4
and —NHC(O)R
4
; and
R
6
is 1-4 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, halogen, —OH, C
1
-C
6
alkoxy, CF
3
, —NH
2
, (C
1
-C
6
)alkylamino, phenyl, C
1
-C
2
alkylenedioxy, and (C
1
-C
6
)alkoxycarbonyl.
In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in a pharmaceutically acceptable carrier. The invention also relates to a method of using a compound of formula I or a pharmaceutical composition comprising a compound of formula I in the treatment of a cognitive disease or neurodegenerative disease comprising administering an effective amount of a compound or composition of this invention to a mammal in need of such treatment.
In still another aspect, the invention relates to a method for treating a cognitive disease or neurodegenerative disease comprising administering to a mammal in need of such treatment an effective amount of a combination of a compound of formula I and an acetylcholinesterase inhibitor.
In a final aspect, the invention relates to a kit for treating a cognitive disease or neurodegenerative disease comprising in separate containers in a single package pharmaceutical compositions for use in combination, in one container a compound of formula I in a pharmaceutically acceptable carrier and in a second container, an acetylcholinesterase inhibitor in a pharmaceutically acceptable carrier, the combined quantities being an effective amount.
DETAILED DESCRIPTION
Referring to formula I, above, one group of preferred compounds is that wherein R
1
is R
5
-phenyl or R
5
-cyclohexyl. R
5
is preferably H, halogen or C
1
-C
6
alkyl, more preferably H, F or —CH
3
.
Another group of preferred compounds is that wherein R
2
is R
6
—C
3
-C
8
cycloalkyl, especially R
6
—C
5
-C
7
cycloalkyl. R
6
is preferably H or C
1
-C
6
alkyl.
R
3
is preferably —CH
3
, and R
4
is preferably H.
Compared to the compounds specifically disclosed in U.S. Pat. No. 6,037,352 or U.S. Pat. No. 6,066,636, none of which contain the R
3
moiety, compounds of the present invention show greater m2 selectivity.
As used herein, the term “alkyl” represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. If the number of carbon atoms is not specified, e.g., if the term lower alkyl is used, chain lengths of 1 to 6 carbons are intended.
“Cycloalkyl” represents a saturated carbocyclic ring having 3 to 8 carbon atoms. Bridged cycloalkyl refers to cycloalkyl rings wherein two non-adjacent ring members are joined by a C
1
-C
2
alkyl chain.
The term “heterocycloalkyl ” refers to 4- to 7-membered saturated rings comprising 1 to 3 heteroatoms independently selected from the group consisting of —O—, —S—and —NR
7
—, wherein R
7
is H or C
1
-C
6
alkyl, and wherein the remaining ring members are carbon. Where a heterocyclic ring comprises more than one heteroatom, no rings are formed where there are adjacent oxygen atoms, adjacent sulfur atoms, or three consecutive heteroatoms. Examples of heterocyclic rings are tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. Bridged heterocycloalkyl refers to heterocycloalkyl rings wherein two non-adjacent carbon ring members are joined by a C
1
-C
2
alkyl chain.
Halogen represents fluoro, chloro, bromo or iodo.
Aryl represents phenyl or naphthyl.
Heteroaryl means a 5 or 6-membered aromatic ring comprising 1 to 3 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 heteroaryl groups are pyridyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl.
When a variable appears more than once in the structural formula, for example R
5
, the identity of each variable appearing more than once may be independently selected from the definition for that variable.
Compounds of the invention have at least one asymmetrical carbon atom, i.e., the carbon to which R
3
is attached. All isomers, including diastereomers, enantiomers and rotational isomers are contemplated as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I. The preferred stereochemistry of compounds of the invention is shown in formula IA:
Compounds 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, methanesulfonic 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 can be prepared using methods well known to those skilled in the art, for example by procedures disclosed in U.S. Pat. No. 6,037,352, incorporated herein by reference, or by parallel synthesis or combinatorial chemistry. The skilled artisan will recognize that other procedures may be applicable, and that the procedu
Guo Guihua
McKittrick Brian A.
Ye Yuanzan
Zhu Zhaoning
Coppins Janet L
Magatti Anita W.
Rotman Alan L.
Schering Corporation
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