Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-17
2004-01-27
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S305000, C546S135000
Reexamination Certificate
active
06683090
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This is a 371 filing of International Application No. PCT/SE00/02262 filed Nov. 16, 2000, pending, which claims priority under the Paris Convention of Application No. 9904176-6 filed in Sweden on Nov. 18, 1999.
TECHNICAL FIELD
This invention relates to new medical use of quinuclidine acrylamides or pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing them. The present invention also relates to certain novel quinuclidine acrylamides or pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing them. In particular the invention relates to the use of quinuclidine acrylamnides for the preparation of medicaments for the treatment or prophylaxis of psychotic disorders or intellectual impairment disorders, as well as in the treatment and/or prophylaxis of human diseases or conditions in which activation of the &agr;7 nicotininc receptor is beneficial.
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.
The use of certain quinuclidine acrylamide derivatives, as to which the present invention has found a new pharmacological use, is known from EP 581165-A2 to have effect as antitussives. The antitussive activity of the compounds was described as being “without effects on the central nervous system”, and the use of the compounds for the treatment of diseases involving the central nervous system was not suggested.
DISCLOSURE OF THE INVENTION
According to the present invention it has been found that compounds of the general formula I:
wherein:
A represents:
D represents oxygen, or sulfur;
R
1
represents hydrogen or methyl;
R
2
represents hydrogen, or C
1
-C
4
alkyl;
R
3
represents:
R
4
, R
5
, and R
6
are independently hydrogen, halogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, —CO
2
R
7
, —CN, —CF
3
, or Ar, provided that at least one of R
4
and R
5
represents Ar; 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 atoms, and zero to one sulfur atoms which may optionally be substituted with one or more substituents selected from the following: hydrogen, halogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, aryl, heteroaryl, —CO
2
R
7
, —CN, —NO
2
, —NR
8
R
9
, —CF
3
, —OR
10
;
R
8
, R
9
, and R
10
are independently hydrogen, C
1
-C
4
alkyl, aryl, heteroaryl, —C(O)R
11
, —C(O)NHR
12
, —C(O)R
13
, —SO
2
R
14
or R
8
and R
9
may together be (CH
2
)
j
Q(CH
2
)
k
where Q is O, S, NR
15
, or a bond;
j is 2 to 4;
k is 0 to 2;
R
7
, R
10
, R
11
, R
12
, R
13
, R
14
, and R
15
, are independently C
1
-C
4
alkyl, aryl, or heteroaryl;
or an enantiomer thereof, and pharmaceutically acceptable salts thereof, are useful for the preparation of a medicament for the treatment or prophylaxis of psychotic disorders or intellectual impairment disorders.
Examples of such conditions, diseases or disorders are Alzheimers disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia, mania or manic depression, Lewy Body Dementia, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders in which there is loss of cholinergic synapse, jetlag, cessation of smoking, nicotinic addiction including that resulting from exposure to products containing nicotine, pain, and for ulcerative colitis.
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
-
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
7
, —CN, —NO
2
, —NR
8
R
9
, CF
3
, —OR
10
.
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.
Preferred embodiments of the invention include compounds of formula I, wherein A represents:
or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
Preferred embodiments of the invention also include compounds of formula I, wherein D represents oxygen; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
Preferred embodiments of the invention also include compounds of formula I, wherein R
2
represents hydrogen; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
Preferred embodiments of the invention also include compounds of formula I, wherein R
3
represents:
or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
Preferred embodiments of the invention also include compounds of formula I, wherein R
3
represents:
when R
4
represents Ar; R
5
represents hydrogen, or C
1
-C
4
alkyl; R
6
represents hydrogen, or halogen; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
Preferred embodiments of the invention also include compounds of formula I, wherein A represents:
D represents oxygen;
R
2
represents hydrogen;
R
3
represents:
or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
Preferred embodiments of the invention also include compounds of formula I, wherein A represents:
D represents oxygen;
R
2
represents hydrogen;
R
3
represents:
R
4
represents Ar;
R
5
represents hydrogen, or C
1
-C
4
alkyl;
R
6
represents hydrogen, or halogen;
or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
Preferred embodiments of the invention also include 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, or an 8-, 9- or 10-membered fused aromatic or heteroaromatic ring system containing zero to four nitrogen atoms, zero to one oxygen atoms, and zero to one sulfur atoms which may optionally be substituted with one or more substituents selected from the following: hydrogen, halogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, aryl, heteroaryl, —CO
2
R
7
, —CN, —NO
2
, —NR
8
R
9
, —CF
3
, —OR
10
; or an en
Balestra Michael
Mullen George
Phillips Eifion
Schmiesing Richard
Astrazeneca AB
Desai Rita
Mitchell Kenneth F.
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