Spiroazabicyclic heterocyclic compounds

Details Spiroazabicyclic heterocyclic compounds Spiroazabicyclic heterocyclic compounds

1998-10-29

2000-08-29

Ramsuer, Robert W.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544 70, 544230, 546 14, 546 18, 540543, A61K 315377, A61P 2528, C07P49921

Patent

active

061109142

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to novel spiroazabicyclic heterocyclic amines 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 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.
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, vol. 48, 465-466 (1993) along with their local anesthetic 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).
Furopyridines useful in controlling synaptic transmission are disclosed in WO 97/05139.


DISCLOSURE OF THE INVENTION

According to the invention it has been found that a compound of formula I ##STR2## wherein n is 0 or 1; m is 0 or 1; least one of Y, A, G, and D is nitrogen or NO; -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, aryl, heteroaryl, OH, OC.sub.1 -C.sub.4 alkyl, CO.sub.2 R.sup.1, --CN, --NO.sub.2, --NR.sup.5 R.sup.6, --CF.sub.3, --OSO.sub.2 CF.sub.3, or R.sup.2 and R.sup.3, or R.sup.3 and R.sup.4, respectively, may together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively containing between zero and two nitrogen atoms, and substituted with one to two of the following substituents: independently hydrogen, halogen, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, aryl, heteroaryl, OH, OC.sub.1 -C.sub.4 alkyl, CO.sub.2 R.sup.1, --CN, --NO.sub.2, --NR.sup.5 R.sup.6, --CF.sub.3, OSO.sub.2 CF.sub.3 ; C(O)R.sup.7, C(O)NHR.sup.8, C(O)OR.sup.9, SO.sub.2 R.sup.10 or may together be (CH.sub.2).sub.j Q(CH.sub.2).sub.k where Q is O, S, NR.sup.11, or a bond; -C.sub.4 alkyl, aryl, or heteroaryl, or an enantiomer thereof, and the pharmaceutically acceptable salts thereof is a potent ligand for nicotinic acetylcholine receptors.
Unless otherwise indicated, the C.sub.1 -C.sub.4 alkyl groups referred to herein, e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl, s-butyl, may be straight-chained or branched, and the C.sub.3 -C.sub.4 alkyl groups may also be cyclic, e.g., cyclopropyl,cyclobutyl.
Unless otherwise indicated, the C.sub.1 -C.sub.6 alkyl groups referred to herein, e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl, s-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, or i-hexyl may be straight-chained or branched, and the C.sub.3 -C.sub.6 alkyl groups may also be cyclic, e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Unless otherwise indicated, the C.sub.1 -C.sub.4 alkoxy groups referred to herein, e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, s-butoxy, may be straight-chained or branched.
Unless otherwise indicated, the C.sub.2 -C.sub.4 alkenyl groups referred to herein may contain one or two double bonds, e.g., ethenyl, i-propenyl, n-butenyl, i-butenyl, allyl, 1,3-butadienyl.
Unless otherwise indicated, the C.sub

REFERENCES:
patent: 3681363 (1972-08-01), Elkin et al.
patent: 5468875 (1995-11-01), Saab et al.
Pharmazie 48, pp. 465-466 (1993), H. 6.
Nilsson et al, "Studies on carbanilic acid esters of cyclic amino alcohols," Acta Pham. Succica 7, pp. 239-246 (1970).
McDonald et al, "Chaper 5. Nicotinic Acetylcholine Receptors: Molecular. . . ,"Annual Reports in Medicinal Chemistry 30, pp. 41-50 (1995).
Williams et al, "Neuronal Nicotinic Actylcholine Receptors,"DN&P, vol. 7, No. 4, pp. 206-222 (1994).
Nordvall et al, "3-(2-Benzofuranyl)quinuclidin-2ene Derivatives . . . ,"J. Med. Chem., Voo. 39, pp. 3269-3277 (1996).
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