Quinuclidine acrylamides

Details Quinuclidine acrylamides Quinuclidine acrylamides

2002-04-15

2003-11-04

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S305000, C514S304000, C514S412000, C514S414000, C514S299000, C544S316000, C546S133000, C546S112000, C546S121000, C546S124000, C546S125000, C546S126000, C548S452000, C548S465000

Reexamination Certificate

active

06642246

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel quinuclidine acrylamides or pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. A further object is to provide active compounds that are potent ligands for nicotinic acetylcholine receptors (nAChRs).
BACKGROUND OF THE INVENTION
The use of compounds which bind nicotinic acetylcholine receptors in the treatment of a range of disorders involving reduced cholinergic function such as Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, neuroprotection, schizophrenia, analgesia, Tourette's syndrome, and Parkinson's disease has been discussed in McDonald et al. (1995) “Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry and Pharmacology”, Chapter 5 in Annual Reports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc., San Diego, Calif.; and in Williams et al. (1994) “Neuronal Nicotinic Acetylcholine Receptors,” Drug News & Perspectives, vol. 7, pp. 205-223.
Quinuclidine acrylamide derivatives as potential antitussive agents are known in the art, in EP-A2-581,165. Indole derivatives are known in the art, e.g. in WO94/20465.
DISCLOSURE OF THE INVENTION
According to the invention it has been found that compounds of formula I, wherein:
A represents:
R represents hydrogen or methyl;
R
1
and R
2
are independently hydrogen, or C
1
-C
4
alkyl;
R
3
and R
4
are independently hydrogen, C
1
-C
4
alkyl or SAr, provided that at least one of R
3
and R
4
represents SAr;
Ar represents a 5- or 6-membered aromatic or heteroaromatic ring containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom or an 8-, 9- or 10-membered fused aromatic or heteroaromatic ring system containing zero to four nitrogen atoms, zero to one oxygen atom, and zero to one sulfur atom which may optionally be substituted with one or more substituents selected from: hydrogen, halogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, aryl, heteroaryl, —CO
2
R
5
, —CN, —NO
2
, —NR
6
R
7
, —CF
3
, —OR
8
;
R
5
, R
6
, R
7
, and R
8
are independently hydrogen, C
1
-C
4
alkyl, aryl, heteroaryl, —C(O)R
9
, —C(O)NHR
10
, —C(O)R
11
, —SO
2
R
12
, or,
R
6
and R
7
may together be (CH
2
)
j
Q(CH
2
)
k
where Q is O, S, NR
13
, or, a bond;
j is 2 to 7;
k is 0 to 2;
R
9
, R
10
, R
11
, R
12
, and R
13
, are independently C
1
-C
4
alkyl, aryl, or heteroaryl;
or an enantiomer thereof, and the pharmaceutically acceptable salts thereof are potent ligands for nicotinic acetylcholine receptors.
Unless otherwise indicated, the C
1
-C
4
alkyl groups referred to herein, e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl, s-butyl, whether alone or part of another group, may be straight-chained or branched, and the C
3
-C
4
alkyl groups may also be cyclic, e.g., cyclopropyl, cyclobutyl.
Unless otherwise indicated, aryl refers to a phenyl ring which may optionally be substituted with one to three of the following substituents chosen from among the following: halogen, C
1-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, CO
2
R
7
, —CN, —NO
2
, —NR
8
R
9
, —CF
3
, —OR
10
.
Unless otherwise indicated, heteroaryl refers to a 5- or 6-membered aromatic or heteroaromatic ring containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom, provided that the ring contains at least one nitrogen, oxygen, or sulfur atom, which may optionally be substituted with one or more substituents chosen from among the following: halogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, CO
2
R
5
, —CN, —NO
2
,—NR
6
R
7
, —CF
3
, —OR
8
.
Unless otherwise indicated, halogen refers to fluorine, chlorine, bromine, or iodine.
Pharmaceutically acceptable derivatives include solvates and salts. For example, the compounds of formula I can form acid addition salts with acids, such as the conventional pharmaceutically acceptable acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic acids.
In a preferred embodiment of this aspect of the invention, is compound according to formula I, wherein A represents:
or an enantiomer thereof, and the pharmaceutically acceptable salts thereof.
Preferred compounds of the invention include compounds of formula I wherein R
1
, R
2
, and one of R
3
or R
4
are hydrogen;
Preferred compounds of the invention further comprise compounds of formula I wherein Ar represents a 5- or 6-membered aromatic or heteroaromatic ring containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom, including phenyl, 2-pyridyl, or 2-pyrimidinyl, any of which may optionally be substituted with one or more substituents chosen from among the following: hydrogen, halogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, —CO
2
R
5
, —CN, —NO
2
, —NR
6
R
7
, —CF
3
, —OR
8
.
Preferred compounds of the invention further comprise compounds of formula I wherein Ar is an heteroaromatic ring.
Preferred compounds of the invention further comprise compounds of formula I wherein Ar is a 6-membered aromatic or heteroaromatic ring, containing zero to two nitrogen atoms.
Preferred compounds of the invention include the following:
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(phenylthio)propenamide]hydrochloride;
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(4-methylphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(4-methylphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(3-methylphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(3-methylphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(2-methylphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(2-methylphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(4-methoxyphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(4-methoxyphenylthio)propenamide]:
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(3-methoxyphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(3-methoxyphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(2-methoxyphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(2-methoxyphenylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(2-pyridylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(2-pyridylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(4-pyridylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(4-pyridylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(2-pyrimidinylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(2-pyrimidinylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(2-methyl-3-furanylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(2-methyl-3-furanylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(2-imidazolylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(phenylthio)-3-(methyl)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(2-benzothiazolylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(2-benzothiazolylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(1-methyl-2-imidazolylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(1-methyl-2-imidazolylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[E-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)propenamide];
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)[Z-3-(4-chlorophenylthio)pr

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