Compounds

Details Compounds Compounds

2000-06-16

2002-04-09

Ramsuer, Robert W. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen in the nitrogen containing substituent

C540S541000, C544S229000, C546S013000

Reexamination Certificate

active

06369224

ABSTRACT:

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
wherein
n is 0 or 1;
m is 0 or 1;
p is 0 or 1;
Y is CH, N or NO
X is oxygen or sulfur;
W is oxygen, H
2
or F
2
;
A is N or C(R
2
);
G is N or C(R
3
);
D is N or C(R
4
);
with the proviso that no more than one of A, G, and D is nitrogen but at least one of Y, A, G, and D is nitrogen or NO;
R
1
is hydrogen or C
1
-C
4
alkyl;
R
2
, R
3
, and R
4
are independently hydrogen, halogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, aryl, heteroaryl, OH, OC
1
-C
4
alkyl, CO
2
R
1
, —N, —NO
2
, —NR
5
R
6
, —CF
3
, —OSO
2
CF
3
, or R
2
and R
3
, or R
3
and R
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
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, aryl, heteroaryl, OH, OC
1
-C
4
alkyl, CO
2
R
1
, —CN, —NO
2
, —NR
5
R
6
, —CF
3
, OSO
2
CF
3
;
R
5
and R
6
are independently hydrogen, C
1
-C
4
alkyl, C(O)R
7
, C(O)NHR
8
, C(O)OR
9
, SO
2
R
10
or may together be (CH
2
)
j
Q(CH
2
)
k
where Q is O, S, NR
11
, or a bond;
j is 2 to 7;
k is 0 to 2;
R
7
, R
8
, R
9
, R
10
, and R
11
are independently C
1
-C
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
1
-C
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
3
-C
4
alkyl groups may also be cyclic, e.g., cyclopropyl, cyclobutyl.
Unless otherwise indicated, the C
1
-C
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
3
-C
6
alkyl groups may also be cyclic, e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Unless otherwise indicated, the C
1
-C
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
2
-C
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
2
-C
4
alkynyl groups referred to herein contain one triple bond, e.g., ethynyl, propynyl, 1- or 2-butynyl.
Halogen referred to herein may be fluoride, chloride, bromide, or iodide.
Unless otherwise indicated, aryl refers to a phenyl ring optionally substituted with one to three of the following substituents: hydrogen, halogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, OH, OC
1
-C
4
alkyl, CO
2
R
1
, —CN, —NO
2
, —NR
5
R
6
, —CF
3
;
Unless otherwise indicated, heteroaryl refers to a five- or six-membered aromatic ring containing one or two nitrogen atoms, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl or pyrazolyl, with the carbon atoms of that ring optionally substituted with one to three of the following substituents: hydrogen, halogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, OH, OC
1
-C
4
alkyl, CO
2
R
1
, —CN, —NO
2
, —NR
5
R
6
, —CF
3
; R
5
and R
6
may together be (CH
2
)
j
Q(CH
2
)
k
where Q is O, S, NR
11
, or a bond, and where j is 2 to 7, preferably 2 to 3, and k is 0 to 2, so as to form a 3-7 membered ring, preferably a 5- or 6-membered ring, for example pyrrolidinyl, imidazolidinyl piperazinyl, piperidyl, morpholinyl, or thiomorpholinyl.
R
2
and R
3
may together form another six membered aromatic or heteroaromatic ring sharing A and G containing between zero and two nitrogen atoms refers to groups such as quinoline, 1,5-, 1,6-, 1,7-, or 1,8-diazanaphthalene.
R
3
and R
4
may together form another six membered aromatic or heteroaromatic ring sharing G and D containing between zero and two nitrogen atoms refers to groups such as soquinoline, 2,5-, 2,6-, 2,7-, or 2,8-diazanaphthalene.
Preferred compounds of the invention are compounds of formula I wherein m is 1; n is 0; p is 0; X is oxygen; W is H
2
; A is C(R
2
) ; G is C(R
3
) ; D is C(R
4
).
Preferred compounds of the invention include the following:
spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
1′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]isoquinoline];
5′-(phenylcarboxamido)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-(phenylaminocarbonylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-(phenylsulfonylamido)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-N-methylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-N,N-dimethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-N,N-diethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-N-ethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-N-benzylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];
5′-N-formamidospiro[1-azabicyclo[2.2.2]octane-3,2&p

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