Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-06-13
1999-12-07
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546183, 546137, 546112, 548512, A61K 31435, C07D22102
Patent
active
059984295
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to novel azabicyclic esters of carbamic acids 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 which are potent ligands for nicotinic acetylcholine receptors (nAChR's).
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 "Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry, and Pharmacology", Chapter 5 in Annual Reports in Medicinal Chemistry, Volume 30, pp. 41-50, Academic Press Inc., San Diego, Calif. (1995) and in "Neuronal Nicotinic Acetylcholine Receptors," Drug News & Perspectives, Volume 7, pp. 205-223 (1994).
U.S. Pat. No. 5,468,875 discloses N-alkylcarbamic acid 1-azabicyclo[2.2.1]hept-3-yl esters which are centrally active muscarinic agents useful in the treatment of Alzheimer's disease and other disorders.
N-(2-Alkoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl esters are disclosed in Pharmazie, 48, 465-466 (1993) along with their local anaesthetic activity.
N-Phenylcarbamic acid 1-azabicyclo[2.2.2]octan-3-yl esters substituted at the ortho position on the phenyl ring are described as local anaesthetics in Acta Pharm. Suecica, 7, 239-246 (1970).
Disclosure of the Invention
According to the invention we provide a compound of formula ##STR3## wherein:
A is ##STR4##
X is O or S;
Y is O or S;
G and D are independently nitrogen or carbon with the proviso that no more than one of G, D, or E is nitrogen;
E is N or C-R.sub.4 ;
R.sub.1 is hydrogen or methyl;
R.sub.2 is hydrogen or fluoro;
R.sub.3 is hydrogen, halogen, C.sub.1 to C.sub.3 alkyl, --OR.sub.5, --CN, --CONH.sub.2, --CO.sub.2 R.sub.5, --NR.sub.5 R.sub.6 or phenyl optionally substituted with one to three of the following substituents: halogen, C.sub.1 to C.sub.3 alkyl, --NO.sub.2, --CN, or --OCH.sub.3 ;
R.sub.4 is hydrogen, halogen, C.sub.1 to C.sub.3 alkyl, --OR.sub.5, --CN, --CONH.sub.2, --CO.sub.2 R.sub.5, --NR.sub.5 R.sub.6 or phenyl optionally substituted with one to three of the following substituents: halogen, C.sub.1 to C.sub.3 alkyl, --NO.sub.2, --CN, or --OCH.sub.3 ;
or R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4 may together represent a fused phenyl ring optionally substituted with one or two of the following substituents: halogen, C.sub.1 to C.sub.3 alkyl, --NO.sub.2, --CN, or --OCH.sub.3 ;
R.sub.5 and R.sub.6 are independently hydrogen or C.sub.1 to C.sub.3 alkyl;
or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
The compounds of formula I are potent ligands for nicotinic acetylcholine receptors.
Unless otherwise indicated, the term "C.sub.1 -C.sub.3 alkyl" referred to herein denotes a straight or branched chain alkyl group having from 1 to 3 carbon atoms or a cyclic alkyl group having 3 carbon atoms. Examples of such groups are methyl, ethyl, n-propyl, i-propyl and cyclopropyl.
Unless otherwise indicated, the term "halogen" referred to herein denotes fluoro, chloro, bromo or iodo.
Preferred compounds of the invention are compounds of formula I wherein A is formula II or IV; R.sub.2 is hydrogen; X and Y are oxygen and G, D, and E are carbon.
Particularly preferred compounds of the invention include the following:
N-phenylcarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;
N-(4-bromophenyl)carbamic acid 1-azabicyclo[2.2.2.]octan-3-yl ester;
N-(4-methylphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;
N-(4-methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;
N-(3,4-dichlorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;
N-(4-cyanophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;
N-phenylcarbamic acid 1-azabicyclo[2.2.1]heptan-3-yl ester
REFERENCES:
patent: 5468875 (1995-11-01), Sabb et al.
Acta Pharm. Suecica 7, 239-246 (1970),Studies on carbanilic acid esters of cyclic amino alcohols, J. Lars G. Nilsson, Richard Dahlbom and Bengt Akerman.
Acta Pharm. Suecica 4, 211-216 (1970), 3,4,5-trimethoxyphenylcarbamic acid esters of some cyclic amino alcohols, Richard Dahlbom, Bo Karlen and Lars Nilsson.
Pharmazie, 48, 465-466 (1993), Synthesis and local anaesthetic activities of 3-(2-alkoxyphenylcarbamoyloxy)chinuclidinium chlorides, F. Gregan, J. Durinda, E. Racanska, and J. Zamocka.
Chemical Abstracts, vol. 124, No. 5, Abstr. No. 55799b (1996).
Chemical Abstracts, vol. 108, No. 17, Abstr. No. 150772r (1988).
Macor John
Wu Edwin
Astra AB
Aulakh Charanjit S.
Kight John
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